WO2004085401A1 - 1,2,4-substituted 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity - Google Patents

1,2,4-substituted 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity Download PDF

Info

Publication number
WO2004085401A1
WO2004085401A1 PCT/IB2004/000836 IB2004000836W WO2004085401A1 WO 2004085401 A1 WO2004085401 A1 WO 2004085401A1 IB 2004000836 W IB2004000836 W IB 2004000836W WO 2004085401 A1 WO2004085401 A1 WO 2004085401A1
Authority
WO
WIPO (PCT)
Prior art keywords
trifluoromethyl
methyl
bis
phenyl
substituted
Prior art date
Application number
PCT/IB2004/000836
Other languages
French (fr)
Other versions
WO2004085401A8 (en
Inventor
George Chang
Mary Theresa Didiuk
Jari Ilmari Finneman
Ravi Shanker Garigipati
Ryan Michael Kelley
David Austen Perry
Roger Benjamin Ruggeri
Bruce Michael Bechle
Michael P. Pollastri
Original Assignee
Pfizer Products Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to EP04720668A priority Critical patent/EP1622872A1/en
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Priority to CA002520405A priority patent/CA2520405A1/en
Priority to EA200501376A priority patent/EA200501376A1/en
Priority to BRPI0408897-2A priority patent/BRPI0408897A/en
Priority to JP2006506369A priority patent/JP2006521344A/en
Priority to AU2004224082A priority patent/AU2004224082A1/en
Priority to MXPA05010456A priority patent/MXPA05010456A/en
Publication of WO2004085401A1 publication Critical patent/WO2004085401A1/en
Priority to IS8021A priority patent/IS8021A/en
Priority to HR20050859A priority patent/HRP20050859A2/en
Priority to TNP2005000243A priority patent/TNSN05243A1/en
Priority to NO20054989A priority patent/NO20054989L/en
Publication of WO2004085401A8 publication Critical patent/WO2004085401A8/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • 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
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • 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
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Toxicology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Biochemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Quinoline and quinoxaline compounds of formula I and III wherein the subtituent are as defined in claims 1 and 15, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

Description

1,2,4-SUBSTITTJERTE 1,2,3,4-TETRAHYDRO-AND 1,2 DIHYDRO-QUINOLINE AND 1,2,3,4- TETRAHYDRO-QUINOXALINE DERIVATIVES AS CETP INHIBITORS FOR THE TREATMENT OF ATHEROSCLEROSIS AND OBESITY
BACKGROUND OF INVENTION 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.
Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease
(CHD) remains the most common cause of death in the U.S., where cardiovascular disease accounts for 44% of all deaths, with 53% of these associated with atherosclerotic coronary heart disease.
Risk for development of this condition has been shown to be strongly correlated with certain plasma lipid levels. While elevated LDL-C may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to CHD. Low HDL-C is also a known risk factor for CHD (Gordon, D.J., et al.,: "High-density Lipoprotein Cholesterol and Cardiovascular Disease", Circulation, (1989), 79: 8-15). High LDL-cholesterol and triglyceride levels are positively correlated, while high levels of HDL-cholesterol are negatively correlated with the risk for developing cardiovascular diseases. Thus, dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations.
Among the many factors controlling plasma levels of these disease dependent principles, cholesteryl ester transfer protein (CETP) activity affects all three. The role of this 70,000 dalton plasma glycoprotein found in a number of animal species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. 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.
No wholly satisfactory HDL-elevating therapies are on the market today. Niacin can significantly increase HDL, but has serious toleration issues which reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL-C, but in some patients, the result is an increase of modest porportions (-10-12%). As a result, there is an unmet medical need for an approved therapeutic agent that elevates plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.
Thus, although there are a variety of anti-atherosclerosis therapies, there is a continuing need and a continuing search in this field of art for alternative therapies.
SUMMARY OF THE INVENTION This invention is directed to compounds according to Formula I
Figure imgf000004_0001
Formula I
Wherein 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;
R1 is Y, W-X or W-Y1; 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 chain is optionally mono-substituted with Z; and Y1 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 chain is optionally mono-substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C2-C6)alkenyl, (CrC-e) alkyl, hydroxy, (C C6)alkoxy, (C1-C_1)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino wherein said (C C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C C6)alkoxy, (C -C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino, said (C C6)alkyl or (C C6)alkoxy substituent is also optionally substituted with from one to nine fluorines;
R2 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 R2 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 R2 ring is optionally attached through (C C4)alkyl; wherein said R2 ring is optionally mono-, di- or tri-substituted independently with halo, (C2-C6)alkenyl, (C C6) alkyl, hydroxy, (C C6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino wherein said (C-ι-C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (Cι-C6)alkoxy, (C C4)alkylthio, oxo or (C C6)alkyloxycarbonyl;
