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WO2008019309A1 - Nouveaux inhibiteurs du fructose 1,6-bisphosphatase - Google Patents

Nouveaux inhibiteurs du fructose 1,6-bisphosphatase Download PDF

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WO2008019309A1
WO2008019309A1 PCT/US2007/075159 US2007075159W WO2008019309A1 WO 2008019309 A1 WO2008019309 A1 WO 2008019309A1 US 2007075159 W US2007075159 W US 2007075159W WO 2008019309 A1 WO2008019309 A1 WO 2008019309A1
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group
alkyl
compound
aryl
optionally substituted
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Raja K. Reddy
Mark D. Erion
Qun Dang
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Metabasis Therapeutics Inc
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Metabasis Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention is directed towards novel nucleoside analogs, including deazapurine nucleoside analogs that are potent inhibitors of fructose 1,6-bisphosphatase (FBPase).
  • FBPase fructose 1,6-bisphosphatase
  • the invention is directed toward phosphonic acids and prodrugs thereof.
  • the present invention is directed to the preparation and the clinical use of these FBPase inhibitors as a method of treatment or prevention of diseases responsive to inhibition of gluconeogenesis and in diseases responsive to lower blood glucose levels.
  • the compounds are also useful in treating or preventing excess glycogen storage diseases and diseases such as metabolic disordersincluding hypercholesterolemia, hyperlipidemia which are exacerbated by hyperinsulinema and hyperglycemia.
  • Diabetes mellitus is one of the most prevalent diseases in the world today. Diabetic patients have been divided into two classes, namely type 1 and type 2 diabetes. Type 2 accounts for approximately 90% of all diabetics and is estimated to affect 12-14 million adults in the U. S. alone (6.6% of the population). Type 2 diabetes is characterized by both fasting hyperglycemia and exaggerated postprandial increases in plasma glucose levels. Type 2 diabetes is associated with a variety of long-term complications, including microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease. Numerous studies in animal models demonstrate a causal relationship between long term hyperglycemia and complications.
  • Gluconeogenesis from pyruvate and other 3-carbon precursors is a highly regulated biosynthetic pathway requiring eleven enzymes. Seven enzymes catalyze reversible reactions and are common to both gluconeogenesis and glycolysis. Four enzymes catalyze reactions unique to gluconeogenesis, namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose- 1,6-bisphosphatase and glucose-6-phosphatase. Overall flux through the pathway is controlled by the specific activities of these enzymes, the enzymes that catalyzed the corresponding steps in the glycolytic direction, and by substrate availability.
  • Dietary factors (glucose, fat) and hormones (insulin, glucagon, glucocorticoids, epinephrine) coordinatively regulate enzyme activities in the gluconeogenesis and glycolysis pathways through gene expression and post-translational mechanisms.
  • nucleosides can lower blood glucose in the whole animal through inhibition of FBPase. These compounds exert their activity by first undergoing phosphorylation to the corresponding monophosphate (EP 0427 799 Bl).
  • Patent 6,054,587 described novel indole and azaindole compounds containing a phosphonate group that are inhibitors of FBPase. Dang et al., U.S. Patent 6,284,748, described novel purine compounds containing a phosphonate group that are inhibitors of FBPase. Bookser et al., U.S. Patent 6,919,322, described novel aryl phosphonate compounds that are inhibitors of FBPase. Kasibhatla, et al., U.S. Patnent No. 6,399,782, described benzimidazole compounds containing a phosphonate group that are inhibitors of FBPase.
  • the present invention relates to compounds and pharmaceutical compositions of Formula I-III and IX-XIII, including pharmaceutically acceptable salts, co-crystals and prodrugs thereof.
  • Acyl refers to -C(O)R S where R s is alkyl, heterocycloalkyl, or aryl.
  • Acylalkyl refers to an alkyl-C(O)-alk-, wherein “alk” is alkylene.
  • Acylamino refers to and R W C(O)-NR W -, wherein R w is -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • Acyloxy refers to the ester group -0-C(O)R 1 , where R 1 is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.
  • Alicyclic refers to a cyclic group or compound which combines the properties of aliphatic and cyclic compounds and include cycloalkyl and bridged cycloalkyl compounds.
  • the cyclic compound includes heterocycles. Cyclohexenylethyl, cyclohexanylethyl, and norbornyl are suitable alicyclic groups. Such groups may be optionally substituted.
  • Alkanoyl refers to the group alkyl-C(O)-.
  • Alkenyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups included alkenylene and alkynylene. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. "1-alkenyl” refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, it is attached at the first carbon.
  • Alkylaminoalkyl- refers to the group -alk-NR u -alk- wherein “alk” is alkylene, and R u is H or lower alkyl.
  • Lower alkylaminoalkyl- refers to groups where the alkyl and the alkylene group are lower alkyl and alkylene, respectively.
  • Alkylaminoalkylcarboxy refers to the group alkyl-NR u -alk-C(O)-O- where "alk” is an alkylene group, and R u is a H or lower alkyl.
  • Alk is an alkylene group
  • R u is a H or lower alkyl.
  • Alkylaminoaryl- refers to the group alkyl-NR vl -aryl- wherein “aryl” is a divalent group and R v! is -H, alkyl, aralkyl, or heterocycloalkyl. In “lower alkylaminoaryl-", the alkyl group is lower alkyl.
  • Alkylaminocarbonyl refers to the group alk-NR-C(O)- where R is a H or lower alkyl, and "alk” is an alkyl group. "-Alkylaminocarbonyl-” refers to same group, except when “alk” is alkylene. When X is - alkylaminocarbonyl- the alkyl portion is attached to M and the carbonyl portion to Gg.
  • alkylcarbonylamino- refers to the group -alk-C(O)-NR- where "alk” is an alkylene group, and R is a H or lower alkyl.
  • alk is an alkylene group
  • R is a H or lower alkyl.
  • Alkoxy- or alkyloxy- refers to the group alkyl-O.
  • -Alkoxy- or -alkyloxy- refers to the group -alkylene-O-.
  • X is -alkoxy- or - alkyloxy-, the alkyl portion is attached to M.
  • Alkoxyalkyl- or “alkyloxyalkyl-” refers to the group alkyl-O-alk- wherein “alk” is an alkylene group.
  • X is -alkoxyalkyl-" or “-alkyloxyalkyl-” then the terms refer to -alk-O-alk- wherein “alk” is an alkylene group.
  • lower alkoxyalkyl- each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • Alkoxyaryl- refers to an aryl group substituted with an alkyloxy group. In “lower alkyloxyaryl-”, the alkyl group is lower alkyl.
  • Alkoxycarbonyloxy- refers to alky 1-0-C(O)-O-.
  • Alkyl refers to a straight or branched chain or cyclic chain hydrocarbon radical with only single carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which may be optionally substituted. Alkyl groups are Ci-C 12 .
  • Alkylaryl- refers to alkyl-arylene-.
  • -Alkylaryl- refers to -alkylene- arylene-.
  • X alkylaryl
  • the alkylene is attached to M and the arylene is attached to G 8 .
  • “Lower alkylaryl-” refers to such groups where alkyl is lower alkyl.
  • Alkylene-aryl- refers to a divalent aklylene substituted aryl group, with one valency on the aryl group and one valency on the alkylene group.
  • Lower alkylaryl- refers to such groups where alkyl is lower alkyl.
  • Alkylene refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In another aspect the alkylene chain contains up to and including 6 atoms. In a further aspect the alkylene groups contains up to and including 4 atoms. The alkylene group can be either straight, branched chain or cyclic.
  • Alkylthio- refers to the group alkyl-S- and -alkylthio- refers to - alkylene-S-.
  • X is -alkylthio-, the alkyl group is attached to M.
  • Alkylthioalkyl- refers to the group alkyl-S-alk- wherein “alk” is an alkylene group.
  • -Alkylthioalkyl- refers to -alkylene-S-alkylene-.
  • lower alkylthioalkyl- each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • Alkylthiocarbonyloxy- refers to alkyl-S-C(O)-O-.
  • Alkynyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. "1 -alkynyl” refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1-alkynyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon.
  • Amino refers to -NR xl R xl wherein each R xl is independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H aarree ooppttiionally substituted, or wherein both R xl together form a cyclic ring system.
  • Aminocarbonylamino refers to - NR ⁇ C(O)-NR'-, where R' is selected from a bond, -H, alkyl, aryl, aralkyl, and heterocycloalkyl
  • Aminoalkyl refers to the group NRVaIk- wherein “alk” is an alkylene group and R* is selected from a bond, -H, alkyl, aryl, aralkyl, and heterocycloalkyl .
  • aminocarboxamidoalkyl refers to the group
  • Animal includes birds and mammals, in one embodiment a mammal, including a dog, cat, cow, horse, goat, sheep, pig or human. In one embodiment the animal is a human. In another embodiment the animal is a male. In another embodiment the animal is a female.
  • Alkyl refers to aryl -alkylene-. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. "-Aralkyl-” refers to -arylene-alkylene-. When X is aralkyl, the arylene is attached to M and the alkylene is attached to G 8 .
  • Alkyloxyalkyl- refers to the group aryl-alk-O-alk- wherein “alk” is an alkylene group. "Lower aralkyloxyalkyl-” refers to such groups where the alkylene groups are lower alkylene.
  • Aroyl refers to the group aryl-C(O)-.
  • Aryl refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl, bicylic aryl (e.g., naphthyl) and biaryl groups (e.g., biphenyl), all of which may be optionally substituted.
  • Arylamino refers to the group aryl-NH-.
  • Alkylamino refers to the group -NR-alk- wherein “alk” is alkylene and R is a H or lower alkyl. When X is alkylamino, the alkylene group is attached to M and the amino group to G 8 .
  • Alk refers to the group -NR-alk-aryl wherein “alk” is alkylene.
  • Arylene refers to divalent aromatic ring systems which have 5-14 atoms and at least one ring having a conjugated pi electron system and includes carbocyclic arylene, heterocyclic arylene and biarylene groups, all of which may be optionally substituted.
  • Arylaminoalkyl- refers to the group aryl-N(R w )-alk- wherein “alk” is an alkylene group and R w is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • R w is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • the alkylene group is lower alkylene.
  • Aryloxy refers to aryl-O-.
  • Aryloxyalkyl- refers to an alkyl group substituted with an aryloxy group.
  • Aryloxycarbonyl refers to the group aryl-O-C(O)-.
  • Aryloxycarbonyloxy- refers to ary 1-0-C(O)-O-.
  • Atherosclerosis refers to a condition characterized by irregularly distributed lipid deposits in the intima of large and medium-sized arteries wherein such deposits provoke fibrosis and calcification. Atherosclerosis raises the risk of angina, stroke, heart attack, or other cardiac or cardiovascular conditions.
  • Biaryl represents aryl groups which have 5-14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
  • Binding means the specific association of the compound of interest to the target of interest, .e.g., a receptor.
  • C 2 - 6 -perfluoroalkyl refers to a 2 to 6 carbon alkyl group where all of the carbon atoms are exhaustively substituted with fluorine.
  • Non limiting examples include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, pentafluorocyclopropyl, and the like.
  • C 4 _ 8 -cycloalkenyl refers to a non-aromatic, carbocyclic group having 4 to 8 carbon atoms and containing at least one double bond.
  • C 3 _ 8 -cycloalkyloxy refers to -O-C ⁇ g-cycloalkyl where Cv 8 - cycloalkyl is an aliphatic carbocyclic group having 3 to 8 carbon atoms
  • C 3 - 8 -cycloalkylthio refers to -S-C 3 -g-cycloalkyl where Cv 8 - cycloalkyl is a 3 to 8 aliphatic carbocyclic group having 3 to 8 carbon atoms
  • Carboxylamido or “carboxamido” refer to NR W 2 -C(0)-, wherein each R w include -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • Carboxamidoalkylaryl refers to NR w 2 -C(O)-alk-aryl- where “alk” is alkyl and R w includes H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • Carboxamidoaryl refers to NR w -C(O)-aryl- wherein “alk” is alkylene and R w include H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • Carbocyclic aryl groups are groups which have 6-14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
  • Carbonylalkyl refers to -C(O)-alk-, where “alk” is alkylene.
  • X is carbonylalkyl
  • the carbonyl is attached to M and the alkylene is attached to G 8 .
  • Carboxy esters refers to -C(O)OR Z where R z is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, each optionally substituted.
  • Carboxyl refers to -C(O)OH.
  • Cyclic alkyl or “cycloalkyl” refers to alkyl groups that are cyclic of 3 to 10 carbon atoms, and, in one aspect, are 3 to 6 carbon atoms.
