EP1622872A1 - 1,2,4-substituierte 1,2,3,4-tetrahydro- und 1,2 dihydro-chinolin und 1,2,3,4-tetrahydrochinoxalinderivate als cetp-inhibitoren zur behandlung von atherosklerose und obesitas - Google Patents

1,2,4-substituierte 1,2,3,4-tetrahydro- und 1,2 dihydro-chinolin und 1,2,3,4-tetrahydrochinoxalinderivate als cetp-inhibitoren zur behandlung von atherosklerose und obesitas

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Publication number
EP1622872A1
EP1622872A1 EP04720668A EP04720668A EP1622872A1 EP 1622872 A1 EP1622872 A1 EP 1622872A1 EP 04720668 A EP04720668 A EP 04720668A EP 04720668 A EP04720668 A EP 04720668A EP 1622872 A1 EP1622872 A1 EP 1622872A1
Authority
EP
European Patent Office
Prior art keywords
trifluoromethyl
methyl
bis
phenyl
optionally
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04720668A
Other languages
English (en)
French (fr)
Inventor
George Pfizer Global R & D CHANG
Mary Theresa Pfizer Global R & D DIDIUK
Jari Ilmari Pfizer Global R & D FINNEMAN
Ravi Shanker Pfizer Global R & D GARIGIPATI
Ryan Michael Pfizer Global R & D KELLEY
David Austen Pfizer Global R & D PERRY
Roger Benjamin Pfizer Global R & D RUGGERI
Bruce Michael Pfizer Global R & D BECHLE
Michael P. Pollastri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Products Inc
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Pfizer Products Inc
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Filing date
Publication date
Application filed by Pfizer Products Inc filed Critical Pfizer Products Inc
Publication of EP1622872A1 publication Critical patent/EP1622872A1/de
Withdrawn legal-status Critical Current

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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P39/00—General protective or antinoxious agents
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    • A—HUMAN NECESSITIES
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • This invention relates to quinoline and quinoxaline compounds, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein (HDL)-cholesterol and to lower certain other plasma lipid levels, such as low density lipoprotein (LDL)-cholesterol and triglycerides and accordingly to treat diseases which are affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in certain mammals (i.e., those which have CETP in their plasma), including humans.
  • HDL high density lipoprotein
  • LDL low density lipoprotein
  • Atherosclerosis and its associated coronary artery disease is the leading cause of mortality in the industrialized world.
  • CAD coronary artery disease
  • CHD cardiovascular disease
  • dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations.
  • cholesteryl ester transfer protein activity affects all three.
  • the net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.
  • C3 is carbon
  • J is nitrogen or carbon, wherein if J is carbon, then the bond between C3 and J is a single or double bond and if J is nitrogen, then the bond between C3 and J is a single bond;
  • R 1 is Y, W-X or W-Y 1 ; wherein W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is -O-Y, -S-Y, -N(H)-Y or -N-(Y) 2 ; Y for each occurrence is independently Z or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono- substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon
  • R 2 is a partially saturated, fully saturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen and sulfur, and said carbon is optionally mono-, di- or tri- substituted independently with halo, said carbon chain is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo,; or said R 2 is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to two heteroatoms selected independently from oxygen and sulfur, wherein said R 2 ring is optionally attached through (C C 4 )alkyl; wherein said R 2 ring is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C C 6 ) alkyl,
  • R 3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain containing C4a, wherein C4a is a carbon atom that connects to J, wherein each carbon in the carbon chain may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono- substituted with oxo or nitrogen, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with hydrogen or oxo, and said carbon chain is mono, di-, or tri-substituted with V at C4a or the R 3 carbon adjacent to C4a; provided that in R 3 , when J is carbon, it is other than C4a that is optionally replaced with one heteroatom; and provided that in R 3 , when J is
  • R 4 and R 5 , R 5 and R 6 , and/or R 6 and R 7 may optionally be taken together and can form at least one ring that is a partially saturated or fully unsaturated four to eight membered ring optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein each ring formed by R 4 and R 5 , or R 5 and R 6 , and/or R 6 and R 7 is optionally mono-, di- or tri-substituted independently with halo, (C C 6 )alkyl, (C C 4 )alkylsulfonyl, (C 2 -C 6 )alkenyl, hydroxy, (C C 6 )alkoxy, (C C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C C 6 )alkylamino wherein said (C C 6 )alky
  • X is -O-Y
  • Y for each occurrence is independently (C C 6 )alkyl, said (CrC 6 )alkyl optionally having one to nine fluorines or said (C C 6 )alkyl optionally mono- substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C C 4 )alkyl, (CrC )alkoxy, (C 1 -C 4 )alkylthio, nitro, cyano, oxo, or (C C 4 )alkyloxycarbonyl, said (C- ⁇ -C 4 )alkyl optionally substituted with from one to nine fluorines;
  • R 2 is a partially saturated, fully saturated or fully unsaturated (C C 4 ) straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one heteroatom selected independently from oxygen and sulfur wherein said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon chain is optionally mono-substituted with oxo, said carbon is optionally mon-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo,; or said R 2 is a partially saturated, fully saturated or fully unsaturated three to five membered ring optionally having one heteroatom selected independently from oxygen and sulfur; wherein said R 2 ring is optionally mono-, di- or tri-substituted independently with halo or (C C 6 )alkoxy; wherein R 3 is -CH 2 NR 8 R 9 or -C(O)NR 8 R 9 ; wherein R 8 and R 9 are independently hydrogen or a
  • R 5 and R 6 are each independently hydrogen, halo, T, (C C 6 )alkoxy or (C C 6 )alkyl, said (C C 6 )alkoxy or (C C 6 )alkyl substituent optionally having from one to nine fluorines or said (C r C 6 )alkoxy or (C C 6 )alkyl substituent optionally mono- substituted with T; wherein T is a partially saturated, fully saturated or fully unsaturated five to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said T substituent is optionally mono-, di- or tri-substituted independently with halo, (C C 6 )alkyl, hydroxy, (C ⁇ -C 6 )alkoxy, (CrC 4 )alkylthio, amino, oxo, carboxy, (CrC 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C ⁇ -C 6 )
  • R 7 is hydrogen; or a pharmaceutically acceptable salt or prodrug thereof.
  • C3 is carbon
  • n is zero if the bond between C3 and J is a double bond or one if the bond between C3 and J is a single bond;
  • R 2 is (C C 4 )alkyl, cyclopropyl or cyclobutyl;
  • R 5 is CF 3 ;
  • R 6 is hydrogen;
  • R 10 is a fully saturated (C C 4 ) straight or branched carbon chain;
  • R 11 js halo, hydroxy, -C(O)(O(C C 4 )alkyl), -C(O)C(O)(O(C C 4 )alkyl), - C(O)NH(O(C 1 -C 4 )alkyl), or -C(0)N((C C 4 )alkyl)(O(CrC 4 )alkyl);
  • R 12 is hydrogen or halo, wherein R 1 is not halo when R 12 is halo; or R 11 and R 12 are taken together to form oxo or N 2 ; or a pharmaceutically acceptable salt or prodrug thereof.
  • the present invention provides methods for treating atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial- hypercholesterolemia or myocardial infarction in a mammal by administering to a mammal in need of such treatment an atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction treating amount of a compound of the present invention, or a pharmaceutically acceptable form of said compound.
  • compositions which comprise a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable form of said compound and a pharmaceutically acceptable vehicle, diluent or carrier.
  • the present invention provides pharmaceutical compositions for the treatment of atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction in a mammal which comprise a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable form of said compound and a pharmaceutically acceptable vehicle, diluent or carrier.
  • the present invention provides pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of the present invention, or a pharmaceutically acceptable form of said compound; a second compound, said second compound being an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant (preferably an HMG-CoA reductase inhibitor, a PPAR modulator, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin); and
  • composition may be used to treat the aforementioned diseases, including atherosclerosis.
  • the present invention provides a kit 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 claim 1 , 8, 12, or 13, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, a second therapeutic agent comprising a therapeutically effective amount of an HMG CoA reductase inhibitor, a PPAR modulator, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion- exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier and directions for administration of said first and second agents to achieve the therapeutic effect.
  • 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, i ⁇ , 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 (i.e., 1 ,1 '-methylene-bis-(2-hydroxy-3- naphthoate)) salts.
  • pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nit
  • 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 (e.g., potassium and sodium) and alkaline earth metal cations (e.g., 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.
  • 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.
  • trans 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).
  • Beta refers 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-labeled 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-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 4 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., 3 H), and carbon-14 (i.e., 14 C), isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically 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.
  • mammals is meant to refer to all mammals which contain CETP in their plasma, for example, rabbits and primates such as monkeys and humans, including males and females. Certain other mammals e.g., dogs, cats, cattle, goats, sheep and horses do not contain CETP in their plasma and so are not included herein.
  • treating includes preventative (e.g., prophylactic) and palliative treatment.
  • 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.g., cis and trans isomers) and all optical isomers (e.g., 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 (C C )alkyl, (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 4 to
  • Exemplary five to six membered aromatic rings optionally having one or two heteroatoms selected independently from oxygen, nitrogen and sulfur include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl.
  • Exemplary partially saturated, fully saturated or fully unsaturated five to eight membered rings optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl.
  • Further 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 ,2,4-triazolyl, 1 ,
  • FIG. 1 For exemplary six membered rings, include 2H-pyranyl, 4H-pyranyl, pyridinyl, 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, H-1 ,2-oxazinyl, 2H-1 ,3-oxazinyl, 6H-1.3- oxazinyl, 6H-1 ,2-oxazinyl, 1 ,4-oxazinyl, 2H-1 ,2-oxazinyl, 4
  • FIG. 1 Further exemplary eight membered 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
  • alkylene saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of two adjacent carbons.
  • exemplary of such groups are methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene).
  • halo or halogen is meant chloro, bromo, iodo, or fluoro.
  • alkyl is meant straight chain saturated hydrocarbon or branched chain saturated hydrocarbon.
  • alkyl groups 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.
  • Alkenyl referred to herein may be linear or branched, and they may also be cyclic (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl) or bicyclic or contain cyclic groups. 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.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy .
  • the term "mono-N-" or "di-N,N-(CrC x )alkyl" refers to the (C
  • C x )alkyl moiety taken independently when it is di-N,N-(CrC x )alkyl (x refers to integers).
  • references to a "nitrogen... di-substituted with oxo" herein refer to a terminal nitrogen which constitutes a nitro functionality. It is to be understood that if 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
  • the term “thienyl” means 2- or 3-thienyl, and so forth.
  • DTT means dithiothreitol.
  • DMSO means dimethyl sulfoxide.
  • EDTA means ethylenediamine tetraacetic acid.
  • reaction-inert solvent and “inert solvent” refer to a solvent or a mixture thereof which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • W is carbonyl
  • X is -O-Y; Y for each occurrence is independently (C ⁇ -C 6 )alkyl, said (C-i-C 6 )alkyl optionally having one to nine fluorines or said (CrC 6 )alkyl optionally mono-substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C r C )alkyl, (C C 4 )alkoxy, (C C 4 )alkylthio, nitro, cyano, oxo, or (C C 4 )alkyloxycarbonyl, said (C C 4 )alkyl or (C -C 4 )alkoxy is optionally substituted with from one to nine fluorines;
  • R 2 is beta and is a partially saturated, fully saturated or fully unsaturated (C-,- C ) straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one heteroatom selected independently from oxygen and sulfur wherein said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon chain is optionally mono- substituted with oxo or hydroxy, said sulfur is optionally mono- or di-substituted with oxo,; or said R 2 is a partially saturated, fully saturated or fully unsaturated three to five membered ring optionally having one heteroatom selected independently from oxygen and sulfur; wherein said R 2 ring is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C C 6 )alkoxy, amino, nitro, (CrC 4 )alkyloxycarbonyl or carboxy; wherein R 3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered
  • R 4 is hydrogen
  • R 5 and R 6 are each independently hydrogen, halo, T, (CrC 6 )alkoxy or (C C 6 )alkyl, said (C r C 6 )alkoxy or (C C 6 )alkyl substituent optionally having from one to nine fluorines or said (C C 6 )alkoxy or (C 1 -C 6 )alkyl substituent optionally mono- substituted with T; wherein T is a partially saturated, fully saturated or fully unsaturated five to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said T substituent is optionally mono-, di- or tri-substituted independently with halo, (C C 6 )alkyl, hydroxy, (C C 6 )alkoxy, (C C 4 )alkylthio, amino, oxo, carboxy, (C C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C C 6 )alky
  • R 7 is hydrogen
  • Y is (C ⁇ -C 4 )alkyl, wherein said (C r C 4 )alkyl substituent optionally has one to nine fluorines;
  • R 2 is (CrC 4 )alkyl, cyclopropyl or cyclobutyl;
  • R 3 is -((C C 4 )alkyl)(NH 2 )(V), -((C 1 -C 3 )alkyl)(NH(C 1 -C 2 )alkyl))(V), -((C C 4 )alkyl)(OH)(V), -((C C 4 )alkyl)(F)(V), -((C 1 -C 2 )alkyl)(O-C(O)(C 1 -C 2 )alkyl)(V), -C(O)- V, -C(OH)(C(O)O(C C 3 )alkyl)(V), -CF 2 (V), -((C 1 -C 2 )alkyl)(NHC(O)(C 1 -C 2 )alkyl)(V), - CH 2 (V), -((C 1 -C 2 )alkyl)(C(O)O(C 1 -C 2 )al
  • V is phenyl optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, hydroxy, (CrC 6 )alkoxy, nitro, cyano or oxo wherein said (CrC ⁇ alkyl or (C 1 -C 6 )alkoxy substituent optionally has from one to nine fluorines;
  • R 5 and R 6 are each independently hydrogen, halo, (C C 3 )alkoxy or (C C 6 )alkyl, said (C C 3 )alkoxy optionally having from one to seven halo, said (C C 6 )alkyl optionally having from one to nine halo.