R3 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 R3 carbon adjacent to C4a; provided that in R3 , when J is carbon, it is other than C4a that is optionally replaced with one heteroatom; and provided that in R3, when J is nitrogen, it is other than C4a that is optionally replaced with a heteroatom and it is other than C4a that is optionally mono-substituted with hydroxy or nitrogen; wherein V is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four 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 R3 group; a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; or a tricyclic ring consisting of three fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said V substituent is optionally mono-, di-, tri-, tetra- or penta-substituted independently with V1, (C C6)alkyl-V1, C(O)-V1, O-(C0-C6)alkyl-V1, (CrC6)alkyl-O-V1, C(O)-mono-N- or di-N,N-(C C6)alkyl-V1, halo, (CrC6)alkyl, (C2-C6)alkenyl, hydroxy, (C-,-Cβ)alkoxy, (C1-C4)alkylthio, (C C4)alkylsulfinyl, (C C4)alkylsulfonyl, mono-N- or di-N,N-(C1-C6)alkylsulfonyl, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di- N,N-(C C6) alkylcarboxamoyl, carboxy, (C-r alkyloxycarbonyl, mono-N- or di-N,N- (C C6)alkylamino, wherein said (CrC6)alkyl or (C2-C6)alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C C6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino, wherein each (C C6)alkyl, (C C6)alkoxy, (C C4)alkylthio, (CrC4)alkylsulfonyl or (C2-C6)alkenyl substituents are also optionally substituted with from one to nine fluorines; wherein V1 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, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said V1 substituent is optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (C C6)alkyl, (C C6)alkoxy, hydroxy, oxo, amino, nitro, cyano, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino wherein said (C C6)alkyl substituent is optionally mono-substituted with oxo, said (CrC6)alkyl or (C C6)alkoxy substituent is also optionally substituted with from one to nine fluorines; and each of R4, R5, R6 and R7are independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T or a partially saturated, fully saturated or fully unsaturated (C C12) straight or branched carbon chain wherein each carbon may optionally be replaced with one or two heteroatoms per carbon chain wherein the heteroatoms are selected independently from oxygen, sulfur and nitrogen, wherein 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 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 optionally mono-substituted with T; wherein T is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said T substituent is optionally mono-, di- or tri-substituted independently with halo, (C C6)alkyl, (C2-C6)alkenyl, hydroxy, (CrC6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino wherein said (C C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C C6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(Cr C6)alkylamino, said (C C6)alkyl or (C C6)alkoxy substituent also optionally has from one to nine fluorines;
R4and R5, R5 and R6, and/or R6 and R7 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 R4 and R5, or R5 and R6, and/or R6 and R7 is optionally mono-, di- or tri-substituted independently with halo, (C C6)alkyl, (C C4)alkylsulfonyl, (C2-C6)alkenyl, hydroxy, (C C6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino wherein said (C C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C C6)alkoxy, (CrC4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C-ι- C6)alkylamino, said (C C6)alkyl substituent also optionally has from one to nine fluorines; or a pharmaceutically acceptable salt or prodrug thereof; with the following provisos: a) when there is a single bond between C3 and J, and R3 is a fully saturated one to six membered straight or branched carbon chain substituted on C4a with V then R1 is other than C(O)-(C C4)alkyl optionally mono-, di- or tri-substituted with halo and R1 is other than C(O)-monocyclicaromatic ring; or b) when there is a single bond between C3 and J, and R3 is -C(O)-O-V, and R2 is phenyl then R1 is other than (d-C4)alkyl; and c) when there is a double bond between C3 and J, and R2 is methyl then R3 is other than -CH2-O-V, -CH2-V or -CH2-CH2-V.
Furthermore, the present invention is directed to compounds according to Formula II
Figure imgf000009_0001
Formula II wherein R1 is W-X; W is carbonyl;
X is -O-Y;
Y for each occurrence is independently (C C6)alkyl, said (CrC6)alkyl optionally having one to nine fluorines or said (C C6)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 C4)alkyl, (CrC )alkoxy, (C1-C4)alkylthio, nitro, cyano, oxo, or (C C4)alkyloxycarbonyl, said (C-ι-C4)alkyl optionally substituted with from one to nine fluorines;
R2 is a partially saturated, fully saturated or fully unsaturated (C C4) 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 R2 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 R2 ring is optionally mono-, di- or tri-substituted independently with halo or (C C6)alkoxy; wherein R3 is -CH2NR8R9 or -C(O)NR8R9; wherein R8and R9are independently hydrogen or a (C C2) straight carbon chain wherein at least one of R8 and R9 are not hydrogen and wherein said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon, other than the connecting carbon, is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, and said carbon chain is optionally mono, di-, or tri-substituted with V3, wherein either R8 or R9 is substituted with V3, or both R8 and R9 is substituted with V3; wherein V3is 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, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said V3 substituent is optionally mono-, di-, tri-, tetra- or penta- substituted independently with V4, (CrC6)alkyl-V4, C(O)-V4, O-(C0-C6)alkyl-V4, (C C6)alkyl-O-V4, halo, (C C6)alkyl, (CrC6)alkoxy, hydroxy, oxo, amino, nitro, cyano, (d-C4)alkylthio, (C C )alkylsulfinyl, (CrC4)alkylsulfonyl, mono-N- or di-N,N-(C C6)alkylsulfonyl, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino, wherein said (C C6)alkyl substituent is optionally mono-substituted with oxo, wherein said (Cι-C6)alkyl substituent is optionally mono-substituted with hydroxy, said (C C6)alkyl or (C C6)alkoxy substituents are also optionally substituted with from one to nine fluorines; wherein V4is 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, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said V4 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (CrC6)alkyl, (C C6)alkoxy, hydroxy, oxo, amino, nitro, cyano, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(Cι-C6)alkylamino wherein said (C1-C6)alkyl substituent is optionally mono-substituted with oxo, said (Cι-C6)alkyl or (C C6)alkoxy substituent is also optionally substituted with from one to nine fluorines; or wherein R8and R9 are taken together to form a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur, and nitrogen or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, selected independently from nitrogen, sulfur and oxygen; R4 is hydrogen;
R5 and R6 are each independently hydrogen, halo, T, (C C6)alkoxy or (C C6)alkyl, said (C C6)alkoxy or (C C6)alkyl substituent optionally having from one to nine fluorines or said (CrC6)alkoxy or (C C6)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 C6)alkyl, hydroxy, (Cι-C6)alkoxy, (CrC4)alkylthio, amino, oxo, carboxy, (CrC6)alkyloxycarbonyl, mono-N- or di-N,N-(Cι-C6)alkylamino wherein said (GτG6)alkyl substituent optionally has from one to nine fluorines;
R7 is hydrogen; or a pharmaceutically acceptable salt or prodrug thereof.