  • the cycloalkyl groups include fused cyclic, bridged cyclic and spirocyclic groups.
  • cyclic alkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalin, bicycle[3.1.1]heptane, bycyclo[2.2.1]heptane, bycyclo[2.2.2]octane, bicycle[3.2.2]nonane, spiro[2.5]octane, spiro[3.5]nonane, adamantyl and the like. Such groups may be substituted.
  • Cycloalkyloxy refers to the group cycloalkyl-O-.
  • Cycloalkylalkoxy refers to the group cycloalkyl-alkyl-O-.
  • Co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature that are H-bonded.
  • Coronary heart disease or “coronary disease” refers to an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. "Diabetes” refers to a heterogeneous group of disorders that share glucose intolerance in common.
  • Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision.
  • the vast majority of cases of diabetes fall into two broad etiopathogenetic categories.
  • type 1 diabetes the cause is an absolute deficiency of insulin secretion.
  • Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers.
  • type 2 diabetes the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response.
  • a degree of hyperglycemia sufficient to cause pathologic and functional changes in various target tissues, but without clinical symptoms, may be present for a long period of time before diabetes is detected.
  • this asymptomatic period it is possible to demonstrate an abnormality in carbohydrate metabolism by measurement of plasma glucose in the fasting state or after a challenge with an oral glucose load.
  • Criteria for the diagnosis of diabetes include: 1. Symptoms of diabetes plus casual plasma glucose concentration 200 mg/dl (11.1 mmol/1). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss; or
  • FPG 126 mg/dl (7.0 mmol/1). Fasting is defined as no caloric intake for at least 8 h; or
  • Etiologic classification of diabetes mellitus are as follows:
  • Type 1 diabetes ⁇ -cell destruction, usually leading to absolute insulin deficiency
  • Type 2 diabetes may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance
  • III Other specific types
  • GDM Gestational diabetes mellitus
  • Energy expenditure means basal or resting metabolic rate as defined by Schoeller et al, J Appl Physiol. ;53(4):955-9 (1982). Increases in the resting metabolic rate can be also be measured using increases in O 2 consumption and/or CO 2 efflux and/or increases in organ or body temperature.
  • Enhanced oral bioavailability refers to an increase of at least 50% of the absorption of the dose of the parent drug, unless otherwise specified. In an additional aspect the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least 100% (at least a doubling of the absorption). Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drag metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following systemic administration of the compound administered orally.
  • “Enhancing” refers to increasing or improving a specific property.
  • the term “perhalo” refers to groups wherein every C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include -CF3 and -CFCI 2 .
  • Haloalkyl refers to an alkyl group substituted with one halo (halogen group).
  • Halogen or "halo” refers to -F, -Cl, -Br and -I.
  • Heteroalicyclic refers to an alicyclic group or compound having 1 to 4 heteroatoms selected from nitrogen, sulfur, phosphorus and oxygen.
  • Heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
  • Heteroarylene refers to a divalent, aromatic, heterocyclic ring containing 5-14 ring atoms wherein 1 to 4 heteroatoms in the aromatic ring are ring atoms and the remainder of the ring atoms being carbon atoms.
  • Heteroarylene refers to a divalent heterocyclic aryl or heteroaryl group.
  • Heterocyclic or “heterocyclyl” refer to cyclic groups of 3 to 10 atoms or cyclic groups of 3 to 6 atoms. These groups contain at least one heteroatom, and in some aspects contain 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or carbon atom in the ring. Heterocyclic and heterocyclyl cyclic groups include, e.g., heterocyclic alkyl or heterocycloalkyl groups. The heterocyclic alkyl groups include unsaturated cyclic, fused cyclic and spirocyclic groups. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
  • Heterocyclic aryl or “heteroaryl groups” are groups which have 5-14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, and the like, all optionally substituted.
  • Hydroalkyl refers to an alkyl group substituted with one -OH.
  • “Hypercholesterolemia” refers to presence of an abnormally large amount of cholesterol in the cells and plasma of the circulating blood.
  • Hyperinsulinemia refers to a patient with a fasting serum insulin concentration of at least 12 uU/mL.
  • Hydrolipemia refers to the presence of an abnormally large amount of lipids in the circulating blood.
  • Insulin resistance is defined clinically as the impaired ability of a known quantity of exogenous or endogenous insulin to increase whole body glucose uptake and utilization.
  • IGT Internet glucose tolerance
  • IGT refers to a condition known to precede the development of overt Type 2 diabetes. It is characterized by abnormal blood glucose excursions following a meal. The current criteria for the diagnosis of IGT are based on 2-h plasma glucose levels post a 75g oral glucose test (144-199 mg/dL). Although variable from population to population studied, IGT progresses to full-blown NIDDM at a rate of 1.5 to 7.3% per year, with a mean of 3-4% per year. Individuals with IGT are believed to have a 6 to 10-fold increased risk in developing Type 2 diabetes. IGT is an independent risk factor for the development of cardiovascular disease.
  • “Increased or enhanced liver specificity” refers to an increase in the liver specificity ratio in animals treated with a compound of the present invention and a control compound.
  • One aspect of this invention provides organic radicals or compounds as containing up to and including 6 carbon atoms.
  • Yet another aspect of the invention provides organic radicals or compounds that contain one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.
  • Liver refers to the liver organ.
  • Liver specificity refers to the ratio:
  • the ratio can be determined by measuring tissue levels at a specific time or may represent an AUC based on values measured at three or more time points.
  • Methodabolic disease includes diseases and conditions such as obesity, diabetes and lipid disorders such as hypercholesterolemia, hyperlipidemia, hypertriglyceridemia as well as disorders that are associated with abnormal levels of lipoproteins, lipids, carbohydrates and insulin such as metabolic syndrome X, diabetes, impaired glucose tolerance, atherosclerosis, coronary heart disease, cardiovascular disease.
  • lipid disorders such as hypercholesterolemia, hyperlipidemia, hypertriglyceridemia as well as disorders that are associated with abnormal levels of lipoproteins, lipids, carbohydrates and insulin such as metabolic syndrome X, diabetes, impaired glucose tolerance, atherosclerosis, coronary heart disease, cardiovascular disease.
  • Methods or “Metabolic Syndrome X” to a condition identified by the presence of three or more of these components:
  • Obsity refers to the condition of being obese. Being obese is defined as a BMI of 30.0 or greater; and extreme obesity is defined at a BMI of 40 or greater.
  • “Overweight” is defined as a body mass index of 25.0 to 29.9.
  • Perhalo refers to groups wherein every C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group.
  • Non-linking examples of perhaloalkyl groups include -CF 3 and -CFCl 2 .
  • “Pharmaceutically acceptable salt” includes salts of compounds of the invention derived from the combination of a compound of this invention and an organic or inorganic acid or base. Suitable acids include acetic acid, adipic acid, benzenesulfonic acid,
  • Patient means an animal. In one embodiement a patient is a mammal. In one embodiment a patient is a human.
  • Preventing includes a slowing of the progress or development of a disease before onset or precluding onset of a disease.
  • Prodrug refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each.
  • Standard prodrugs are formed using groups attached to functionality, e.g., HO-, HS-, HOOC-, .NHR, associated with the drug, that cleave in vivo.
  • Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
  • the groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of the invention, fall within this scope. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound.
  • the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, and/or pharmacodynamic half-life, etc.
  • Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.
  • Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992.
  • “Significant” or “statistically significant” means a result (i.e. experimental assay result) where the p-value is ⁇ 0.05 (i.e. the chance of a type I error is less than 5%) as determined by an art-accepted measure of statistical significance appropriate to the experimental design.
  • Substituted or “optionally substituted” includes groups substituted by one to six substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl, -carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower -carboxamidoalkylaryl, lower -carboxamido
  • Substituted aryl and “substituted heteroaryl” refers to aryl and heteroaryl groups substituted with 1-3 substituents. These substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino.
  • “Sulphonate” or “sulfonate” refers to -SO 2 OR", where R w is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • “Sulphonyl” or “sulfonyl” refers to -SO 2 R W , where R w is alkyl, aryl, aralkyl, or heterocycloalkyl.
  • “Therapeutically effective amount” means an amount of a compound or a combination of compounds that ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition.
  • Treating" or “treatment” of a disease includes a slowing of the progress or development of a disease after onset or actually reversing some or all of the disease affects. Treatment also includes palliative treatment.
  • Type 1 diabetes (formerly known as “childhood,” “juvenile,” “insulin-dependent” diabetes) is a form of diabetes characterized by an absolute deficiency of insulin secretion. Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers. Type 1 diabetes may be caused by immune mediated beta-cell destruction, usually leading to absolute insulin deficiency or may be idiopathic, having no known etiologies.
  • Type 2 diabetes refers to a heterogeneous disorder characterized by impaired insulin secretion by the pancreas and insulin resistance in tissues such as the liver, muscle and adipose tissue.
  • the manifestations of the disease include one or more of the following: impaired glucose tolerance, fasting hyperglycemia, glycosuria, decreased levels of insulin, increased levels of glucagon, increased hepatic glucose output, reduced hepatic glucose uptake and glycogen storage, reduced whole body glucose uptake and utilization, dyslipidemia, fatty liver, ketoacidosis, microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease.
  • Phosphonate, phosphonic acid monoester and phosphinate prodrug refers to compounds that break down chemically or enzymatically to a phosphonic acid or phosphinc acid group in vivo.
  • the term includes, but is not limited to, the following groups and combinations of these groups:
  • acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g., Freed et al., Biochem. Pharm., 38: 3193-3198 (1989)).
  • alkyloxycarbonyloxymethyl esters as shown in formula A, where R a is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino; each R c is independently -H, alkyl, aryl, alkylaryl, or heterocycloalkyl have been studied in the area of ⁇ -lactam antibiotics (Nishimura et al., J. Antibiotics, 40(1): 81-90 (1987); for a review see Ferres, H., Drugs of Today, 19: 499 (1983)). More recently Cathy, M. S., et al.
  • R a and R c are independently H, alkyl, aryl, alkylaryl, and alicyclic; (see WO 90/08155; WO 90/10636) and R b , for e.g., is selected from -OH, -CH 3 , -H, -0-CH 3 or monoester prodrug moiety.
  • acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed such as shown in formula B. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g., Freed et al., Biochem. Pharm., 38: 3193-3198 (1989)).
  • R d is -H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, or cycloalkyl.
  • Aryl esters have also been used as phosphonate prodrugs (e.g., DeLambert et al., J. Med. Chem. 37(7): 498-511 (1994); Serafinowska et al., J. Med. Chem. 38(8): 1372-9 (1995). Phenyl as well as mono and poly- substituted phenyl proesters have generated the parent phosphonic acid in studies conducted in animals and in man (Formula C). Another approach has been described where R e is a carboxylic ester ortho to the phosphate (Khamnei et al., J. Med. Chem. 39: 4109-15 (1996)).
  • R e is -H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, or heterocycloalkyl and R b is selected, for e.g., from -OH, -CH 3 , -H, -O-CH 3 or monoester prodrug moiety.
  • Benzyl esters have also been reported to generate the parent phosphonic acid. In some cases, using substituents at the para-position can accelerate the hydrolysis.
  • R and R 8 are independently -H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; R is selected, for e.g., from -OH, -CH 3 , -H, -O-CH 3 or monoester prodrug moiety, as described therein.
  • R h and R 1 are independently -H, alkyl, aryl, alkylaryl, halogen, or cyclic alkyl.
  • Thio-containing phosphonate proesters may also be useful in the delivery of drugs to hepatocytes. These proesters contain a protected thioethyl moiety as shown in formula E. One or more of the oxygens of the phosphonate can be esterified. Since the mechanism that results in de- esterification requires the generation of a free thiolate, a variety of thiol protecting groups are possible. For example, the disulfide is reduced by a reductase-mediated process (Puech et al., Antiviral Res. 22: 155-174 (1993)). Thioesters will also generate free thiolates after esterase-mediated hydrolysis Benzaria, et al., J. Med. Chem., 39(25): 4958-65 (1996)). Cyclic analogs are also possible and were shown to liberate phosphonate in isolated rat hepatocytes. The cyclic disulfide shown below has not been previously described and is novel.
  • R J is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio and R b is selected, for e.g., from -OH, -CH 3 , -H, -O-CH 3 or monoester prodrug moiety.
  • prodrugs include proester classes exemplified by Biller and Magnin (U.S. 5,157,027); Serafinowska et al., J. Med. Chem,. 38(8): 1372-9 (1995); Starrett et al., J. Med. Chem, 37: 1857 (1994); Martin et al. J. Pharm. Sci. 76: 180 (1987); Alexander et al., Collect. Czech. Chem. Commun, 59: 1853 (1994); and EP 0 632048 Al.
