WO2007091140A1 - Composés substitués de phénylsulfamoyle agonistes du ppar - Google Patents

Composés substitués de phénylsulfamoyle agonistes du ppar Download PDF

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Publication number
WO2007091140A1
WO2007091140A1 PCT/IB2007/000256 IB2007000256W WO2007091140A1 WO 2007091140 A1 WO2007091140 A1 WO 2007091140A1 IB 2007000256 W IB2007000256 W IB 2007000256W WO 2007091140 A1 WO2007091140 A1 WO 2007091140A1
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Prior art keywords
inhibitor
compound
halo
compounds
optionally substituted
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PCT/IB2007/000256
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English (en)
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Ernest Seiichi Hamanaka
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Pfizer Products Inc.
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Publication of WO2007091140A1 publication Critical patent/WO2007091140A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the present invention relates to substituted phenylsulfamoyl- compounds, pharmaceutical compositions containing such compounds and the use of such compounds as peroxisome proliferator activator receptor (PPAR) agonists.
  • PPAR peroxisome proliferator activator receptor
  • the subject compounds are particularly useful as PPAR ⁇ agonists and to treat atherosclerosis, hypercholesterolemia, hypertriglyceridemia, diabetes, obesity, osteoporosis and Syndrome X (also known as metabolic syndrome) in mammals, including humans.
  • the compounds are also useful for the treatment of negative energy balance (NEB) and associated diseases in ruminants.
  • NEB negative energy balance
  • Atherosclerosis a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well known.
  • fatty streaks in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Further, it is postulated that most of the cholesterol found within the fatty streaks, in turn, gives rise to development of the "fibrous plaque,” which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. These cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid.
  • the lipid is primarily free and esterified cholesterol.
  • the fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the "complicated lesion," which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.
  • CVD cardiovascular disease
  • leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD.
  • the upper limits of "normal” are now known to be significantly lower than heretofore appreciated.
  • Additional independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex.
  • Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
  • Type Il diabetes usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and in more severe cases, insulin.
  • oral hypoglycemic agents e.g., thiazolidenediones
  • the clinically available hypoglycemic agents can have side effects that limit their use.
  • insulin dependent diabetes mellitus Type I
  • insulin is usually the primary course of therapy.
  • oug ere are arie y o a i-a erosc erosis
  • ere is a continuing need and a continuing search in this field of art for alternative therapies.
  • each R 1 is independently hydrogen, halo, (CrC 5 )alkyl optionally substituted with one to eleven halo or with (C 1 -C 3 )alkoxy, (CVCsJalkoxy optionally substituted with one to eleven halo, (Ci-C 5 )alkylthio optionally substituted with one to eleven halo, or R 1 in conjunction with the two adjacent carbon atoms forms a C 5 -C 6 fused fully saturated, partially unsaturated or fully unsaturated five or six membered carbocyclic ring wherein each carbon in the carbon chain may optionally be replaced with one heteroatom selected from oxygen and sulfur;
  • R 2 is hydrogen or (C 1 -C 5 )alkyl optionally substituted with CrC 3 alkoxy;
  • X is -COOR 4 , -0-(CR ⁇ ) W -COOR 4 , -S-(CR 3 2 ) W -COOR 4 , -CH 2 -((CR 5 ) 2 ) W -COOR 4 , 1 H-tetrazol-5-yl-E- or thiazolidinedione-5-yl-G-; wherein w is 0, 1 or 2; E is (CH 2 ) r and r is 0, 1 , 2 or 3, and G is (CH 2 ) S or methylidene and s is 0 or 1 ; each R 3 is independently hydrogen, (CrC 4 )alkyl optionally substituted with one to nine halo or with (C 1 -C 3 )BIkOXy optionally substituted with one to seven halo, or R 3 and the carbon to which it is attached form a 3, 4, 5, or 6 membered carbocyclic ring;
  • R 4 is H, (C 1 -C 4 )alkyl, benzyl or p-nitrobenzyl; each R 5 is independently hydrogen, (CrC 4 )alkyl optionally substituted with one to nine halo or with
  • Ar 1 is pyridyl or pyrimidyl, wherein Ar 1 is optionally mono-, di- or tri-substituted independently with: halo, (CrC 3 )alkyl optionally substituted with one to seven halo or (d-C 3 )alkoxy optionally substituted with one to seven halo or (CrC 3 )alkylthio optionally substituted with one to seven halo;
  • the present application also is directed to methods for treating dyslipidemia, obesity, overweight condition, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetes mellitus (Type I and/or Type II), hyperinsullnemia, impaired glucose tolerance, insulin resistance, diabetic complications, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, inflammation, osteoporosis, thrombosis, peripheral vascular disease, cognitive dysfunction, or congestive heart failure in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the present invention, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug.
  • compositions which comprises a therapeutically effective amount of a compound of formula I, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug and a pharmaceutically acceptable carrier, vehicle or diluent.
  • the present application is directed to pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of formula I, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug; a second compound, said second compound being a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP/Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase/squalene cyclase inhibitor,
  • the present invention is directed to methods for treating atherosclerosis in a mammal comprising administering to a mammal in need of treatment thereof; a first compound, said first compound being a compound of formula I, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug; and a seco poun , sa secon compo n i i or, an - o re uc ase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP/Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene e
  • kits for achieving a therapeutic effect in a mammal comprising packaged in association a first therapeutic agent comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, a second therapeutic agent comprising a therapeutically effective amount of an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP/Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase/squalene cyclase inhibitor, a fibrate
  • Another aspect of the invention is the use of a compound of formula I, in the manufacture of a medicament for the palliative, prophylactic or curative treatment of negative energy balance or a ruminant disease associated with negative energy balance in ruminants, wherein the excessive accumulation of triglycerides in liver tissue is prevented or alleviated, and/or the excessive elevation of non-esterified fatty acid levels in serum is prevented or alleviated.
  • the ruminant disease associated with negative energy balance in ruminants includes one or more diseases selected independently from fatty liver syndrome, dystocia, immune dysfunction, impaired immune function, toxification, primary and secondary ketosis, downer cow syndrome, indigestion, inappetence, retained placenta, displaced abomasum, mastitis, (endo-)-metritis, infertility, low fertility and lameness, preferably fatty liver syndrome, primary ketosis, downer cow syndrome, (endo-)-metritis and low fertility.
  • diseases selected independently from fatty liver syndrome, dystocia, immune dysfunction, impaired immune function, toxification, primary and secondary ketosis, downer cow syndrome, indigestion, inappetence, retained placenta, displaced abomasum, mastitis, (endo-)-metritis, infertility, low fertility and lameness, preferably fatty liver syndrome, primary ketosis, downer cow syndrome, (endo-)-metritis and low fertility.
  • Another aspect of the invention is the use of a compound of formula I, in the improvement of fertility, including decreased return to service rates, normal oestrus cycling, improved conception rates, and improved foetal viability.
  • Another aspect of the invention is the use of a compound of formula I, in the manufacture of a medicament for the management of effective homeorhesis to accommodate parturition and lactogenesis.
  • Another aspect of the invention is the use of a compound of formula I, in the manufacture of a medicament for improving or maintaining the functioning of the ruminant liver and homeostatic signals during the transition period.
  • o e aspec o e nve on, u ⁇ ng e perio ram days prepartum to 70 days postpartum.
  • the compound of formula I is administered prepartum and, optionally, also at parturition. In yet another aspect of the invention, the compound of formula I is administered postpartum.
  • the compound of formula I is administered at parturition.
  • the compound of formula I is administered during the period from 3 weeks prepartum to 3 weeks postpartum.
  • the compound of formula I is administered up to three times during the first seven days postpartum.
  • the compound of formula I is administered once during the first 24 hours postpartum.
  • the compound of formula I is administered prepartum and up to four times postpartum.
  • the compound of formula I is administered at parturition and then up to four times postpartum.
  • Another aspect of the invention is the use of the compound of formula I in the manufacture of a medicament for the palliative, prophylactic or curative treatment of negative energy balance in ruminants and to increase ruminant milk quality and/or milk yield.
  • the milk quality increase is seen in a reduction in the levels of ketone bodies in ruminant milk.
  • peak milk yield is increased.
  • the ruminant is a cow or sheep.
  • an overall increase in ruminant milk yield is obtained during the 305 days of the bovine lactation period.
  • an overall increase in ruminant milk yield is obtained during the first 60 days of the bovine lactation period.
  • the overall increase in ruminant milk yield, or the increase in peak milk yield, or the increase in milk quality is obtained from a dairy cow.
  • the increase in ruminant milk quality and/or milk yield is obtained after administration of a compound of formula I to a healthy ruminant.
  • a compound of formula I for use in veterinary medicine.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, Le., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (Le., 1 ,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts.
  • pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, s
  • the invention also relates to base addition salts of the compounds of the present invention.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the present invention that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (ejj., potassium and sodium) and alkaline earth metal cations (ex[., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • R and S refer respectively to each stereogenic center in ascending numerical order (1 , 2, 3, etc.) according to the conventional IUPAC number schemes for each molecule.
  • R and S refer respectively to each stereogenic center in ascending numerical order (1 , 2, 3, etc.) according to the conventional IUPAC number schemes for each molecule.
  • the compounds of the present invention possess one or more stereogenic centers and no stereochemistry is given in the name or structure, it is understood that the name or structure is intended to encompass all forms of the compound, including the racemic form.
  • the compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
  • cis refers to the orientation of two substituents with reference to each other and the plane of the ring (either both “up” or both “down”).
  • trans refers to the orientation of two substituents with reference to each other and the plane of the ring (the substituents being on opposite sides of the ring).
  • Alpha and Beta refer to the orientation of a substituent with reference to the plane of the ring. Beta is above the plane of the ring and Alpha is below the plane of the ring.
  • This invention also includes isotopically-Iabeled compounds, which are identical to those described by Formulas I and II, except for the fact that one or more atoms are replaced by one or more atoms having specific atomic mass or mass numbers.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 18 F, and 36 CI respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or of the prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-Iabeled compounds of the present invention for example those into which radioactive iso opes sucn as 11 are i a e , are se i an or su s ra e issue is ri u ion assays.
  • Tritiated (i.e., 3 H), and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • treating includes preventative (e.g., prophylactic) and palliative treatment.
  • terapéuticaally effective amount of a compound means an amount that is effective to exhibit therapeutic or biological activity at the site(s) of activity in a mammalian subject, without undue adverse side effects (such as undue toxicity, irritation or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of the present invention.
  • ischemic diseases e.g., transient
  • ischemic stroke transient
  • acute stroke cerebral apoplexy
  • hemorrhagic stroke neurologic deficits post-stroke
  • first stroke recurrent stroke
  • shortened recovery time after stroke shortened recovery time after stroke and provision of thrombolytic therapy for stroke.
  • Preferable patient populations include patients with or without pre-existing stroke or coronary heart disease.
  • coronary artery disease is selected, but not limited to, the group consisting of atherosclerotic plaque (e.g., prevention, regression, stabilization), vulnerable plaque (e.g., prevention, regression, stabilization), vulnerable plaque area (reduction), arterial calcification (e.g., calcific aortic stenosis), increased coronary artery calcium score, dysfunctional vascular reactivity, vasodilation disorders, coronary artery spasm, first myocardial infarction, myocardia re-infarction, ischemic cardiomyopathy, stent restenosis, PTCA restenosis, arterial restenosis, coronary bypass graft restenosis, vascular bypass restenosis, decreased exercise treadmill time, angina pectoris/chest pain, unstable angina pectoris, exertional dyspnea, decreased exercise capacity, ischemia (reduce time to), silent ischemia (reduce time to), increased severity and frequency of ischemic symptoms, reperfusion after
  • hypertension is selected, but not limited to, the group consisting of lipid disorders with hypertension, systolic hypertension and diastolic hypertension.