In addition, the present invention provides compounds of Formula III
Figure imgf000011_0001
Formula III wherein
C3 is carbon;
J is carbon, wherein the bond between C3 and J is a single or double bond; 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;
R2 is (C C4)alkyl, cyclopropyl or cyclobutyl;
R5 is CF3;
R6 is hydrogen; R10 is a fully saturated (C C4) straight or branched carbon chain; R11 js halo, hydroxy, -C(O)(O(C C4)alkyl), -C(O)C(O)(O(C C4)alkyl), - C(O)NH(O(C1-C4)alkyl), or -C(0)N((C C4)alkyl)(O(CrC4)alkyl);
R12 is hydrogen or halo, wherein R 1 is not halo when R12 is halo; or R11 and R12 are taken together to form oxo or N2; or a pharmaceutically acceptable salt or prodrug thereof.
In addition, 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.
In addition, the present invention provides pharmaceutical 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.
In addition, 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. Moreover, 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 a pharmaceutical vehicle, diluent or carrier. This composition may be used to treat the aforementioned diseases, including atherosclerosis. Also, 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.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
DETAILED DESCRIPTION OF THE INVENTION
The present invention may be understood more readily by reference to the following detailed description of exemplary embodiments of the invention and the examples included therein.
Before the present compounds, compositions and methods are disclosed and described, it is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the present invention. 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.
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.
The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Hydrates and solvates of the compounds of this invention are also included.
Where the compounds of the present invention possess two or more stereogenic centers and the absolute or relative stereochemistry is given in the name, the designations 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. Where 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. The term "cis" refers to the orientation of two substituents with reference to each other and the plane of the ring (either both "up" or both "down"). Analogously, the term "trans" refers to the orientation of two substituents with reference to each other and the plane of the ring (the substituents being on opposite sides of the ring).
Alpha and Beta refer to the orientation of a substituent with reference to the plane of the ring. Beta is above the plane of the ring and Alpha is below the plane of the ring.
This invention also includes isotopically-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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine such as 2H, 3H, 13C, 14C, 15N, 180, 170, 18F, and 36CI 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. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 4C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., 3H), and carbon-14 (i.e., 14C), isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H), 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. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:
As used herein, the term 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.
The term "treating", "treat" or "treatment" as used herein includes preventative (e.g., prophylactic) and palliative treatment.
By "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. By "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. Various types of tautomerism can occur, including keto-enol, ring- chain and ring-ring tautomerism. The expression "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, (C2-C7)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 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(CrC2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C C2)alkylcarbamoyl-(C C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl. The following paragraphs describe exemplary ring(s) for the generic ring descriptions contained herein.
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 ,3, 4-th iad iazolyl, 1 ,2,3,4-oxatriazolyl, 1 ,2,3,5-oxalriazolyl, 3H-1 ,2,3-dioxazolyl, 1 ,2,4-dioxazolyl, 1 ,3,2-dioxazolyl, 1 ,3,4-dioxazolyl, 5H-1 ,2,5- oxathiazolyl and 1 ,3-oxathiolyl.
Further 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, 4H-1 ,4-oxazinyl, 1 ,2,5- oxathiazinyl, 1 ,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1 ,2,5-oxathiazinyl, 1 ,2,6- oxathiazinyl, 1 ,4,2-oxadiazinyl and 1 ,3,5,2-oxadiazinyl. Further exemplary seven membered rings include azepinyl, oxepinyl, and thiepinyl.
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, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)- pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1 ,3-benzoxazinyl, 2H-1 ,4- benzoxazinyl, 1 H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1 ,2-benzoxazinyl and 4H-1 ,4-benzoxazinyl.
By "alkylene" is meant saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of two adjacent carbons. Exemplary of such groups (assuming the designated length encompasses the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene).
By "halo" or "halogen" is meant chloro, bromo, iodo, or fluoro.
By "alkyl" is meant straight chain saturated hydrocarbon or branched chain saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1- methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
"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. By "alkoxy" is meant straight chain saturated alkyl or branched chain saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy . As used herein the term "mono-N-" or "di-N,N-(CrCx)alkyl" refers to the (C
Cx)alkyl moiety taken independently when it is di-N,N-(CrCx)alkyl (x refers to integers).
References (e.g., claim 1) to "said carbon" in the phrase "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" refers to each of the carbons in the carbon chain including the connecting carbon.
References to a "nitrogen... di-substituted with oxo" herein (e.g., claim 1) 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. For example, the term "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.
As used herein, the expressions "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.