  • R m is -H, alkyl, cycloalkyl, or heterocycloalkyl
  • R b is selected, for e.g., from -OH, -CH 3 , -H, -O-CH 3 or monoester prodrug moiety
  • R k is - H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy, halogen, amino, heterocycloalkyl, or alkoxy carbonyl.
  • the prodrugs of Formula E6 are an example of "optionally substituted heterocycloalkyl where the cyclic moiety contains a carbonate or thiocarbonate.”
  • Propyl phosphonate proesters can also be used to deliver drugs into hepatocytes. These proesters may contain a hydroxyl and hydroxyl group derivatives at the 3-position of the propyl group as shown in formula F2.
  • the R n and R p groups can form a cyclic ring system as shown in formula F2.
  • One or more of the oxygens of the phosphonate can be esterified.
  • R n is alkyl, aryl, or heteroaryl
  • R p is alkylcarbonyloxy, or alkyloxycarbonyloxy
  • R b is selected, for e.g., from -OH, -CH 3 , -H, -O-CH3 or monoester prodrug moiety ;
  • R q is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy, or amino.
  • Phosphoramidate derivatives have been explored as phosphate prodrugs (e.g., McGuigan et al., J. Med. Chem., 42: 393 (1999) and references cited therein) as shown in Formula G and H, wherein R r , for example.is lower alkyl, lower aryl, lower aralkyl, and as described therein..
  • Cyclic phosphoramidates have also been studied as phosphonate prodrugs because of their speculated higher stability compared to non-cyclic phosphoramidates (e.g., Starrett et al., J. Med. Chem., 37: 1857 (1994)).
  • prodrugs are possible based on literature reports such as substituted ethyls for example, bis(trichloroethyl)esters as disclosed by McGuigan, et al., Bioorg Med. Chem. Lett., 3:1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters reported by Meier, C. et al., Bioorg. Med. Chem. Lett. 7:99-104 (1997).
  • V and W defined herein
  • cyclic phosphonate ester of 1,3-propane diol refers to the following:
  • the structure shown above (left) has an additional 3 carbon atoms that forms a five member cyclic group. Such cyclic groups must possess the listed substitution to be oxidized.
  • the structure above has an acyloxy substituent that is three carbon atoms from a Y, and an optional substituent, -CH 3 , on the new 6-membered ring.
  • the phrase "together W and W are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl” includes the following:
  • V aryl, and a spiro-fused cyclopropyl group for W and W.
  • cyclic phosphon(amid)ate refers to:
  • trans stereochemistry for the same moiety refers to the spatial relationship of the V group and the carbon, attached to the phosphorus atom, on the six-membered ring.
  • the formula below shows a trans- stereochemistry.
  • R-configuration refers to the absolute configuration R of carbon C .
  • R-isomer refers to the absolute configuration R of carbon C .
  • R-prodrug refers to the absolute configuration R of carbon C .
  • the formula below shows the R-stereochemistry.
  • percent enantiomeric excess refers to optical purity. It is obtained by using the following formula:
  • enantioenriched or “enantiomerically enriched” refers to a sample of a chiral compound that consists of more of one enantiomer than the other. The extent to which a sample is enantiomerically enriched is quantitated by the enantiomeric ratio or the enantiomeric excess.
  • the present invention relates to compounds of general Formulas I- III and IX-XIII and pharmaceutically acceptable salts, co-crystals and prodrugs thereof, and methods of making and using the same.
  • One aspect of the present invention provides for compounds of general Formulas I-III:
  • Gi, G 2 , G 3 , G 6 , G 7 and G 9 are each independently selected from the group consisting of C and N;
  • A is selected from the group consisting of absent, -H, -NR 8 2 , -NO 2 , - OR 7 , -SR 7 , -C(O)NR 5 2 , halo, -C(O)R 11 , -SO 2 R 9 , guanidine, -C(NH)NR 5 2 , - NHSO 2 R 20 , -SO 2 NR 5 2 , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Q-Csalkyl, C ⁇ Csalkenyl, C 2 -C 5 alkynyl, and lower alicyclic;
  • L is selected from the group consisting of absent, -H, -NR 2 , -NO 2 , - OR 7 , -SR 7 , -C(O)NR 5 2 , halo, -C(O)R 11 , -SO 2 R 9 , guanidine, -C(NH)NR 5 2 , - NHSO 2 R 20 , -SO 2 NR 5 2 , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Ci-Csalkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, and lower alicyclic; or together A and L form a cyclic group;
  • E is selected from the group consisting of absent, -H, -NR 8 2 , -NO 2 , - OR 7 , -SR 7 , -C(O)NR 5 2 , halo, -C(O)R 11 , -SO 2 R 9 , guanidine, -C(NH)NR 5 2 , - NHSO 2 R 20 , -SO 2 NR 5 2 , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Ci-Csalkyl, C 2 -Csalkenyl, C 2 -Csalkynyl, and lower alicyclic; or together E and J form a cyclic group; or
  • J is selected from the group consisting of absent, -H, -NR 2 , -NO 2 , - OR 7 , -SR 7 , -C(O)NR 5 2 , halo, -C(O)R 11 , -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl; or together J and D form a cyclic group;
  • D is selected from the group consisting of absent, -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C(O)R 9 , -S(O) 2 R 9 , -C(O)R 11 ,-C(O)-OR 9 , -CONHR 9 , -NR 2 2 , and -OR 9 , each, except H, optionally substituted; or together D and X form a cyclic group;
  • X is selected from the group consisting of -alkylamino-, - alkylene(hydroxy)-, -alkylene(carboxyl)-, -alkylene(phosphonate)-, -alkylene-, -alkenylene-, -alkynylene-, -alkylene(sulfonate)-, -arylene-, -carbonylalkyl-, - (l,l-dihalo)alkylene-, -aminocarbonylamino-, -alkylaminoalkyl-, - alkoxyalkyl-, -alkylthioalkyl-, -alkylthio-, - alkylaminocarbonyl -, - alkylcarbonylamino-, -alicyclic-, -aralkyl-, and -alkylaryl-, each optionally substituted; or together X and D form a cyclic group; M is -P
  • Y and Y' are each independently selected from the group consisting of -0-, and -NR V -; when Y and Y' are both -0-, R 21 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R 52 ) 2 OC(O)NR 52 2 , -NR 52 -C(O)-R 53 , -C(R 52 ) 2 -OC(O)R 5 ⁇ -C(R 52 ) 2 -O-C(O)OR 53 , -C(R 52 ) 2 OC(O)S R 53 , -alkyl-S-C(O)R 53 , -alkyl-S-S-alkyl
  • R 21 attached to -NR V - is independently selected from the group consisting of -H, -[C(R 52 ) 2 ] P -COOR 53 , -C(R X ) 2 COOR 53 , -[C(R 52 ) 2 ] P -C(O)SR 53 , and -cycloalkylene-COOR 53 ; wherein if both R 21 are alkyl, at least one is higher alkyl; or when Y and Y' are independently selected from -O- and -NR V -, then R 21 and R 21 together form a cyclic group comprising -alkyl-S-S-alkyl-, or R 21 and R 21 together are the group:
  • V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; and
  • Z is selected from the group consisting of - CHR 52 OH, -CHR 52 OC(O)R 53 ,
  • W and W are as defined above and together V and Z are connected via (a) an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining ring atoms are carbon, optionally substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus, or (b) an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, wherein said cyclic group is fused to an aryl group at the beta and gamma position to a Y or Y that is attached to the phosphorus; or
  • W and Z are as defined above and together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon ring atoms optionally substituted with one substituent selected from hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy, said substituent attached to one of said carbon ring atoms that is three atoms from a Y or Y' that is attached to the phosphorus; or
  • W is as defined above, V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining ring atoms are carbon; or
  • Z is as defined above, V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and together W and W are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining ring atoms are carbon;
  • R 52 is selected from the group consisting of R 53 and -H;
  • R 53 is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
  • R x is independently selected from the group consisting of -H, and alkyl, or together R x and R x form a cycloalkyl group;
  • R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; p is an integer 2 or 3;
  • R is selected from the group consisting of R and -H;
  • R is selected from the group consisting of -H, lower alkyl, lower alicyclic, lower aralkyl, and lower aryl;
  • R is selected from the group consisting of -H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and -C(O)R 10 ;
  • R 8 is selected from the group consisting of -H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C(O)R 10 , or together they form a bidentate alkyl;
  • R 9 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
  • R is selected from the group consisting of -H, lower alkyl, -NH 2 , lower aryl, and lower perhaloalkyl;
  • R is selected from the group consisting of alkyl, aryl, -OH, -NH 2 and
  • R 2 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; wherein, a) V, Z, W, W are not all -H, b) when Z is -R 52 , then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl, and, c) said compound of Formula I-III is not a compound of Formulas IV-VIII as represented by
  • Formula VIII or a pharmaceutically acceptable salt, co-crystal or prodrug thereof.
  • the present invention provides for compounds of Formulas IX or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula IX, wherein the substituents (Gi-G ⁇ , G7-G9, L, E, J, D, X and M) are as defined above; B is C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 - C 5 alkynyl, lower alicyclic or aralkyl; and, X " is Cl “ or Br " :
  • the present invention provides for compounds of Formula X or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula X, wherein the substituents (G7-G9, L, E, J, D, X and M) are as defined above:
  • the present invention provides for compounds of Formula XI or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula XI, wherein the substituents (Gi, G 2 , Ge 5 G 7 -Gg, A, L, E, D, X and M) are as defined above; B is C r C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, lower alicyclic or aralkyl; and, X " is Cl " or Br "
  • the present invention provides for compounds of Formula XII or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula XII, wherein the substituents (Gi, G 2 , G 6 , G 7 -G9, A, L, E, D, X and M) are as defined above.
  • the present invention provides for compounds of Formula XIII or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula XIII, wherein the substituents (G7-G 9 , A, L, E,D, X and M) are as defined above:
  • A, L, and E are independently selected from the group consisting of absent-H, -NR 2 , -NO 2 , hydroxy, alkylaminocarbonyl, halogen, - OR 7 , -SR 7 , lower perhaloalkyl, and C)-C 5 alkyl.
  • L and E are independently selected from the group consisting of absent -NR 8 2 , -H, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and lower alkyl.
  • A is selected from the group consisting of absent - NR 8 2 , -H, halogen, lower perhaloalkyl, and lower alkyl.
  • L and E are independently selected from the group consisting of absent -H, lower alkoxy, lower alkyl, and halogen.
  • J is selected from the group consisting of absent -H, halogen, lower alkyl, lower hydroxylalkyl, -NR 8 2 , lower R 8 2 N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic.
  • J is selected from the group consisting of absent -H, halogen, and lower alkyl-, lower hydroxyalkyl-, -NR 8 2 , lower R 8 2 N-alkyl-, lower haloalkyl, lower alkenyl, alicyclic, and aryl.
  • J is selected from the group consisting of alicyclic and lower alkyl.
  • a and L together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
  • L and E together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
  • E and J together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
  • D and J together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
  • D and X together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
  • X is selected from the group consisting of -alkylene-, -alkynylene-, -arylene-, -alkoxyalkyl-, -alkylthio-, -alkylaminocarbonyl-, - alkylcarbonylamino-, -(l,l-dihalo)alkylene, -carbonylalkyl-, -alkylene(OH)-, and -alkylene(sulfonate)-.
  • X is selected from the group consisting of - heteroarylene-, -alkylaminocarbonyl-, -(l,l-dihalo)alkylene-, - alkylene(sulfonate)-, and -alkoxyalkyl-.
  • X is selected from the group consisting of - heteroarylene-, -alkylaminocarbonyl-, and -alkoxyalkyl-.
  • X is selected from the group consisting of - methylaminocarbonyl-, - methoxymethyl-, and furan-2,5-diyl.
  • X is not substituted with a phosphonic acid or ester.
  • X when X is -arylene- or -alkylaryl-, X does not link Gs and M through position 1 and 4 a 6-membered aromatic ring.
  • X is Furan-2,5-diyl, Pyridin-2,6-diyl, Oxazol-2,5- diyl, -C(O)-OCH2-, -C(O)-NHCH2-, -C(O)-SOE-, -C(0)-N(Me)CH2-, - NHC(0)-CH2-, -CH2 ⁇ CH2-, wherein the direction of X is from G 8 to M.
  • R 20 and R 7 are independently selected from the group consisting of -H, and lower alkyl.