  • ventricular dysfunction is selected, but not limited to, the group consisting of systolic dysfunction, diastolic dysfunction, heart failure, congestive heart failure, dilated cardiomyopathy, idiopathic dilated cardiomyopathy, and non-dilated cardiomopathy.
  • cardiac arrhythmia is selected, but not limited to, the group consisting of atrial arrhythmias, supraventricular arrhythmias, ventricular arrhythmias and sudden death syndrome.
  • pulmonary vascular disease is selected, but not limited to, the group consisting of pulmonary hypertension, peripheral artery block, and pulmonary embolism.
  • e erm per p era vascu ar sease as use erein, i , no imi e o, e group consisting of peripheral vascular disease and claudication.
  • vascular hemostatic disease is selected, but not limited to, the group consisting of deep venous thrombosis, vaso-occlusive complications of sickle cell anemia, varicose veins, pulmonary embolism, transient ischemic attacks, embolic events, including stroke, in patients with mechanical heart valves, embolic events, including stroke, in patients with right or left ventricular assist devices, embolic events, including stroke, in patients with intra-aortic balloon pump support, embolic events, including stroke, in patients with artificial hearts, embolic events, including stroke, in patients with cardiomyopathy, embolic events, including stroke, in patients with atrial fibrillation or atrial flutter.
  • diabetes refers to any of a number of diabetogenic states including type I diabetes, type Il diabetes, Syndrome X, Metabolic syndrome, lipid disorders associated with insulin resistance, impaired glucose tolerance, non-insulin dependent diabetes, microvascular diabetic complications, reduced nerve conduction velocity, reduced or loss of vision, diabetic retinopathy, increased risk of amputation, decreased kidney function, kidney failure, insulin resistance syndrome, pluri-metabolic syndrome, central adiposity (visceral)(upper body), diabetic dyslipidemia, decreased insulin sensitization, diabetic retinopathy/neuropathy, diabetic nephropathy/micro and macro angiopathy and micro/macro albuminuria, diabetic cardiomyopathy, diabetic gastroparesis, obesity, increased hemoglobin glycoslation (including HbAIC), improved glucose control, impaired renal function (dialysis, endstage) and hepatic function (mild, moderate, severe).
  • HbAIC hemoglobin glycoslation
  • improved glucose control impaired renal function (dialysis, endstage
  • inflammatory disease is selected, but not limited to, the group consisting of multiple sclerosis, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, irritable bowel disease, Crohn's disease, colitis, vasculitis, lupus erythematosis, sarcoidosis, amyloidosis, apoptosis, and disorders of the complement systems.
  • cognitive dysfunction is selected, but not limited to, the group consisting of dementia secondary to atherosclerosis, transient cerebral ischemic attacks, neurodegeneration (including Parkinson's, Huntington's disease, amyloid deposition and amylotrophic lateral sclerosis), neuronal deficient, and delayed onset or procession of Alzheimer's disease.
  • the "transition period” means from 30 days prepartum to 70 days postpartum
  • treating includes prophylactic, palliative and curative treatment.
  • “Negative energy balance” as used herein means that energy via food does not meet the requirements of maintenance and production (milk).
  • cow as used herein includes heifer, primiparous and multiparous cow.
  • Healthy ruminant means where the ruminant does not show signs of the following indications: fatty liver syndrome, dystocia, immune dysfunction, impaired immune function, toxification, primary and secondary ketosis, downer cow syndrome, indigestion, inappetence, retained placenta, displaced abomasum, mastitis, (endo-)-metritis, infertility, low fertility and/or lameness.
  • Milk “quality” as used herein refers to the levels in milk of protein, fat, lactose, somatic cells, and ketone bodies. An increase in milk quality is obtained on an increase in fat, protein or lactose content, or a decrease in somatic cell levels or ketone bodies levels.
  • n increase n m y e can mean an increase in mi so i s or mi a or m ⁇ proiein conten , as well as, or instead of, an increase in the volume of milk produced.
  • Excessive accumulation of triglycerides as used herein means greater than the physiological triglyceride content of 10%w/w in liver tissue.
  • Excessive elevation of non-esterified fatty acid levels in serum as used herein means non- esterified fatty acid levels of greater than 800 ⁇ mol/L in serum.
  • prepartum means 3 weeks before calving until the day of calving.
  • postpartum means from when the newborn is “expelled” from the uterus to 6 weeks after the newborn was expelled from the uterus.
  • At parturition means the 24 hours after the newborn was expelled from the uterus.
  • Periodurient means the period from the beginning of the prepartum period, to the end of the postpartum period.
  • Methodabolic syndrome also known as “Syndrome X” refers to a common clinical disorder that is defined as the presence of increased insulin concentrations in association with other disorders including viceral obesity, hyperlipidemia, dyslipidemia, hyperglycemia, hypertension, and potentially hyperuricemis and renal dysfunction.
  • pharmaceutically acceptable is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • Compounds when used herein includes any pharmaceutically acceptable derivative or variation, including conformational isomers (e ⁇ , cis and trans isomers) and all optical isomers (exu- enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs.
  • tautomers is meant chemical compounds that may exist in two or more forms of different structure (isomers) in equilibrium, the forms differing, usually, in the position of a hydrogen atom.
  • prodrug refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
  • Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of the present invention include but are not limited to those having a carboxyl moiety wherein the free hydrogen is replaced by (Ci-C 4 )alkyi, (C 2 - C 7 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)- ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from
  • av ng one or wo e eroa om se ec e independently from oxygen, nitrogen and sulfur include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridiazinyl, pyrimidinyl and pyrazinyl.
  • Exemplary partially saturated, fully saturated or fully unsaturated five to eight membered carbocyclic rings optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl.
  • Exemplary five membered rings include 2H-pyrrolyl, 3H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1 ,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1 ,2-dithiolyl, 1 ,3-dithiolyl, 3H-1 ,2-oxathiolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-triazolyl, 1 ,2,3-triazolyl, 1
  • Exemplary six membered rings include 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1 ,2-dioxinyl, 1 ,3-dioxinyl, 1 ,4-dioxanyl, morpholinyl, 1 ,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1 ,3,5-triazinyl, 1 ,2,4-triazinyl, 1 ,2,3-triazinyl, 1 ,3,5-trithianyl, 4H-1 ,2-oxazinyl, 2H-1 ,3-oxazinyl, 6H-1 ,3-oxazinyl, 6H-1 ,2-oxazinyl, 1 ,4-oxazinyl, 2H-1 ,2-oxazinyl, 4H-1
  • Further exemplary seven membered rings include azepinyl, oxepinyl, and thiepinyl. Further exemplary eight membered carbocyclic rings include cyclooctyl, cyclooctenyl and cyclooctadienyl.
  • Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen include indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1 H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1 H-indazolyl, indoxazinyl, benzoxazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxaliny
  • C f C 1 indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • C 1 -C 3 alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, and all isomeric forms and straight and branched forms thereof.
  • aryl is meant an optionally substituted six-membered aromatic ring, including polyaromatic rings. Examples of aryl include phenyl, naphthyl and biphenyl.
  • Heteroaryl as used herein means an optionally substituted five- or six-membered aromatic ring, including polyaromatic rings where appropriate carbon atoms are substituted by nitrogen, sulfur or oxygen.
  • heteroaryl include pyridine, pyrimidine, thiazole, oxazole, quinoline, quinazoline, benzothiazole and benzoxazole.
  • y a o or a ogen s mean c oro, romo, io o, o .
  • alkyl is meant straight chain saturated hydrocarbon or branched chain saturated hydrocarbon.
  • alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1- methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
  • This term also includes a saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons.
  • alkenyl referred to herein may be linear or branched. They contain 1 -3 carbon-carbon double bonds, which can be cis or trans.
  • alkoxy is meant straight chain saturated alkyl or branched chain saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy .
  • a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom.
  • pyridyl means 2-, 3- or 4-pyridyl
  • thienyl means 2- or 3-thienyl, and so forth.
  • HMG CoA reductase inhibitor is selected, but not limited to, the group consisting of lovastatin, simvastatin, pravastatin, fluindostatin, velostatin, dihydrocompactin, compactin, fluvastatin, atorvastatin, glenvastatin, dalvastatin, carvastatin, crilvastatin, bervastatin, cerivastatin, rosuvastatin, pitavastatin, mevastatin, or rivastatin, or a pharmaceutically acceptable salt thereof.
  • antihypertensive agent is selected, but not limited to, a calcium channel blocker (including, but not limited to, verapamil, diltiazem, mibefradil, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, avanidpine, amlodipine, amlodipine besylate, manidipine, cilinidipine, lercanidipine and felodipine), an ACE inhibitor (including, but not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, trandolapri, ramipril, zestril, zofenopril, cilaapril, temocapril, spirapril, moexi
  • Ar 1 is:
  • Ar 1 is optionally mono- or di-substituted.
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 1 is pyridyl; and Ar 2 is phenyl or phenyl fused to a ring selected from the group consisting of: phenyl, pyridyl, thienyl, thiazolyl, oxazolyl, and imidazolyl.
  • X is -COOR 4 ;
  • B is a bond, -L-(CY 2 ) n - or -(CY 2 ) n -L-, and L is O or S, and n is 0, 1 or 2;
  • Ar 1 is pyridyl; and
  • Ar 2 is phenyl or phenyl fused to a ring selected from the group consisting of: phenyl, pyridyl, thienyl, thiazolyl, oxazolyl, and imidazolyl.
  • Ar 1 is:
  • q is 1 or 2 and each J is independently halo, (d-C 3 )alkyl optionally substituted with one to three halo, or (C 1 -C 3 )BIkOXy optionally substituted with one to three halo.
  • p is 1 and R 4 is H or (Ci-C 3 )alkyl.
  • L is S, n is 1, and halo is fluoro.
  • the compound is selected from the group consisting of: S-l ⁇ -KS ⁇ -Dichloro-phenyOmethylsulfanyO-pyridin-S-ylsulfamoylJ-a.S-dimethyl-benzoic acid; ⁇ -t ⁇ tert-Butyl-benzylsulfanyO-pyridin-S-ylsulfamoylJ ⁇ .S-dimethyl-benzoic acid; 2,3-Dimethyl-5-[6-(4-trifluoromethyl-benzylsulfanyl)-pyridin-3-ylsulfamoyl]-benzoic acid; S ⁇ - ⁇ -Dimethyl-phenyOmethylsulfanyO-pyridin-S-ylsulfamoylJ ⁇ -methyl-benzoic acid; 2-MethyI-5-t6-(4-trifluoromethyl-benzylsulfanyl)-pyridin-3-ylsulfamoylJ-
  • Atherosclerosis is treated.
  • peripheral vascular disease is treated.
  • dyslipidemia is treated.
  • diabetes is treated.
  • hypoalphalipoproteinemia is treated.
  • hypercholesterolemia is treated.
  • hypertriglyceridemia is treated.
  • obesity is treated.
  • osteoporosis is treated.
  • metabolic syndrome is treated.
  • the pharmaceutical composition is for the treatment of atherosclerosis in a mammal which comprises an atherosclerosis treating amount of a compound of formula I, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug and a pharmaceutically acceptable carrier, vehicle or diluent.
  • the second compound is an HMG-CoA reductase inhibitor or a CETP inhibitor.
  • the second compound is rosuvastatin, rivastatin, pitavastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or cerivastatin or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug.
  • the second compound is [2R,4S] 4-[(3, ⁇ -bis-trifluoromethyl-benzyl)-methoxycarbonyl- amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
  • the composition further comprises a cholesterol absorption inhibitor.
  • the cholesterol absorption inhibitor is ezetimibe.