In one embodiment of formula I compounds of the present invention,
J is carbon; R1 is W-X;
W is carbonyl;
X is -O-Y; Y for each occurrence is independently (Cι-C6)alkyl, said (C-i-C6)alkyl optionally having one to nine fluorines or said (CrC6)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, (CrC )alkyl, (C C4)alkoxy, (C C4)alkylthio, nitro, cyano, oxo, or (C C4)alkyloxycarbonyl, said (C C4)alkyl or (C -C4)alkoxy is optionally substituted with from one to nine fluorines;
R2 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 R2 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 R2 ring is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C C6)alkoxy, amino, nitro, (CrC4)alkyloxycarbonyl or carboxy; wherein R3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than C4a, may optionally be replaced with one heteroatom selected 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 cyano, 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 optionally mono, di-, or tri-substituted with V at C4a or at the R3 carbon adjacent to C4a; V is a three, four, 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 R3 group; wherein said V ring is optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (CrC6)alkyl, hydroxy, (C C6)alkoxy, (CrC6)alkoxycarbonyl, nitro, cyano or oxo, wherein said (C C6)alkyl or (C C6)alkoxy substituent optionally has from one to nine fluorines;
R4 is hydrogen;
R5 and R6 are each independently hydrogen, halo, T, (CrC6)alkoxy or (C C6)alkyl, said (CrC6)alkoxy or (C C6)alkyl substituent optionally having from one to nine fluorines or said (C C6)alkoxy or (C1-C6)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 C6)alkyl, hydroxy, (C C6)alkoxy, (C C4)alkylthio, amino, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino wherein said (Cι-C6)alkyl or (C C6)alkoxy substituent optionally has from one to nine fluorines; and
R7 is hydrogen.
In another embodiment of formula I compounds of the present invention, Y is (Cι-C4)alkyl, wherein said (CrC4)alkyl substituent optionally has one to nine fluorines;
R2 is (CrC4)alkyl, cyclopropyl or cyclobutyl;
R3 is -((C C4)alkyl)(NH2)(V), -((C1-C3)alkyl)(NH(C1-C2)alkyl))(V), -((C C4)alkyl)(OH)(V), -((C C4)alkyl)(F)(V), -((C1-C2)alkyl)(O-C(O)(C1-C2)alkyl)(V), -C(O)- V, -C(OH)(C(O)O(C C3)alkyl)(V), -CF2(V), -((C1-C2)alkyl)(NHC(O)(C1-C2)alkyl)(V), - CH2(V), -((C1-C2)alkyl)(C(O)O(C1-C2)alkyl)(V), -((C1-C4)alkyl)(C(O)NH2)(V) -((C1- C4)alkyl)(CN)(V), or-((C1-C3)alkyl)((C1-C3)alkoxy)(V),
V is phenyl optionally mono-, di- or tri-substituted independently with halo, (C1-C6)alkyl, hydroxy, (CrC6)alkoxy, nitro, cyano or oxo wherein said (CrC^alkyl or (C1-C6)alkoxy substituent optionally has from one to nine fluorines;
R5 and R6 are each independently hydrogen, halo, (C C3)alkoxy or (C C6)alkyl, said (C C3)alkoxy optionally having from one to seven halo, said (C C6)alkyl optionally having from one to nine halo.
In a further embodiment of formula I compounds of the present invention, Y is methyl, ethyl, 1-propyl, 2-propyl or tert-butyl;
R2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl; R3 is -C(O)-V, -C(OH)(C(O)OCH3)(V), -CH(F)(V), -CF2(V), -CH(OCH3)(V), - CH(C(O)OCH3)(V), -CH(CN)(V), -CH(OH)(V), -CH2(V), -CH(NH2)(V), - CH(NH(CH3))(V), -CH(C(O)NH2)(V), -CH(CH2OH)V, -CH(CH2OCH3)V, - CH(CH2OC(O)CH3)V, -CH(CH2F)V, or -CH(CH2NH2)V; and
V is phenyl optionally mono-, di- or tri-substituted independently with halo, nitro, or (CrC2)alkyl, wherein said (C C2)alkyl optionally has from one to five fluorines;
R5 and R6 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.
In another embodiment of the present invention, formula I compounds include substituents wherein
V is ethyl; R2 is ethyl or methyl;
R3 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)-methylamine-methyl; 1 -(3,5-bis- (trifluoromethyl)-phenyl)-2-amino-ethyl; 1-(3,5-bis-(trifluoromethyl)-phenyl)-2-fluoro- ethyl; 1 -(3,5-bis-(trifluoromethyl)-phenyl)-2-methoxy-ethyl; 1 -(3,5-bis-(trifluoromethyl)- phenyl)-2-hydroxy-ethyl; or 2-acetoxy-1 -(3,5-bis-(trifluoromethyl)-phenyl)-ethyl;
R5 is methoxy or trifluoromethyl; and
R6 is hydrogen or methoxy.
In another embodiment of compounds of formula I, the bond between C3 and J is a single bond.
In yet another embodiment of compounds of formula I, the bond between C3 and J is a double bond.
In another embodiment, 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;
(R, S, S)-4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, ?)-4-(3,5-bis-trifluoromethyl-benzyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, ?)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]-
6,7-dimethoxy-2-methyl-2rV-quinoline-1 -carboxylic acid ethyl ester;
(R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 6, 7-dimethoxy-2-methyl-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S, R)- 4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl- methoxycarbonyl- methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[(3,5-bis-triflμoromethyl-phenyl)-hydroxyl-methoxycarbonyl- methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl- methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl- methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6,7- dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, ?)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[2-Acetoxy-1 -(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S, S)-4-[2-Acetoxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-fluoro-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[1 -(3,5-Bis-trif luoromethyl-phenyl)-2-fluoro-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-amino-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-amino-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-elhyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(f?,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S)-4-(3,5-Bis-trifluoromelhyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4- dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester;
(R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester; (R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R)-4-(3,5-bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S)-4-(3,5-bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester; (R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester;
(R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester;
(R,RJS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; and
(R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt or prodrug thereof.