  • Y is methyl, ethyl, 1-propyl, 2-propyl or tert-butyl;
  • R 2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl;
  • R 3 is -C(O)-V, -C(OH)(C(O)OCH 3 )(V), -CH(F)(V), -CF 2 (V), -CH(OCH 3 )(V), - CH(C(O)OCH 3 )(V), -CH(CN)(V), -CH(OH)(V), -CH 2 (V), -CH(NH 2 )(V), - CH(NH(CH 3 ))(V), -CH(C(O)NH 2 )(V), -CH(CH 2 OH)V, -CH(CH 2 OCH 3 )V, - CH(CH 2 OC(O)CH 3 )V, -CH(CH 2 F)V, or -CH(CH 2 NH 2 )V; and
  • V is phenyl optionally mono-, di- or tri-substituted independently with halo, nitro, or (CrC 2 )alkyl, wherein said (C C 2 )alkyl optionally has from one to five fluorines;
  • R 5 and R 6 are each independently hydrogen, methyl, methoxy or chloro; said methoxy optionally having from one to three fluorines, said methyl optionally having from one to three fluorines.
  • formula I compounds include substituents wherein
  • V is ethyl
  • R 2 is ethyl or methyl
  • R 3 is (3,5-bis-(trifluoromethyl)-phenyl)-hydroxy-methoxycarbonyl-methyl; (3,5- bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl; (3,5-bis-trifluoromethyl-phenyl)- cyano-methyl, 3,5-bis-trifluoromethyl-benzoyl; (3,5-bis-trifluoromethyl-phenyl)- hydroxy-methyl; (3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl; (3,5-bis- trifluoromethyl-phenyl)-difluoro-methyl; (3,5-bis-(trifluoromethyl)-benzyl); (3,5-bis- trifluoromethyl-phenylcarbamoyl)-methyl; amino-(3,5-bis-(trifluoromethyl)-phenyl)- methyl; (3,5-bis-(trifluoromethyl)-phenyl)-methyl
  • R 5 is methoxy or trifluoromethyl
  • R 6 is hydrogen or methoxy.
  • the bond between C3 and J is a single bond.
  • the bond between C3 and J is a double bond.
  • the compounds of formula I are selected from the group consisting of: (R, R, S)-4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2r-/-quinoline-1 -carboxylic acid ethyl ester;
  • J is nitrogen; the bond between C3 and J is a single bond;
  • R 1 is W-X
  • W is carbonyl
  • X is -O-Y; Y for each occurrence is independently (d-C- ⁇ Jalkyl, said (C C 6 )alkyl optionally having one to nine fluorines or said (CrG 6 )alkyl optionally mono- substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C C )alkyl, (C C 4 )alkoxy, (d-C 4 )alkylthio, nitro, cyano, oxo, or (C C 4 )alkyloxycarbonyl, said (C C 4 )alkyl or (C C 4 )alkoxy optionally substituted with from one to nine fluorines; R 2 is a partially saturated, fully saturated or fully unsaturated (C r C 4 ) straight
  • V is a five or six membered partially saturated, fully saturated or fully unsaturated ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen such that V is not imidazolyl or a fully saturated heterocyclic nitrogen-containing ring wherein nitrogen of the ring is connected to the R 3 group; wherein said V ring is optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (CrC 6 )alkyl, hydroxy, (C C 6 )alkoxy, (C C 6 )alkoxycarbonyl, nitro, cyano or oxo, wherein said (C C 6 )alkyl or (C C 6 )alkoxy substituent optionally has from one to nine fluorines; R 4 is hydrogen;
  • R 5 and R 6 are each independently hydrogen, halo, T, (C C 6 )alkoxy or (C C 6 )alkyl, said (C C 6 )alkoxy or (C C 6 )alkyl substituent optionally having from one to nine fluorines or said (C r C 6 )alkoxy or (C C 6 )alkyl substituent optionally mono- substituted with T; wherein T is a partially saturated, fully saturated or fully unsaturated five to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said T substituent is optionally mono-, di- or tri-substituted independently with halo, (C C 6 )alkyl, hydroxy, (C C 6 )alkoxy, (C C )alkylthio, amino, oxo, carboxy, (C ⁇ -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(CrC 6 )alkylamin
  • R 7 is hydrogen.
  • Y is (C r C 4 )alkyl, wherein said (C C 4 )alkyl substituent optionally has one to nine fluorines;
  • R 2 is (C C 4 )alkyl, cyclopropyl or cyclobutyl;
  • R 3 is -C(O)-V, -CH(C(O)O(C C 3 )alkyl)(V), or -CH(CN)(V);
  • V is phenyl optionally mono-, di- or tri-substituted independently with halo,
  • (C 1 -C 6 )alkyl hydroxy, (C 1 -C 6 )alkoxy, nitro, cyano or oxo wherein said (C C 6 )alkyl substituent optionally has from one to nine fluorines;
  • R 5 and R 6 are each independently hydrogen, (C ⁇ -C 3 )alkoxy or (CrC 6 )alkyl, said (C C 3 )alkoxy optionally having from one to nine fluorines, said (C- ⁇ -C 6 )alkyl optionally having from one to seven fluorines; or a pharmaceutically acceptable salt thereof.
  • Y is methyl, ethyl, 1-propyl, 2-propyl or tert-butyl;
  • R 2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl;
  • R 3 is 3,5-bis-trifluoromethyl-benzoyl, (3,5-bis-trifluoromethyl-phenyl)-cyano- methyl, or (3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl;
  • R 5 is methyl or trifluoromethyl
  • R 6 is hydrogen or methyl.
  • the compound is selected from the group consisting of:
  • one embodiment of the present invention includes a method for treating atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction in a mammal by administering to a mammal in need of such treatment an atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial- hypercholesterolemia or myocardial infarction treating amount of a compound of formula I or II, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
  • Atherosclerosis is treated.
  • peripheral vascular disease is treated.
  • dyslipidemia is treated.
  • hyperbetalipoproteinemia is treated.
  • hypoalphalipoproteinemia is treated.
  • familial-hypercholesterolemia is treated.
  • the present invention includes a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula I or II, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable vehicle, diluent or carrier.
  • the present invention is a pharmaceutical composition for the treatment of atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction in a mammal which comprises a therapeutically effective amount of a compound of formula I or II, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable vehicle, diluent or carrier.
  • the present invention is a pharmaceutical composition for the treatment of atherosclerosis in a mammal which comprises an atherosclerosis treating amount of a compound of formula I or II, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable vehicle, diluent or carrier.
  • the present invention includes a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising: a first compound, said first compound being a compound of formula I or II, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; a second compound, said second compound being an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant; and a pharmaceutical vehicle, diluent or carrier.
  • the present invention includes a pharmaceutical combination composition wherein the second compound is an HMG-CoA reductase inhibitor or a PPAR modulator.
  • the present invention includes a pharmaceutical combination composition wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.
  • the present invention includes a pharmaceutical combination composition further comprising a cholesterol absorption inhibitor.
  • the cholesterol absorption inhibitor is ezetimibe.
  • One further embodiment of the present invention includes a method 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), a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and a second compound, said second compound being an HMG CoA reductase inhibitor, a PPAR modulator, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant; wherein the amounts of first and second compounds result in a therapeutic effect.
  • the present invention includes a method for treating atherosclerosis wherein the second compound is an HMG-CoA reductase inhibitor or a PPAR modulator. In another embodiment, the present invention includes a method for treating atherosclerosis wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.
  • the present invention includes a method for treating atherosclerosis wherein the method further comprises administering a cholesterol absorption inhibitor.
  • the cholesterol absorption inhibitor is ezetimibe.
  • a further embodiment of the present invention includes a kit 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 claim 1 , 8, 12, or 13, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, a second therapeutic agent comprising a therapeutically effective amount of an HMG CoA reductase inhibitor, a PPAR modulator, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier and directions for administration of said first and second agents to achieve the therapeutic effect.
  • the present invention includes a kit wherein said second compound is an HMG-CoA reductase inhibitor or a PPAR modulator
  • the present invention includes a kit wherein said second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.
  • the present invention includes a kit that further comprises a cholesterol absorption inhibitor.
  • the cholesterol absorption inhibitor is ezetimibe.
  • Specific compounds of formula III include: 2-Ethyl-4-iodo-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; 2-Ethyl-4-iodo-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; 4-Chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
  • the compounds of this invention can be made by processes which 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. Analogous processes are disclosed in the following U.S. patents, which are hereby incorporated by reference herein in their entirety: U.S. Patent 6,140,342; U.S. Patent 6,362,198; U.S. Patent 6,147,090; U.S. Patent 6, 395,751 ; U.S. Patent 6,147,089; U.S. Patent 6,310,075; U.S. Patent No. 6,197,786; U.S. Patent 6,140,343; U.S. Patent 6,489,478; and International Publication No. WO 00/17164.
  • reaction Scheme 1 the desired compounds wherein J is carbon, the optional double bond is absent, R 3 is a group CH(V)(L) wherein L is a (C C 6 ) alkoxycarbonyl group and V, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above (depicted in Scheme 1 as Formula II compounds) may be prepared as a mixture of diastereoisomers from the corresponding Scheme 1 , Formula III compounds by reduction of the double bond or L is R 3 as defined herein.
  • This may be achieved by hydrogenation in a reaction inert solvent such as methanol, ethanol or acetic acid with a catalyst such as palladium or rhodium on carbon under a hydrogen pressure equal to 15-50 psi for a period between 2-24hrs, or by transfer hydrogenation using ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a temperature between 0°C to 80°C, typically 25°C to 60°C.
  • This method of preparing these particular Formula I compounds typically provides a preponderance of those diastereoisomers in which the R 2 and R 3 groups are cis to one another.
  • the desired Formula III compounds wherein L, V, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula IV compounds by removal of the hydroxyl group.
  • This may be achieved by treatment with a chlorinating agent such as phosphorus (III) chloride or thionyl chloride in a reaction inert solvent such as methylene chloride or chloroform optionally containing a base such as pyridine, diisopropylethylamine or 2,6-di-tert- butyl-4-methylpyridine at a temperature between 0°C to 60°C, typically ambient, for a period between 1 to 24hr.
  • a chlorinating agent such as phosphorus (III) chloride or thionyl chloride
  • a reaction inert solvent such as methylene chloride or chloroform
  • a base such as pyridine, diisopropyleth
  • the chloro-derivative thus formed is then treated with a finely divided metal such as zinc in the presence of an acid, or mixture of acids, such as acetic acid or hydrochloric acid in a suitable solvent, or mixture of solvents such as methanol, water or tetrahydrofuran at a temperature between 25°C to 60°C, typically ambient, to provide the desired product of Formula III.
  • a finely divided metal such as zinc in the presence of an acid, or mixture of acids, such as acetic acid or hydrochloric acid in a suitable solvent, or mixture of solvents such as methanol, water or tetrahydrofuran at a temperature between 25°C to 60°C, typically ambient, to provide the desired product of Formula III.
  • the desired Formula IV compounds wherein L is a (C C 6 ) alkoxycarbonyl group and V, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula V compounds by reaction with a suitable organometallic derivative of the V group such as a magnesium or lithium derivative, prepared in turn from a compound V-Hal where Hal represents a chlorine, bromine or iodine atom, using methods well known to those skilled in the art, for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995.
  • This reaction is conducted in a suitable reaction inert solvent such tetrahydrofuran or diethyl ether at a temperature between -78°C to 25°C, typically -78°C, to provide the desired product of Formula IV.
  • -C 6 ) alkoxycarbonyl group and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula VI compounds by reaction with an acyl compound KCOL wherein K is a leaving group such as chlorine or bromine, at a temperature between 0°C to 25°C, typically ambient, in a reaction inert solvent such as acetonitrile or toluene optionally in the presence of a base such as diisopropylethylamine or triethylamine to remove traces of HK which may be present.
  • the Formula V compound may be obtained as a mixture with the corresponding Formula VII compound.
  • the desired Formula VI compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula VIII compounds by reaction with a suitable oxidizing agent, typically manganese (IV) oxide, in a suitable reaction inert solvent such as diethyl ether at a temperature between 0°C to 25°C, typically ambient. Since this reaction produces an equivalent of water, which may be deleterious in the subsequent step, this may optionally be removed by addition of a solvent suitable for the next reaction such as acetonitrile or toluene and evaporation of the solvent mixture to a volume somewhat less than that of the added solvent, but not to dryness.