  • L, and E are independently selected from the group consisting of absent -H, lower alkyl, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and -NR 8 2 ;
  • X is selected from the group consisting of - arylene-, -alkoxyalkyl-, -alkylene-, -alkylthio-, -(l,l-dihalo)alkylene-, - carbonyl-, -alkylene-, -alkylene(hydroxy)-, -alkylene(sulfonate)-, - alkylaminocarbonyl-, and -alkylcarbonylamino-; and each R 5 and R 7 is independently -H, or lower alkyl.
  • L, and E are independently selected from the group consisting of absent -H, lower alkyl, halogen, and -NR 8 2 ;
  • J is selected from the group consisting of -H, halogen, haloalkyl, hydroxyalkyl, R 2 N-alkyl, lower alkyl, lower aryl, heterocyclic, and alicyclic, or together with D forms a cyclic group;
  • X is selected from the group consisting of -heteroarylene-, - alkylaminocarbonyl-, -(l,l-dihalo)alkylene-, and -alkoxyalkyl-.
  • A is selected from the group consisting of -H, -NH 2 , - F, and -CH 3 ;
  • L is selected from the group consisting of -H, -F, -OCH 3 , -Cl, and -CH 3 ;
  • E is selected from the group consisting of -H and -Cl;
  • J is selected from the group consisting of -H, halo, C 1 -C 5 hydroxyalkyl, C1-C5 haloalkyl, R 8 2 N- Ci-Csalkyl, Q-Csalicyclic, and Q-Csalkyl;
  • X is selected from the group consisting Of -CH 2 OCHi- and furan-2,5-diyl; and, D is lower alkyl.
  • M is selected from the group consisting of -P(O)[-OCR 52 2 OC(O)R 53 ] 2 , -P(O)[-OCR 52 2 OC(O)OR"] 2 , -P(O)[-N(H)CR 52 2 C(O)OR 53 ] 2 , -P(O)[-N(H)CR 52 2 C(O)OR 53 ][-OR ⁇ ], -P(O) [-OCH(V)CH 2 CH 2 O-], -P(O)(OH)(OR 11 ), -P(O)(OR e )(OR e ), -P(O)[-OCR 52 2 OC(O)R 53 ](OR e ), -P(O)[-OCR 52 2 OC(O)OR 53 ](OR e ), and -P(O)[-N(H)CR 52 2 C(O)OR 53 ](OR e ); wherein:
  • V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl;
  • R e is selected from the group consisting of optionally substituted -C 1 -C 12 alkyl, optionally substituted -C 2 -Ci 2 alkenyl, optionally substituted -C 2 -Ci 2 alkynyl, optionally substituted -(CR 57 2 ) n aryl, optionally substituted -(CR 57 2 ) n cycloalkyl, and optionally substituted -(CR 57 2 ) n heterocycloalky 1 ; n is an integer from 1 to 3; each R 57 is independently selected from the group consisting of hydrogen, optionally substituted -Q-C 4 alkyl, halogen, optionally substituted -0-Ci-C 4 alkyl, -OCF 3 , optionally substituted -S-Ci-C 4 alkyl, -NR 58 R 59 , optionally substituted -C 2 -C 4 alkenyl, and optionally substituted -C 2 -C 4 alky
  • R 58 is selected from hydrogen and optionally substituted -Ci-C 4 alkyl; and, R 59 is selected from the group consisting of hydrogen and optionally substituted -Q-C 4 alkyl, optionally substituted -C(O)-Ci-C 4 alkyl and -C(O)H.
  • the asymmetric carbon of alpha-amino esters is of the L-configuration.
  • M is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCR 52 2 OC(O)R 53 ] 2 , -P(O)[-OCR 52 2 OC(O)OR 53 ] 2 , -P(O)[-N(H)CR 52 2C(O)OR"]2, -P(O)[-N(H)CR 52 2 C(O)OR 53 ][-OR ⁇ ], -P(O) [-OCH(V)CH 2 CH 2 O-], , -P(O)(OR e XOR e ), -P(O)[-OCR 52 2 OC(O)R 53 ](OR e ), -P(O)[-OCR 52 2 OC(O)OR 53 ](OR e ), -P(O)[-OCR 52 2 OC(O)OR 53 ](OR e ), -P(O)[-N(H)CR 52 2 C
  • M is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCH 2 OC(O)-r-butyl] 2 , -P(O)[-OCH 2 OC(O)O-i-propyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)O CH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 , -P(0)[-N(H)CH (CH 3 )C(O)OCH 2 CH 3 ][3,4-methylenedioxyphenyl], -P(O)[-N(H)C (CH 3 ) 2 C(O)OCH 2 CH 3 ] [3,4-methylenedioxyphenyl] , -P(0)[-0CH (3-chlorophenyl)CH 2 CH 2 O-], -P(O)[-OCH 2 CH
  • M is selected from wherein Y and Y' are each independently selected from -O- and -NR V -; together R 2 ' and R 21 are the group:
  • V is substituted aryl or substituted heteroaryl.
  • Z is selected from hydrogen, W is hydrogen, and W is hydrogen.
  • V is selected from the group consisting of 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, pyrid-4-yl, pyrid-3-yl and 3,5-dichlorophenyl.
  • Another aspect provides for the use of a compound of the invention for the manufacture of a medicament for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which an FBPase inhibitor(s) is indicated.
  • Another aspect provides for the use of a compound of the invention for the manufacture of a medicament for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition responsive to inhibition of gluconeogenesis or responsive to lowered blood glucose levels, the method comprising the step of administering to a patient a therapeutically effective amount a compound of the invention, or a pharmaceutically acceptable salt or prodrugs thereof.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of Type I diabetes, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of Type II diabetes, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of impaired glucose tolerance, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of insulin resistance, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of hyperglycemia, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset of or reducing the risk for the development or progression accelerated gluconeogenesis, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset of or reducing the risk for the development or progression increased or excessive (greater than normal levels) hepatic glucose output, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically exceptable excipient.
  • compositions comprising a salt or co-crystal of a compound of Formula I-III or IX-XIII and a pharmaceutically exceptable excipient.
  • compounds of the invention are administered in a total daily dose of 0.01 to 2500 mg. In one aspect the range is about 1 mg to about 1000 mg. In one aspect the range is about 1 mg to about 500 mg. In one aspect the range is about 10 mg to about 500 mg.
  • the dose may be administered in as many divided doses as is convenient or necessary.
  • compounds of the invention are administered in a unit dose of a range between 0.01 to 1000 mg. In one aspect the range is about 0.1 mg to about 500 mg. In one aspect the range is about 0.1 mg to about 100 mg. In one aspect the range is about 1 mg to about 1000 mg. In one aspect the range is about 1 mg to about 500 mg. In one aspect the range is about 1 mg to about 100 mg. In one aspect the range is about 1 mg to about 10 mg. In one aspect the range is about 10 mg to about 1000 mg. In one aspect the range is about 10 mg to about 500 mg. In one aspect the range is about 10 mg to about 100 mg. In one aspect, the unit dose is 10 mg. In one aspect, the unit dose is 25 mg. In one aspect, the unit dose is 50 mg.
  • the unit dose is 75 mg. In one aspect, the unit dose is 100 mg. In one aspect, the unit dose is 150 mg. In one aspect, the unit dose is 200 mg. In one aspect, the unit dose is 250 mg. In one aspect, the unit dose is 300 mg. In one aspect, the unit dose is 400 mg. In one aspect, the unit dose is 500 mg. In one aspect, the unit dose is 600 mg. In one aspect, the unit dose is 700 mg. In one aspect, the unit dose is 800 mg. In one aspect, the unit dose is 900 mg. In one aspect, the unit dose is 1000 mg.
  • the compound is administered QD (once a day). In another aspect the compound is administered BID (twice a day). In another aspect the compound is administered TID (three times a day). In another aspect the compound is administered QID (four times a day). In one aspect the compound is administered before a meal. In one aspect the compound is administered after a meal. In one aspect the compound is administered in the morning hours. In one aspect the compound is administered upon awaking in the morning. In one aspect the compound is administered in the evening hours. In one aspect the compound is administered at bedtime in the evening. Compounds of this invention may be used in combination with other pharmaceutical agents. The compounds may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid).
  • Administration of the compound may occur at or near the time in which the other pharmaceutical agent is administered or at a different time.
  • the compounds of this invention may be used in a multidrug regimen, also known as combination or 'cocktail' therapy, wherein, multiple agents may be administered together, may be administered separately at the same time or at different intervals, or administered sequentially.
  • the compounds of this invention may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy by another agent in a treatment program.
  • the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques.
  • Intraarterial and intravenous injection as used herein includes administration through catheters. Intravenous administration is generally preferred.
  • Pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucoranate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, subsalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide.
  • compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • One aspect relates to the administration of a pharmaceutically acceptable composition of the present invention by controlled- or delayed-release means. Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts.
  • a variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the crystalline forms of the invention. Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598, 123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5, 639,476; 5,354,556; 5,733,566; and 6,365,185; each of which is incorporated herein by reference.
  • dosage forms can be used to provide delayed or controlled- release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS, Alza Corporation, Mountain View, Calif. USA), multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • ion exchange materials can be used to prepare immobilized, adsorbed co-crystals and thus effect controlled delivery of the drug. Examples of specific anion exchangers include, but are not limited to, Duolite A568 and Duolite AP143 (Rohm & Haas, Spring House, PA, USA).
  • One aspect of the invention encompasses a unit dosage form which comprises a pharmaceutically acceptable composition comprising a crystalline form of a compound of the present invention and one or more pharmaceutically acceptable excipients or diluents, wherein the pharmaceutical composition, medicament or dosage forms is formulated for controlled-release.
  • the dosage form utilizes an osmotic drug delivery system.
  • OROS osmotic drug delivery system
  • This technology can readily be adapted for the delivery of compounds and compositions of the invention.
  • Various aspects of the technology are disclosed in U.S. Pat. Nos. 6, 375, 978; 6,368,626 ; 6,342,249; 6,333,050; 6,287,295; 6, 283,953; 6,270,787; 6,245,357; and 6,132,420; each of which is incorporated herein by reference.
  • OROS that can be used to administer compounds and compositions of the invention
  • OROS include, but are not limited to, the OROS; Push- PuIl, Delayed Push-Pull, Multi-Layer Push- Pull, and Push-Stick Systems, all of which are well known. See, e.g., http://www. alza.com.
  • Additional OROS systems that can be used for the controlled oral delivery of compounds and compositions ofthe invention include OROS- CT and L-OROS (Id.; see also, Delivery Times, vol. II, issue II (Alza Corporation).
  • OROS oral dosage forms are made by compressing a drug powder (e.g. a crystalline form selected from Forms A-D) into a hard tablet, coating the tablet with cellulose derivatives to form a semi-permeable membrane, and then drilling an orifice in the coating (e.g., with a laser).
  • a drug powder e.g. a crystalline form selected from Forms A-D
  • Kim Cherug-ju, Controlled Release Dosage Form Design, 231-238 (Technomic Publishing, Lancaster, PA: 2000).
  • the advantage of such dosage forms is that the delivery rate of the drug is not influenced by physiological or experimental conditions. Even a drug with a pH-dependent solubility can be delivered at a constant rate regardless of the pH of the delivery medium. But because these advantages are provided by a build-up of osmotic pressure within the dosage form after administration, conventional OROS drug delivery systems cannot be used to effectively deliver drugs with low water solubility. Id. at 234.
  • a specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a dry or substantially dry state drug layer located within the cavity adjacent to the exit orifice and in direct or indirect contacting relationship with the expandable layer; and a flow-promoting layer interposed between the inner surface of the wall and at least the external surface of the drag layer located within the cavity, wherein the drug layer comprises a crystalline form of a compound of the present invention. See U.S. Pat. No. 6,368,626, the entirety of which is incorporated herein by reference.
  • Another specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation of the liquid, active agent formulation, the dosage form optionally having a placebo layer between the exit orifice and the drug layer, wherein the active agent formulation comprises a crystalline form of a compound of the present invention. See U. S. Pat. No. 6,342,249, the entirety of which is incorporated herein by reference.
  • a pharmaceutical composition or medicament comprising a crystalline form of a compound of the present invention is administered transdermally.
  • TD transdermal
  • a "pill-and-patch" strategy can be taken, where only a fraction of the daily dose is delivered through the skin to generate basal systemic levels, onto which oral therapy is added.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monoo
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachid oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1 ,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. This is particularly advantageous with the compounds of the invention when such compounds are susceptible to acid hydrolysis.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations suitable for parenteral administration may be administered in a continuous infusion manner via an indwelling pump or via a hospital bag.
  • Continuous infusion includes the infusion by an external pump.