In a further embodiment of compounds of formula I of the present invention, J is nitrogen; the bond between C3 and J is a single bond;
R1 is W-X;
W is carbonyl;
X is -O-Y; Y for each occurrence is independently (d-C-βJalkyl, said (C C6)alkyl optionally having one to nine fluorines or said (CrG6)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 C4)alkoxy, (d-C4)alkylthio, nitro, cyano, oxo, or (C C4)alkyloxycarbonyl, said (C C4)alkyl or (C C4)alkoxy optionally substituted with from one to nine fluorines; R2 is a partially saturated, fully saturated or fully unsaturated (CrC4) straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one heteroatom selected independently from oxygenand 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 monosubstituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo,; or said R2 is a partially saturated, fully saturated or fully unsaturated three to five membered ring optionally having one heteroatom selected independently from oxygenand sulfur; wherein said R2 ring is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C C6)alkoxy, amino, nitro, (C C4)alkyloxycarbonyl or carboxy; wherein R3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than C4a or the R3 carbon adjacent to C4a, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon, other than C4a, is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with cyano, 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 optionally mono, di-, or tri-substituted with V at C4a or at the the R3 carbon adjacent to C4a;
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 R3 group; wherein said V ring is optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (CrC6)alkyl, hydroxy, (C C6)alkoxy, (C C6)alkoxycarbonyl, nitro, cyano or oxo, wherein said (C C6)alkyl or (C C6)alkoxy substituent optionally has from one to nine fluorines; R4 is hydrogen;
R5 and R6 are each independently hydrogen, halo, T, (C C6)alkoxy or (C C6)alkyl, said (C C6)alkoxy or (C C6)alkyl substituent optionally having from one to nine fluorines or said (CrC6)alkoxy or (C C6)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 C6)alkyl, hydroxy, (C C6)alkoxy, (C C )alkylthio, amino, oxo, carboxy, (Cι-C6)alkyloxycarbonyl, mono-N- or di-N,N-(CrC6)alkylamino wherein said (C C6)alkyl or (C C6)alkoxy substituent optionally has from one to nine fluorines;
R7 is hydrogen. In a further embodiment of compounds of formula I of the present invention,
Y is (CrC4)alkyl, wherein said (C C4)alkyl substituent optionally has one to nine fluorines;
R2 is (C C4)alkyl, cyclopropyl or cyclobutyl; R3 is -C(O)-V, -CH(C(O)O(C C3)alkyl)(V), or -CH(CN)(V); V is phenyl optionally mono-, di- or tri-substituted independently with halo,
(C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, nitro, cyano or oxo wherein said (C C6)alkyl substituent optionally has from one to nine fluorines;
R5 and R6 are each independently hydrogen, (Cι-C3)alkoxy or (CrC6)alkyl, said (C C3)alkoxy optionally having from one to nine fluorines, said (C-ι-C6)alkyl optionally having from one to seven fluorines; or a pharmaceutically acceptable salt thereof.
In a further embodiment of compounds of formula I of the present invention,
Y is methyl, ethyl, 1-propyl, 2-propyl or tert-butyl;
R2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl; R3 is 3,5-bis-trifluoromethyl-benzoyl, (3,5-bis-trifluoromethyl-phenyl)-cyano- methyl, or (3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl;
R5 is methyl or trifluoromethyl;
R6 is hydrogen or methyl.
In yet another embodiment of formula I compounds, the compound is selected from the group consisting of:
(R)-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl- 3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl-
3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid methyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-
6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid methyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester;
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; and
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt or prodrug thereof.
Moreover, 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.
In another embodiment, atherosclerosis is treated.
In another embodiment, peripheral vascular disease is treated. In another embodiment, dyslipidemia is treated.
In another embodiment, hyperbetalipoproteinemia is treated.
In another embodiment, hypoalphalipoproteinemia is treated.
In another embodiment, familial-hypercholesterolemia is treated.
In another embodiment, coronary artery disease is treated. In another embodiment, myocardial infarction is treated. Furthermore, 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.
In one embodiment, 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. In another embodiment, 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. In another embodiment, the present invention includes 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. In another embodiment, the present invention includes a pharmaceutical combination composition wherein the second compound is an HMG-CoA reductase inhibitor or a PPAR modulator. In another embodiment, the present invention includes a pharmaceutical combination composition wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.
In another embodiment, the present invention includes a pharmaceutical combination composition further comprising a cholesterol absorption inhibitor. In another embodiment, 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.
In another embodiment, 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.
In another embodiment, the present invention includes a method for treating atherosclerosis wherein the method further comprises administering a cholesterol absorption inhibitor. In another embodiment, 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. In another embodiment, the present invention includes a kit wherein said second compound is an HMG-CoA reductase inhibitor or a PPAR modulator.
In a further embodiment, the present invention includes a kit wherein said second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.
In another embodiment, the present invention includes a kit that further comprises a cholesterol absorption inhibitor. In another embodiment, 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;
4-Bromo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
4-Diazo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
4-Chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 ,4-dicarboxylic acid 1 -ethyl ester 4-methyl ester;
2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 ,4-dicarboxylic acid-1 -ethyl ester-4-methyl ester; 2-Ethyl-4-(methoxy-methyl-carbamoyl)-6-trifluoromethyll-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester;
2-Ethyl-6-trifluoromethyl-2H-quinoline-1 ,4-dicarboxylic acid-1 -ethyl ester-4-methyl ester;
4-Chloro-2-ethyl-4-methoxycarboncarbonyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester;
2-Ethyl-4-methoxycarboncarbonyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid-ethyl ester;
4-Diazo-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; 6,7-Dimethoxy-4-methoxycarboncarbonyl-2-methyl- 2H-quinoline-1-carboxylic acid-ethyl ester;
6,7-Dimethoxy- 2-methyl- 3,4-dihydro-2H-quinoline-1 ,4-dicarboxylic acid-1 -ethyl ester-4-methyl ester; 6,7-Dimethoxy-4-(methoxy-methyl-carbamoyl)-2-methyl-3,4-dihydro-2H-quinoline-
1 -carboxylic acid ethyl ester;
2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid methyl ester;
2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid methyl ester; 2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid
1 -propyl ester;
2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid 1 - propyl ester;
2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid 2- propyl ester;
2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid 2- propyl ester;
2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid tert-butyl ester; 2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid tert- butyl ester; and
2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 ,4-dicarboxylic acid-1 -ethyl ester-4-methyl ester.