  • a suitable oxidizing agent typically manganese (IV) oxide
  • the desired Formula VIII compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula IX compounds by reaction with hydrazine hydrate in a suitable reaction inert solvent such as ethanol or toluene at a temperature between 25°C to 180°C, typically 80°C to 170°C.
  • a suitable reaction inert solvent such as ethanol or toluene
  • the hydrazone formation may be assisted by continuous removal of water, such as by the use of a Dean-Stark apparatus, or by heating in a closed vessel to a temperature beyond the boiling point of the solvent such as by a microwave oven.
  • (C C 6 ) alkoxycarbonyl group and V, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be accomplished from the corresponding Formula X compounds by treatment with a chlorinating agent such as phosphorus (III) chloride or thionyl chloride in a reaction inert solvent such as methylene chloride or chloroform optionally containing a base such as pyridine, diisopropylethylamine or 2,6-di-tert-butyl-4- methylpyridine at a temperature between 0°C to 60°C, typically ambient, for a period between 1 to 24hr.
  • a chlorinating agent such as phosphorus (III) chloride or thionyl chloride
  • a reaction inert solvent such as methylene chloride or chloroform
  • a base such as pyridine, diisopropylethylamine or 2,6-di-tert-butyl-4- methyl
  • the chloro-derivative thus formed as a mixture of diastereoisomers is then treated with a finely divided metal such as zinc in the presence of an acid, or mixture of acids, such as acetic acid or hydrochloric acid in a suitable solvent, or mixture of solvents such as methanol, water or tetrahydrofuran at a temperature between 25°C to 60°C, typically ambient, to provide the desired product of Formula II.
  • a finely divided metal such as zinc in the presence of an acid, or mixture of acids, such as acetic acid or hydrochloric acid in a suitable solvent, or mixture of solvents such as methanol, water or tetrahydrofuran at a temperature between 25°C to 60°C, typically ambient, to provide the desired product of Formula II.
  • the desired Formula X compounds wherein L is a (C ⁇ -C 6 ) alkoxycarbonyl group and V, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula XI compounds by reaction with a suitable organometallic derivative of the V group such as a magnesium or lithium derivative, prepared in turn from a compound V-Hal where Hal represents a chlorine, bromine or iodine atom, using methods well known to those skilled in the art, for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995.
  • This reaction is conducted in a suitable reaction inert solvent such tetrahydrofuran or diethyl ether at a temperature between -78°C to 25°C, typically -78°C, to provide the desired product of Formula X.
  • a suitable reaction inert solvent such tetrahydrofuran or diethyl ether at a temperature between -78°C to 25°C, typically -78°C.
  • the desired Formula XI compounds wherein L is a (C C 6 ) alkoxycarbonyl group and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula V compounds by reduction of the double bond.
  • This may be achieved by hydrogenation in a reaction inert solvent such as methanol, ethanol or acetic acid with a catalyst such as palladium or rhodium on carbon under a hydrogen pressure equal to 15-50 psi for a period of 2-24hrs, or by transfer hydrogenation using ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a temperature between 0°C to 80°C, typically 25°C to 60°C.
  • An alternative preparation of the desired Formula X compounds wherein L is a (C ⁇ -C 6 ) alkoxycarbonyl group and V, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula XII compounds, wherein K is a leaving group such as chlorine or bromine, by hydrogenation in a reaction inert solvent such as methanol, ethanol or acetic acid with a catalyst such as palladium or rhodium on carbon under a hydrogen pressure equal to 15-50 psi for a period between 2-24hrs, or by transfer hydrogenation using ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a temperature between 0°C to 80°C, typically 25°C to 60°C to provide the desired product of Formula X.
  • a reaction inert solvent such
  • This may be accomplished by hydrogenation in a reaction inert solvent such as methanol, ethanol or acetic acid with a catalyst such as palladium or rhodium on carbon under a hydrogen pressure equal to 15-50 psi for a period between 2-24hrs, or by transfer hydrogenation using ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a temperature between 0°C to 80°C, typically 25°C to 60°C to provide the desired product of Formula X.
  • a reaction inert solvent such as methanol, ethanol or acetic acid
  • a catalyst such as palladium or rhodium on carbon
  • An alternative method of reduction involves treatment with diimide which is generated in situ in a reaction-inert solvent in the presence of the Formula IV compounds by a number of methods known to those skilled in the arts, such as those described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995.
  • the desired Formula XII compounds wherein L is a (C C 6 ) alkoxycarbonyl group, K is a leaving group such as chlorine or bromine, and V, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula VII compounds by reaction with a suitable organometallic derivative of the V group such as a magnesium or lithium derivative, prepared in turn from a compound V-Hal where Hal represents a chlorine, bromine or iodine atom.
  • This reaction is conducted in a suitable reaction inert solvent such tetrahydrofuran or diethyl ether at a temperature between -78°C to 25°C, typically - 78°C, to provide the desired product of Formula XII.
  • a suitable reaction inert solvent such tetrahydrofuran or diethyl ether
  • the desired Formula VII compounds wherein L is a (C C 6 ) alkoxycarbonyl group, K is a leaving group such as chlorine or bromine, and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula VI compounds by reaction with an acyl compound KCOL at a temperature between 0°C to 25°C, typically ambient, in a reaction inert solvent such as acetonitrile or toluene, optionally in the presence of a base such as diisopropylethylamine or triethylamine to remove traces of HK which may be present.
  • the Formula VII compound may be obtained as a mixture with the corresponding Formula V compound.
  • the desired Formula XIII compounds wherein M is a (C C 6 ) alkoxy group and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula VI compounds by reaction with phosgene at a temperature between 0°C to 25°C, typically ambient, in a reaction inert solvent such as acetonitrile or toluene in the presence of a base such as diisopropylethylamine or triethylamine. Addition of the desired alcohol MOH to the acid chloride in the presence of excess base then provides the desired Formula XIII compound.
  • This may be achieved by hydrogenation in a reaction inert solvent such as methanol, ethanol or acetic acid with a catalyst such as palladium or rhodium on carbon under a hydrogen pressure equal to 15-50 psi for a period between 2- 24hrs, or by transfer hydrogenation using ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a temperature between 0°C to 80°C, typically 25°C to 60°C.
  • the Formula XIII compounds may be treated with a finely divided metal such as zinc in the presence of an acid, or mixture of acids, such as acetic acid or hydrochloric acid in a suitable solvent, or mixture of solvents such as methanol, water or tetrahydrofuran at a temperature between 25°C to 60°C, typically ambient, to provide the desired Formula XIV compounds.
  • a finely divided metal such as zinc
  • an acid, or mixture of acids such as acetic acid or hydrochloric acid
  • suitable solvent such as methanol, water or tetrahydrofuran
  • aqueous base preferably, lithium, sodium, or potassium hydroxide
  • a polar solvent preferably dioxane
  • R 3 is a group CH(V)(L) wherein L is a (C r C 6 ) alkoxycarbonyl group or a cyano group and V, R , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above (depicted as Formula XVI compounds) may be prepared as a mixture of diastereoisomers from the corresponding Formula XVII compounds by reaction with a compound VCH 2 L in the presence of a suitable base such as 1 ,8- diazab ' ⁇ cyclo[5.4.0]undec-7-ene , diisopropylethylamine, triethylamine or sodium hydride in a reaction inert solvent such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile or toluene at a temperature between 0°C to 60°C, typically ambient
  • the desired Formula XVII compounds wherein Q is a leaving group such as chlorine, bromine, methanesulfonyloxy or p-toluenesulfonyloxy and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula XVIII compounds by reaction with the appropriate reagent such as methanesulfonyl chloride or toluenesulfonyl chloride in the presence of a suitable base such as diisopropylethylamine or triethylamine in a reaction inert solvent such as N,N-dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride or toluene at a temperature between 0°C to 60°C, typically ambient.
  • a suitable base such as diisopropylethylamine or triethylamine
  • Suitable reagents for formation of the Formula XVII compounds include phosphorus (III) chloride, phosphorus (III) bromide and thionyl chloride optionally in a reaction inert solvent such as chloroform, methylene chloride, pyridine or toluene at a temperature between 0°C lo 60°C, typically ambient.
  • the desired Formula XVIII compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be obtained by treatment of the corresponding Formula XIX compounds with sodium nitrite in the presence of an acid, preferably acetic acid, followed by hydrolysis with a suitable base such as lithium, sodium, or potassium hydroxide, preferably sodium hydroxide in a suitable hydroxylic solvent such as ethanol to give the desired Formula XIX compounds.
  • a suitable base such as lithium, sodium, or potassium hydroxide, preferably sodium hydroxide in a suitable hydroxylic solvent such as ethanol
  • the desired Formula IX compounds wherein R 1 is an alkoxycarbonyl group and R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding 4-methoxyquinoline compounds of Formula XX by treatment with an organomagnesium derivative of the R 2 group together with an acylating agent such as ethyl chloroformate at a temperature between -100°C to 70°C, typically -78°C in a reaction inert solvent such as tetrahydrofuran followed by warming to a temperature between 0°C and about 70°C (preferably ambient) for between 0.1 and 24hr, preferably 1hr, followed by hydrolysis in aqueous acid, preferably 1 N hydrochloric acid to give the desired Formula IX compounds, as described in US Patent 6197786.
  • an acylating agent such as ethyl chloroformate
  • a reaction inert solvent such as tetrahydrofuran
  • R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be obtained by oxidation of the corresponding Formula XVIII compounds using a variety of methods and reagents well known to those skilled in the arts, such as can be found in L.A.
  • the desired Formula XXI compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 are as described above may be prepared from the corresponding Formula IX compounds by treatment with trimethylsilylcyanide in an inert solvent such as an aromatic hydrocarbon (e.g..benzene, toluene, xylene) in the presence of a catalytic amount of Lewis acid, preferably zinc iodide, at a temperature of about 25 °C to about 140 °C, preferably about 80 °C to about 100 °C, for 1-12 hours , preferably 5 hours.
  • a polar solvent e.g., methanol, ethanol
  • a solution of acid (preferably hydrochloric) in a polar aprotic solvent (preferably dioxane) is added to the solution and the mixture is stirred at a temperature from 0 °C to about 100 °C, preferably room temperature, for 1 to 24 hours, preferably 12 hours, to yield the Formula XXI compounds.
  • a polar aprotic solvent preferably dioxane
  • the desired Formula XXII compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 are as described above may be prepared from the corresponding Formula XXI compounds by treatment with a reducing agent such as sodium borohydride or sodium cyanoborohydride in a reaction inert solvent such as methanol or ethanol, preferably ethanol, at a temperature of about 0 °C to about 100 °C (preferably reflux temperature) for 0.1 to 5 hours (preferably 0.75 hour) to provide the desired Formula XXII compounds.
  • a reducing agent such as sodium borohydride or sodium cyanoborohydride
  • a reaction inert solvent such as methanol or ethanol, preferably ethanol
  • R 7 are as described above may be prepared from the corresponding Formula XVII compounds, wherein Q is a leaving group as described above, by treatment with a cyanide salt such as lithium, sodium, potassium or a tetraalkylammonium cyanide in a reaction inert solvent such as dimethylformamide at a temperature between 0 °C to 100 °C for 1 to 12 hours, to provide the Formula XXII compounds.
  • a cyanide salt such as lithium, sodium, potassium or a tetraalkylammonium cyanide
  • a reaction inert solvent such as dimethylformamide
  • the desired Formula XXIII compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 are as described above may be prepared from the corresponding Formula XXII compounds by dissolving in concentrated sulfuric acid containing five equivalents of water at a temperature from 0°C to 100°C (preferably room temperature) for 1 to 20 hours.
  • the resulting amide is then dissolved in a polar solvent (preferably methylene chloride) and treated with trimethyloxonium tetrafluoroborate at a temperature from 0°C to 100°C (preferably room temperature) for 1-20 hours (preferably 12 hours).
  • the resulting imino ester is then treated with an aqueous base, preferably, lithium, sodium, or potassium hydroxide, in a polar solvent, preferably dioxane, at a temperature between 0°C and 100°C (preferably room temperature) for between 1 to 20 hours to provide the Formula XXIII Compounds.
  • an aqueous base preferably, lithium, sodium, or potassium hydroxide
  • a polar solvent preferably dioxane
  • the desired Formula XXIV compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as described above may be prepared from the corresponding Formula XXIII compounds by treating the acid in a reaction inert solvent (preferably dichloromethane) with the corresponding amine (NHR 8 R 9 ) in the presence of 1- hydroxybenzotriazole hydrate (HOBT) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) at a temperature between 0°C to 100°C (preferably ambient temperature) for 1 to 24 hours (preferably 12 hours).
  • a reaction inert solvent preferably dichloromethane
  • EDCI 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • the desired Formula XXV compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 are as described above and V 2 is a group V or CH 2 V where V is as described above may be prepared from the corresponding Formula XXIV compounds when R 8 is methyl and R 9 is methoxy (the 'Weinreb' amide) by treatment with a variety of V 2 Met compounds where Met is a metal, preferably magnesium or lithium, to produce the desired Formula XXV compounds.