  • the infusions may be done through a Hickman or PICC or any other suitable means of administering a formulation either parenterally or i.v.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
  • Synthesis of the compounds encompassed by the present invention typically includes some or all of the following general steps: (1) synthesis of the prodrug ; (2) phosphonate deprotection; (3) substitution of the heterocycle; (4) substitution or modification of 2-substituent; (5) cyclization to generate bicyclic base ring system; (6) synthesis of the linker-PO ⁇ ; and (7) synthesis of the monocyclic base precursor. A detailed discussion of each step is given below.
  • Prodrugs can be introduced at different stages of the synthesis. Most often these prodrugs are made from the phosphonic acids of compounds of the invention because of their lability.
  • Phosphonic acids of compounds of the invention can be alkylated with electrophiles such as alkyl halides and alkyl sulfonates under nucleophilic substitution conditions to give phosphonate esters.
  • compounds of invention wherein YR 21 is an acyloxyalkyl group can be prepared by direct alkylation of compounds of invention with an appropriate acyloxyalkyl halide (e.g., Cl, Br, I; Phosphorus Sulfur 54:143 (1990); Synthesis 62 (1988)) in the presence of a suitable base (e.g., pyridine, TEA, diisopropylethylamine) in suitable solvents such as DMF (J. Med. Chem. 37:1875 (1994)).
  • the carboxylate component of these acyloxyalkyl halides includes but is not limited to acetate, propionate, isobutyrate, pivalate, benzoate, carbonate and other carboxylates.
  • Dimethylformamide dialkyl acetals can also be used for the alkylation of phosphonic acids (Collect. Czech Chem. Comma. 59:1853 (1994)).
  • Compounds of invention wherein YR 21 is a cyclic carbonate, a lactone or a phthalidyl group can also be synthesized by direct alkylation of the free phosphonic acids with appropriate halides in the presence of a suitable base such as NaH or diisopropylethylamine (/. Med. Chem. 38:1372 (1995); J. Med. Chem. 57:1857 (1994); J. Pharm. ScL 76:180 (1987)).
  • these phosphonate prodrugs can be synthesized by the reactions of the corresponding dichlorophosphonates and an alcohol (Collect Czech Chem. Commun. 59:1853 (1994)).
  • a dichlorophosphonate is reacted with substituted phenols and arylalkyl alcohols in the presence of a base such as pyridine or TEA to give the compounds of of the invention wherein YR 21 is an aryl group (J. Med. Chem. 39:4109 (1996); J. Med. Chem. 38:1372 (1995); J. Med. Chem. 37:498 (1994)) or an arylalkyl group (J. Chem. Soc. Perkin Trans.
  • the disulfide-containing prodrugs can be prepared from a dichlorophosphonate and 2-hydroxyethyldisulfide under standard conditions. Dichlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs.
  • treatment of a dichlorophosphonate with ammonia gives both a monophosphonamide and a diphosphonamide
  • treatment of a dichlorophosphonate with l-amino-3- propanol gives a cyclic 1 ,3-propylphosphonamide
  • treatment of a chlorophosphonate monophenyl ester with an amino acid ester in the presence of a suitable base gives a substituted monophenyl monophosphonamidate.
  • Such reactive dichlorophosphonates can be generated from the corresponding phosphonic acids with a chlorinating agent (e.g., thionyl chloride, J. Med. Chem. 1857 (1994); oxalyl chloride, Tetrahedron Lett. 37:3261 (1990); phosphorous pentachloride, Synthesis 490 (1974)).
  • a dichlorophosphonate can be generated from its corresponding disilyl phosphonate esters (Synth. Comma. 17:107 '1 (1987)) or dialkyl phosphonate esters (Tetrahedron Lett. 24:4405 (1983); Bull. Soc. CMm. 750:485 (1993)).
  • compounds of the invention can be mixed phosphonate ester (e.g., phenyl and benzyl esters, or phenyl and acyloxyalkyl esters) including the chemically combined mixed esters such as phenyl and benzyl combined prodrugs reported in Bioorg. Med. Chem. Lett. 7:99 (1997).
  • mixed phosphonate ester e.g., phenyl and benzyl esters, or phenyl and acyloxyalkyl esters
  • Dichlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs.
  • a dichlorophosphonate with an amine e.g. an amino acid alkyl ester such as L- alanine ethyl ester
  • a suitable base e.g. triethylamine, pyridine, etc.
  • treatment of a dichlorophosphonate with l-amino-3-propanol gives a cyclic 1,3- propylphosphonamide
  • treatment of a chlorophosphonate monophenyl ester with an amino acid ester in the presence of a suitable base gives a substituted monophenyl monophosphonamidate.
  • the SATE (5-acetyl thioethyl) prodrugs can be synthesized by the coupling reaction of the phosphonic acids of compounds of the invention and S-acyl-2-thioethanol in the presence of DCC, EDCI or PyBOP (J. Med. Chem. 59:1981 (1996)).
  • Cyclic phosphonate esters of substituted 1 ,3-propane diols can be synthesized by either reactions of the corresponding dichlorophosphonate with a substituted 1,3-propanediol or coupling reactions using suitable coupling reagents (e.g., DCC, EDCI, PyBOP; Synthesis 62 (1988)).
  • the reactive dichlorophosphonate intermediates can be prepared from the corresponding acids and chlorinating agents such as thionyl chloride (J. Med. Chem. 1857 (1994)), oxalyl chloride (Tetrahedron Lett. 57:3261 (1990)) and phosphorus pentachloride (Synthesis 490 (1974)).
  • these dichlorophosphonates can also be generated from disilyl esters (Synth. Commun. 77:1071 (1987)) and dialkyl esters (Tetrahedron Lett. 24:4405 (1983); Bull. Soc. Chim. Fr., 750:485 (1993)).
  • these cyclic phosphonate esters of substituted 1,3- propane diols are prepared from phosphonic acids by coupling with diols under Mitsunobu reaction conditions (Synthesis 1 (1981); J.Org. Chem. 52:6331 (1992)), and other acid coupling reagents including, but not limited to, carbodiimides (Collect. Czech. Chem. Commun.
  • Phosphonic acids also undergo cyclic prodrug formation with cyclic acetals or cyclic ortho esters of substituted propane-l,3-diols to provide prodrugs as in the case of carboxylic acid esters (HeIv. Chim. Acta. 48:1746 (1965)).
  • cyclic sulfites or sulfates are also suitable coupling precursors to react with phosphonic acid salts. These precursors can be made from the corresponding diols as described in the literature.
  • cyclic phosphonate esters of substituted 1,3-propane diols can be synthesized by trans esterification reaction with substituted 1,3- propane diol under suitable conditions.
  • Mixed anhydrides of parent phosphonic acids generated in situ under appropriate conditions react with diols to give prodrugs as in the case of carboxylic acid esters (Bull. Chem. Soc. Jpn. 52:1989 (1979)).
  • Aryl esters of phosphonates are also known to undergo transesterification with alkoxy intermediates (Tetrahedron Lett. 38:2597 (1997); Synthesis 968 (1993)).
  • One aspect of the present invention provides methods to synthesize and isolate single isomers of prodrugs of phosphonic acids of compounds of the invention. Because phosphorus is a stereogenic atom, formation of a prodrug with a substituted- 1,3-propane-diol will produce a mixture of isomers. For example, formation of a prodrug with a racemic l-(V)-substituted- 1,3-propane diol gives a racemic mixture of cis-prodrugs and a racemic mixture of trans- prodrags.
  • the use of the enantioenriched substituted- 1,3- propane diol with the R-configuration gives enantioenriched R-cis-and R- trans-prodrugs.
  • These compounds can be separated by a combination of column chromatography and/or fractional crystallization.
  • YR 21 can also be introduced at an early stage of the synthesis.
  • compounds of the invention where R 21 is phenyl can be prepared by phosphorylation of 2-furanyl bicyclic base subjected to a strong base (e.g. LDA) and chlorodiphenyl phosphonate.
  • such compounds can be prepared by alkylation of lithiated furfuraldehyde followed by ring closure to the bicyclic base.
  • compounds of the invention can be mixed phosphonate esters (e.g. phenyl benzyl phosphonate esters, phenyl acyloxyalkyl phosphonate esters, phenyl aminoacid esters etc).
  • phosphonate esters e.g. phenyl benzyl phosphonate esters, phenyl acyloxyalkyl phosphonate esters, phenyl aminoacid esters etc.
  • the chemically combined phenyl-benzyl prodrugs are reported by Meier, et al. Bioorg. Med. Chem. Lett, 1997, 7: 99.
  • the substituted cyclic propyl phosphonate esters of compounds of the invention can be synthesized by reaction of the corresponding dichlorophosphonate and the substituted 1,3-propane diol. The following are some methods to prepare the substituted 1,3-propane diols.
  • This step includes various synthetic methods for the preparation of the following types of propane- 1,3-diols: i) 1 -substituted; ii) 2- substituted; and iii) 1,2- or 1 ,3-annulated.
  • Different groups on the prodrug part of the molecule i.e., on the propane diol moiety can be introduced or modified either during the synthesis of the diols or after the synthesis of the prodrugs.
  • 1 ,3-Propanediols useful in the synthesis of compounds in the present invention can be prepared using various synthetic methods. As described in Scheme A, additions of an aryl Grignard to a l-hydroxy-propan-3-al give 1-aryl-substituted 1 ,3-propanediols (path a). This method is suitable for the conversion of various aryl halides to l-arylsubstituted-l,3-propanediols (J. Org. Chem. 1988, 55, 911).
  • Conversions of aryl halides to 1-substituted 1,3-propanediols can also be achieved using Heck reactions (e.g., couplings with a 1 ,3-diox-4-ene) followed by reductions and subsequent hydrolysis reactions (Tetrahedron Lett. 1992, 33, 6845).
  • Various aromatic aldehydes can also be converted to 1-substituted- 1,3-propanediols using alkenyl Grignard addition reactions followed by hydroboration-oxidation reactions (path b).
  • A OR, NR(R) 1 wherein each R is independently selected from groups including alkyl and aralkly(e.g., Bn);
  • R' is a protecting group such as Bn, Si(R")(R")-, wherein each R" is independently alkyl or aryl, or -C-O-Me.
  • Aldol reactions between an enolate (e.g., lithium, boron, tin enolates) of a carboxylic acid derivative (e.g., tert-butyl acetate) and an aldehyde (e.g., the Evans's aldol reactions) are especially useful for the asymmetric synthesis of enantioenriched 1 ,3-propanediols.
  • reaction of a metal enolate of f-butyl acetate with an aromatic aldehyde followed by reduction of the ester gives a 1,3-propanediol (J. Org. Chem. 1990, 55 4744).
  • epoxidation of cinnamyl alcohols using known methods e.g., Sharpless epoxidations and other asymmetric epoxidation reactions
  • reduction reactions e.g., using Red- Al
  • Enantioenriched 1 ,3-propanediols can be obtained via asymmetric reduction reactions (e.g., enantioselective borane reductions) of 3-hydroxy-ketones (Tetrahedron Lett. 1997, 38761).
  • resolution of racemic 1,3-propanediols using various methods e.g., enzymatic or chemical methods
  • Propan-3-ols with a 1-heteroaryl substituent e.g., a pyridyl, a quinolinyl or an isoquinolinyl
  • a 1-heteroaryl substituent e.g., a pyridyl, a quinolinyl or an isoquinolinyl
  • a variety of 2-substituted 1 ,3-propanediols useful for the synthesis of compounds of Formula I can be prepared from various other 1 ,3-propanediols (e.g., 2-(hydroxymethy I)- 1,3-propanediols) using conventional chemistry (Comprehensive Organic Transformations, VCH, New York, 1989).
  • 1 ,3-propanediols e.g., 2-(hydroxymethy I)- 1,3-propanediols
  • reductions of a trialkoxycarbonylmethane under known conditions give a triol via complete reduction (path a) or a bis(hydroxymethyl)acetic acid via selective hydrolysis of one of the ester groups followed by reduction of the remaining two other ester groups.
  • Nitrotriols are also known to give triols via reductive elimination (path b) (Synthesis 1987, 8, 742). Furthermore, a 2-(hydroxy methyl)- 1,3-propanediol can be converted to a mono acylated derivative (e.g., acetyl, methoxycarbonyl) using an acyl chloride or an alkyl chloroformate (e.g., acetyl chloride or methyl chloroformate) (path d) using known chemistry (Protective Groups In Organic Synthesis ; Wiley, New York, 1990).
  • a mono acylated derivative e.g., acetyl, methoxycarbonyl
  • an alkyl chloroformate e.g., acetyl chloride or methyl chloroformate
  • Prodrugs of formula I where V - Z or V - W are fused by three carbons are made from cyclohexane diol derivatives.