In general, 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.
The Reaction Schemes herein described are intended to provide a general description of the methodology employed in the preparation of many of the Examples given. However, it will be evident from the detailed descriptions given in the Experimental section that the modes of preparation employed extend further than the general procedures described herein. In particular, it is noted that the compounds prepared according to these Schemes may be modified further to provide new Examples within the scope of this invention. For example, an ester functionality may be reacted further using procedures well known to those skilled in the art to give another ester, an amide, a carbinol or a ketone.
SCHEME 1
Figure imgf000035_0001
IX VIII VI
Figure imgf000035_0002
SCHEME 1 According to reaction Scheme 1 , the desired compounds wherein J is carbon, the optional double bond is absent, R3 is a group CH(V)(L) wherein L is a (C C6) alkoxycarbonyl group and V, R1, R2, R4, R5, R6, and R7 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 R3 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 R2 and R3 groups are cis to one another. The desired Formula III compounds wherein L, V, R1, R2, R4, R5, R6, and R7 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. 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.
The desired Formula IV compounds wherein L is a (C C6) alkoxycarbonyl group and V, R1, R2, R4, R5, R6, and R7 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.
The desired Formula V compounds wherein L is a (C-|-C6) alkoxycarbonyl group and R1, R2, R4, R5, R6, and R7 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. Depending on the nature of the substitutents on the Formula VI compounds and the nature of L, the Formula V compound may be obtained as a mixture with the corresponding Formula VII compound.
The desired Formula VI compounds wherein R1, R2, R4, R5, R6, and R7 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.
The desired Formula VIII compounds wherein R1, R2, R4, R5, R6, and R7 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. 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. An alternative preparation of the desired Formula II compounds wherein L is a
(C C6) alkoxycarbonyl group and V, R1, R2, R4, R5, R6, and R7 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. 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.
The desired Formula X compounds wherein L is a (Cι-C6) alkoxycarbonyl group and V, R1, R2, R4, R5, R6, and R7 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. The desired Formula XI compounds wherein L is a (C C6) alkoxycarbonyl group and R1, R2, R4, R5, R6, and R7 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~ι-C6) alkoxycarbonyl group and V, R1, R2, R4, R5, R6, and R7 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.
Another alternative preparation of the desired Formula X compounds wherein L is a (C C6) alkoxycarbonyl group and V, R1, R2, R4, R5, R6, and R7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula IV compounds by reduction of the double bond. 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. 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 C6) alkoxycarbonyl group, K is a leaving group such as chlorine or bromine, and V, R1, R2, R4, R5, R6, and R7 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.
As referred to above, the desired Formula VII compounds wherein L is a (C C6) alkoxycarbonyl group, K is a leaving group such as chlorine or bromine, and R1, R2, R4, R5, R6, and R7 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. Depending on the nature of the substitutents on the Formula VI compounds and the nature of L, 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 C6) alkoxy group and R1, R2, R4, R5, R6, and R7 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.
The desired Formula XIV compounds wherein M is a (CrC6) alkoxy group and R1, R2, R4, R5, R6, and R7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula XIII compounds by hydrogenolysis. 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. Alternatively, 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. The desired Formula XV compounds wherein R1, R2, R4, R5, R6, and R7 are as described above may be prepared by hydrolysis of the ester group of the Formula XIV compounds, using methods well known to those skilled in the arts, such as can be found in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995, for example, by treatment 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 desired Formula XV compounds.
SCHEME 2
Figure imgf000041_0001
XXVIII
SCHEME 2 According to reaction Scheme 2, the desired compounds wherein J is carbon, the optional double bond is absent, R3 is a group CH(V)(L) wherein L is a (CrC6) alkoxycarbonyl group or a cyano group and V, R , R2, R4, R5, R6, and R7 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 VCH2L in the presence of a suitable base such as 1 ,8- diazab'ιcyclo[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 R1, R2, R4, R5, R6, and R7 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. Other 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 R1, R2, R4, R5, R6, and R7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula IX compounds by reduction of the carbonyl group using methods and reagents well known to those skilled in the arts, such as can be found in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995, for example using sodium borohydride in an alcohol solvent such as methanol of ethanol at a temperature between 0°C to 60°C, typically ambient or using potassium tri-sec-butylborohydride (K-Selectride®) in a reaction inert solvent such as tetrahydrofuran or diethyl ether at a temperature between -78°C to 25°C, typically 0°C.
In an alternative procedure, the desired Formula XVIII compounds wherein R1, R2, R4, R5, R6, and R7 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. Methods for the preparation of Formula XIX compounds are described in US Patent 6197786 and International Application WO 0140190.
The desired Formula IX compounds wherein R1 is an alkoxycarbonyl group and R2, R4, R5, R6, and R7 are as described above may be prepared from the corresponding 4-methoxyquinoline compounds of Formula XX by treatment with an organomagnesium derivative of the R2 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. In an alternative procedure, the desired Formula IX compounds wherein R1,
R2, R4, R5, R6, and R7 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. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995, for example pyridinium chlorochromate, aqueous sodium hypochlorite in the presence of a catalytic amount of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) free radical and catalytic potassium bromide in a suitable reaction inert solvent such as methylene chloride, or alternatively with acetic anhydride and dimethylsulfoxide. The desired Formula XXI compounds wherein R1, R2, R4, R5, R6, R7 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. The resulting solution is concentrated to dryness and added directly without further purification to 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.