  • the desired Formula XXVI compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 may be prepared from the corresponding Formula XXIV compounds by reduction with a hydride source, preferably sodium borohydride, in the presence of an acid such as trifluoroacetic acid in a reaction inert solvent (preferably tetrahydrofuran) at a temperature of between 0 °C and 100 °C for 1 to 20 hours (preferably 12 hour).
  • a reaction inert solvent preferably tetrahydrofuran
  • the amine may be acylated using standard amide coupling conditions known to those skilled in the art such as those described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995, to produce further Formula XXVI compounds.
  • the desired Formula XXVII compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and V 2 are as described above and X 1 is OH, F, or H, may be prepared from the corresponding Formula XXV compounds by treatment with a reducing agent such as sodium borohydride in a polar solvent such as methanol or ethanol at a temperature of about 0 °C to about 100 °C for 1 to 10 hours (preferably 1 hour) to produce Formula XXVII compounds wherein X 1 is OH.
  • a reducing agent such as sodium borohydride
  • a polar solvent such as methanol or ethanol
  • One skilled in the art can convert NH 2 to NR 1 H by standard reductive amination conditions using the correspounding aldehyde and reducing agent, such as sodium borohydride or sodium cyano borohydrite.
  • NR 1 H can be converted to NR 1 R 2 using the same conditions of reductive amination to produce NR 1 R 2 .
  • X 1 is NH 2
  • the corresponding primary amine NH 2 may be converted to NHR 1 by treatment with ethyl formate at a temperature between 0 °C to 100 °C between 1-24 hours (preferably 12 hours).
  • the resulting formamide is added directly without further purification to a nonpolar solvent (e.g., benzene, toluene, preferably toluene) and a reducing agent such as borane methyl sulfide complex at a temperature between 0 °C to 100 °C between 1-24 hours (preferably 12 hours) to provide the desired mono methyl amine product.
  • a nonpolar solvent e.g., benzene, toluene, preferably toluene
  • a reducing agent such as borane methyl sulfide complex
  • the corresponding primary amine NH 2 may be converted to NHR 1 by standard reductive amination conditions by treatment with an aldehyde R 1 in a polar solvent such as methanol or ethanol in the presence of sodium borohydride or sodium cyanoborohydride at a temperature between 0 °C to 100 °C between 1-24 hours (preferably 12 hours).
  • a polar solvent such as methanol or ethanol
  • sodium borohydride or sodium cyanoborohydride at a temperature between 0 °C to 100 °C between 1-24 hours (preferably 12 hours).
  • X 1 is NR 1 R 2
  • the corresponding secondary amine NHR 1 may be converted to NR 1 R 2 by standard reductive as described above.
  • Compound XXV may also be converted to NH 2 , NHR 1 , and NR R 2 by standard reductive amination conditions with the corresponding aldehyde or ketone as described above. This method produces a mixture of amine diastereomers that
  • Formula XXVI I compounds where X 1 is F may be converted to the corresponding Formula XXVI I compounds where X 1 is F by treatment with a fluorinating agent, such as diethylaminosulfur trifluoride (DAST) or [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxyfluor) in a reaction inert solvent such as dichloromethane or 1 ,2 dichloroethane at a temperature between -78 °C to about 100°C (preferably ambient temperature) for 0.1 to 10 hours (preferably 1 hour).
  • a fluorinating agent such as diethylaminosulfur trifluoride (DAST) or [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxyfluor) in a reaction inert solvent such as dichloromethane or 1 ,2 dichloroethane at a temperature between -78 °C to about 100°C (preferably ambient temperature)
  • Formula XXVII compounds wherein X 1 is H by reduction with a suitable hydride source such as diisobutyl aluminum hydride in a reaction inert solvent such as tetrahydrofuran at a temperature between -78 °C to about 100 °C, preferably about 0 °C, for 0.1 to 10 hours.
  • a suitable hydride source such as diisobutyl aluminum hydride
  • a reaction inert solvent such as tetrahydrofuran
  • the desired Formula XXVIII compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 are as described above and V 2 is a group V or CH 2 V where V is as described above may be prepared from the corresponding Formula XXV compounds by treatment with a fluorinating agent, such as diethylaminosulfur trifluoride (DAST) or [bis(2- methoxyethyl)amino]sulfur trifluoride (Deoxyfluor) in a reaction inert solvent such as dichloromethane or 1 ,2-dichloroethane at a temperature between -78 °C to about 100°C (preferably ambient temperature) for 0.1 to 24 hours (preferably 12 hours).
  • a fluorinating agent such as diethylaminosulfur trifluoride (DAST) or [bis(2- methoxyethyl)amino]sulfur trifluoride (Deoxyfluor) in a reaction inert solvent such as dich
  • the desired Formula XXIX compounds wherein J is nitrogen, the optional double bond is absent, and R 2 , R 4 , R 5 , R 6 , and R 7 are as described above, may be prepared from the corresponding Formula XXX compounds by reaction with an alpha-ketocarboxylic acid R 2 COCO 2 H in a protic solvent, such as ethanol or methanol at high temperature.
  • a protic solvent such as ethanol or methanol
  • These temperatures can be conveniently and safely achieved using a microwave apparatus familiar to one skilled in the art, such as a Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) or Milestone microwave (Milestone Laboratories, Sorisole, Italy).
  • the resulting reaction mixture is concentrated to dryness and the Formula XXIX compounds can be usually crystallized or alternatively can be purified by flash chromatography on silica gel.
  • the desired Formula XXXI compounds wherein R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula XXIX compounds by treatment with a chlorinating agent such as phosphorus (III) chloride, phosphorus (V) oxychloride, thionyl chloride or triphenylphosphine/carbon tetrachloride.
  • a chlorinating agent such as phosphorus (III) chloride, phosphorus (V) oxychloride, thionyl chloride or triphenylphosphine/carbon tetrachloride.
  • Formula XXIX compounds are dissolved in excess phosphorus oxychloride and the mixture is heated to about 100°C, for 12-18h. After cooling excess phosphorus (V) oxychloride is distilled off and the residue is carefully quenched with saturated NaHCO 3 .
  • the resulting aqueous suspension is extracted with an appropriate organic solvent,
  • the desired Formula XXXII compounds wherein R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula XXXI compounds by catalytic hydrogenation in the presence of standard catalysts well known to those skilled in the art, for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995.
  • the compound is dissolved in an organic solvent, preferably a polar solvent such as acetic acid. Additives such as sodium acetate are usually added to improve the reaction rate.
  • An appropriate catalyst is chosen, such as palladium on carbon. Hydrogenation is carried out at elevated pressures in an appropriate apparatus, preferably for about 6 h. The catalyst is filtered off to yield the Formula XXXII compound, which is typically isolated after chromatography on silica gel.
  • the desired Formula XXXIII compounds wherein R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula XXXII compounds by reaction with boc-anhydride as described in the T. W. Greene and G.M. Wuts, Protective Groups in Organic Synthesis, Wiley Interscience, 1991. Typically, the reaction is carried out in a solvent such as methylene chloride at -78°C to 0°C, typically -40°C. In general, in this procedure, there is a selective functionalization of the less hindered nitrogen in Formula XXXII compounds.
  • the Formula XXXIII compounds can be purified by standard silica gel chromatography, if needed.
  • the desired Formula XXXIV compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula XXXIII compounds by introducing the acyl, carbamoyl, sulfinyl or sulfonyl group R 1 .
  • This may be achieved by treatment with an appropriate reagent, for example, ethyl chloroformate or isopropyl chloroformate, in a suitable reaction inert solvent such as methylene chloride or chloroform optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at a temperature between 0°C to 60°C, typically ambient, for a period of 1 to 24hr. At times, the reaction is carried out in pyridine as a solvent.
  • the product is usually isolated by standard extractive workup and flash chromatography on silica gel.
  • the desired Formula XXXV compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula XXXIV compound by treatment with an acid as described in the T. W. Greene and G.M. Wuts, Protective Groups in Organic Synthesis, Wiley Interscience, 1991.
  • the bis-carbamate is treated with trifluoroacetic acid at ambient temperature for 1-24hr, typically 3hr.
  • the acid is removed by evaporation and the residue is partitioned between an organic solvent, preferably methylene chloride and aqueous sodium hydrogen carbonate. Evaporation of the organic solvent affords the desired Formula XXXV compounds.
  • the desired compounds wherein J is nitrogen, the optional double bond is absent, R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are as described above and R 3 is as described above wherein the connecting carbon is oxo substituted (depicted as Formula XXXVI compounds) may be prepared from the corresponding Formula XXXV compounds by reaction with an acid chloride, in a solvent such as methylene chloride or chloroform, optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine, at a temperature between 0°C to 60°C, typically ambient, for a period of 1 to 24hr.
  • a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine
  • the mixture is washed with aqueous acid and brine to afford the Formula XXXVI compounds after silica gel chromatography.
  • the acid chloride can be generated in situ, from the corresponding carboxylic acid and triphenylphosphine in conjunction with agents such as carbon tetrachloride, hexachloroethane or trichloroacetonitrile. This latter procedure can be carried out with resin bound triphenylphosphine which makes it amenable to automated chemistry. Filtration of the resin followed by evaporation and purification on silica gel yields the required compound of Formula XXXVI.
  • the desired Formula XXXVII compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above and R 3 is as described above, wherein the group V is attached to the connecting carbon, may be prepared from the corresponding Formula XXXV compounds by alkylation with the appropriate alkyl bromides. These alkylations are typically carried out in a polar solvent such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone etc. in the presence of a base (e.g., potassium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine, lutidine) at a temperature between 25°C to 200°C, typically 150°C.
  • a base e.g., potassium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine, lutidine
  • Alkylations can be performed with a variety of alkyl bromides, such as arylmethyl bromides or alpha-substituted arylmethyl bromides.
  • suitable microwave equipment such as the Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) or Milestone microwave (Milestone Laboratories, Sorisole, Italy) facilitates these reactions.
  • the desired Formula XXXVIII compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and V are as described above may be prepared from the corresponding alpha- bromoester VCHBrCO 2 Me compounds.
  • a polar solvent such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone etc.
  • a base e.g., potassium carbonate, triethylamine, pyridine, 4- dimethylaminopyridine, lutidine
  • a base e.g., potassium carbonate, triethylamine, pyridine, 4- dimethylaminopyridine, lutidine
  • heating in the microwave at the appropriate temperature is particularly suitable for this procedure.
  • suitable microwave equipment such as the Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) or Milestone microwave (Milestone Laboratories, Sorisole, Italy) facilitates these reactions.
  • Formula XXXIX compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and V are as described above may be prepared from the corresponding Formula XXXVIII compounds by the reduction of the ester functionality using reagents and conditions well known to those skilled in the art.
  • Formula XXXVIII compounds can be treated with lithium aluminum hydride in anhydrous ethereal solvents such as tetrahydrofuran and ether at temperatures ranging between -78°C and 0°C.
  • the desired Formula L compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and V are as described above may be prepared from the corresponding Formula XXXIX compounds by using an appropriate alkylating agent, such as an alkyl iodide or bromide and a base, such as sodium hydride, in a reaction inert solvent such as tetrahydrofuran or dimethylformamide to obtain the desired Formula L compounds.
  • an appropriate alkylating agent such as an alkyl iodide or bromide
  • a base such as sodium hydride
  • the desired Formula LI compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and V are as described above and Ac is an acyl group (which are within the scope of the present invention) may be prepared from the corresponding Formula XXXIX compounds by using a suitable acyl chloride and a base such as pyridine, triethylamine or 4-dimethylaminopyridine in an anhydrous solvent such as dichloromethane. Depending on the reactivity of the acyl chloride, one can use the base, such as pyridine, as the solvent.
  • the products can usually be isolated by concentrating the reaction mixture and purifying the product by silica gel chromatography.
  • R 2 CH(CH 2 OH)NH 2 which is first bound to a resin by the method described by V. Krchnak etal., Tetrahedron Lett. 42, 2443-2446 (2001). This is then treated with the corresponding Formula Llll compounds typically in a polar solvent such as dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone or dimethylacetamide which is capable of allowing polystyrene based resin to swell as known to one skilled in the art. The reaction is carried out for 12-36h, and the resin is then washed to isolate the desired resin bound Formula Lll compounds.
  • a polar solvent such as dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone or dimethylacetamide
  • the desired resin bound Formula LIV compounds wherein R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding resin bound alcohol of Formula Lll compounds by activating the alcohol functionality as familiar to one skilled in the art. This involves the conversion of the alcohol to a sulfonate (such as a methanesulfonate or toluenesulfonate), halide (such as chloride or bromide) or an acetate.
  • a sulfonate such as a methanesulfonate or toluenesulfonate
  • halide such as chloride or bromide
  • the reaction is carried out by treatment of the resin bound Formula Lll compounds with methanesulfonyl chloride in the presence of a base such as pyridine, 4-dimethylaminopyridine or proton sponge in solvents such as dichloromethane or dichloroethane in which case the reaction is typically carried out for 1-5 h.