  • Commercially available cis, cis- 1,3,5-cyclohexane triol can be used for prodrug formation.
  • This cyclohexanetriol can also be modified as described in the case of 2-substituted propan-l,3-diols to give various analogues. These modifications can either be made before or after formation of prodrugs.
  • Various 1 ,3-cyclohexane diols can be made by Diels- Alder methodology using pyrone as the diene (Posner, et.
  • Cyclohexyl diol derivatives are also made by nitrile oxide olefin-additions (Curran, et. al., J. Am. Chem. Soc, 1985, 107, 6023).
  • cyclohexyl precursors can be made from quinic acid (Rao, et. al., Tetrahedron Lett., 1991, 32, 547.)
  • Compounds of formula 6, may be prepared from phosphonate esters of formula 5, using known phosphate and phosphonate ester cleavage conditions.
  • silyl halides have been used to cleave the various phosphonate esters, followed by mild hydrolysis of the resulting silyl phosphonate esters to give the desired phosphonic acids.
  • acid scavengers such as 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc.
  • Such silyl halides include, chlorotrimethylsilane (Rabinowitz, J. Org.
  • phosphonate esters can be cleaved under strong acid conditions, (e.g HBr, HCl, etc.) in polar solvents, preferably acetic acid (Moffatt, et al, U.S. Patent 3,524,846, 1970) or water.
  • esters can also be cleaved via dichlorophosphonates, prepared by treating the esters with halogenating agents e.g. phosphorus pentachloride, thionyl chloride, BBr 3 , etc.(Pelchowicz, et al, J. Chem. Soc, 1961, 238) followed by aqueous hydrolysis to give phosphonic acids.
  • halogenating agents e.g. phosphorus pentachloride, thionyl chloride, BBr 3 , etc.
  • Aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis conditions (Lejczak, et al, Synthesis, 1982, 412; Elliott, et al, J. Med.
  • the bicyclic base ring system of formula 4 may require further elaboration to provide desired compounds of formula 5.
  • Substitution of the 6-membered Ring Electrophilic and nucleophilic substitution reactions enable inco ⁇ oration of the desired substitutions encompassed by the formula 5.
  • G6 is C
  • A is NH 2
  • L and J are hydrogens
  • Compounds of formula 5, where A is NO 2 , L and/or J are alkenyl, alkynyl, alkyl, or aryl groups, and Y is H or alkyl, may be prepared from compounds of formula 4, where A is NO 2 , R is H or alkyl, and L and/or J are halogens, preferably bromide or iodide, through Stille coupling (Stille, Angew. Chem. Int. Ed. Engl. 1986, 25: 508- 524). Treatment of the compounds of formula 4, where A is NO 2 , and L and/or J are bromides, with a coupling reagent (e.g.
  • the compounds thus obtained can be modified as needed.
  • vinyl or propargyl alcohol derivatives can be hydrogenated to give the ethyl or propyl alcohol derivatives respectively.
  • These alcohols can be further modified as required via alkyl halides (ref. Wagner et al.
  • alkyl sulfonates etc. to a number of substituted alky Is such as amino alkyl compounds by subjecting them to nucleophilic substitution reactions (March, Advanced Organic Chemistry , Wiley-Interscience, Fourth Edition, 1992, 293- 500). Alternatively, these substitutions can also be done by metal exchange followed by quenching with an appropriate nucleophile (Jerry March, Advanced Organic Chemistry , Wiley-Interscience, 1992, 606-609). Nucleophilic addition reactions can also be useful in preparing compounds of formula 5. For example, when A is NO 2 , L and/or J are halogens, nucleophiles such as alkoxides, thiols, amines, etc.
  • these substituted compounds can be further modified to the desired products.
  • reduction of the NO 2 to NH 2 may be done in many different ways, e.g. Pd/C, H 2 , aq. Na 2 S 2 O 4 , etc. (Larock, Comprehensive Organic Transformations , VCH, 412-415).
  • These primary aromatic amines can also be modified as needed.
  • N-acetyl derivatives can be prepared by treatment with acetyl chloride or acetic anhydride in the presence of a base such as pyridine.
  • the mono- or di- alkylamines can be synthesized by direct alkylation, using a base such as NaH in polar solvents such as DMF or by reductive alkylation methods (ref. Abdel- Magid et al. Tetrahedron Lett. 1990, 31, 5595; also see ref. March, Advanced Organic Chemistry , Wiley-Interscience, Fourth Edition, 1992, 898-900 for more methods).
  • deaza-purine analogs can be prepared from corresponding diaminoprecursors.
  • Diaminoprecursors of variety of nitrogen heterocycles, such as pyridyl, pyrazinyl and pyridazinyl bases can be further transformed into bicyclic systems as shown in the following synthesis of 1- deaza analogs. These compounds may be functionalized as shown below by activation to N-oxide.
  • the resulting phosphonate substituted bicyclic systems may be further transformed to alpha-haloamines via nitration (Wanner, et al, Nucleosides, Nucleotides & Nucleic Acids 2004, 23: 1313, Cristalli, et al., J. Med. Chem., 1987, 30: 1686)
  • Alkylation of the bicyclic base ring system of formula 4 is achieved by treatment of an alcohol, triphenylphosphine and dialkylazodicarboxylate with heterocycle and a non-nucleophilic base such as Hunigs base in polar solvents such as CH 3 CN (Zwierzak et al, Liebigs Ann. Chem. 1986, 402). b) Base Alkylation
  • the bicyclic base ring system of formula 4 can be deprotonated with a suitable base, preferably cesium carbonate in a polar aprotic solvent such as DMF, and the resulting anion is alkylated with an appropriate electrophilic component Y-L' , where L' is a leaving group preferably bromide or iodide.
  • a heterosubstituted methyl phosphonates can also be prepared by displacement reactions on phosphonomethyl halides or sulfonates (Phillion et al, Tetrahedron Lett., 1986, 27: 1477.) with an appropriate nucleophile e.g. 2-hydroxylmethylbicyclic base compound which can be prepared using a variety of methods, including oxidation of the substituted 2-methylbicyclic bases.
  • compounds of formula 1, where X is carboxypropyl or sulfonopropyl can be prepared from the reaction of 2-(2-iodoethyl) bicyclic base and corresponding phosphonomethylcarboxylate or phosphonomethylsulfonate (Carretero et al., Tetrahedron, 1987, 43, 5125) in the presence of base such as NaH in polar aprotic solvents such as DMF.
  • the substituted 2-(2-iodoethyl) bicyclic base can be prepared from condensation of the corresponding substituted diamine and 3-halopropanaldehyde. Also see ref. Magnin, D. R. et al. J. Med. Chem. 1996, 39, 657 for the preparation of ⁇ - phosphosulfonic acids.
  • the componds of formula 4 where X is all carbon e.g. -(CH 2 ) 3 - can be prepared by Stille coupling (Stille Angew. Chem. Int. Ed. Engl. 1986, 25: 508- 524) of the dialkylphosphopropenyl tributylstanne (J. Org. Chem. 1993, 58: 6531.) and appropriate 2-bromobicyclic base (Misery, et al, Tetrahedron Lett., 1986, 27: 1051).
  • the componds of formula 4 where X is an amide linker e.g. -CONHCH 2 - can be synthesized using the following two steps.
  • Treatment of the appropriate 1,2-1,2-diamine with trihalomethylacetamidate preferably trichloromethylacetamidate in polar solvent such as acetic acid followed by hydrolysis of the trihalomethyl group with strong aqueous base (e.g. KOH) gives the bicyclic base-2-carboxylic acid (Eur. J. Med. Chem., 1993, 28: 71).
  • Condensation of the acid with an amino phosphonate e.g. diethyl(aminomethyl)phosphonate in presence of a coupling agent (e.g. pyBOP) in a polar solvent such as methylene chloride provides the amide linked phosphonate.
  • a coupling agent e.g. pyBOP
  • the componds of formula 4 where X is an amide linker e.g. -NHCOCH 2 - can be synthesized using the following two steps.
  • Treatment of the appropriate 1 ,2-diamine with cyanogenbromide Johnson, et al, J. Med. Chem., 1993, 36: 3361
  • polar solvent such as MeOH
  • Condensation of the 2-aminobicyclic base with a carboxylic acid e.g. diethyl(carboxymethyl)phosphonate using standard coupling conditions (Klausner, et al, Synthesis, 1972, 453) provides the amide linked phosphonate.
  • the 2-aminobicyclic bases can also be prepared from the 2- bromobicyclic base via the 2-azidobicyclic base using known methods (Chem. Rev. 1988, SS: 297).
  • the bicyclic base ring systems of formula 4 is preferably assembled by condensation of substituted 1,2-diamines with an aldehyde (RCHO, where R is e.g. aliphatic, heteroaliphatic, aromatic or heteroaromatic etc.) using known methods; (a) in presence of Fe 3+ salts, preferably FeCl 3 , in polar solvents such as DMF, EtOH etc., (b) reflux in non-polar solvents such as toluene followed by oxidation, preferably with iodine (Bistocchi et al, Collect. Czech. Chem.
  • RCHO aldehyde
  • the first condensation can be achieved in the presence of a dilute inorganic acid, preferably 10 % H 2 SO 4 , in polar solvents such as THF, followed by oxidation with I 2 .
  • a dilute inorganic acid preferably 10 % H 2 SO 4
  • polar solvents such as THF
  • these bicyclic base ring systems can be constructed using solid phase synthesis (ref: Phillips et al. Jet. Lett., 1996, 37: 4887; Lee et al, Tet. Lett, 1998: 35: 201.
  • Aryl functionalized phosphonate linkers can be prepared by lithiation of an aromatic ring using methods well described in literature (Gschwend, Org. React. 1979, 26, 1; Durst, Comprehensive Carbanion Chemistry, Vol. 5, Elsevier, New York, 1984) followed by addition of phosphorylating agents (e.g. ClPO 3 R 2 ). Phosphonate esters are also introduced by Arbuzov-Michaelis reaction of primary halides (Brill, T. B., Chem Rev., 1984, 84: 577). Aryl halides undergo Ni 2+ catalysed reaction with trialkylphosphites to give aryl phosphonate containing compounds (Balthazar, et al, J. Org.
  • Aromatic triflates are known to result in phosphonates with ClPO 3 R 2 in the presence of a palladium catalyst (Petrakis, et al, J. Am. Chem. Soc, 1987, 109: 2831; Lu, et al, Synthesis, 1987, 726).
  • aryl phosphonate esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel, et al, Synthesis, 1991, 691).
  • arylphosphate esters, where X is aryloxy can also be made.
  • N-Alkoxy aryl salts with alkali metal derivatives of dialkyl phosphonate provide general synthesis for heteroaryl-2-phosphonate linkers (Redmore, J. Org. Chem., 1970, 55: 4114).
  • aldehyde, ketone, or carboxylic acid functionalities can also be introduced after the phosphonate ester is formed.
  • a lithiation reaction can be used to incorporate the aldehyde or ketone functionalities, although other methods known to generate aromatic aldehydes or ketones can be envisioned as well (e.g. Vilsmeier-Hack reaction, Reimar-Teimann reaction etc.; Pizey, Synthetic reagents, 1974, 7: 1; Wynberg, H., et al, Org. React. 1982, 28: 1; palladium catalyzed coupling reaction of acid halides and organotin compounds).
  • the lithiated aromatic ring can be treated with reagents that directly generate the aldehyde (e.g. DMF, HCOOR, efc.)(Einchorn, J., et al, Tetrahedron Lett., 1986, 27: 1791), or the ketone (e.g. Weinreb's amide, RCOOR').
  • the lithiated aromatic ring can also be treated with reagents that lead to a group that is subsequently transformed into the aldehyde or ketone group using known chemistry (synthesis of aldehyde and ketone from alcohol, ester, cyano, alkene, etc.).
  • the sequence of these reactions can be reversed, i.e. the aldehyde and ketone moieties can be incorporated first, followed by the phosphorylation reaction.
  • the order of the reaction will depend on reaction conditions and protecting groups. Prior to the phosphorylation it is also envisioned that it may be advantageous to protect the aldehyde or ketone using well-known methods (acetal, aminal, hydrazone, ketal, etc.), and then the aldehyde or ketone is unmasked after phosphorylation. (Protective groups in Organic Synthesis, Greene, T. W., 1991, Wiley, New York).
  • heteroaryl linkers e.g. pyridine, furan, thiophene etc.