  • the composition further comprises an antihypertensive agent. . _ one n o e p armaceu ica com ina ions, me o s an s o e present invention, said antihypertensive agent is a calcium channel blocker, an ACE inhibitor, an A-Il antagonist, a diuretic, a beta-adrenergic receptor blocker or an alpha-adrenergic receptor blocker.
  • the antihypertensive agent is a calcium channel blocker, said calcium channel blocker being verapamil, diltiazem, mibefradil, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, avanidpine, amlodipine, amlodipine besylate, manidipine, cilinidipine, lercanidipine or felodipine or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug.
  • the compounds of this invention can be made by processes that include processes analogous to those known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes may be described in the experimental section.
  • Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the compound.
  • the compounds of formula 1 d which are compounds of formula I wherein X is -COOR 4 , R 2 is H, Ar 1 is pyridyl, R (optionally present) is halo, alkyl, alkoxy or alkylthio and R 1 , B, Ar 2 , J, p and q are as described above are prepared by procedures well known in the art.
  • chlorosulfonic acid halo is chloro
  • treatment of the benzoic acid or ester 1a with chlorosulfonic acid (halo is chloro) at temperatures between about 9O 0 C and110 0 C, preferably 100 0 C, for a period of about 15 minutes to 3 hours, preferably 2.5 hours for the acid and 15 minutes for the ester, leads to the halogenated sulfonyl 1b.
  • reaction of sulfonyl chloride 1 b with appropriately substituted pyridin-3-amines 1 e preparation of pyridin-3-amines 1e described in Schemes 4, 5, and 6) to form the ester compounds 1c may be performed under reaction conditions well known to those skilled in the art.
  • the reaction of sulfonyl chloride 1b and a pyridin-3-amine 1e may be performed in an inert solvent such as tetrahydrofuran, dimethylformamide or a mixture of acetone and water, in the presence of a base such as pyridine, potassium carbonate or sodium carbonate, at temperatures between 2O 0 C and 65 0 C, preferably at room temperature for a period of about 10 to 36 hours, preferably about 20 hours.
  • the ester product 1c may be converted to the benzoic acid 1d by hydrolysis with an alkali metal hydroxide, preferably sodium hydroxide, in a mixture of an alcohol, preferably methanol, and water at a temperature of about 5O 0 C to 100 0 C preferably at reflux temperature, for a period of about 2 to 30 hours.
  • an alkali metal hydroxide preferably sodium hydroxide
  • Ar 1 is pyridyl
  • B is a bond
  • Ar 2 is phenyl
  • R (optionally present) is halo, alkyl, alkoxy or alkylthio
  • R 1 , J, p and q are as described above, are prepared by reacting a sulfonyl halide (wherein halo is chloro) 1b and 6- halopyridin-3-amine 2a (wherein halo is bromo or iodo) in an inert solvent such as tetrahydrofuran or dimethylformamide or a solvent mixture such as acetone and water, in the presence of an amine base such as pyridine/triethylamine or an inorganic base such as potassium carbonate or sodium carbonate, at a temperature of about 2O 0 C to 5O 0 C, preferably room temperature, for a period of about 20 hours to form the halogenated ester compound 2b.
  • the ester group of compound 2d (X, -COOR 4 ) may be converted to an acid group by basic hydrolysis.
  • the desired Formula I componds wherein X is -COOR 4 , R 2 is alkyl, Ar 1 is pyrimidyl, R (optionally present) is halo, alkyl, alkoxy or alkylthio, and R 1 , R 2 , B, Ar 2 , J, p and q are as described above, are prepared by treating a sulfonamide 3a with a base such as sodium hydride, potassium hydride or potassium t-butoxide in an inert solvent such as tetrahydrofuran or dioxane at temperatures between O 0 C and 35 0 C, preferably sodium hydride in tetrahydrofuran at room temperature, to form the sulfonamide anion which is treated with an appropriate halogenated alkyl (wherein halo is bromo or iodo) at temperatures between 25 0 C and 7O 0 C, preferably at reflux temperature to yield the n-alkyl
  • a base
  • the n-alkylsulfonamide ester 3b may be prepared by the Mitsunobu reaction, for example, by the reaction of sulfonamide 3a with an appropriate alcohol, in the presence of diethyl azodicarboxylate (DEAD) and triphenylphosphine (Ph 3 P), in a solvent such as tetrahydrofuran, dimethylformamide, methylene chloride or dioxane, at about 15 0 C to 35° C for about 10 to 30 hours, preferably in tetrahydrofuran at room temperature overnight (Scheme 6a).
  • DEAD diethyl azodicarboxylate
  • Ph 3 P triphenylphosphine
  • Formula 1e4 compounds which are compounds of formula I wherein R 2 is hydrogen, Ar 1 is pyridyl, R (optionally present) is halo, alkyl, alkoxy or alkylthio, B is a bond, Ar 2 is a phenyl ring fused to an imidazole, oxazole, or thiazole ring (D is N, O or S) and J and q are as described above, may be prepared as depicted by Schemes 4a and 4b or by similar synthetic routes familiar to those skilled in the art.
  • a 2-aminophenol, 2-aminothiophenol or 2-aminoaniline derivative 4a is heated with an appropriately substituted 5-aminopyridine-2-carboxylic acid 4b in polyphosphoric acid at about 170 0 C to 200° C for about 4 to10 hours, preferably 190° C for 6 hours, to yield the corresponding pyridinamine derivatives 1 e4.
  • DEAD diethyl azodicarboxylate
  • Ph 3 P triphenylphosphine
  • the nitro group in 4e may be reduced to form the pyridinamine 1e4 by procedures familiar to those skilled in the art. For example, heating the nitro compound 4e with iron powder and calcium chloride in aqueous alcohol such as ethanol at about 6O 0 C to100 0 C for 4 to 10 hours, preferably at reflux for 5 hours yields the pyridinamine 1e4.
  • aqueous alcohol such as ethanol
  • Other reducing reagents such as iron and acetic acid, zinc and aqueous hydrochloric acid and catalytic hydrogenation are exemplified in Richard Larock, Comprehensive Organic Transformations, VCH Publishers, New York, 1989412.
  • Ar 1 is pyridyl
  • B is a bond
  • Ar 2 is an oxadiazole ring
  • J is as described above, may be prepared by Scheme 5 or by similar synthetic routes familiar to those skilled in the art.
  • Reduction of the nitro group to amine by methods known to those skilled in the art yields the pyridinamine 1e5.
  • the reduction may be performed, as previously shown in Scheme 4b, with iron powder and calcium chloride in aqueous ethanol.
  • the desired Formula 1e6 compounds which are compounds of formula I wherein R 2 is hydrogen, Ar 1 is pyridyl, B is -L-CH 2 - Or-CH 2 -L-, Ar 2 is phenyl and J and q are as described above, may be prepared by the synthesis depicted in 6a or 6b of Scheme 6 or by similar synthetic routes familiar to those skilled in the art.
  • Scheme 6a depicts the synthesis of a nitro compound 6c by treating a 5-nitropyridine compound 6a with a benzyl mercaptan 6b in the presence of a base such as sodium hydride, cesium carbonate or sodium tert-butoxide, in a solvent such as tetrahydrofuran, dimethylformamide or dimethoxyethane, preferably tetrahydrofuran, at a temperature of about 2O 0 C to 7O 0 C for about 8 to 30 hours, preferably at room temperature overnight.
  • Reduction of the nitro group of 6c by methods known to those skilled in the art, including those exemplified in Scheme 4b and reduction with sodium dithionite and ethanol, yields the corresponding pyridinamine 1e6.
  • benzylsulfanylpyridinamine 1e6-1 may be synthesized by treating 5- nitropyridine-2-thiol 6d with an appropriately substituted benzyl chloride 6e in the presence of a base such as sodium hydride, cesium carbonate or sodium tert-butoxide, in a solvent such as tetrahydrofuran, dimethylformamide or dimethoxyethane, preferably tetrahydrofuran, at a temperature of about 20 0 C to 7O 0 C for about 8 to 30 hours, preferably at room temperature overnight, to yield nitro compound 6f.
  • Nitro compound 6f yields benzylsulfanylpyridinamine 1e6-1 by reduction of the nitro group as described above.
  • the desired Formula 1e compounds which are compounds of formula I wherein R 2 is hydrogen, Ar 1 is pyridyl, R (optionally present) is halo, alkyl, alkoxy or alkylthio, B is a bond, and Ar 2 is phenyl, may be prepared by the synthesis depicted in Scheme 7 or by similar synthetic routes familiar to those skilled in the art 6-Phenylpyridin-3-amine derivatives 1e7may be synthesized by a Suzuki coupling of 2-halo-5- nitropyridine 7a wherein halo is bromo or iodo and an appropriately substituted phenylboronic acid derivative 7b, using procedures known to those skilled in the art.
  • the desired Formula 1e8 compounds which are compounds of formula I wherein R 2 is hydrogen, Ar 1 is pyridyl, R (optionally present) is halo, alkyl, alkoxy or alkylthio, B is L, Ar 2 is phenyl and J and q are as described above, may be prepared by the synthesis depicted in Scheme 8 or by similar synthetic routes familiar to those skilled in the art.
  • Phenoxypyridinamine and phenylsulfanylpyridinamine derivatives 1e8 may be prepared by reaction of 2-halo-5-nitropyridine 8b, wherein halo is chloro, bromo or iodo, with an appropriate phenol or thiophenol 8a in the presence of a base such sodium hydride, sodium tert-butoxide or cesium carbonate in an inert solvent such as dimethylformamide, tetrahydrofuran or dimethoxyethane, at about 6O 0 C to 90 0 C for about 10 to 30 hours, preferably at 9O 0 C overnight yields the nitro derivative 8c.
  • Pyridine 1e8 may be produced by reducing the nitro derivative 8c, using procedures known to those skilled in the art, such as those previously exemplified in Scheme 4b.
  • G- G is (CH 2 ) S , s is 0, R 2 is H, Ar 1 is pyridyl, R (optionally present) is halo, alkyl, alkoxy or alkylthio and R 1 , B, Ar 2 , J, p and q are as described above, may be prepared by the synthetic sequence outlined in Scheme 9, as taught by J. Med. Chem.,29, 773 (1986) and Chem. Pharm. Bull., 30, 3601 (1982).
  • benzaldehyde 9a is treated with sodium cyanide in a mixture of water, acetic acid and ethylene glycol monomethyl ether at room temperature for 1.5 hours followed by the addition of thiourea and concentrated hydrochloric acid and heating at about 100 0 C for 18 hours to yield thiazolidinedione 9c (Chem. Pharm. Bull., 45, 1984 (1997).
  • G- G is methylidine or (CH 2 ) S and s is 1 , R 2 is H, Ar 1 is pyrimidyl, R (optionally present) is halo, alkyl, aikoxy or alkylthio and R 1 , B, Ar 2 , J, p and q are as described above, may be synthesized by the reaction sequence outlined in Scheme 10, as taught by Chem. Pharm. Bull.. 45. 1984 (1997).
  • quinol acetate compound 11b is converted to sulfonic acid compound 11c.
  • Sul ony chloride compoun s prepare y ea ng su on c ac compound nc with phosphorus pentachloride at about 110 0 C to 13O 0 C for about 25 to 55 minutes, preferably about 120 0 C for about 30 minutes.
  • Compounds of Formula 12e which are compounds of formula I wherein X is -CH 2 (CR 5 W )-COOR 4 and R 5 is CH 3 CH 2 , w is 1 , R 2 is H, Ar 1 is pyridyl, R (optionally present) is halo, alkyl, alkoxy or alkylthio and R 1 , B, Ar 2 , J, p and q are as described above, may be synthesized by the reaction sequence outlined in Scheme 12.