  • a base such as pyridine, 4-dimethylaminopyridine or proton sponge
  • solvents such as dichloromethane or dichloroethane in which case the reaction is typically carried out for 1-5 h.
  • the resulting resin bound sulfonate is washed of all the reagents and the nitro group can be reduced by a variety of reducing agents well known to those skilled in the art, for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995.
  • tin (II) chloride in a polar solvent such as N- methylpyrrolidone or dimethylformamide, which are capable of swelling a polystyrene based resin.
  • the reaction is typically carried out for 1-5h, the reagents are washed away and the resulting primary amine undergoes an intramolecular ring closure to afford the resin bound Formula LIV compounds.
  • an activating group other than a methanesulfonate as described above, the reaction times for the ring closure might be longer as known to one skilled in the art.
  • the resin bound Formula LV compounds wherein R 2 , R 4 , R 5 , R 6 , R 7 and V are as described above may be prepared from the corresponding Formula LIV compounds, by reaction with an acid chloride VOCI, in a solvent such as methylene chloride or chloroform optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at a temperature between 0°C to 60°C, typically ambient, for a period of 1 to 24hr.
  • the resin bound Formula LV compound is subsequently filtered and repeatedly washed with solvents such as dichloromethane, methanol and water to remove the excess reagents.
  • the desired Formula LVI compounds wherein R 2 , R 4 , R 5 , R 6 , R 7 and V are as described above may be prepared from the corresponding resin bound Formula LV compounds, by treatment with a strong acid well known to those skilled in the art, such as trifluoroacetic acid or hydrofluoric acid, optionally in a reaction-inert solvent such as dichloromethane or dichloroethane.
  • a strong acid well known to those skilled in the art, such as trifluoroacetic acid or hydrofluoric acid
  • a reaction-inert solvent such as dichloromethane or dichloroethane.
  • the desired Formula LVI compounds can be isolated by filtration and washing of the resin with an appropriate organic solvent such as dichloromethane, dichloroethane or tetrahydrofuran. If necessary, the Formula LVI compounds can be further purified by silica gel chromatography under standard conditions.
  • the desired Formula LVI I compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and V are as described above may be prepared from the corresponding Formula LVI compounds by treatment with an appropriate reagent, for example, ethyl chloroformate or isopropyl chloroformate, in a reaction inert solvent such as methylene chloride or chloroform, optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at a temperature between 0°C to 60°C, typically ambient, for a period of 1 to 24hr.
  • an appropriate reagent for example, ethyl chloroformate or isopropyl chloroformate
  • a reaction inert solvent such as methylene chloride or chloroform
  • optionally containing a base such as pyridine, diisopropylethylamine,
  • the reaction is carried out in pyridine as a solvent.
  • R 1 is a carbamate or urea
  • the product can be obtained by treating Formula LVI compounds with phosgene in toluene, optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at a temperature between 0°C to 60°C, followed by treatment with, respectively, an alcohol or an amine to afford the desired carbamate or urea of Formula LVI I.
  • the product is usually isolated by standard extractive workup and flash chromatography on silica gel.
  • the desired resin bound Formula LVI 11 compounds wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above and R 3 is as described above, wherein the group V is attached to the connecting carbon, may be prepared from the corresponding resin bound Formula LIV compounds by alkylation with the appropriate alkyl bromides or iodides. These alkylations are typically carried out in a polar solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone in the presence of a base (triethylamine, pyridine, 4-dimethylaminopyridine, lutidine).
  • a polar solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone
  • the solvents used in this reaction are capable of allowing the polystyrene resin to swell as familiar to one skilled in the art. These reactions are usually carried out from ambient temperatures to about 150°C. Due to the unreactivity of quinoxalines, heating in a microwave oven at an appropriate temperature is preferred.
  • Alkylations can be performed with a variety of alkyl bromides such as arylmethyl bromides or alpha-substituted arylmethyl bromides. The alkylation reactions typically proceed in better yield if the bromides are substituted with an alpha electron-withdrawing group (such as in the preparation of the Formula XXXVIII compounds in Scheme 4).
  • the quinoxaline compounds of Formula LIX wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding resin bound Formula LVI 11 compounds, by treatment with strong acids well known to those skilled in the art, such as trifluoroacetic acid or hydrofluoric acid, with or without additional solvents (such as dichloromethane or dichloroethane).
  • strong acids well known to those skilled in the art, such as trifluoroacetic acid or hydrofluoric acid
  • additional solvents such as dichloromethane or dichloroethane
  • the quinoxaline compounds of Formula LIX can be isolated by filtration and washing of the resin with an appropriate organic solvent such as dichloromethane, dichloroethane or tetrahydrofuran. Evaporation of the solvent usually affords clean desired Formula LIX compounds. If necessary, the isolated products can be further purified by silica gel chromatography under standard conditions.
  • the desired Formula LX compounds wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula LIX compound by treatment with an acylating/sulfonating agent solvent, for example ethyl or isopropyl chloroformate in a reaction-inert solvent such as methylene chloride or chloroform optionally containing a base such as pyridine, diisopropylethylamine, 4- dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at a temperature between 0°C to 60°C, typically ambient, for a period of 1 to 24hr.
  • an acylating/sulfonating agent solvent for example ethyl or isopropyl chloroformate in a reaction-inert solvent such as methylene chloride or chloroform
  • a base such as pyridine, diisopropylethylamine,
  • the reaction is carried out in pyridine as a solvent.
  • R is a carbamate or urea
  • the product can be obtained by treating Formula LX compound with phosgene in toluene optionally containing a base such as pyridine, diisopropylethylamine, 4- dimethylaminopyridine 2,6-di-tert-butyl-4-methylpyridine at a temperature between 0°C to 60°C, followed by treatment with, respectively, an alcohol or an amine to afford the desired carbamate or urea Formula LX compound.
  • the product is usually isolated by standard extractive workup and flash chromatography on silica gel.
  • the less hindered nitrogen atom of the quinoxaline preferentially undergoes acylation to give the desired Formula LVI compounds.
  • the desired compounds of Formula LVI I wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 are as described above and R 3 is as described above, wherein the group V is attached to the connecting carbon, may be achieved from the corresponding Formula LVI compounds by alkylation or acylation, using procedures as described above.
  • Alkylations can be performed with a variety of alkyl bromides such as arylmethyl bromides, alpha- substituted arylmethyl bromides. Typically under these conditions, when R 2 is other than hydrogen, the less hindered nitrogen atom of the quinoxaline preferentially undergoes alkylation to give the desired Formula LIX compounds.
  • the desired Formula XXXV compounds wherein R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding resin bound Formula LIV compounds by treatment with strong acids well known to those skilled in the art, such as trifluoroacetic acid or hydrofluoric acid, optionally in a reaction inert solvent such as dichloromethane or dichloroethane.
  • strong acids well known to those skilled in the art, such as trifluoroacetic acid or hydrofluoric acid, optionally in a reaction inert solvent such as dichloromethane or dichloroethane.
  • R 3 is a group COV and V
  • R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above (depicted as Formula LXII I compounds)
  • R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above (depicted as Formula LXII I compounds)
  • R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above (depicted as Formula LXII I compounds) can be prepared from the corresponding Formula LXII compounds by oxidation of the alcohol. This may be achieved by a wide variety of methods well known to those skilled in the art, for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995.
  • Formula LXII compounds can be treated with activated manganese (IV) oxide in a suitable reaction inert solvent such as tetrahydrofuran, diethyl ether or dichloromethane at a temperature between 0°C to 25°C, typically ambient, to provide the desired product of Formula LXII I.
  • a suitable reaction inert solvent such as tetrahydrofuran, diethyl ether or dichloromethane
  • the desired Formula LXII compounds wherein V, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above can be prepared as a mixture of diastereoisomers from the corresponding Formula LXI compounds by treatment with a suitable transmetallating agent such as an alkyllithium compound, such as n-butyllthium or s-butyllithium, or an alkylmagnesium halide such as isopropylmagnesium chloride in a suitable reaction inert solvent such as tetrahydrofuran or diethyl ether at a temperature between - 120°C to 0°C, typically -78°C, to provide a vinyllithium species which is then reacted with the appropriate aldehyde of formula VCHO at a temperature between -120°C to 0°C, typically -78°C to -23°C, to provide the desired product of Formula LXII.
  • a suitable transmetallating agent such as an
  • transmetallation agent it is convenient to add the transmetallation agent to a mixture of the ketone and the iodide.
  • preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in intermediates).
  • remote functionality e.g., primary amine, secondary amine, carboxyl in intermediates.
  • the need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art.
  • the use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step.
  • 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.
  • Prodrugs of the compounds of the present invention may be prepared according to methods known to those skilled in the art. Exemplary processes are described below.
  • Prodrugs of this invention where a carboxyl group in a carboxylic acid of the compounds is replaced by an ester may be prepared by combining the carboxylic acid with the appropriate alkyl halide in the presence of a base such as potassium carbonate in an inert solvent such as dimethylformamide at a temperature of about 0 to 100°C for about 1 to about 24 hours.
  • a base such as potassium carbonate
  • an inert solvent such as dimethylformamide
  • the acid is combined with appropriate alcohol as solvent in the presence of a catalytic amount of acid such as concentrated sulfuric acid at a temperature of about 20 to 100°C, preferably at a reflux, for about 1 hour to about 24 hours.
  • Another method is the reaction of the acid with a stoichiometric amount of the alcohol in the presence of a catalytic amount of acid in an inert solvent such as toluene or tetrahydrofuran, with concomitant removal of the water being produced by physical (e.g., Dean-Stark trap) or chemical (e.g., molecular sieves) means.
  • a catalytic amount of acid in an inert solvent such as toluene or tetrahydrofuran
  • Prodrugs of this invention where an alcohol function has been derivatized as an ether may be prepared by combining the alcohol with the appropriate alkyl bromide or iodide in the presence of a base such as potassium carbonate in an inert solvent such as dimethylformamide at a temperature of about 0 to 100°C for about 1 to about 24 hours.
  • Alkanoylaminomethyl ethers may be obtained by reaction of the alcohol with a bis-(alkanoylamino)methane in the presence of a catalytic amount of acid in an inert solvent such as tetrahydrofuran, according to a method described in US 4,997,984.
  • these compounds may be prepared by the methods described by Hoffman et al. in J. Org. Chem. 1994, 59, 3530.
  • Glycosides are prepared by reaction of the alcohol and a carbohydrate in an inert solvent such as toluene in the presence of acid. Typically the water formed in the reaction is removed as it is being formed as described above.
  • An alternate procedure is the reaction of the alcohol with a suitably protected glycosyl halide in the presence of base followed by deprotection.
  • N-(l-hydroxyalkyl) amides, N-(1-hydroxy-1-(alkoxycarbonyl)methyl) amides may be prepared by the reaction of the parent amide with the appropriate aldehyde under neutral or basic conditions (e.g., sodium ethoxide in ethanol) at temperatures between 25 and 70°C.
  • N-alkoxymethyl or N-1-(alkoxy)alkyl derivatives can be obtained by reaction of the N-unsubstituted compound with the necessary alkyl halide in the presence of a base in an inert solvent.
  • 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 MTP/Apo B secretion inhibitor, a 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 an ileal bile acid transporter inhibitor, an ACC inhibitor, an antihypertensive (such as NORVASC®), 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
  • This combination therapy is known as ADVICOR® (Kos Pharmaceuticals Inc.)
  • ADVICOR® Kos Pharmaceuticals Inc.
  • 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.
  • PPAR modulator refers to compounds which modulate peroxisome proliferator activator receptor (PPAR) activity in mammals, particularly humans. Such modulation is readily determined by those skilled in the art according to standard assays known in the literature.
  • such compounds by modulating the PPAR receptor, regulate transcription of key genes involved in lipid and glucose metabolism such as those in fatty 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 compounds also reduce plasma levels of triglycerides, VLDL cholesterol, LDL cholesterol and their associated components such as apolipoprotein B in mammals, particularly humans, as well as increasing HDL cholesterol and apolipoprotein Al.
  • 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:
  • HMG-CoA synthase inhibitor refers to compounds which inhibit the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Such inhibition is readily determined by those skilled in the art according to standard assays (Meth Enzymol. 1975; 35:155-160: Meth. Enzymol. 1985; 110:19-26 and references cited therein). A variety of these compounds are described and referenced below, however other HMG-CoA synthase inhibitors will be known to those skilled in the art.
  • U.S. Pat. No. 5,120,729 discloses certain beta-lactam derivatives.
  • U.S. Pat. No. 5,064,856 discloses certain spiro-lactone derivatives prepared by culturing a microorganism (MF5253).
  • U.S. Pat. No. 4,847,271 discloses certain oxetane compounds such as 11-(3-hydroxymethyl-4- oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undeca-dienoic acid derivatives.
  • 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.
  • Such compounds may cause this effect by decreasing levels of SREBP (sterol receptor binding protein) by inhibiting the activity of site-1 protease (S1P) or agonizing the oxzgenal receptor or SCAP.