  • Ar(Z)alkyl phosphonates can be prepared from the reaction of substituted aryls e.g. salicylaldehyde with an appropriate phosphonate electrophile [L(CfO) n PO 3 R 2 , L is a leaving group, preferably iodine; Walsh et al, J. Am. Chem. Soc, 1956, 78, 4455.] in the presence of a base, preferably K 2 CO 3 or NaH, in a polar aprotic solvent, such as DMF or DMSO.
  • a base preferably K 2 CO 3 or NaH
  • a polar aprotic solvent such as DMF or DMSO.
  • linkers of formula 3, where X is alkyloxymethyl can be synthesized through direct alkylation of the hydroxymethyl phosphonate ester, with the desired alkyl halide [L(CH2) n CH(OMe)2, L is a leaving group, preferably bromine or iodine] in the presence of a base, preferably NaH, in a polar aprotic solvent, such as DMF or DMSO.
  • L alkyl halide
  • L is a leaving group, preferably bromine or iodine
  • substituted heteroarylhalides F,Cl,Br,I
  • nucleophilic addition e.g. NH 3 , NH 2 OH, etc
  • Diamines of formula 2 R is alkyl, can be produced using alkylamine displacement of alpha-haloheterocycles. Such resulting alpha- alkylamino heterocycles can then be transformed to nitro-amines via nitration. The nitro group can be reduced with number of reagents preferably sodium dithionite to provide the corresponding diamine. This diamine is then subjected to cyclization.
  • diamines of formula 2 where R is not H are prepared by reductive alkylation of the amino substituted pyridine, pyrimidine or pyrazines with various aldehydes(e.g. akyl, aryl etc.) in the presence of a reducing agent preferably NaB(OAc) 3 followed by reduction (e.g. Na 2 S 2 O 4 ; Pd/C, H 2 etc.) of the nitro group (Magid et al Tetrahedron Lett. 1990, 31: 5595).
  • a reducing agent preferably NaB(OAc) 3 followed by reduction (e.g. Na 2 S 2 O 4 ; Pd/C, H 2 etc.) of the nitro group (Magid et al Tetrahedron Lett. 1990, 31: 5595).
  • Alkylation precursor was made as described in steps A and B of example 1.
  • Example 3 Compounds of example 3 were made starting from commercially available 3,4-diamino-pyridine following steps A-D of example 2.
  • Step A General procedure of alkylamine substitution of alpha-halopyridine:
  • Step B Preparation of 1,2-diamines via dithionite reduction:
  • Steps C and D were carried-out as described in example steps B and C of example 1.
  • Example 2.1 was made as described in steps A-C.
  • example 2.1 420 mg, 1.1 mmol
  • acetic acid 1 mL
  • 30% hydrogen peroxide 0.25 mL
  • the reaction mixture was then evaporated to dryness and azeotroped with toluene (2 X 10 mL).
  • the crude product was chromatographed with 5% MeOH-CH 2 Cl 2 to give 150 mg of N-oxide.
  • step A Diamine obtained in step A was coupled and cyclized with 2-Furaldehyde-5- diethylphosphonate utilizing the procedure described in step B of example 1.
  • N-oxide was made as described in step E of example 5.
  • Step G To a solution of amino compound (30 mg, 0.076 mmol) in methanol (2 mL) was added N-chlorosuccinimide. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated upon completion of the reaction and the crude product was chromatographed using 2% to 5% MeOH-dichloromethane to provide the pure chlorinated product (23 mg).
  • step B Diamine obtained in step B was coupled and cyclized with 2-Furaldehyde-5- diethylphosphonate utilizing the procedure described in step B of example 1.
  • Example 8 7-Methyl-6-chloro-2-[2-(5-phosphono)furanyl] imidazo[4,5-b]pyridine-N4-ethyl bromide.
  • Examples of use of the method of the invention includes the following. Examples A and E were actually performed. The remaining examples are prophetic. It will be understood that these examples are exemplary and that the method of the invention is not limited solely to these examples. Besides the following Examples, assays that may be useful for identifying compounds which inhibit gluconeogenesis include the following animal models of diabetes: i. Animals with pancreatic beta-cells destroyed by specific chemical cytotoxins such as Alloxan or Streptozotocin (e.g. the Streptozotocin-treated mouse, rat, dog, and monkey).
  • specific chemical cytotoxins such as Alloxan or Streptozotocin (e.g. the Streptozotocin-treated mouse, rat, dog, and monkey).
  • mice such as the C57BL/Ks db/db, C57BL/Ks ob/ob, and C57BL/6J ob/ob strains from Jackson Laboratory, Bar Harbor, and others such as Yellow Obese, T-KK, and New Zealand Obese.
  • Example A Inhibition of Human Liver FBPase.
  • E. coli strain BL21 transformed with a human liver FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at the State University of New York at Stony Brook.
  • hlFBPase was typically purified from 10 liters of E. coli culture as described (M. Gidh-Jain et al., The Journal of Biological Chemistry 1994, 269, 27732-27738).
  • Enzymatic activity was measured spectrophotometrically in reactions that coupled the formation of product (fructose 6-phosphate) to the reduction of dimethylthiazoldiphenyltetrazolium bromide (MTT) via NADP and phenazine methosulfate (PMS) , using phosphoglucose isomerase and glucose 6-phosphate dehydrogenase as the coupling enzymes.
  • Reaction mixtures (200 ⁇ L) were made up in 96-well microtitre plates, and consisted of 50 mM Tris-HCl, pH 7.4, 100 mM KCl, 5 mM EGTA, 2 mM MgCl2, 0.2 mM NADP, 1 mg/mL BSA, 1 mM MTT, 0.6 mM PMS, 1 unit/mL phosphoglucose isomerase, 2 units/mL glucose 6- phosphate dehydrogenase, and 0.150 mM substrate (fructose 1 ,6- bisphosphate). Inhibitor concentrations were varied from 0.01 ⁇ M to 10 ⁇ M.
  • Example B In vitro Inhibition of Rat Liver and Mouse Liver FBPase.
  • Inhibitors of FBPase may also be identified by assaying rat and mouse liver FBPase.
  • E. coli strain BL21 transformed with a rat liver FBPase-encoding plasmid is purified as described in El-Maghrabi, M.R., and Pilkis, SJ. Biochem. Biophys. Res. Commun. 1991, 776, 137-144.
  • Mouse liver FBPase is obtained by homogenizing freshly isolated mouse liver in 100 mM Tris-HCl buffer, pH 7.4, containing 1 mM EGTA, and 10 % glycerol. The homogenate is clarified by centrifugation, and the 45-75 % ammonium sulfate fraction prepared.
  • rat liver and mouse liver FBPase are assayed as described for human liver FBPase. Generally, as reflected by the higher IC50 values, the rat and mouse liver enzymes are less sensitive to inhibition by the compounds tested than the human liver enzyme.
  • the enzyme is incubated with radiolabeled AMP in the presence of a range of test compound concentrations.
  • the reaction mixtures are incubated with radiolabeled AMP in the presence of a range of test compound concentrations.
  • AMP bound to FBPase is separated from unbound AMP by means of a centrifugal ultrafiltration unit ("Ultrafree-MC", Millipore) used according to the instructions of the manufacturer.
  • Ultrafree-MC centrifugal ultrafiltration unit
  • the radioactivity in aliquots (100 ⁇ L) of the upper compartment of the unit (the retentate, which contains enzyme and label) and the lower compartment (the filtrate, which contains unbound label) are quantified using a Beckman liquid scintillation counter.
  • the amount of AMP bound to the enzyme is estimated by comparing the counts in the filtrate (the unbound label) to the total counts in the retentate.
  • Adenosine Kinase Human adenosine kinase is purified from an E. coli expression system as described by Spychala et al. (Spychala, J., Datta, N.S., Takabayashi, K., Datta, M., Fox, I.H., Gribbin, T., and Mitchell, B.S. Proc. Natl. Acad. Sci. USA 1996, 93, 1232-1237). Activity is measured essentially as described by Yamada et al. (Yamada, Y., Goto, H., Ogasawara, N. Biochim. Biophys. Acta 1988, 660, 36-43.) with a few minor modifications.
  • Assay mixtures contain 50 mM TRIS-maleate buffer, pH 7.0, 0.1 % BSA, 1 mM ATP 1 mM MgCl2, 1.0 ⁇ M [U- 14 C] adenosine (400-600 mCi/mmol) and varying duplicate concentrations of inhibitor.
  • C-AMP is separated from unreacted C-adenosine by absorption to anion exchange paper (Whatman) and quantified by scintillation counting.
  • Porcine heart AMPDA is purified essentially as described by Smiley et al. (Smiley, K.L., Jr, Berry, AJ., and Suelter, CH. J. Biol. Chem. 1967, 242, 2502-2506) through the phosphocellulose step. Inhibition of AMPDA activity is determined at 37 0 C in a 0.1 mL assay mixture containing inhibitor, -0.005U AMPDA, 0.1 % bovine serum albumin, 10 mM ATP, 250 mM KCl, and 50 mM MOPS at pH 6.5. The concentration of the substrate AMP is varied from 0.125 - 10.0 mM.
  • Catalysis is initiated by the addition of enzyme to the otherwise complete reaction mixture, and terminated after 5 minutes by injection into an HPLC system. Activities are determined from the amount of IMP formed during 5 minutes. IMP is separated from AMP by HPLC using a Beckman Ultrasil- SAX anion exchange column (4.6 mm x 25 cm) with an isocratic buffer system (12.5 mM potassium phosphate, 30 mM KCl, pH 3.5) and detected spectrophotometrically by absorbance at 254 nm.
  • Phosphofructokinase Enzyme (rabbit liver) is purchased from Sigma. Activity is measured at 30 0 C in reactions in which the formation of fructose 1 ,6-bisphosphate is coupled to the oxidation of NADH via the action of aldolase, triosephosphate isomerase, and ⁇ -glycerophosphate dehydrogenase. Reaction mixtures (200 ⁇ L) are made up in 96-well microtitre plates and are read at 340 nm in a Molecular Devices Microplate Reader.
  • the mixtures consist of 200 mM Tris-HCl pH 7.0, 2 mM DTT, 2 mM MgC12, 0.2 mM NADH, 0.2 mM ATP, 0.5 mM Fructose 6-phosphate, 1 unit aldolase/mL, 3 units/mL triosephosphate isomerase, and 4 units/mL ⁇ -glycerophosphate dehydrogenase.
  • Test compound concentrations range from 1 to 500 ⁇ M. Reactions are started by the addition of 0.0025 units of phosphofructokinase and are monitored for 15 minutes.
  • Glycogen Phosphorylase Enzyme (rabbit muscle) is purchased from Sigma. Activity is measured at 37 0 C in reactions in which the formation of glucose 1 -phosphate is coupled to the reduction of NADP via phosphoglucomutase and glucose 6-phosphate dehydrogenase. Assays are performed on 96-well microtitre plates and are read at 340 nm on a Molecular Devices Microplate Reader.
  • Reaction mixtures consist of 20 mM imidazole, pH 7.4, 20 mM MgCl2, 150 mM potassium acetate, 5 mM potassium phosphate, 1 mM DTT, 1 mg/mL BSA, 0.1 mM NADP, 1 unit/mL phosphoglucomutase, 1 unit/mL glucose 6-phosphate dehydrogenase, 0.5 % glycogen. Test compound concentrations range from 1 to 500 ⁇ M. Reactions are started by the addition of 17 ⁇ g enzyme and are monitored for 20 minutes. Adenylate Kinase: Enzyme (rabbit muscle) is purchased from Sigma.
  • Activity is measured at 37 0 C in reaction mixtures (100 ⁇ L) containing 100 mM Hepes, pH 7.4, 45 mM MgCl2, 1 mM EGTA, 100 mM KCl, 2 mg/mL BSA, 1 mM AMP and 2 mM ATP. Reactions are started by addition of 4.4 ng enzyme and terminated after 5 minutes by addition of 17 ⁇ L perchloric acid. Precipitated protein is removed by centrifugation and the supernatant neutralized by addition of 33 ⁇ L 3 M KOH/3 M KH2CO3.
  • the neutralized solution is clarified by centrifugation and filtration and analyzed for ADP content (enzyme activity) by HPLC using a YMC ODS AQ column (25 X 4.6 cm). A gradient is run from 0.1 M KH2PO4, pH 6, 8 mM tetrabutyl ammonium hydrogen sulfate to 75 % acetonitrile. Absorbance is monitored at 254 nM.
  • Example E Inhibition of GIuconeogenesis in Rat Hepatocytes
  • Hepatocytes were prepared from overnight fasted Sprague-Dawley rats (250-300 g) according to the procedure of Berry and Friend (Berry, M.N., Friend, D.S., J. Cell. Biol. 1969, 43, 506-520) as modified by Groen (Groen, A.K., Sips, H.J., Vervoorn, R.C., Tager, J.M., Eur. J. Biochem. 1982, 122, 87- 93).