  • Ester compound 12b is converted to sulfonyl chloride 12c by heating in chlorosulfonic acid at about 55 0 C to 70 0 C for about 15 to 25 minutes, preferably at about 6O 0 C for about 15 minutes.
  • Reaction of sulfonyl chloride compound 12c with appropriately substituted pyridinamines 1 e using methods know to those skilled in the art, such as the process described in Scheme 1 yields sulfonamide compound 12d.
  • Reduction of the olefinic bond of 12c using procedures known to those skilled in the art, such as magnesium in methanol or ethanol at about 60 0 C to 85 0 C until the magnesium is consumed, or catalytic hydrogenation with 10% Pd-C in 1 ,4-dioxane or methanol at about 50 to 60 psi for about 36 to 60 hours, preferably magnesium in methanol at about 65° C, followed by alkaline hydrolysis of the product, yields the desired acid compound 12e.
  • procedures known to those skilled in the art such as magnesium in methanol or ethanol at about 60 0 C to 85 0 C until the magnesium is consumed, or catalytic hydrogenation with 10% Pd-C in 1 ,4-dioxane or methanol at about 50 to 60 psi for about 36 to 60 hours, preferably magnesium in methanol at about 65° C, followed by alkaline hydrolysis of the product, yields the desired acid compound 12e.
  • the compounds of this invention may also be used in conjunction with other pharmaceutical agents (e.g., LDL-cholesterol lowering agents, triglyceride lowering agents) for the treatment of the disease/conditions described herein.
  • other pharmaceutical agents e.g., LDL-cholesterol lowering agents, triglyceride lowering agents
  • they may be used in combination with a HMG-CoA reductase inhibitor, a cholesterol synthesis inhibitor, a cholesterol absorption inhibitor, a CETP inhibitor, a MTP/Apo B secretion inhibitor, another PPAR modulator and other cholesterol lowering agents such as a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor, and a bile acid sequestrant.
  • a bile acid reuptake inhibitor such as a bile acid reuptake inhibitor, an ileal bile acid transporter inhibitor, an ACC inhibitor, an antihypertensive (such as NORV ASC®), a selective estrogen receptor modulator, a selective androgen receptor modulator, an antibiotic, an antidiabetic (such as metformin, a PPARy activator, a sulfonylurea, insulin, an aldose reductase inhibitor (ARI) and a sorbitol dehydrogenase inhibitor (SDI)), and aspirin (acetylsalicylic acid).
  • a slow-release form of niacin is available and is known as Niaspan.
  • Niacin may also be combined with other therapeutic agents such as statins, i.e. lovastatin, which is an HMG-CoA reductase inhibitor and described further below.
  • statins i.e. lovastatin
  • HMG-CoA reductase inhibitor an HMG-CoA reductase inhibitor and described further below.
  • ADVICOR® Kos Pharmaceuticals Inc.
  • both the compounds of this invention and the other drug therapies are administered to mammals (e.g., humans, male or female) by conventional methods.
  • HMG-CoA reductase inhibitor refers to compounds which inhibit the bioconversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such inhibition is readily determined by those skilled in the art according to standard assays (e.g., Meth. Enzymol. 1981 ; 71 :455-509 and references cited therein). A variety of these compounds are described and referenced below however other HMG-CoA reductase inhibitors will be known to those skilled in the art.
  • Atorvastatin calcium i.e., atorvastatin hemicalcium
  • Lipitor ® is currently sold as Lipitor ® and has the formula
  • Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA.
  • atorvastatin calcium is a potent lipid lowering compound.
  • the free carboxylic acid form of atorvastatin may exist predominantly as the lactone of the form ula
  • Statins also include such compounds as rosuvastatin disclosed in U.S. RE37.314 E, pitivastatin disclosed in EP 304063 B1 and US 5,011 ,930, simvastatin, disclosed in U.S. 4,444,784, which is incorporated herein by reference; pravastatin, disclosed in U.S. 4,346,227 which is incorporated herein by reference; cerivastatin, disclosed in U.S. 5,502,199, which is incorporated herein by reference; mevastatin, disclosed in U.S. 3,983,140, which is incorporated herein by reference; velostatin, disclosed in U.S. 4,448,784 and U.S.
  • Any compound that decreases HMG-CoA reductase gene expression may be used in the combination aspect of this invention.
  • These agents may be HMG-CoA reductase transcription inhibitors that block the transcription of DNA or translation inhibitors that prevent or decrease translation of mRNA coding for HMG-CoA reductase into protein.
  • Such compounds may either affect transcription or translation directly, or may be biotransformed to compounds that have the aforementioned activities by one or more enzymes in the cholesterol biosynthetic cascade or may lead to the accumulation of an isoprene metabolite that has the aforementioned activities.
  • CETP inhibitor refers to compounds that inhibit the cholesteryl ester transfer protein (CETP) mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL.
  • CETP inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., U.S. Pat. No. 6,140,343).
  • a variety of CETP inhibitors will be known to those skilled in the art, for example, those disclosed in commonly assigned U.S.
  • Patent Numbers 6,140,343 and 6,197,786 PCT publication WO2004/085401 and PCT applications PCT/IB05/002085, PCT/IB05/002880, PCT/IB05/002879, PCT/IB05/002890, and PCT/IB05/003500.
  • CETP inhibitors disclosed in these patents and patent applications include compounds, such as [2R,4S] 4-[(3,5- bis-trifluoromethyl-benzyO-methoxycarbonyl-aminol ⁇ -ethyl- ⁇ -trifluoromethyl-S ⁇ -dihydro ⁇ H-quinoline-i- carboxylic acid ethyl ester, which is also known as torcetrapib, and [2R,4S]-2-(4- ⁇ 4-[(3,5-bis-trifluoromethyl- benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl ⁇ - cyclohexyl)-acetamide.
  • U.S. Patent Number 5,512,548 discloses certain polypeptide derivatives having activity as CETP inhibitors, while certain CETP-inhibitory rosenonolactone derivatives and phosphate- containing analogs of cholesteryl ester are disclosed in J. Antibiot, 49(8): 815-816 (1996), and Bioorg. Med. Chem. Lett.; 6:1951-1954 (1996), respectively.
  • any other PPAR modulator may be used in the combination aspect of this invention.
  • modulators of PPAR ⁇ and/or PPAR ⁇ may be useful incombination with compounds of the present invention.
  • MTP/Apo B secretion inhibitor refers to compounds which inhibit the secretion of triglycerides, cholesteryl ester, and phospholipids. Such inhibition is readily determined by those skilled in the art according to standard assays (e.g., Wetterau, J. R. 1992; Science 258:999).
  • MTP/Apo B secretion inhibitors include imputapride (Bayer) and additional compounds such as those disclosed in WO 96/40640 and WO 98/23593, (two exemplary publications).
  • MTP/Apo B secretion inhibitors are particularly useful: 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1 H-[1 ,2,4,]triazol-3-ylmethyl)-1 ,2,3,4-tetrahydro- isoquinolin-6-yl]-am ide;
  • Any cholesterol absorption inhibitor can be used as an additional in the combination aspect of the present invention.
  • the term cholesterol absorption inhibition refers to the ability of a compound to prevent cholesterol contained within the lumen of the intestine from entering into the intestinal cells and/or passing from within the intestinal cells into the lymph system and/or into the blood stream. Such cholesterol absorption inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Lipid Res.
  • Cholesterol absorption inhibitors are known to those skilled in the art and are described, for example, in PCT WO 94/00480.
  • An example of a cholesterol absorption inhibitor is ZETIA TM (ezetimibe) (Schering-Plough/Merck).
  • Diabetes can be treated by administering to a patient having diabetes (especially Type II), insulin resistance, impaired glucose tolerance, metabolic syndrome, or the like, or any of the diabetic complications such as neuropathy, nephropathy, retinopathy or cataracts, a therapeutically effective amount of a compound of the present invention in combination with other agents (e.g., insulin) that can be used to treat diabetes.
  • a therapeutically effective amount of a compound of the present invention in combination with other agents e.g., insulin
  • glycogen phosphorylase inhibitor refers to compounds that inhibit the bioconversion of glycogen to glucose-1 -phosphate which is catalyzed by the enzyme glycogen phosphorylase. Such glycogen phosphorylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Med. Chem. 41 (1998) 2934-2938). A variety of glycogen phosphorylase inhibitors are known to those skilled in the art including those described in WO 96/39384 and WO 96/39385.
  • aldose reductase inhibitor refers to compounds that inhibit the bioconversion of glucose to sorbitol, which is catalyzed by the enzyme aldose reductase.
  • Aldose reductase inhibition is readily determined by those skilled in the art according to standard assays (e.g., J. Malone, Diabetes, 29:861-864 (1980). "Red Cell Sorbitol, an Indicator of Diabetic Control”).
  • a variety of aldose reductase inhibitors are known to those skilled in the art, such as those described in U. . atent o. 6,579,b/y, whicn inciu ⁇ es 6- (5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one.
  • sorbitol dehydrogenase inhibitor refers to compounds that inhibit the bioconversion of sorbitol to fructose which is catalyzed by the enzyme sorbitol dehydrogenase.
  • sorbitol dehydrogenase inhibitor activity is readily determined by those skilled in the art according to standard assays (e.g., Analyt. Biochem (2000) 280: 329-331).
  • a variety of sorbitol dehydrogenase inhibitors are known, for example, U.S. Patent Nos.
  • 5,728,704 and 5,866,578 disclose compounds and a method for treating or preventing diabetic complications by inhibiting the enzyme sorbitol dehydrogenase. Any glucosidase inhibitor can be used in combination with a compound of the present invention.
  • a glucosidase inhibitor inhibits the enzymatic hydrolysis of complex carbohydrates by glycoside hydrolases, for example amylase or maltase, into bioavailable simple sugars, for example, glucose.
  • glycoside hydrolases for example amylase or maltase
  • simple sugars for example, glucose.
  • glucosidase inhibitors are known to have utility in accelerating the passage of carbohydrates through the stomach and inhibiting the absorption of glucose from the intestine. Furthermore, the conversion of carbohydrates into lipids of the fatty tissue and the subsequent incorporation of alimentary fat into fatty tissue deposits is accordingly reduced or delayed, with the concomitant benefit of reducing or preventing the deleterious abnormalities resulting therefrom.
  • Such glucosidase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Biochemistry (1969) 8: 4214).
  • a generally preferred glucosidase inhibitor includes an amylase inhibitor.
  • An amylase inhibitor is a glucosidase inhibitor that inhibits the enzymatic degradation of starch or glycogen into maltose.
  • amylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. (1955) 1 : 149). The inhibition of such enzymatic degradation is beneficial in reducing amounts of bioavailable sugars, including glucose and maltose, and the concomitant deleterious conditions resulting therefrom.
  • glucosidase inhibitors are known to one of ordinary skill in the art and examples are provided below.
  • Preferred glucosidase inhibitors are those inhibitors that are selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, camiglibose, tendamistate, trestatin, pradimicin-Q and salbostatin.
  • the glucosidase inhibitor, acarbose, and the various amino sugar derivatives related thereto are disclosed in U.S. Patent Nos. 4,062,950 and 4,174,439 respectively.
  • the glucosidase inhibitor, adiposine is disclosed in U.S.
  • Patent No. 4,254,256 The glucosidase inhibitor, voglibose, 3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyI)ethyl]amino]-2-C-(hydroxymethyl)-D-epi-inositol, and the various N-substituted pseudo-aminosugars related thereto, are disclosed in U.S. Patent No. 4,701 ,559.
  • the glucosidase inhibitor miglitol, (2ft,3fl,4fl,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5- piperidinetriol, and the various 3,4,5-trihydroxypiperidines related thereto, are disclosed in U.S. Patent No. 4,639,436.