  • SREBP site-1 protease
  • SCAP site-1 protease
  • Such regulation is readily determined by those skilled in the art according to standard assays (Meth. Enzymol. 1985; 110:9- 19).
  • S1P site-1 protease
  • SCAP site-1 protease
  • U.S. Pat. No. 5,041 ,432 discloses certain 15-substituted lanosterol derivatives.
  • Other oxygenated sterols that suppress synthesis of HMG-CoA reductase are discussed by E.I. Mercer (Prog.Lip. Res. 1993;32:357-416).
  • squalene synthetase inhibitor refers to compounds which inhibit the condensation of 2 molecules of farnesylpyrophosphate to form squalene, catalyzed by the enzyme squalene synthetase. Such inhibition is readily determined by those skilled in the art according to standard assays (Meth. Enzymol. 1969; 15: 393-454 and Meth. Enzymol. 1985; 110:359-373 and references contained therein). A variety of these compounds are described in and referenced below however other squalene synthetase inhibitors will be known to those skilled in the art. U.S. Pat. No.
  • squalene cyclase inhibitor refers to compounds which inhibit the bioconversion of squalene-2,3-epoxide to lanosterol, catalyzed by the enzyme squalene cyclase. Such inhibition is readily determined by those skilled in the art according to standard assays (FEBS Lett. 1989;244:347- 350.).
  • the compounds described and referenced below are squalene cyclase inhibitors, however other squalene cyclase inhibitors will also be known to those skilled in the art.
  • PCT publication WO9410150 discloses certain 1 ,2,3,5,6,7,8,8a-octahydro- 5,5,8(beta)-trimethyl-6-isoquinolineamine derivatives, such as N-trifluoroacetyl- 1 ,2,3,5,6 ) 7,8,8a-octahydro-2-allyl-5,5,8(beta)-trimethyl-6(beta)-isoquinolineamine.
  • any combined squalene epoxidase/squalene cyclase inhibitor may be used as the second component in the combination aspect of this invention.
  • the term combined squalene epoxidase/squalene cyclase inhibitor refers to compounds that inhibit the bioconversion of squalene to lanosterol via a squalene-2,3-epoxide intermediate. In some assays it is not possible to distinguish between squalene epoxidase inhibitors and squalene cyclase inhibitors, however, these assays are recognized by those skilled in the art.
  • EP publication 468,434 discloses certain piperidyl ether and thio-ether derivatives such as 2-(1-piperidyl)pentyl isopentyl sulfoxide and 2-(1-piperidyl)ethyl ethyl sulfide.
  • PCT publication WO 9401404 discloses certain acyl-piperidines such as 1-(1-oxopentyl-5-phenylthio)-4-(2-hydroxy-1-methyl)- ethyl)piperidine.
  • 5,102,915 discloses certain cyclopropyloxy-squalene derivatives.
  • the compounds of the present invention can also be administered in combination with naturally occurring compounds that act to lower plasma cholesterol levels. These naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract and niacin. A slow-release form of niacin is available and is known as Niaspan. Niacin may also be combined with other therapeutic agents such as lovastatin, or another is an HMG-CoA reductase inhibitor. This combination therapy with lovastatin is known as ADVICORTM (Kos Pharmaceuticals Inc.).
  • 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.
  • cholesterol absorption inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Lipid Res. (1993) 34: 377-395).
  • 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 recently approved cholesterol absorption inhibitor is ZETIA TM (ezetimibe) (Schering-Plough/Merck).
  • ACAT inhibitor refers to compounds that inhibit the intracellular esterification of dietary cholesterol by the enzyme acyl CoA: cholesterol acyltransferase. Such inhibition may be determined readily by one of skill in the art according to standard assays, such as the method of Heider et al. described in Journal of Lipid Research., 24:1127 (1983). A variety of these compounds are known to those skilled in the art, for example, U.S. Patent No. 5,510,379 discloses certain carboxysulfonates, while WO 96/26948 and WO 96/10559 both disclose urea derivatives having ACAT inhibitory activity. Examples of ACAT inhibitors include compounds such as Avasimibe (Pfizer), CS-505 (Sankyo) and Eflucimibe (Eli Lilly and Pierre Fabre).
  • a lipase inhibitor may be used in the combination therapy aspect of the present invention.
  • a lipase inhibitor is a compound that inhibits the metabolic cleavage of dietary triglycerides or plasma phospholipids into free fatty acids and the corresponding glycerides (e.g. EL, HL, etc.).
  • lipolysis occurs via a two-step process that involves acylation of an activated serine moiety of the lipase enzyme. This leads to the production of a fatty acid-lipase hemiacetal intermediate, which is then cleaved to release a diglyceride.
  • the lipase-fatty acid intermediate is cleaved, resulting in free lipase, a glyceride and fatty acid.
  • the resultant free fatty acids and monoglycerides are incorporated into bile acid-phospholipid micelles, which are subsequently absorbed at the level of the brush border of the small intestine.
  • the micelles eventually enter the peripheral circulation as chylomicrons.
  • lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).
  • pancreatic lipase mediates the metabolic cleavage of fatty acids from triglycerides at the 1- and 3-carbon positions.
  • the primary site of the metabolism of ingested fats is in the duodenum and proximal jejunum by pancreatic lipase, which is usually secreted in vast excess of the amounts necessary for the breakdown of fats in the upper small intestine.
  • pancreatic lipase is the primary enzyme required for the absorption of dietary triglycerides, inhibitors have utility in the treatment of obesity and the other related conditions.
  • pancreatic lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).
  • Gastric lipase is an immunologically distinct lipase that is responsible for approximately 10 to 40% of the digestion of dietary fats. Gastric lipase is secreted in response to mechanical stimulation, ingestion of food, the presence of a fatty meal or by sympathetic agents. Gastric lipolysis of ingested fats is of physiological importance in the provision of fatty acids needed to trigger pancreatic lipase activity in the intestine and is also of importance for fat absorption in a variety of physiological and pathological conditions associated with pancreatic insufficiency. See, for example, C.K. Abrams, et al., Gastroenterology, 92,125 (1987). Such gastric lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).
  • lipase inhibitors are those inhibitors that are selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), valilactone, esterastin, ebelactone A, and ebelactone B.
  • the compound tetrahydrolipstatin is especially preferred.
  • the lipase inhibitor, N-3-trifluoromethylphenyl-N'-3-chloro-4'- trifluoromethylphenylurea, and the various urea derivatives related thereto, are disclosed in U.S. Patent No. 4,405,644.
  • the lipase inhibitor, esteracin is disclosed in U.S.
  • Patent Nos. 4,189,438 and 4,242,453 The lipase inhibitor, cyclo-O,O'-[(1 ,6- hexanediyl)-bis-(iminocarbonyl)]dioxime, and the various bis(iminocarbonyl)dioximes related thereto may be prepared as described in Petersen et al., Liebig's Annalen, 562, 205-229 (1949). A variety of pancreatic lipase inhibitors are described herein below.
  • tetrahydrolipstatin is prepared as described in, e.g., U.S. Patent Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874.
  • the pancreatic lipase inhibitor, FL-386, 1-[4-(2-methylpropyl)cyclohexyl]-2-[(phenylsulfonyl)oxy]- ethanone, and the variously substituted sulfonate derivatives related thereto, are disclosed in U.S. Patent No. 4,452,813.
  • pancreatic lipase inhibitor WAY- 121898, 4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and the various carbamate esters and pharmaceutically acceptable salts related thereto, are disclosed in U.S. Patent Nos. 5,512,565; 5,391 ,571 and 5,602,151.
  • the pancreatic lipase inhibitor, valilactone, and a process for the preparation thereof by the microbial cultivation of Actinomyceies strain MG147-CF2 are disclosed in Kitahara, et al., J. Antibiotics, 40 (11), 1647-1650 (1987).
  • pancreatic lipase inhibitors ebelactone A and ebelactone B
  • a process for the preparation thereof by the microbial cultivation of Actinomyceies strain MG7-G1 are disclosed in Umezawa, et al., J. Antibiotics, 33, 1594-1596 (1980).
  • the use of ebelactones A and B in the suppression of monoglyceride formation is disclosed in Japanese Kokai 08-143457, published June 4, 1996.
  • hyperlipidemia including hypercholesterolemia and which are intended to help prevent or treat atherosclerosis
  • bile acid sequestrants such as Welchol ® , Colestid ® , LoCholest ® and Questran ®
  • fibric acid derivatives such as Atromid ® , Lopid ® and Tricor ® .
  • 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
  • Any glycogen phosphorylase inhibitor can be used as the second agent in combination with a compound of the present invention.
  • glycogen phosphorylase inhibitor refers to compounds that inhibit the bioconversion of glycogen to glucose-1 -phosphate which is catalyzed by the enzyme glycogen phosphorylase.
  • 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.
  • Any aldose reductase inhibitor can be used in combination with a compound of the present invention.
  • 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.
  • 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.
  • the rapid metabolic action of glucosidases particularly following the intake of high levels of carbohydrates, results in a state of alimentary hyperglycemia which, in adipose or diabetic subjects, leads to enhanced secretion of insulin, increased fat synthesis and a reduction in fat degradation. Following such hyperglycemias, hypoglycemia frequently occurs, due to the augmented levels of insulin present.
  • 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 -(hydroxymethyl)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, (2R,3R,4R,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)-3,4,5-trihydroxy-2- (hydroxymethyl)piperidino]ethoxy]-benzoate, the various derivatives related thereto and pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Patent No. 5,192,772.
  • glucosidase inhibitor MDL-25637, 2,6-dideoxy-7-0- ⁇ - 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-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2- (hydroxymethyl)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 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, galan
  • bombesin agonists e.g., a bombesin agonist
  • anorectic agents e.g., a bombesin agonist
  • Neuropeptide-Y antagonists e.g., 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.
  • 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).
  • Examples of presently marketed products containing antihypertensive agents include calcium channel blockers, such as Cardizem ® , Adalat ® , Calan ® , Cardene ® , Covera ® , Dilacor ® , DynaCirc ® ' Procardia XL ® , Sular ® , Tiazac ® , Vascor ® , Verelan ® , Isoptin ® , Nimotop ® ' Norvasc ® , and Plendil ® ; angiotensin converting enzyme (ACE) inhibitors, such as Accupril ® , Altace ® , Captopril ® , Lotensin ® , Mavik ® , Monopril ® , Prinivil ® , Univasc ® , Vasotec ® and Zestril ® .
  • calcium channel blockers such as Cardizem ® , Adalat ® , Calan ® ,
  • Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.
  • the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually.
  • Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
  • the elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population.
  • Worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study has estimated that there will be 4.5 million hip fractures worldwide in 2050.
  • anti-resorptive agents for example progestins, polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists, estrogen, estrogen/progestin combinations, Premarin ® , estrone, estriol or 17 ⁇ - or 17 ⁇ -ethynyl estradiol
  • anti-resorptive agents for example progestins, polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists, estrogen, estrogen/progestin combinations, Premarin ® , estrone, estriol or 17 ⁇ - or 17 ⁇ -ethynyl estradiol
  • progestins are available from commercial sources and include: algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone, dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonorone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, melengestrol acetate, methynodiol diacetate, norethindrone, norethindrone
  • Preferred progestins are medroxyprogestrone, norethindrone and norethynodrel.
  • Exemplary bone resorption inhibiting polyphosphonates include polyphosphonates of the type disclosed in U.S. Patent 3,683,080, the disclosure of which is incorporated herein by reference.
  • Preferred polyphosphonates are geminal diphosphonates (also referred to as bis-phosphonates).
  • Tiludronate disodium is an especially preferred polyphosphonate.
  • Ibandronic acid is an especially preferred polyphosphonate.
  • Alendronate and resindronate are especially preferred polyphosphonates.
  • Zoledronic acid is an especially preferred polyphosphonate.
  • polyphosphonates are 6-amino-1-hydroxy-hexylidene-bisphosphonic acid and 1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid.
  • the polyphosphonates may be administered in the form of the acid, or of a soluble alkali metal salt or alkaline earth metal salt. Hydrolyzable esters of the polyphosphonates are likewise included.
  • Specific examples include ethane-1 -hydroxy 1 ,1-diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1 ,1-diphosphonic acid, methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid, ethane-1 - amino-1 ,1 -diphosphonic acid, ethane-2-amino-1 ,1 -diphosphonic acid, propane-3- amino-1-hydroxy-1 ,1-diphosphonic acid, propane-N,N-dimethyl-3-amino-1-hydroxy- 1 ,1 -diphosphonic acid, propane-3,3-dimethyl-3-amino-1-hydroxy-1 ,1 -diphosphonic acid, phenyl amino methane diphosphonic acid,N,N-dimethylamino methane diphosphonic acid, N(2-hydroxyethyl) amino methane diphosphonic acid, butane-4- amino-1-hydroxy-1 ,1-diphosphonic acid
  • the compounds of this invention may be combined with a mammalian estrogen agonist antagonist.
  • Any estrogen agonist/antagonist may be used in the combination aspect of this invention.