  • Hepatocytes (75 mg wet weight/mL) were incubated in 1 mL Krebs- bicarbonate buffer containing 10 mM Lactate, 1 mM pyruvate, 1 mg/mL BSA, and test compound concentrations from 1 to 500 ⁇ M. Incubations were carried out in a 95 % oxygen, 5 % carbon dioxide atmosphere in closed, 50- mL Falcon tubes submerged in a rapidly shaking water bath (37 0 C). After 1 hour, an aliquot (0.25 mL) was removed, transferred to an Eppendorf tube and centrifuged. 50 ⁇ L of supernatant was then assayed for glucose content using a Sigma Glucose Oxidase kit as per the manufacturer's instructions. Three compounds were tested for their ability to inhibit gluconeogenesis in rat hepatocytes. Two of three compounds tested demonstrated inhibition of gluconeogenesis.
  • Example F Blood Glucose Lowering in Fasted Rats
  • Example G Effect of FBPase Inhibitors on Gluconeogenesis from Lactate/pyruvate in Rat Hepatocytes: Glucose Production Inhibition and Fructose 1,6-bisphosphate Accumulation
  • Isolated rat hepatocytes are prepared as described in Example E and incubated under the identical conditions described. Reactions are terminated by removing an aliquot (250 ⁇ L) of cell suspension and spinning it through a layer of oil (0.8 mL silicone/mineral oil, 4/1) into a 10 % perchloric acid layer (100 ⁇ L). After removal of the oil layer, the acidic cell extract layer is neutralized by addition of l/3rd volume of 3 M KOH/3 M KH2CO3. After thorough mixing and centrifugation, the supernatant is analyzed for glucose content as described in Example E, and also for fructose 1,6-bisphosphate.
  • Fructose 1 ,6-bisphosphate is assayed spectrophotometrically by coupling its enzymatic conversion to glycerol 3-phosphate to the oxidation of NADH, which is monitored at 340 nm.
  • Reaction mixtures (1 mL) consist of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units/mL glycerol 3-phosphate dehydrogenase, 2 units/mL triosephosphate isomerase, and 50-100 ⁇ L cell extract. After a 30 minute preincubation at 37 0 C, 1 unit/mL of aldolase is added and the change in absorbance measured until a stable value is obtained. Two moles of NADH are oxidized in this reaction per mole of fructose 1 ,6- bisphosphate present in the cell extract.
  • the vehicle used for drug administration is 10 mM bicarbonate.
  • One hour post injection rats are anesthetized with halothane and a liver biopsy (approx. 1 g) is taken as well as a blood sample (2 mL) from the posterior vena cava. A heparin flushed syringe and needle is used for blood collection.
  • the liver sample is immediately homogenized in ice-cold 10 % perchloric acid (3 mL), centrifuged, and the supernatant neutralized with l/3rd volume of 3 M KOH/3 M KH2CO3. Following centrifugation and filtration,
  • Example G Blood glucose is measured in the blood sample as described in Example E. Plasma is then quickly prepared by centrifugation and extracted by addition of methanol to 60 % (v/v). The methanolic extract is clarified by centrifugation and filtration and then analyzed by HPLC as described above.
  • Elevation of fructose- 1 ,6-bisphosphate levels in the livers from the drug-treated group is consistent with the inhibition of glucose production at the level of FBPase in the gluconeogenic pathway.
  • Zucker Diabetic Fatty rats purchased at 7 weeks of age are used at age 16 weeks in the 24-hour fasted state.
  • the rats are purchased from Genetics Models Inc. and fed the recommended Purina 5008 diet (6.5 % fat).
  • Their fasting hyperglycemia at 24 hours generally ranges from 150 mg/dLto 310 mg/dLblood glucose.
  • the stock solution is made up at 25 mg/mL in deionized water and adjusted to neutratility by dropwise addition of 5 N NaOH.
  • 5 control animals are dosed with saline. Blood glucose is measured at the time of dosing and 2 hours post dose as described in Example E.
  • Diabetes is induced in male Sprague-Dawley rats (250-300g) by intraperitoneal injection of 55 mg/kg streptozotocin (Sigma Chemical Co.).
  • 24 animals are selected with fed blood glucose values (8 am) between 350 and 600 mg/dL and divided into two statistically equivalent groups.
  • Blood glucose is measured in blood obtained from a tail vein nick by means of a HemoCue Inc. (Mission Viejo, CA) glucose analyzer.
  • One group of 12 subsequently receives inhibitor (100 mg/kg intraperitoneally) and the other 12 (“controls”) an equivalent volume of saline. Food is removed from the animals.
  • Blood glucose is measured in each animal four hours after dosing, and a second dose of drug or saline is then administered. Four hours later, a final blood glucose measurement is made.
  • Prodrugs are dissolved in 10 % ethanol/90 % polyethylene glycol (mw 400) and administered by oral gavage at doses of approximately 20 or 40 mg/kg parent compound equivalents to 6-hour fasted, Sprague Dawley rats (220-240 g). The rats are subsequently placed in metabolic cages and urine is collected for 24 hours. The quantity of parent compound excreted into urine is determined by HPLC analysis. An ODS column eluted with a gradient from potassium phosphate buffer, pH 5.5 to acetonitrile is employed for these measurements. Detection is at 310-325 nm.
  • the percentage oral bioavailability is estimated by comparison of the recovery in urine of the parent compound generated from the prodrug, to that recovered in urine 24 hours after intravenous administration of unsubstitutcd parent compound at approximately 10 mg/kg.
  • Parent compounds are typically dissolved in dimethyl sulfoxide, and administered via the tail vein in animals that are briefly anesthetized with halothane.
  • the compound is prepared in deionized water, adjusted to neutrality with sodium hydroxide, and brought into solution by sonication prior to administration.
  • Blood glucose is measured immediately prior to dosing, and at 1 hour intervals thereafter.
  • Blood samples are obtained from the tail vein, and measurments made by means of a Hemocue glucose analyzer (Hemocue Inc, Mission Viejo, California) used according to the manufacturer's instructions. A lowering of blood glucose levels is consistent with inhibition of FBPase activity.

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Abstract

L'invention concerne des composés de formule I-III et IX-XIII, leurs promédicaments et sels et co-cristaux. L'invention concerne en outre des traitements et méthodes pour les fabriquer et les utiliser.
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WO2011104261A1 (fr) 2010-02-26 2011-09-01 G+R Technology Group Ag Réacteur pour la carbonisaton hydrothermale de biomasse et procédé permettant de faire fonctionner le réacteur
WO2011104263A1 (fr) 2010-02-26 2011-09-01 G+R Technology Group Ag Système et procédé de préparation d'un mélange à partir de différentes biomasses pour une installation permettant d'obtenir un produit de réaction à partir des différentes biomasses
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012033149A1 (fr) * 2010-09-10 2012-03-15 塩野義製薬株式会社 Dérivé d'imidazole à hétérocycle fusionné ayant un effet d'activation de l'ampk
US8362268B2 (en) 2008-05-30 2013-01-29 University Of Notre Dame Du Lac Anti-bacterial agents from benzo[d]heterocyclic scaffolds for prevention and treatment of multidrug resistant bacteria
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US8431593B2 (en) 2006-11-27 2013-04-30 H. Lundbeck A/S Heteroaryl amide derivatives
US8580812B2 (en) 2007-04-10 2013-11-12 H. Lundbeck A/S Heteroaryl amide analogues as P2X7 antagonists
US8865912B2 (en) 2010-10-06 2014-10-21 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9145419B2 (en) 2010-04-28 2015-09-29 Bristol-Myers Squibb Company Imidazopyridazinyl compounds
US10316040B2 (en) 2015-10-16 2019-06-11 Eisai R&D Management Co., Ltd. EP4 antagonists
US10800782B2 (en) 2016-08-31 2020-10-13 Agios Pharmaceutical, Inc. Inhibitors of cellular metabolic processes
US11560388B2 (en) 2019-03-19 2023-01-24 Boehringer Ingelheim Vetmedica Gmbh Anthelmintic aza-benzothiophene and aza-benzofuran compounds
US11964977B2 (en) 2020-05-29 2024-04-23 Boehringer Ingelheim Animal Health USA Inc. Anthelmintic heterocyclic compounds
US11999742B2 (en) 2021-11-01 2024-06-04 Boehringer Ingelheim Vetmedica Gmbh Substituted pyrrolo[1,2-b]pyridazines as anthelmintics
US12269822B2 (en) 2018-07-09 2025-04-08 Boehringer Ingelheim Animal Health USA Inc. Anthelminthic heterocyclic compounds

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US8431593B2 (en) 2006-11-27 2013-04-30 H. Lundbeck A/S Heteroaryl amide derivatives
US8580812B2 (en) 2007-04-10 2013-11-12 H. Lundbeck A/S Heteroaryl amide analogues as P2X7 antagonists
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
US9617249B2 (en) 2008-05-30 2017-04-11 University Of Notre Dame Du Lac Benzoheterocyclic anti-bacterial agents
US8362268B2 (en) 2008-05-30 2013-01-29 University Of Notre Dame Du Lac Anti-bacterial agents from benzo[d]heterocyclic scaffolds for prevention and treatment of multidrug resistant bacteria
WO2011104261A1 (fr) 2010-02-26 2011-09-01 G+R Technology Group Ag Réacteur pour la carbonisaton hydrothermale de biomasse et procédé permettant de faire fonctionner le réacteur
WO2011104263A1 (fr) 2010-02-26 2011-09-01 G+R Technology Group Ag Système et procédé de préparation d'un mélange à partir de différentes biomasses pour une installation permettant d'obtenir un produit de réaction à partir des différentes biomasses
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
US9145419B2 (en) 2010-04-28 2015-09-29 Bristol-Myers Squibb Company Imidazopyridazinyl compounds
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
AU2011299894B2 (en) * 2010-09-10 2015-08-06 Shionogi & Co., Ltd. Hetero ring-fused imidazole derivative having AMPK activating effect
US9133186B2 (en) 2010-09-10 2015-09-15 Shionogi & Co., Ltd. Hetero ring-fused imidazole derivative having AMPK activating effect
WO2012033149A1 (fr) * 2010-09-10 2012-03-15 塩野義製薬株式会社 Dérivé d'imidazole à hétérocycle fusionné ayant un effet d'activation de l'ampk
CN103209981A (zh) * 2010-09-10 2013-07-17 盐野义制药株式会社 具有ampk活化作用的杂环稠合咪唑衍生物
US10660898B2 (en) 2010-10-06 2020-05-26 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8865912B2 (en) 2010-10-06 2014-10-21 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9062003B2 (en) 2010-10-06 2015-06-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9156797B2 (en) 2010-10-06 2015-10-13 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9872860B2 (en) 2010-10-06 2018-01-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10314845B2 (en) 2010-10-06 2019-06-11 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US10316040B2 (en) 2015-10-16 2019-06-11 Eisai R&D Management Co., Ltd. EP4 antagonists
US10941148B2 (en) 2015-10-16 2021-03-09 Eisai R&D Management Co., Ltd. EP4 antagonists
US11434246B2 (en) 2015-10-16 2022-09-06 Eisai R&D Management Co., Ltd. EP4 antagonists
US10800782B2 (en) 2016-08-31 2020-10-13 Agios Pharmaceutical, Inc. Inhibitors of cellular metabolic processes
US11325914B1 (en) 2016-08-31 2022-05-10 Servier Pharmaceuticals Llc Inhibitors of cellular metabolic processes
USRE49934E1 (en) 2016-08-31 2024-04-23 Servier Pharmaceuticals Llc Inhibitors of cellular metabolic processes
US12269822B2 (en) 2018-07-09 2025-04-08 Boehringer Ingelheim Animal Health USA Inc. Anthelminthic heterocyclic compounds
US11560388B2 (en) 2019-03-19 2023-01-24 Boehringer Ingelheim Vetmedica Gmbh Anthelmintic aza-benzothiophene and aza-benzofuran compounds
US11964977B2 (en) 2020-05-29 2024-04-23 Boehringer Ingelheim Animal Health USA Inc. Anthelmintic heterocyclic compounds
US12312356B2 (en) 2020-05-29 2025-05-27 Boehringer Ingelheim Vetmedica Gmbh Anthelmintic heterocyclic compounds
US11999742B2 (en) 2021-11-01 2024-06-04 Boehringer Ingelheim Vetmedica Gmbh Substituted pyrrolo[1,2-b]pyridazines as anthelmintics

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