  • the glucosidase inhibitor, emiglitate, ethyl p-[2-[(2R,3R,4R,5S)-3A,5-t ⁇ hydroxy-2- y p ⁇ per ⁇ ⁇ no e oxy - e , riva ives re a e ceu ca y acceptable acid addition salts thereof, are disclosed in U.S. Patent No.
  • glucosidase inhibitor MDL-25637, 2,6-dideoxy-7-O- ⁇ -D-glucopyrano-syl-2,6-imino-D-glycero-L-gluco-heptitol, the various homodisaccharides related thereto and the pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Patent No. 4,634,765.
  • the glucosidase inhibitor, camiglibose, methyl 6- deoxy-6-[(2fi,3fl,4fl,5S)-3,4,5-trihydroxy-2-(hydroxymethyI)piperidino]- ⁇ -D-glucopyranoside sesquihydrate, the deoxy-nojirimycin derivatives related thereto, the various pharmaceutically acceptable salts thereof and synthetic methods for the preparation thereof, are disclosed in U.S. Patent Nos. 5,157,116 and 5,504,078.
  • the glycosidase inhibitor, salbostatin and the various pseudosaccharides related thereto, are disclosed in U.S. Patent No. 5,091 ,524.
  • amylase inhibitors are known to one of ordinary skill in the art.
  • the amylase inhibitor, tendamistat and the various cyclic peptides related thereto, are disclosed in U.S. Patent No. 4,451 ,455.
  • the amylase inhibitor AI-3688 and the various cyclic polypeptides related thereto are disclosed in U.S. Patent No. 4,623,714.
  • the amylase inhibitor, trestatin, consisting of a mixture of trestatin A, trestatin B and trestatin C and the various trehalose-containing aminosugars related thereto are disclosed in U.S. Patent No. 4,273,765.
  • Additional anti-diabetic compounds which can be used as the second agent in combination with a compound of the present invention, includes, for example, the following: biguanides (e.g., metformin), insulin secretagogues (e.g., sulfonylureas and glinides), glitazones, non-glitazone PPARy agonists, PPAR ⁇ agonists, inhibitors of DPP-IV, inhibitors of PDE5, inhibitors of GSK-3, glucagon antagonists, inhibitors of f- 1 ,6-BPase(Metabasis/Sankyo), GLP-1/analogs (AC 2993, also known as exendin-4), insulin and insulin mimetics (Merck natural products).
  • biguanides e.g., metformin
  • insulin secretagogues e.g., sulfonylureas and glinides
  • glitazones e.g., non-glit
  • the compounds of the present invention can be used in combination with other anti-obesity agents.
  • Any anti-obesity agent can be used as the second agent in such combinations and examples are provided herein.
  • Such anti-obesity activity is readily determined by those skilled in the art according to standard assays known in the art.
  • Suitable anti-obesity agents include phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, ⁇ 3 adrenergic receptor agonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (e.g., sibutramine), sympathomimetic agents, serotoninergic agents, cannabinoid-1 (CB-1) receptor antagonists (e.g., rimonabant (SR-141.716A)), dopamine agonists (e.g., bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists
  • bombesin agonists e.g., anorectic agents (e.g., a bombesin agonist), Neuropeptide-Y antagonists, thyroxine, thyromimetic agents, dehydroepiandrosterones or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (e.g., AxokineTM), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists, and the like.
  • Rimonabant SR141716A also known under the tradename AcompliaTMavailable from Sanofi-
  • Synthelabo can be prepared as described in U.S. Patent No. 5,624,941.
  • Other suitable CB-1 antagonists include those described in U. . Patent Nos. 5,747,524, 6,432,984 and 6,5ia, ⁇ b4; u.s. Patent
  • apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors for use as anti-obesity agents are gut-selective MTP inhibitors, such as dirlotapide described in U.S. Patent No.
  • thyromimetic can be used as the second agent in combination with a compound of the present invention.
  • thyromimetic activity is readily determined by those skilled in the art according to standard assays (e.g., Atherosclerosis (1996) 126: 53-63).
  • a variety of thyromimetic agents are known to those skilled in the art, for example those disclosed in U.S. Patent Nos. 4,766,121 ; 4,826,876; 4,910,305; 5,061 ,798; 5,284,971 ; 5,401 ,772; 5,654,468; and 5,569,674.
  • Other antiobesity agents include sibutramine which can be prepared as described in U.S. Patent No. 4,929,629. and bromocriptine which can be prepared as described in U.S. Patent Nos. 3,752,814 and 3,752,888.
  • the compounds of the present invention can also be used in combination with other antihypertensive agents.
  • Any anti-hypertensive agent can be used as the second agent in such combinations and examples are provided herein.
  • Such antihypertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements).
  • Amlodipine and related dihydropyridine compounds are disclosed in U.S. Patent No. 4,572,909, which is incorporated herein by reference, as potent anti-ischemic and antihypertensive agents.
  • U.S. Patent No.4,879,303 which is incorporated herein by reference, discloses amlodipine benzenesulfonate salt (also termed amlodipine besylate).
  • Amlodipine and amlodipine besylate are potent and long lasting calcium channel blockers.
  • amlodipine, amlodipine besylate, amlodipine maleate and other pharmaceutically acceptable acid addition salts of amlodipine have utility as antihypertensive agents and as antiischemic agents.
  • Amlodipine besylate is currently sold as Norvasc ® . Amlodipine has the formula
  • the starting materials and reagents for the above-described compounds of the present invention and combination agents are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis.
  • many of the compounds used herein are re a e o, or are er ve rom compoun s n w c ere is a a in eres an commerc a nee , and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.
  • Some of the compounds of the present invention or intermediates in their synthesis have asymmetric carbon atoms and therefore are enantiomers or diastereomers.
  • Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known p_ ⁇ Se 1 , for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by, for example, chiral HPLC methods or converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., alcohol
  • an enantiomeric mixture of the compounds or an intermediate in their synthesis which contain an acidic or basic moiety may be separated into their compounding pure enantiomers by forming a diastereomeric salt with an optically pure chiral base or acid (e.g., 1 -phenyl-ethyl amine or tartaric acid) and separating the diasteromers by fractional crystallization followed by neutralization to break the salt, thus providing the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered as part of the present invention. Also, some of the compounds of the present invention are atropisomers (e.g., substituted biaryls) and are considered as part of the present invention.
  • the compounds of the present invention can be obtained by fractional crystallization of the basic intermediate with an optically pure chiral acid to form a diastereomeric salt. Neutralization techniques are used to remove the salt and provide the enantiomerically pure compounds.
  • the compounds of the present invention may be obtained in enantiomerically enriched form by resolving the racemate of the final compound or an intermediate in its synthesis (preferably the final compound) employing chromatography (preferably high pressure liquid chromatography [HPLC]) on an asymmetric resin (preferably ChiralcelTM AD or OD (obtained from Chiral Technologies, Exton,
  • a mobile phase consisting of a hydrocarbon (preferably heptane or hexane) containing between 0 and 50% isopropanol (preferably between 2 and 20 %) and between 0 and 5% of an alkyl amine (preferably 0.1% of diethylamine).
  • a hydrocarbon preferably heptane or hexane
  • isopropanol preferably between 2 and 20
  • alkyl amine preferably 0.1% of diethylamine
  • salts are within the scope of the present invention and they can be prepared by conventional methods such as combining the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate.
  • the salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
  • the compounds can be obtained in crystalline form by dissolution in an appropriate solvent(s) such as ethanol, hexanes or water/ethanol mixtures.
  • the compounds of the present invention are all adapted to therapeutic use as agents that activate peroxisome proliferator activator receptor (PPAR) activity in mammals, particularly humans.
  • PPAR peroxisome proliferator activator receptor
  • the compounds of the present nvent on, y act vating t e PPAR receptor, s mu a e ranscr pt on o ey genes involved in ratty acid oxidation and also those involved in high density lipoprotein (HDL) assembly (for example apolipoprotein Al gene transcription), accordingly reducing whole body fat and increasing HDL cholesterol.
  • HDL high density lipoprotein
  • these agents By virtue of their activity, these agents also reduce plasma levels of triglycerides, VLDL cholesterol, LDL cholesterol and their associated components in mammals, particularly humans, as well as increasing HDL cholesterol and apolipoprotein Al.
  • these compounds are useful for the treatment and correction of the various dyslipidemias observed to be associated with the development and incidence of atherosclerosis and cardiovascular disease, including hypoalphalipoproteinemia and hypertriglyceridemia.
  • the present compounds are also useful for modulation of plasma and or serum or tissue lipids or lipoproteins, such as HDL subtypes (e.g., increase, including pre-beta HDL, HDL-1 ,-2 and 3 particles) as measured by precipitation or by apo-protein content, size, density, NMR profile, FPLC and charge and particle number and its constituents; and LDL subtypes (including LDL subtypes e.g., decreasing small dense LDL, oxidized LDL, VLDL, apo(a) and Lp(a)) as measured by precipitation, or by apo-protein content, size density, NMR profile, FPLC and charge; IDL and remnants (decrease); phospholipids (e.g., increase HDL phospholipids); apo-lipoproteins (increase A-I, A-Il, A-IV, decrease total and LDL B-100, decrease B- 48, modulate C-Il, C-III, E, J); paraoxonase (
  • the compounds of the present invention Given the positive correlation between triglycerides, LDL cholesterol, and their associated apolipoproteins in blood with the development of cardiovascular, cerebral vascular and peripheral vascular diseases, the compounds of the present invention, their prodrugs and the salts of such compounds and prodrugs, by virtue of their pharmacologic action, are useful for the prevention, arrestment and/or regression of atherosclerosis and its associated disease states.
  • cardiovascular disorders e.g., cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, vascular hemostatic disease, cardiac ischemia and myocardial infarction
  • cardiovascular disorders e.g., cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, vascular hemostatic disease, cardiac ischemia and myocardial infarction
  • cognitive dysfunction including, but not limited to, dementia secondary to atherosclerosis, transient cerebral ischemic attacks, neurodegeneration, neuronal deficient, and delayed onset or procession of Alzheimer's disease.
  • the compounds of the present invention are of use in the treatment of diabetes, including impaired glucose tolerance, diabetic complications, insulin resistance and metabolic syndrome, as described previously.
  • the compounds are useful for the treatment of polycystic ovary syndrome.
  • the compounds are useful in the treatment of obesity given the ability of the compounds of this invention, their prodrugs and the salts of such compounds and prodrugs to increase hepatic fatty acid oxidation.
  • such assays provide a means whereby the activities of the compounds of the present invention, their prodrugs and the salts of such compounds and prodrugs (or the other agents described herein) can be compared to each other and with the activities of other known compounds.
  • the results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
  • the following protocols can of course be varied by those skilled in the art.
  • PPAR FRET Fluorescence Resonance Energy Transfer
  • Binding of ligand to the PPAR LBD causes a conformational change that allows SRC-1 to bind.
  • the donor FRET molecule (europium) comes in close proximity to the acceptor molecule (APC), resulting in fluorescence energy transfer between donor (337 nm excitation and 620 nm emission) and acceptor (620 nm excitation and 665 nm emission).
  • APC acceptor molecule
  • Increases in the ratio of 665nm emission to 620 nm emission is a measure of the ability of the ligand-PPAR LBD to recruit SRC-1 synthetic peptide and therefore a measure of the ability of a ligand to produce a functional response through the PPAR receptor.
  • GST/ PPAR LBD Expression The human PPAR ⁇ LBD (amino acids 235-507) is fused to the carboxy terminus of glutathione S-transferase (GST) in pGEX-6P-1 (Pfizer, Inc.).