  • the term estrogen agonist/antagonist refers to compounds which bind with the estrogen receptor, inhibit bone turnover and/or prevent bone loss.
  • estrogen agonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and mimicking the actions of estrogen in one or more tissue.
  • Estrogen antagonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and blocking the actions of estrogen in one or more tissues.
  • Another preferred estrogen agonist antagonist is 3-(4-(1 ,2-diphenyl-but-1- enyl)-phenyl)-acrylic acid, which is disclosed in Willson et al., Endocrinology, 1997, 138, 3901-3911.
  • Another preferred estrogen agonist/antagonist is tamoxifen: (ethanamine,2-(- 4-(1 ,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl, (Z)-2-, 2-hydroxy-1 ,2,3- propanetricarboxylate(1 :1)) and related compounds which are disclosed in U.S. patent 4,536,516, the disclosure of which is incorporated herein by reference.
  • Another related compound is 4-hydroxy tamoxifen, which is disclosed in U.S. patent 4,623,660, the disclosure of which is incorporated herein by reference.
  • a preferred estrogen agonist antagonist is raloxifene: (methanone, (6- hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)- hydrochloride) which is disclosed in U.S. patent 4,418,068, the disclosure of which is incorporated herein by reference.
  • Another preferred estrogen agonist antagonist is toremifene: (ethanamine, 2- (4-(4-chloro-1 ,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-, 2-hydroxy-1 ,2,3- propanetricarboxylate (1 :1) which is disclosed in U.S. patent 4,996,225, the disclosure of which is incorporated herein by reference.
  • Another preferred estrogen agonist/antagonist is centchroman: 1-(2-((4- (-methoxy-2,2, dimethyl-3-phenyl-chroman-4-yl)-phenoxy)-ethyl)-pyrrolidine, which is disclosed in U.S. patent 3,822,287, the disclosure of which is incorporated herein by reference. Also preferred is levormeloxifene.
  • Another preferred estrogen agonist/antagonist is idoxifene: (E)-1-(2-(4-(1-(4- iodo-phenyl)-2-phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrrolidinone, which is disclosed in U.S. patent 4,839, 155, the disclosure of which is incorporated herein by reference.
  • Another preferred estrogen agonist antagonist is 2-(4-methoxy-phenyl)-3-[4- (2-piperidin-1-yl-ethoxy)-phenoxy]- benzo[b]thiophen-6-ol which is disclosed in U.S. Patent No. 5,488,058, the disclosure of which is incorporated herein by reference.
  • Another preferred estrogen agonist/antagonist is 6-(4-hydroxy-phenyl)-5-(4- (2-piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2-ol, which is disclosed in U.S. patent 5,484,795, the disclosure of which is incorporated herein by reference.
  • Another preferred estrogen agonist/antagonist is (4-(2-(2-aza- bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hydroxy-phenyl)- benzo[b]thiophen-3-yl)-methanone which is disclosed, along with methods of preparation, in PCT publication no. WO 95/10513 assigned to Pfizer Inc.
  • Other preferred estrogen agonist antagonists include the compounds, TSE-
  • estrogen agonist/antagonists include compounds as described in commonly assigned U.S. patent 5,552,412, the disclosure of which is incorporated herein by reference. Especially preferred compounds described therein are: c/s-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8- tetrahydro-naphthalene-2-ol;
  • U.S. patent 4,133,814 discloses derivatives of 2-phenyl-3-aroyl-benzothiophene and 2-phenyl-3- aroylbenzothiophene-1 -oxide.
  • anti-osteoporosis agents which can be used as the second agent in combination with a compound of the present invention, include, for example, the following: parathyroid hormone (PTH) (a bone anabolic agent); parathyroid hormone (PTH) secretagogues (see, e.g., U.S. Patent No. 6,132,774), particularly calcium receptor antagonists; calcitonin; and vitamin D and vitamin D analogs.
  • PTH parathyroid hormone
  • PTH parathyroid hormone
  • PTH parathyroid hormone
  • PTH parathyroid hormone
  • PTH parathyroid hormone
  • secretagogues see, e.g., U.S. Patent No. 6,132,774
  • Any selective androgen receptor modulator (SARM) can be used in combination with a compound of the present invention.
  • a selective androgen receptor modulator (SARM) is a compound that possesses androgenic activity and which exerts tissue-selective effects.
  • SARM compounds can function as androgen receptor agonists, partial agonists, partial antagonists or antagonists.
  • suitable SARMs include compounds such as cyproterone acetate, chlormadinone, flutamide, hydroxyflutamide, bicalutamide, nilutamide, spironolactone, 4- (trifluoromethyl)-2(1 H)-pyrrolidino[3,2-g] quinoline derivatives, 1 ,2-dihydropyridino [5,6-g]quinoline derivatives and piperidino[3,2-g]quinolinone derivatives.
  • Cypterone also known as (1 b,2b)-6-chloro-1 ,2-dihydro-17-hydroxy-3'H- cyclopropa[1 ,2]pregna-1 ,4,6-triene-3,20-dione is disclosed in U.S. Patent 3,234,093.
  • Chlormadinone also known as 17-(acetyloxy)-6-chloropregna-4,6-diene-3,20-dione, in its acetate form, acts as an anti-androgen and is disclosed in U.S. Patent 3,485,852.
  • Nilutamide also known as 5,5-dimethyl-3-[4-nito-3- (trifluoromethyl)phenyl]-2,4-imidazolidinedione and by the trade name Nilandron® is disclosed in U.S. Patent 4,097,578.
  • Flutamide also known as 2-methyl-N-[4-nitro-3- (trifluoromethyl)phenyl] propanamide and the trade name Eulexin® is disclosed in U.S. Patent 3,847,988.
  • Bicalutamide also known as 4'-cyano-a',a',a'-trifluoro-3-(4- fluorophenylsulfonyl)-2-hydroxy-2-methylpropiono-m-toluidide and the trade name Casodex® is disclosed in EP-100172.
  • the enantiomers of biclutamide are discussed by Tucker and Chesterton, J. Med. Chem. 1988, 31 , 885-887.
  • Hydroxyflutamide a known androgen receptor antagonist in most tissues, has been suggested to function as a SARM for effects on IL-6 production by osteoblasts as disclosed in Hofbauer et al. J. Bone Miner. Res. 1999, 14, 1330-1337. Additional SARMs have been disclosed in U.S. Patent 6,017,924; WO 01/16108, WO 01/16133, WO 01/16139, WO
  • Some of the compounds of this 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 ger se, 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 diastereomeric 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 corresponding pure enantiomers by forming a diastereomic 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 this invention for all of the compounds of the present invention, including the compounds of the present invention.
  • some of the compounds of this invention are atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • the compounds of this invention may be obtained in enantiomerically enriched form by resolving the racemate of the final compound or an intermediate in its synthesis, employing chromatography (preferably high pressure liquid chromatography [HPLC]) on an asymmetric resin (preferably
  • ChiralcelTM AD or OD obtained from Chiral Technologies, Exton, Pennsylvania
  • 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). Concentration of the product containing fractions affords the desired materials.
  • a hydrocarbon preferably heptane or hexane
  • isopropanol preferably between 2 and 20
  • an alkyl amine preferably 0.1% of diethylamine
  • Some of the compounds of this invention are acidic and they form a salt with a pharmaceutically acceptable cation. Some of the compounds of this invention are basic and they form a salt with a pharmaceutically acceptable anion. All such salts are within the scope of this 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 this invention form hydrates or solvates they are also within the scope of the invention.
  • the compounds of this invention, their prodrugs and the salts of such compounds and prodrugs are all adapted to therapeutic use as agents that inhibit cholesterol ester transfer protein activity in mammals, particularly humans.
  • the compounds of this invention elevate plasma HDL cholesterol, its associated components, and the functions performed by them in mammals, particularly humans.
  • these agents also reduce plasma levels of triglycerides, VLDL cholesterol, Apo-B, LDL cholesterol and their associated components in mammals, particularly humans.
  • these compounds are useful in equalizing LDL cholesterol and HDL cholesterol.
  • 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 coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, familial- hypercholesterolemia, low HDL and associated components, elevated LDL and associated components, elevated Lp(a), elevated small-dense LDL, elevated VLDL and associated components and post-prandial lipemia.
  • the compounds of this invention Given the negative correlation between the levels of HDL cholesterol and HDL associated lipoproteins, and 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 this 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., angina, ischemia, cardiac ischemia and myocardial infarction
  • complications due to cardiovascular disease therapies e.g., reperfusion injury and angioplastic restenosis
  • hypertension elevated cardiovascular risk associated with hypertension
  • stroke e.g., atherosclerosis associated with organ transplantation
  • cerebrovascular disease e.g., 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), elevated levels of oxidative stress, elevated levels of C- Reactive Protein, Metabolic Syndrome and elevated levels of HbA1C.
  • an agent which inhibits CETP activity in humans by virtue of its HDL increasing ability, also provides valuable avenues for therapy in a number of other disease areas as well.
  • CETP-mediated cholesteryl ester transfer is known to be abnormally increased in both insulin-dependent (Bagdade, J.D., Subbaiah, P.V. and Ritter, M.C. 1991. Eur. J. Clin. Invest. 21 , 161) and non-insulin dependent diabetes (Bagdade. J.D., Ritter, M.C, Lane, J. and Subbaiah. 1993. Atherosclerosis 104, 69). It has been suggested that the abnormal increase in cholesterol transfer results in changes in lipoprotein composition, particularly for VLDL and LDL, that are more atherogenic (Bagdade, J.D., Wagner, J.D., Rudel, L.L., and Clarkson, T.B. 1995. J. Lipid Res. 36, 759). These changes would not necessarily be observed during routine lipid screening. Thus the present invention will be useful in reducing the risk of vascular complications as a result of the diabetic condition.
  • mRNA for CETP is expressed at high levels in adipose tissue.
  • the adipose message increases with fat feeding (Martin, L. J., Connelly, P. W., Nancoo, D., Wood, N., Zhang, Z. J., Maguire, G., Quinet, E., Tall, A. R., Marcel, Y. L. and
  • CETP inhibitors are useful in the treatment of inflammation due to Gram- negative sepsis and septic shock.
  • LPS lipopolysaccharide
  • CETP inhibitors by virtue of the fact that they raise HDL levels, attenuate the development of inflammation and septic shock. These compounds would also be useful in the treatment of endotoxemia, autoimmune diseases and other systemic disease indications, organ or tissue transplant rejection and cancer.
  • the utility of the compounds of the invention, their prodrugs and the salts of such compounds and prodrugs as medical agents in the treatment of the above described disease/conditions in mammals is demonstrated by the activity of the compounds of this invention in conventional assays and the in vivo assay described below.
  • the in vivo assay may be used to determine the activity of other lipid or triglyceride controlling agents as well as the compounds of this invention.
  • the combination protocol described below is useful for demonstrating the utility of the combinations of the lipid and triglyceride agents (e.g., the compounds of this invention) described herein.
  • Such assays also provide a means whereby the activities of the compounds of this 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.
  • the hyperalphacholesterolemic activity of the compounds can be determined by assessing the effect of these compounds on the action of cholesteryl ester transfer protein by measuring the relative transfer ratio of radiolabeled lipids between lipoprotein fractions, essentially as previously described by Morton in J. Biol. Chem. 256, 11992,' 1981 and by Dias in Clin. Chem. 34 > 2322, 1988.
  • CETP IN VITRO ASSAY The following is a brief description of assays of cholesteryl ester transfer in 97% (whole) or diluted human plasma (in vitro) and animal plasma (ex vivo): CETP activity in the presence or absence of drug is assayed by determining the transfer of 3 H-labeled cholesteryl oleate (CO) from exogenous tracer HDL or LDL to the nonHDL or HDL lipoprotein fraction in human plasma, respectively, or from 3 H- labeled LDL to the HDL fraction in animal plasma.
  • CO 3 H-labeled cholesteryl oleate
  • Labeled human lipoprotein substrates are prepared similarly to the method described by Morton in which the endogenous CETP activity in plasma is employed to transfer 3 H-CO from phospholipid liposomes to all the lipoprotein fractions in plasma.
  • 3 H-labeled LDL and HDL are subsequently isolated by sequential ultracentrifugation at the density cuts of 1.019-1.063 and 1.10-1.21 g/ml, respectively.
  • 3 H-labeled HDL is added to plasma at 10-25 nmoles CO/ml and the samples incubated at 37° C for 2.5-3 hrs.
  • Non-HDL lipoproteins are then precipitated by the addition of an equal volume of 20% (wt/vol) polyethylene glycol 8000 (Dias).
  • the samples are centrifuged 750 g x 20 minutes and the radioactivity contained in the HDL-containing supernatant determined by liquid scintillation counting.
  • an in vitro assay using diluted human plasma is utilized.
  • 3 H-labeled LDL is added to plasma at 50 nmoles CO/ml and the samples incubated at 37° C for 7 hrs.
  • Non-HDL lipoproteins are then precipitated by the addition of potassium phosphate to 100 mM final concentration followed by manganese chloride to 20 mM final concentration. After vortexing, the samples are centrifuged 750 g x 20 minutes and the radioactivity contained in the HDL-containing supernatant determined by liquid scintillation counting.