The desired Formula XXII compounds wherein R1, R2, R4, R5, R6, R7 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. Alternatively, the desired Formula XXII compounds wherein R1, R2, R4, R5, R6,
R7 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.
The desired Formula XXIII compounds wherein R1, R2, R4, R5, R6, R7 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.
The desired Formula XXIV compounds wherein R1, R2, R4, R5, R6, R7, R8 and R9 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 (NHR8R9) 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). The desired Formula XXV compounds wherein R1, R2, R4, R5, R6, R7are as described above and V2 is a group V or CH2V where V is as described above may be prepared from the corresponding Formula XXIV compounds when R8 is methyl and R9 is methoxy (the 'Weinreb' amide) by treatment with a variety of V2Met compounds where Met is a metal, preferably magnesium or lithium, to produce the desired Formula XXV compounds.
The desired Formula XXVI compounds wherein R1, R2, R4, R5, R6, R7, R8 and R9 (which are within the scope of the present invention) are as described above 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). When R8 and/or R9 is H, 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.
An alternative preparation of the desired Formula XXVI compounds wherein R1, R2, R4, R5, R6 and R7 are as described above and R8 and R9 are H involves reduction of the corresponding Formula XXII compounds using procedures 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, for example using borane-tetrahydrofuran complex in a reaction inert solvent. These primary amines may subsequently be converted to amides as described above to produce further compounds within the scope of the present invention. The desired Formula XXVII compounds wherein R1, R2, R4, R5, R6, R7and V2 are as described above and X1 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 X1 is OH.
Formula XXVII compounds when X1=N may be prepared from the corresponding alcohol (X1=OH) which is converted to the mesylate and displaced with sodium azide. The azide is hydrogenated to NH2. One skilled in the art can convert NH2 to NR1H by standard reductive amination conditions using the correspounding aldehyde and reducing agent, such as sodium borohydride or sodium cyano borohydrite. NR1H can be converted to NR1R2 using the same conditions of reductive amination to produce NR1R2.
Moreover, when X1 is NH2, the corresponding alcohol (X1=OH) may be converted to the mesylate, displaced with an azide and reduced with hydrogen to produce one single diastereomer. When X1 is NHR1 (R1=Me), the corresponding primary amine NH2 may be converted to NHR1 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. When X1 is NHR1, the corresponding primary amine NH2 may be converted to NHR1 by standard reductive amination conditions by treatment with an aldehyde R1 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). When X1 is NR1R2, the corresponding secondary amine NHR1 may be converted to NR1R2by standard reductive as described above. Compound XXV may also be converted to NH2, NHR1, and NR R2 by standard reductive amination conditions with the corresponding aldehyde or ketone as described above. This method produces a mixture of amine diastereomers that may be separated by silica gel chromatography.
These may be converted to the corresponding Formula XXVI I compounds where X1 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). These may be converted to the corresponding Formula XXVII compounds wherein X1 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. The desired Formula XXVIII compounds wherein R1, R2, R4, R5, R6, R7are as described above and V2 is a group V or CH2V 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).
SCHEME 3
Figure imgf000047_0001
xxx XXIX
Figure imgf000047_0002
XXXII XXXIII
Figure imgf000047_0003
xxxiv xxxv
SCHEME 3
According to Scheme 3, the desired Formula XXIX compounds wherein J is nitrogen, the optional double bond is absent, and R2, R4, R5, R6, and R7 are as described above, may be prepared from the corresponding Formula XXX compounds by reaction with an alpha-ketocarboxylic acid R2COCO2H in a protic solvent, such as ethanol or methanol at high temperature. 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 R2, R4, R5, R6, and R7 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. Typically 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 NaHCO3. The resulting aqueous suspension is extracted with an appropriate organic solvent, preferably methylene chloride.
The desired Formula XXXII compounds wherein R2, R4, R5, R6, and R7 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. Typically, 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 R2, R4, R5, R6, and R7 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 R1, R2, R4, R5, R6, and R7 are as described above may be prepared from the corresponding Formula XXXIII compounds by introducing the acyl, carbamoyl, sulfinyl or sulfonyl group R1. 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 R1, R2, R4, R5, R6, and R7 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. In a typical procedure, the bis-carbamate is treated with trifluoroacetic acid at ambient temperature for 1-24hr, typically 3hr. Upon completion, 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.
SCHEME 4
Figure imgf000050_0001
LI
Figure imgf000050_0002
XXXVII
XXXVIII XXXV
Figure imgf000050_0003
XXXVI
SCHEME 4 According to Scheme 4, the desired compounds wherein J is nitrogen, the optional double bond is absent, R1, R2, R4, R5, R6 and R7 are as described above and R3 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. Upon completion of the reaction, the mixture is washed with aqueous acid and brine to afford the Formula XXXVI compounds after silica gel chromatography. If desired, 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 R1, R2, R4, R5, R6, and R7 are as described above and R3 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. Due to the unreactivity of quinoxalines, heating in the microwave at the appropriate temperature is particularly suitable for this procedure. Alkylations can be performed with a variety of alkyl bromides, such as arylmethyl bromides or alpha-substituted arylmethyl bromides. Use of 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 R1, R2, R4, R5, R6, R7and V are as described above may be prepared from the corresponding alpha- bromoester VCHBrCO2Me compounds. 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. Due to the unreactivity of quinoxalines, heating in the microwave at the appropriate temperature is particularly suitable for this procedure. Use of 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 XXXIX compounds, wherein R1, R2, R4, R5, R6, R7and 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. For example, 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. Typically treating the reaction mixture with sodium sulfate hexahydrate or silica gel/chloroform and removal of the solids by filtration gives a crude product from which Formula XXXIX compounds are typically isolated by silica gel chromatography.