  • GST/PPAR ⁇ LBD fusion protein is expressed in BL21[DE3]pLysS cells using a 50 uM IPTG induction at room temperature for 16 hr (cells induced at an A 600 Of -0.6). Fusion protein is purified on glutathione sepharose 4B beads, eluted in 10 mM reduced glutathione, and diaiyzed against 1x PBS at 4 0 C.
  • Fusion protein is quantitated by Bradford assay (M. M. Bradford, Analst. Biochem. 72:248-254; 1976), and stored at -2O 0 C in 1x PBS containing 40% glycerol and 5 mM dithiothreitol.
  • the FRET assay reaction mix consists of 1x FRET buffer (50 mM Tris-CI pH 8.0, 50 mM KCI, 0.1 mg/ml BSA, 1 mM EDTA, and 2 mM dithiothreitol) containing 20 nM GST/ PPAR ⁇ LBD, 40 nM of SRC-1 peptide (amino acids 676-700, 5'-long chain biotin-CPSSHSSLTERHKILHRLLQEGSPS- NH 2 , purchased from American Peptide Co., Sunnyvale, CA), 2 nM of europium-conjugated anti-GST antibody (Wallac, Gaithersburg, MD), 40 nM of streptavidin-conjugated APC (Wallac), and control and test compounds.
  • 1x FRET buffer 50 mM Tris-CI pH 8.0, 50 mM KCI, 0.1 mg/ml BSA, 1 mM EDTA, and 2 mM dithiothre
  • the final volume is brought to 100 ul with water and transferred to a black 96-well plate (Microfuor B, Dynex (Chantilly, VA)).
  • the reaction mixes are incubated for 1 hour at 4 0 C and fluorescence is read in Victor 2 plate reader (Wallac). Data is presented as a ratio of the emission at 665 nm to the emission at 615 nm.
  • mice Triglyceride lowering.
  • the hypolipidemic treating activity of the compounds of the present invention can be demonstrated by methods based on standard procedures. For example, the in vivo ac i ing p asma e ermine in y ⁇ B6CBAF1/J mice.
  • mice Male B6CVAF1/J mice (8-11 week old) are obtained from The Jackson Laboratory and housed 4- 5/cage and maintained in a 12hr light/12hr dark cycle. Animals have ad lib. access to Purina rodent chow and water. The animals are dosed daily (9 AM) by oral gavage with vehicle (water or 0.5% methyl cellulose 0.05% Tween 80) or with vehicle containing test compound at the desired concentration. Plasma triglycerides levels are determined 24 hours after the administration of the last dose (day 3) from blood collected retro-orbitally with heparinized hematocrit tubes. Triglyceride determinations are performed using a commercially available Triglyceride E kit from Wako (Osaka, Japan).
  • [2] HDL cholesterol elevation The activity of the compounds of the present invention for raising the plasma level of high density lipoprotein (HDL) in a mammal can be demonstrated in transgenic mice expressing the human apoAI and CETP transgenes (HuAICETPTg).
  • the transgenic mice for use in this study are described previously in Walsh et al., J. Lipid Res. 1993, 34: 617-623, Agellon et al., J. Biol. Chem. 1991 , 266: 10796-10801.
  • Mice expressing the human apoAI and CETP transgenes are obtained by mating transgenic mice expressing the human apoAI transgene (HuAITg) with CETP mice (HuCETPTg).
  • mice Male HuAICETPTg mice (8-11 week old) are grouped according to their human apo Al levels and have free access to Purina rodent chow and water. Animals are dosed daily by oral gavage with vehicle (water or 0.5% methylcellulose 0.05% Tween 80) or with vehicle containing test compound at the desired dose for 5 days. HDL-cholesterol and human apoAI are determined initially (day 0) and 90 minutes post dose (day 5) using methods based on standard procedures. Mouse HDL is separated from apoB- containing lipoproteins by dextran sulfate precipitation as described elsewhere (Francone et al., J. Lipid. Res. 1996, 37:1268-1277).
  • Cholesterol is measured enzymatically using a commercially available cholesterol/HP Reagent kit (Boehringer MannHeim, Indianapolis, IND) and spectrophotometrically quantitated on a microplate reader. Human apoAI is measured by a sandwich enzyme-linked immunosorbent assay as previously described (Francone et al., J. Lipid. Res. 1996, 37:1268-1277).
  • hypoglycemic activity of the compounds of the present invention can be determined by the amount of test compound that reduces glucose levels relative to a vehicle without test compound in male ob/ob mice.
  • the test also allows the determination of an approximate minimal effective dose (MED) value for the in vivo reduction of plasma glucose concentration in such mice for such test compounds.
  • MED minimal effective dose
  • mice Five to eight week old male C57BL/6J-ob/ob mice (obtained from Jackson Laboratory, Bar Harbor, ME) are housed five per cage under standard animal care practices. After a one-week acclimation period, the animals are weighed and 25 microliters of blood are collected from the retro-orbital sinus prior to any treatment. The blood sample is immediately diluted 1 :5 with saline containing 0.025% sodium heparin, and held on ice for metabolite analysis. Animals are assigned to treatment groups so that each group has a similar mean for plasma glucose concentration.
  • mice are dosed orally each day for four days with the vehicle consisting of either: (1) 0.25% w/v methyl cellulose in water without pH adjustment; or (2) 0.1% Pluronic ® P105 Block Copolymer Surfactant (BASF Corporation, Parsippany, NJ) in 0.1 % saline without pH adjustment.
  • the animals are weighed again and then dosed orally with a test compound or the vehicle alone. All compounds are administered in vehicle consisting of either: (1) . o v me y ce u ose in a er; . u oni . p a jus men ; or 3) neat PEG 400 without pH adjustment.
  • hypoglycemic activity of the test compounds is determined by statistical analysis (unpaired t-test) of the mean plasma glucose concentration between the test compound group and vehicle-treated group on day 5.
  • the above assay carried out with a range of doses of a test compound allows the determination of an approximate minimal effective dose (MED) value for the in vivo reduction of plasma glucose concentration.
  • MED minimal effective dose
  • the compounds of the present invention are readily adapted to clinical use as hyperinsulinemia reversing agents, triglyceride lowering agents and hypocholesterolemic agents. Such activity can be determined by the amount of test compound that reduces insulin, triglycerides or cholesterol levels relative to a control vehicle without test compound in male ob/ob mice.
  • the compounds of the present invention since the concentration of cholesterol in blood is closely related to the development of cardiovascular, cerebral vascular or peripheral vascular disorders, the compounds of the present invention, by virtue of their hypocholesterolemic action, prevent, arrest and/or regress atherosclerosis.
  • the compounds of the present invention since the concentration of insulin in blood is related to the promotion of vascular cell growth and increased renal sodium retention, (in addition to the other actions, e.g., promotion of glucose utilization) and these functions are known causes of hypertension, the compounds of the present invention, by virtue of their hypoinsulinemic action, prevent, arrest and/or regress hypertension.
  • the compounds of the present invention by virtue of their triglyceride lowering and/or free fatty acid lowering activity prevent, arrest and/or regress hyperlipidemia.
  • Free fatty acids contribute to the overall level of blood lipids and independently have been negatively correlated with insulin sensitivity in a variety of physiologic and pathologic states.
  • mice Five to eight week old male C57BL/6J-ob/ob mice (obtained from Jackson Laboratory, Bar Harbor, ME) are housed five per cage under standard animal care practices and fed standard rodent diet ad libitum. After a one-week acclimation period, the animals are weighed and 25 microliters of blood are collected from the retro-orbital sinus prior to any treatment. The blood sample is immediately diluted 1 :5 with saline containing 0.025% sodium heparin, and held on ice for plasma glucose analysis. Animals are assigned to treatment groups so that each group has a similar mean for plasma glucose concentration. The compound o . o .
  • the compound to be tested can be administered by oral gavage dissolved in or in suspension in neat PEG 400.
  • Single daily dosing (s.i.d.) or twice daily dosing (b.i.d.) is maintained for 1 to, for example, 15 days.
  • Control mice receive the 10% DMSO/0.1% Pluronic ® P105 in 0.1% saline without pH adjustment or the 0.25% w/v methylcellulose in water without pH adjustment, or the neat PEG 400 without pH adjustment.
  • the animals are sacrificed and blood is collected into 0.5 ml serum separator tubes containing 3.6 mg of a 1 :1 weight/weight sodium fluoride: potassium oxalate mixture.
  • the freshly collected samples are centrifuged for two minutes at 10,000 x g at room temperature, and the serum supernatant is transferred and diluted 1 :1 volume/volume with a 1TIU/ml aprotinin solution in 0.1% saline without pH adjustment.
  • the diluted serum samples are then stored at -80 0 C until analysis.
  • the thawed, diluted serum samples are analyzed for insulin, triglycerides, free fatty acids and cholesterol levels.
  • Serum insulin concentration is determined using Equate ® RIA INSULIN kits (double antibody method; as specified by the manufacturer) available from Binax, South Portland, ME.
  • the interassay coefficient of variation is ⁇ 10%.
  • Serum triglycerides are determined using the Abbott VPTM and VP Super System ® Autoanalyzer (Abbott Laboratories, Irving, TX), or the Abbott Spectrum CCX TM (Abbott Laboratories, Irving, TX) using the A-GentTM Triglycerides Test reagent system (Abbott Laboratories, Diagnostics Division, Irving, TX) (lipase-coupled enzyme method; a modification of the method of Sampson, et al., Clinical Chemistry 21 : 1983 (1975)).
  • Serum total cholesterol levels are determined using the Abbott VPTM and VP Super System ® Autoanalyzer (Abbott Laboratories, Irving, TX), and A-GentTM Cholesterol Test reagent system (cholesterol esterase- coupled enzyme method; a modification of the method of Allain, et al. Clinical Chemistry 20: 470 (1974)) using 100 and 300 mg/dl standards.
  • Serum free fatty acid concentration is determined utilizing a kit from WAKO (Osaka, Japan), as adapted for use with the Abbott VPTM and VP Super System® Autoanalyzer (Abbott Laboratories, Irving, TX), or the Abbott Spectrum CCXTM (Abbott Laboratories, Irving, TX).
  • the animals dosed with vehicle maintain substantially unchanged, elevated serum insulin (e.g., 275 ⁇ U/ml), serum triglycerides (e.g., 235 mg/dl), serum free fatty acid (1500 mEq/ml) and serum total cholesterol (e.g., 190 mg/dl) levels.
  • serum insulin, triglycerides, free fatty acid and total cholesterol lowering activity of the test compounds are determined by statistical analysis (unpaired t-test) of the mean serum insulin, triglycerides, or total cholesterol concentration between the test compound group and the vehicle-treated control group.
  • thermogenesis the concomitant evolution of heat
  • thermogenic response can be demonstrated according to the following protocol:
  • This in vivo screen is designed to evaluate the efficacy of compounds that are PPAR agonists, using as an efficacy endpoint measurement of whole body oxygen consumption.
  • the protocol involves: (a) dosing fatty Zucker rats for about 6 days, and (b) measuring oxygen consumption.
  • Male fatty Zucker rats having a body weight range of from about 400 g to about 500 g are housed for from about 3 to about 7 days in individual cages under standard laboratory conditions prior to the initiation of the study.
  • a compound of the present invention and a vehicle is administered by oral gavage as a single daily dose given between about 3 p.m. to about 6 p.m. for about 6 days.
  • a compound of the present invention is dissolved in vehicle containing about 0.25 % of methyl cellulose.
  • the dosing volume is about 1 ml.
  • oxygen consumption is measured using an open circuit, indirect calorimeter (Oxymax, Columbus Instruments, Columbus, OH 43204).
  • the Oxymax gas sensors are calibrated with N 2 gas and a gas mixture (about 0.5 % of CO 2 , about 20.5 % of O 2 , about 79 % of N 2 ) before each experiment.