  • CETP IN VIVO ASSAY Activity of these compounds in vivo can be determined by the amount of agent required to be administered, relative to control, to inhibit cholesteryl ester transfer activity by 50% at various time points ex vivo or to elevate HDL cholesterol by a given percentage in a CETP-containing animal species.
  • Transgenic mice expressing both human CETP and human apolipoprotein Al may be used to assess compounds in vivo.
  • the compounds to be examined are administered by oral gavage in an emulsion vehicle containing 20% (v:v) olive oil and 80% sodium taurocholate (0.5%). Blood is taken from mice retroorbitally before dosing, if a predose blood sample is desirable.
  • CETP activity is determined by a method similar to that described above except that 3 H-cholesteryl oleate-containing LDL is used as the donor source as opposed to HDL. The values obtained for lipids and transfer activity are compared to those obtained prior to dosing and/or to those from mice receiving vehicle alone.
  • PLASMA LIPIDS ASSAY The activity of these compounds may also be demonstrated by determining the amount of agent required to alter plasma lipid levels, for example HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides, in the plasma of certain mammals, for example marmosets that possess CETP activity and a plasma lipoprotein profile similar to that of humans (Crook et al. Arteriosclerosis 10, 625, 1990).
  • Adult marmosets are assigned to treatment groups so that each group has a similar mean ⁇ SD for total, HDL, and/or LDL plasma cholesterol concentrations. After group assignment, marmosets are dosed daily with compound as a dietary admix or by intragastric intubation for from one to eight days.
  • Control marmosets receive only the dosing vehicle.
  • Plasma total, LDL VLDL and HDL cholesterol values can be determined at any point during the study by obtaining blood from an antecubital vein and separating plasma lipoproteins into their individual subclasses by density gradient centrifugation, and by measuring cholesterol concentration as previously described (Crook et al. Arteriosclerosis 10, 625, 1990).
  • Anti-atherosclerotic effects of the compounds 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, triglyceride concentration and/or cholesteryl ester transfer protein activity. 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 values and cholesteryl ester transfer protein activity can be determined at any point during the study by obtaining blood from the marginal 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 analyzed unstained or stained with Sudan IV as described by Holman et. al. (Lab. Invest. 1958, 7, 42-47).
  • the percent of the lesioned surface area is quantitated by densitometry using an Optimas Image Analyzing System (Image Processing Systems). Reduced lipid deposition is indicated by a reduction in the percent of lesioned surface area in the compound- receiving group in comparison with the control rabbits.
  • ANTIOBESITY PROTOCOL The ability of CETP inhibitors to cause weight loss can be assessed in obese human subjects with body mass index (BMI) > 30 kg/m 2 . Doses of inhibitor are administered sufficient to result in an increase of > 25% in HDL cholesterol levels. BMI and body fat distribution, defined as waist (W) to hip (H) ratio (WHR), are monitored during the course of the 3-6 month studies, and the results for treatment groups compared to those receiving placebo.
  • Administration of the compounds of this 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 for the target 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 this invention is used that is sufficient to achieve the therapeutic effect desired (e.g., HDL elevation).
  • an effective dosage for the compounds of this invention is about 0.001 to 100 mg/kg/day of the compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
  • An especially preferred dosage is about 0.01 to 10 mg/kg/day of the compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
  • a dosage of the combination pharmaceutical agents to be used in conjuction with the CETP inhibitors is used that is effective for the indication being treated.
  • typically an effective dosage for HMG-CoA reductase inhibitors is in the range of 0.01 to 100 mg/kg/day.
  • an effect dosage for a PPAR modulator is in the range of 0.01 to 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 as described below.
  • 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.
  • 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, a vegetable oil, such as olive oil; triglycerides such as those marketed under the name, MiglyolTM; or mono- or diglycerides such as those marketed under the name, CapmulTM, for example, in a soft gelatin capsule.
  • Antioxidants may be added to prevent long-term degradation as appropriate.
  • the compounds of this 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.
  • Pharmaceutical compositions comprising a solid amorphous dispersion of a cholesteryl ester transfer protein (CETP) inhibitor and a concentration-enhancing polymer are described in International Publication No. WO 02/11710, which is hereby incorporated by reference herein.
  • Self-emulsifying formulations of cholesteryl ester transfer protein (CETP) inhibitors are described in International Publication No.
  • WO 03/000295 which is hereby incorporated by reference herein.
  • Methods for depositing small drug crystals on excipients are set forth in the literature, such as in J. Pharm. Pharmacol. 1987, 39:769-773, which is hereby incorporated by reference herein.
  • 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.
  • Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • These 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.
  • compositions according to the invention may contain 0.1%- 95% of the compound(s) of this invention, preferably 1%-70%.
  • the composition or formulation to be administered will contain a quantity of a compound(s) according to the invention in an amount effective to treat the disease/condition of the subject being treated, e.g., atherosclerosis.
  • kits comprises two separate pharmaceutical compositions: a compound of the present invention, a prodrug thereof or a salt of such compound or prodrug and a second compound as described above.
  • the kit comprises means for containing the separate compositions such as a container, a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components.
  • kits 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.
  • An example of such a kit is a so-called blister pack.
  • 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.
  • 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.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a 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 compounds 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 this invention.
  • Formulation 1 Gelatin Capsules
  • Hard gelatin capsules are prepared using the following: Ingredient Quantity (mg/capsule)
  • a tablet formulation is prepared using the ingredients below: Formulation 2: 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.
  • the active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form 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
  • 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 solution of the above ingredients is intravenously administered to a patient at a rate of about 1 mL per minute.
  • Soft gelatin capsules are prepared using the following: Formulation 8: Soft Gelatin Capsule with Oil Formulation
  • the active ingredient above may also be a combination of agents.
  • GENERAL EXPERIMENTAL PROCEDURES The following examples are put forth so as to provide those of ordinary skill in the art with a disclosure and description of how the compounds, compositions, and methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Unless indicated otherwise, percent is percent by weight given the component and the total weight of the composition, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. Commercial reagents were utilized without further purification. Room or ambient temperature refers to 20-25 °C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields.
  • 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, multiple! 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 II 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
  • the expected intensity ratio was observed (approximately 3:1 for 35 CI/ 37 CI-containing ions and 1 :1 for 79 Br/ 81 Br-containing ions) and the position of only the lower mass ion is given.
  • Preparative HPLC-MS was performed on an identical system, modified with a QP- 8000 mass spectrometer operating in positive or negative single ion monitoring mode, utilizing electrospray ionization or atmospheric pressure chemical ionization. Elution was carried out using water/acetonitrile gradients containing either 0.1% formic acid or ammonium hydroxide as a modifier.
  • typical columns used include Waters Symmetry C8, 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).
  • Phenomenex Synergi Max-RP 4 ⁇ m, 21.2x50mm or 30x50mm columns were used.
  • 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.
  • the solvent was removed under vacuum, the residue dissolved in methylene chloride (2006ml), and the solution was washed with saturated sodium hydrogen carbonate solution.
  • the solvent was removed by distillation at atmospheric pressure and the residue was dissolved in anhydrous ethanol (2688ml) and treated with aqueous sodium hydroxide (62.2gm, 1.55mol).
  • the solvent was removed under vacuum, the residue dissolved in methylene chloride (2000 ml), washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under vacuum to give the title compound as an oil (1219gm) which was used without further purification in the following procedure.
  • a 6 % aqueous sodium hypochlorite solution (7748ml), which had been buffered to pH 8.6 to 9.5 with solid sodium hydrogen carbonate (78gm), was slowly added at 0 to 5°C.
  • the aqueous layer was washed with methylene chloride (1208ml).
  • the combined organic layers were washed with 1.
  • N hydrochloric acid 1493ml to which potassium iodide (12.8gm, 0.076moles) had been added, then aqueous sodium thiosulfate (60.8gm, 0.381 mol) dissolved in water (1208ml) and finally water (1691 ml).
  • the organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness under vacuum to give the title compound as a yellow oil (1193gm).
  • Preparation 12 4-Chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Method 1)
  • the product from the previous preparation (Preparation 11 , 2.83mmol) was dissolved in anhydrous methylene chloride (30mL), cooled to 0°C and triethylamine (LOmL, 7.17mmol) followed by methanesulfonyl chloride (245 ⁇ l, 3.16mmol) were added.
  • the catalyst was removed by filtration through Celite® and the solvent was removed under vacuum. The residue was chromatographed on silica eluting with an ethyl acetate - hexanes gradient from 0% to 10% to give the title compounds.
  • Example 10 Further elution of the silica column with ethyl acetate - hexanes (1 :4) provided the title compound of Example 10 as a yellow oil (54mg).
  • Trimethyloxonium tetrafluoroborate (1.29gm, 8.76mmol, 1.26 eq) was added to the solution followed by 12.2mL more of methylene chloride. After 12 hr at ambient temperature the reaction mixture was concentrated to dryness and used without further purification. The product (2.84gm, 6.95mmol, 1 eq) was dissolved in water (20mL) and stirred for several hours at room temperature. The mixture was saturated with sodium chloride solution, extracted 3 times with ethyl acetate, dried over sodium sulfate, filtered and concentrated to dryness. Flash chromatography eluting with 80/20 hexanes/ethyl acetate provided the title compounds (1.65gm, 4.88mmol, 70% yield). LCMS (ESI+): 338 (MH+).
  • reaction mixture was cooled to 0 °C, and di-/so- propylethylamine (0.18gm, 2.0mmol, 1.3 eq) was added followed by addition of N,0- di-methylhydroxylamine hydrochloride (1.1 eq), 4-dimethylaminopyridine (0.1 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 eq).
  • the reaction mixture was stirred at room temperature. After 12 hr, the reaction mixture was quenched with water and extracted 3 times with ethyl acetate. The organic layers were collected, dried, filtered, and concentrated to provide the title compounds (0.56gm, 1.52mmol, 98% yield) that were used without further purification.
  • reaction mixture was concentrated to a minimum volume and partitioned between 1.0 N aqueous sodium hydroxide and diethyl ether.
  • the aqueous layer was collected, acidified with concentrated hydrochloric acid and extracted with ethyl acetate.
  • the organic layer was collected, dried over magnesium sulfate, filtered and concentrated to provide the title compounds (0.067gm, 0.194mmol, 99% yield).
  • Method B A mixture of (RS)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1 -carboxylic acid ethyl ester (652mg, 1eq, 2.5mmol), bromo-4-(3,5-bis-trifluoromethyl- phenyl)-acetic acid methyl ester (1.0gm, 1.1 eq, 2.74mmol) and 2,6-lutidine (0.87mL, 3eq, 7.47mmol) in dimethylformamide (3mL) were stirred at room temperature for 24 hours. The mixture was partitioned between methylene chloride and water, and the phases were separated.
  • the reaction was partitioned between ethyl acetate and water, and the phases were separated.
  • the aqueous phase was extracted 3 times with ethyl acetate, and the combined organic extracts were washed 2 times with water, 1 time with brine, dried over anhydrous sodium sulfate, filtered and evaporated.
  • Chromatography on silica gel using a gradient of 10-30% ethyl acetate in hexanes as eluant provided the desired nitrile as a mixture of two diastereoisomers (1.5:1)(900mg, 29%).
  • Method B A mixture of 2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester (1g, 1eq, 3.81 mmol), 3,5-bis-(trifluoromethyl-phenyl)- bromo-acetonitrile (Preparation 40, 1.27gm, 1eq, 3.81 mmol) and 2,6-lutidine (3eq, 11.43mmol) in N,N-dimethylformamide (5mL) was stirred at room temperature for 24 hours. The reaction was partitioned between ethyl acetate and water, and the phases were separated.
  • the solutions were evaporated using a Genevac Mega660 centrifugal evaporator (Genevac Ltd.. Suffolk, UK) and the residues were redissolved in dimethyl sulfoxide (0.2mL) and purified using the Shimadzu preparative HPLC system (Shimadzu Corporation, Kyoto, Japan) eluting with a 30-100%) acetonitrile/water/0.1% formic acid gradient on a 19x50mm Waters Symmetry Column (Waters Corp, Milford, MA) ⁇ min run, 6 min gradient, 25mL/min, UV triggered collection, observing at 210nm.
  • the product-containing fractions were evaporated to dryness using the Genevac Mega660 centrifugal evaporator (Genevac Ltd., Suffolk, UK).
  • Examples 1 ⁇ 4-409 were made as racemic mixtures in an analogous manner to Example 183:

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EP04720668A 2003-03-28 2004-03-15 1,2,4-substituierte 1,2,3,4-tetrahydro- und 1,2 dihydro-chinolin und 1,2,3,4-tetrahydrochinoxalinderivate als cetp-inhibitoren zur behandlung von atherosklerose und obesitas Withdrawn EP1622872A1 (de)

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MA27828A1 (fr) 2006-04-03
WO2004085401A1 (en) 2004-10-07
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BRPI0408897A (pt) 2006-04-18
CN1795177A (zh) 2006-06-28
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WO2004085401A8 (en) 2005-12-01
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OA13153A (en) 2006-12-13
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