  • the subject rats are removed from their home cages and their body weights recorded.
  • the rats are placed into the sealed chambers (43 x 43 x 10 cm) of the Oxymax, the chambers are placed in the activity monitors, and the air flow rate through the chambers is then set at from about 1.6 L/min to about 1.7 L/min.
  • the Oxymax software calculates the oxygen consumption (mL/kg/h) by the rats based on the flow rate of air through the chambers and the difference in oxygen content at the inlet and output ports.
  • the activity monitors have 15 infrared light beams spaced about one inch apart on each axis, and ambulatory activity is recorded when two consecutive beams are broken, and the results are recorded as counts.
  • Oxygen consumption and ambulatory activity are measured about every 10 minutes for from about 5 hours to about 6.5 hours. Resting oxygen consumption is calculated on individual rats by averaging the values excluding the first 5 values and the values obtained during time periods where ambulatory activity exceeds about 100 counts.
  • Anti-atherosclerotic effects of the compounds of the present invention can be determined by the amount of compound required to reduce the lipid deposition in rabbit aorta.
  • Male New Zealand White rabbits are fed a diet containing 0.2% cholesterol and 10% coconut oil for 4 days (meal-fed once per day). Rabbits are bled from the marginal ear vein and total plasma cholesterol values are determined from these samples. The rabbits are then assigned to treatment groups so that each group has a similar mean ⁇ SD for total plasma cholesterol concentration, HDL cholesterol concentration and triglyceride concentration. After group assignment, rabbits are dosed daily with compound given as a dietary admix or on a small piece of gelatin based confection. Control rabbits receive only the dosing vehicle, be it the food or the gelatin confection.
  • the cholesterol/coconut oil diet is continued along with the compound administration throughout the study.
  • Plasma cholesterol, HDL-cholesterol, LDL cholesterol and _ _ ues can e e ermine a any poi uring e s e margina ear vein.
  • the rabbits are sacrificed and the aortae are removed from the thoracic arch to the branch of the iliac arteries.
  • the aortae are cleaned of adventitia, opened longitudinally and then stained with Sudan IV as described by Holman et. al. (Lab. Invest. 1958, 7, 42-47).
  • the percent of the surface area stained is quantitated by densitometry using an Optimas Image Analyzing System (Image Processing Solutions; North Reading MA). Reduced lipid deposition is indicated by a reduction in the percent surface area stained in the compound-receiving group in comparison with the control rabbits.
  • Negative energy balance is a problem frequently encountered in ruminants particularly dairy cows. NEB may be experienced at any time during the cows life but it is particularly prevalent during the transition period.
  • the ruminant transition period is defined as the period spanning late gestation to early lactation. This is sometimes defined as from 3 weeks before to three weeks after parturition, but has been expanded to 30 days prepartum to 70 days postpartum (J N Spain and W A Scheer, Tri-State Dairy Nutrition Conference, 2001 , 13).
  • Energy balance is defined as energy intake minus energy output and an animal is descibed as being in negative energy balance if energy intake is insufficient to meet the demands on maintenance and production (eg milk).
  • a cow in NEB has to find the energy to meet the deficit from its body reserves.
  • cows in NEB tend to lose body condition and liveweight, with cows that are more energy deficient tending to lose condition and weight at a faster rate.
  • NEFAs Long chain fatty acids (or non esterified fatty acids, NEFAs) are also mobilised from body fat. NEFAs, already elevated from around 7 days prepartum, are a significant source of energy to the cow during the early postpartum period, and the greater the energy deficit the higher the concentration of NEFA in the blood. Some workers suggest that in early lactation (Bell and references therein-see above) mammary uptake of NEFAs accounts for some milk fat synthesis. The circulating NEFAs are taken up by the liver and are oxidised to carbon dioxide or ketone bodies, including 3-hydroxybutyrate, by mitochondria, or reconverted via esterification into triglycerides and stored.
  • CPT-1 carnitine palmitoyltransferase
  • NEFA uptake by the bovine liver becomes excessive, accumulation of ketone bodies can lead to ketosis, and excessive storage of triglycerides may lead to fatty liver.
  • Fatty liver can lead to prolonged recovery for other disorders, increased incidence of health problems, and development of "downer cows" that die. , , r y g p o , e transition period that negatively impacts disease resistance (abomasal displacement, lameness), immune function (mastitits, metritis), reproductive performance (oestrus, calving interval, foetal viability, ovarian cysts, metritis, retained placenta), and milk production (peak milk yield, 305 day milk yield).
  • Fatty liver has largely developed by the day after parturition and precedes an induced (secondary) ketosis. It usually results from increased esterification of NEFA absorbed from blood coupled with the low ability of ruminant liver to secrete triglycerides as very low-density lipoproteins.
  • NEFAs or ketone bodies serum concentrations of NEFAs or ketone bodies, or levels of triglycerides in liver tissues. Higher than 'normal' levels of NEFA's and/or triglycerides and/or ketone bodies are indicators of negative energy balance. Levels considered 'higher than normal' or 'excessive' are: NEFA's >800 ⁇ mol/L in serum.
  • Triglycerides >10% w/w in liver tissue. Ketone bodies >1.2 ⁇ mol/L in serum.
  • NEFA blood non-esterified fatty acid
  • liver triglycerides levels Compounds are administered once or several times in the transition period at dose levels predicted to be effective by comparing results of in-vitro receptor affinity tests in laboratory species and pharmacokinetic evaluations in cattle. NEFA levels are determined via standard laboratory methods, for example, using the commercial WAKO NEFA kit (Wako Chemical Co., USA, Dallas, TX, 994-75409), and liver triglyceride content is determined using the method as described in the literature (J. K. Drackley, J. J. Veenhuizen, M. J. Richard and J. W. Young, J Dairy Sci, 1991 , 74, 4254)).
  • All animals may be obtained from a commercial dairy farm approximately thirty days prior to anticipated calving date.
  • the cows are moved into separate building, approximately 10-14 days prior to their anticipated calving dates and switched to the TMR-Close-Up dry diet. Enrolment of animals in the study begins approximately 7 days prior to their anticipated calving dates.
  • the animals may be moved to the "on- test" pen, weighed and are locked each AM into feed stanchions. At that time, appropriate doses are administered and appropriate blood samples obtained (see table below for sample data for a PPAR alpha agonist, compound Z, 2-Methyl-5-(4'-trifluoromethoxy-biphenyl-4-ylsulfamoyl)-benzoic acid.
  • Animals enrolled in T01 were treated with vehicle control every other day (eod) beginning at the estimated Day -7 prior to calving, and once again at calving.
  • Animals enrolled in T02 were treated with compound Z, 2-Methyl-5-(4'-trifluoromethoxy-biphenyl-4-ylsulfamoyl)-benzoic acid, every other day beginning at the estimated Day -7 prior to calving, and once again at calving.
  • ketone bodies in serum can be measured by standard methods well known to the person skilled in the art, for example, by using the commercially available kits for this purpose, including Sigma BHBA kit of order number 310-A.. Milk content:
  • Machines to assay for milk protein, fat, or lactose content are commercially available (MilkoScanTM 50, MilkoScanTM 4000, MilkoScanTM FT 6000 available from Foss Group).
  • Machines to assay for somatic cell content are also commercially available (Fossomatic TM FC, Fossomatic TM Minor available from Foss Group).
  • Compounds used in this invention may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof).
  • compounds of this invention can also be mixed with one or more biologically active compounds or agents selected from sedatives, analgesics, antiinflammatories, analeptics, antibacterials, antidiarrhoeals, anti-endotoxin, antifungals, respiratory stimulants, corticosteroids, diuretics, parasiticides, electrolyte preparations and nutritional supplements, growth promoters, hormones, and metabolic disease treatments, giving an even broader spectrum of veterinary or agricultural utility.
  • biologically active compounds or agents selected from sedatives, analgesics, antiinflammatories, analeptics, antibacterials, antidiarrhoeals, anti-endotoxin, antifungals, respiratory stimulants, corticosteroids, diuretics, parasiticides, electrolyte preparations and nutritional supplements, growth promoters, hormones, and metabolic disease treatments, giving an even broader spectrum of veterinary or agricultural utility.
  • Amylase inhibitors Acarbose
  • Glucosidase Inhibitors Acarbose; Sedatives: xylazine;
  • Analgesics and antiinflammatories Lignocaine, Procaine, flunixin, oxytetracycline, ketoprofen, meloxicam and carprofen;
  • Analeptics Etamiphylline, Doxapram, Diprenorphine, Hyoscine, Ketoprofen, Meloxicam, Pethidine,
  • Antidiarrhoeals Hyoscine, Dipyrone, charcoal, attapulgite, kaolin, lsphaghula husk;
  • Anti-endotoxins Flunixin, ketoprofen
  • Antifungals Enilconazole, Natamycin; Respiratory stimulants: florfenicol;
  • Corticosteroids dexamethasone, betamethasone;
  • Electrolyte preparations and nutritional supplements dextrose, lactose, propylene glycol, whey, glucose, glycine, calcium, cobalt, copper, iodine, iron, magnesium, manganese, phosphorous, selenium, zinc, Biotin, vitamin B 12 , Vitamin E, and other vitamins;
  • Growth Promoters monensin, flavophospholipol, bambermycin, salinomycin, tylosin; Hormones: chorionic gonadotrophin, serum gonadotrophin, atropine, melatonin, oxytocin, dinoprost, cloprostenol, etiproston, luprostiol, buserelin, oestradiol, progesterone, and bovine somatotropin; and
  • Metabolic Disease Treatments calcium gluconate, calcium borogluconate, propylene glycol, magnesium sulphate.
  • Compounds of this invention can also be mixed with one or more biologically active compounds or agents selected from antiprotozoals such as imidocarb, bloat remedies such as dimethicone and poloxalene, and probiotics such as Lactobacilli and streptococcus.
  • antiprotozoals such as imidocarb
  • bloat remedies such as dimethicone and poloxalene
  • probiotics such as Lactobacilli and streptococcus.
  • Administration of the compounds of the present invention can be via any method which delivers a compound of this invention systemically and/or locally. These methods include oral routes, parenteral, intraduodenal routes, etc. Generally, the compounds of this invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous or intramedullary) may be utilized, for example, where oral administration is inappropriate or where the patient is unable to ingest the drug.
  • parenteral administration e.g., intravenous, intramuscular, subcutaneous or intramedullary
  • an amount of a compound of the present invention is used that is sufficient to achieve the therapeutic effect desired (e.g., lipid lowering).
  • an effective dosage for the compounds of the present invention is in the range of about 0.001 to about 100 mg/kg/day, preferably about 0.005 to about 5 mg/kg/day.
  • a dosage of the combination pharmaceutical agents to be used in conjuction with the PPAR agonists is used that is effective for the indication being treated. Such dosages can be determined by standard assays such as those referenced above and provided herein.
  • the combination agents may be administered simultaneously or sequentially in any order. _ - , - o re c e o about 0.01 to about 100 mg/kg/day.
  • the compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable vehicle, diluent or carrier.
  • a pharmaceutically acceptable vehicle diluent or carrier.
  • the compounds of the present invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form.
  • a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
  • Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • a preferred formulation is a solution or suspension in an oil, for example olive oil, MiglyolTM or CapmulTM, in a soft gelatin capsule.
  • Antioxidants may be added to prevent long term degradation as appropriate.
  • the compounds of the present invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the sterile aqueous media employed are all readily obtainable by standard techniques well known to those skilled in the art.
  • dilute sterile, aqueous or partially aqueous solutions are prepared.
  • aqueous or partially aqueous solutions are prepared.
  • Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art.
  • methods of preparing pharmaceutical compositions see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 19th Edition (1995).
  • compositions according to the present invention may contain 0.1%-95% of the compound(s) of the present invention, preferably 1 %-70%.
  • the composition or formulation to be administered will contain a quantity of a compound(s) according to the present invention in an amount effective to treat the disease/condition of the subject being treated, e.g., atherosclerosis.
  • the present invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingredients, which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form.
  • the kit comprises two separate pharmaceutical compositions: a compound of the present invention, a prodrug thereof or a salt of suc o a ove.
  • e i or examp e comprses means for containing the separate compositions such as a container, a divided bottle or a divided foil packet.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, ...etc.... Second Week, Monday, Tuesday, etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a compound of the present invention can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
  • a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • active ingredient means a compound of the present invention. ormu a on : e a n apsu es
  • Hard gelatin capsules are prepared using the following:
  • a tablet formulation is prepared using the ingredients below: Formulation 2: Tablets
  • the components are blended and compressed to form tablets.
  • tablets each containing 0.25-100 mg of active ingredients are made up as follows: Formulation 3: Tablets
  • the active ingredients, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50° - 60 ⁇ C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
  • Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose are made as follows: o : spensions
  • the active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • Aerosol solution is prepared containing the following ingredients: Formulation 5: Aerosol
  • Propellant 22 (Chlorodifluoromethane) 70.00
  • the active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30°C, and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container.
  • Suppositories are prepared as follows: Formulation 6: Suppositories
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimal necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
  • An intravenous formulation is prepared as follows: Formulation 7: Intravenous Solution
  • the active ingredient above may also be a combination of therapeutic agents.
  • NMR spectra were recorded on a Varian Unity 400 (Varian Co., Palo Alto, CA) NMR spectrometer at ambient temperature. Chemical shifts are expressed in parts per million ( ⁇ ) relative to an external standard (tetramethylsilane). The peak shapes are denoted as follows: s, singlet; d, doublet, t, triplet, q, quartet, m, multiplet with the prefix br indicating a broadened signal.
  • the coupling constant (J) data given have a maximum error of ⁇ 0.41 Hz due to the digitization of the spectra that are acquired.
  • Mass spectra were obtained by (1) atmospheric pressure chemical ionization (APCI) in alternating positive and negative ion mode using a Fisons Platform Il Spectrometer or a Micromass MZD Spectrometer (Micromass, Manchester, UK) or (2) electrospray ionization in alternating positive and negative ion mode using a Micromass MZD Spectrometer (Micromass, Manchester, UK) with a Gilson LC-MS interface (Gilson Instruments, Middleton, Wl) or (3) a QP-8000 mass spectrometer (Shimadzu Corporation, Kyoto, Japan) operating in positive or negative single ion monitoring mode, utilizing electrospray ionization or atmospheric pressure chemical ionization.
  • APCI atmospheric pressure chemical ionization
  • Elution was carried out using water/acetonitrile gradients containing either 0.1% formic acid or am . , c u e a ers ymme ry , 5 ⁇ m, 19x50mm or 30x50mm, Waters XTerra C18, 5 ⁇ m, 50x50 (Waters Corp, Milford, MA) or Phenomenex Synergi Max-RP 4 ⁇ m, 50x50mm (Phenomenex Inc., Torrance, CA). In basic mode, the Phenomenex Synergi Max-RP 4 ⁇ m, 21.2x50mm or 30x50mm columns (Phenomenex Inc., Torrance, CA) were used.
  • Optical rotations were determined using a Jasco P-1020 Polarimeter Jasco Inc., Easton, MD) Dimethylformamide, tetrahydrofuran, toluene and dichloromethane were the anhydrous grade supplied by Aldrich Chemical Company (Milwaukee, Wl). Unless otherwise specified, reagents were used as obtained from commercial sources.
  • concentration and “evaporated” refer to removal of solvent at 1-200 mm of mercury pressure on a rotary evaporator with a bath temperature of less than 45°C.
  • the abbreviation “min” stand for "minutes” and “h” or “hr” stand for "hours.”
  • the abbreviation “gm” or “g” stand for grams.
  • the abbreviation “ ⁇ l” or “ ⁇ l_” stand for microliters.
  • ⁇ -Chlorosulfonyl ⁇ -methyl-benzoic acid methyl ester (0.44 g, 1.78 mmol) was added to a solution of 6-(4- fluoro-benzylsulfanyl)-pyridin-3-ylamine (0.418 g, 1.78 mmol) in 15 ml dichloromethane, followed by the addition of pyridine (0.42 g, 5.34 mmol). The resulting solution was stirred at room temperature overnight, then diluted with 100 ml ethyl acetate.
  • EXAMPLE 62b 5-(6-Chloro-pyridin-3-ylsulfamov ⁇ -2-methyl-benzoic acid methyl ester A mixture of 5-amino-2-chloropyridine (1.56 g, 12.1 mmol), ⁇ -chlorosulfonyl ⁇ -methylbenzoic acid methyl ester (3 g, 12.1 mmol) and pyridine (2.9 ml, 36.3 mmol) in 20 ml anhydrous tetrahydrofuran was heated at 60 0 C under nitrogen for 30 hours.
  • Benzene boronic acid (0.143 g, 1.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 g) were added to a mixture of sodium carbonate (0.238 g, 2.24 mmol) and 5-(6-bromo-pyridin-3-ylsulfamoyl)-2- methyl-benzoic acid methyl ester (0.375 g, 0.975 mmol) in 10 ml 1 ,2-dimethoxyethane and 2 ml water. The reaction mixture was degassed and heated overnight at reflux under nitrogen! The reaction mixture was then concentrated to dryness under reduced pressure and taken up in 50 ml water.
  • 6-(4-Ethyl-phenyl)-pyridin-3-ylamine 42 mg, 0.212mmol was added to a solution of 5-chlorosulfonyl-2- methylbenzoic acid methyl ester (53 mg, 0.212 mmol)) and triethylamine (0.03 ml, 0.212 mmol) in 3 ml dichloromethane and the reaction mixture was heated at reflux overnight under nitrogen.
  • Another equivalent of both S-chlorosulfonyl ⁇ -methylbenzoic acid methyl ester and triethylamine was added and reaction mixture was heated at reflux for 3 hours.
  • a catalytic amount of 4-dimethylaminopyridine was then added and the reaction mixture was heated at reflux for 2 hours.
  • EXAMPLE 82 2-(3,4-Difluoro-benzylsulfanyl)-5-nitro-pyridine 33% yield.
  • EXAMPLE 94 6-(3,4-Difluoro-benzylsulfanyl)-pyridin-3-ylamine 46% yield.
  • 1 H NMR 500 MHz, DMSO-D 6 ): ⁇ 4.22 (s, 2H), 5.26 (m, 2H), 6.86 (m, 1 H), 6.96 (m, 1 H), 7.3 (m, 3H), 7.9 (S, 1 H).
  • EXAMPLE 99 6-(4-tert-Butyl-benzylsulfanyl)-pyridin-3-ylamine 39% yield.
  • 1 H NMR 500 MHz, DMSO-D 6 ): ⁇ 1.24 (s, 9H), 4.2 (s, 2H), 5.22 (m, 2H), 6.87 (m, 1 H), 6.96 (m, 1 H), 7.2 (m, 2H), 7.3 (m, 2H), 7.9 (s, 1 H).
  • the reaction was heated at reflux for 1.5 hours, then cooled to room temperature.
  • the solution was concentrated to half volume under reduced pressure, diluted with 250 mi ethyl acetate and the resulting solution was filtered through a pad of diatomaceous earth (Celite).
  • the filtrate was washed with 150 ml saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure.
  • the crude product was purified by flash column chromatography on silica gel, eluting with 99:1 hexane/ethyl acetate to yield the product (4.9 g, 100% yield).
  • EXAMPLE 102 ⁇ -Chlorosulfonyl ⁇ -methyl-benzoic acid A mixture of o-toluic acid (15 g, 0.11 mol) and chlorosulfonic acid (30 ml) was heated at 100 0 C under nitrogen for 2.5 h. The reaction mixture was then poured onto ice (500 ml) and the resulting precipitate was filtered, yielding the title compound as an off-white solid (20 g, 78% yield). MP 151-155 0 C. MS: 233.4 (M- 1)
  • EXAMPLE 110 ⁇ -Chlorosulfonyl ⁇ -ethoxy-benzoic acid ethyl ester
  • EXAMPLE 111 ⁇ -Chlorosulfonyl ⁇ -methylsulfanyl-benzoic acid methyl ester 58% yield.
  • 1 H NMR 400 MHz, CDCI 3 ) ⁇ 2.55 (s, 3H), 3.98 (s, 3H), 7.47 (d, 1 H), 8.05 (m, 1 H), 8.64 (d, 1 H).

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Abstract

L'invention porte: sur des composés substitués de phénylsulfamoyle, des préparations pharmaceutiques les contenant, et l'utilisation desdits composés comme agonistes du récepteur PPAR; sur des activateurs alpha du PPAR, des préparations pharmaceutiques les contenant, et l'utilisation desdits composés pour élever les niveaux de certains lipides plasmiques dont le cholestérol HDL, et abaisser le niveau de certains lipides plasmiques dont le cholestérol LDL et les triglycérides. L'invention peut par conséquent traiter les maladies exacerbées par de faibles niveaux de cholestérol HDL et des niveaux élevés de cholestérol LDL et de triglycérides, telles que athérosclérose et les troubles cardio-vasculaires, chez les mammifères dont l'homme. Ces composés s'avèrent en outre utiles pour traiter le bilan énergétique négatif et les maladies associées des ruminants.
PCT/IB2007/000256 2006-02-06 2007-01-23 Composés substitués de phénylsulfamoyle agonistes du ppar WO2007091140A1 (fr)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2010125831A1 (fr) * 2009-05-01 2010-11-04 Raqualia Pharma Inc. Dérivés d'acide sulfamoyl benzoïque en tant qu'antagonistes de trpm8
WO2012004748A1 (fr) 2010-07-08 2012-01-12 Wyeth Llc Nouveaux esters de quinoléine utiles pour le traitement de troubles cutanés
US8383827B2 (en) 2009-05-15 2013-02-26 Novartis Ag Aryl pyridine as aldosterone synthase inhibitors
US10287282B2 (en) 2014-12-31 2019-05-14 Angion Biomedica Corp. Methods and agents for treating disease
US11459319B2 (en) 2014-08-11 2022-10-04 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof

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GB2295616A (en) * 1994-12-01 1996-06-05 Zeneca Ltd N-Diazine-benzenesulphonamide derivatives as endothelin receptor antagonists
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010125831A1 (fr) * 2009-05-01 2010-11-04 Raqualia Pharma Inc. Dérivés d'acide sulfamoyl benzoïque en tant qu'antagonistes de trpm8
US8383827B2 (en) 2009-05-15 2013-02-26 Novartis Ag Aryl pyridine as aldosterone synthase inhibitors
US8519142B2 (en) 2009-05-15 2013-08-27 Novartis Ag Aryl pyridine as aldosterone synthase inhibitors
US8809545B2 (en) 2009-05-15 2014-08-19 Novartis Ag Aryl pyridine as aldosterone synthase inhibitors
WO2012004748A1 (fr) 2010-07-08 2012-01-12 Wyeth Llc Nouveaux esters de quinoléine utiles pour le traitement de troubles cutanés
US11459319B2 (en) 2014-08-11 2022-10-04 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
US10287282B2 (en) 2014-12-31 2019-05-14 Angion Biomedica Corp. Methods and agents for treating disease
US10851095B2 (en) 2014-12-31 2020-12-01 Angion Biomedica Corp. Methods and agents for treating disease
US11434234B2 (en) 2014-12-31 2022-09-06 Angion Biomedica Corp. Methods and agents for treating disease

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