The desired Formula L compounds, wherein R1, R2, R4, R5, R6, R7and 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.
The desired Formula LI compounds, wherein R1, R2, R4, R5, R6, R7and 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.
SCHEME 5
Figure imgf000053_0001
LVII LX
SCHEME 5 Scheme 5 describes the preparation of further compounds, in which J is nitrogen and the optional double bond is absent (i.e. quinoxalines), using solid phase chemistry similar to that described by V. Krchnak etal., Tetrahedron Lett. 42, 2443- 2446 (2001), and which offers several advantages. This chemistry can also be carried out in the solution phase by substituting the resin with an electron rich arylmethyl group, such as 4-methoxybenzyl or 2,4-dimethoxybenzyl and using it like a protecting group and cleaving under appropriate conditions as described in T.W. Greene and G.M. Wuts, Protective Groups in Organic Synthesis, Wiley Interscience, 1991. In particular, this scheme provides a method for preparation of chiral quinoxalines from chiral aminoalcohols, which are readily prepared from widely available chiral aminoacids using methods and reagents well known to those skilled in the art.
The resin bound Formula Lll compounds wherein R2, R4, R5, R6and R7are as described above can be prepared from the corresponding aminoalcohol
R2CH(CH2OH)NH2 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.
The desired resin bound Formula LIV compounds, wherein R2, R4, R5, R6, and R7 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. Preferably 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. 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. For example, one can use 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. If one uses 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 R2, R4, R5, R6, R7 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 R2, R4, R5, R6, R7 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. Typically 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 R1, R2, R4, R5, R6, R7 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. At times, the reaction is carried out in pyridine as a solvent. In the particular case where R1 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 R1, R2, R4, R5, R6, and R7 are as described above and R3 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). 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 R1, R2, R4, R5, R6, and R7 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). Typically, 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 R1, R2, R3, R4, R5, R6, and R7 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. At times, the reaction is carried out in pyridine as a solvent. In the particular case when 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.
An alternative preparation of the desired Formula LVI compounds wherein R2, R4, R5, R6, R7 and V are as described above may be achieved from the corresponding Formula XXXV compounds by reaction with an acylating agent such as 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. Typically under these conditions, when R2 is other than hydrogen, 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 R1, R2, R4, R5, R6, R7 are as described above and R3 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.
An alternative preparation of the desired Formula LIX compounds wherein R2, R4, R5, R6, R7 are as described above and R3 is as described above, wherein the group V is attached to the connecting carbon, may be achieved from the corresponding Formula XXXV compounds, via the compounds of Formula LIX, by alkylation with the appropriate alkyl bromides or iodides. These alkylations are typically carried out in a polar solvent such as dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone in the presence of a base (e.g., triethylamine, pyridine, 4- dimethylaminopyridine, lutidine). 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, alpha- substituted arylmethyl bromides. Typically under these conditions, when R2 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 R2, R4, R5, R6, and R7 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.
SCHEME 6
Figure imgf000058_0001
IV LXII I
SCHEME 6
According to reaction Scheme 6, the desired compounds wherein J is carbon, the optional double bond is present, R3 is a group COV and V, R1, R2, R4, R5, R6, and R7 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. For example the 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.
The desired Formula LXII compounds wherein V, R1, R2, R4, R5, R6, and R7 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. In some cases, it is convenient to add the transmetallation agent to a mixture of the aldehyde and the iodide.
The desired Formula LXI compounds wherein R1, R2, R4, R5, R6, and R7 are as described above can be prepared from the corresponding Formula VIII compounds (prepared as described in Scheme I) using the general procedure described by D.H.R. Barton et al. (Tetrahedron Letters 1983 24, 1605) in which the hydrazone is reacted with iodine in the presence of a suitable hindered base such as 1 ,1,3,3-tetramethylguanidine in a suitable reaction inert solvent such as tetrahydrofuran at a temperature between 25°C to 100°C, typically 25°C to 85°C, removing the solvent in the course of the reaction, to provide the desired product of Formula LXI.
An alternative preparation of the desired Formula IV compounds wherein L is a (C C6)alkoxycarbonyl group and V, R1, R2, R4, R5, R6, and R7 are as described above can be accomplished in a manner similar to that described for the preparation of the Formula LXII compounds 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 ketone of formula VCOL at a temperature between -120°C to 0°C, typically -78°C to - 23°C, to provide the desired product of Formula IV. In some cases, it is convenient to add the transmetallation agent to a mixture of the ketone and the iodide. As an initial note, in the preparation of compounds, it is noted that some of the 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). 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. For example, in the reaction schemes, 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. Alternatively 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.
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. Alternatively, 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. For example, 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. Other pharmaceutical agents would also include the following: a bile acid reuptake inhibitor, 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. This combination therapy is known as ADVICOR® (Kos Pharmaceuticals Inc.) In combination therapy treatment, both the compounds of this invention and the other drug therapies are administered to mammals (e.g., humans, male or female) by conventional methods. Any HMG-CoA reductase inhibitor may be used in the combination aspect of this invention. The term HMG-CoA reductase inhibitor refers to compounds which inhibit the bioconversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such inhibition is readily determined by those skilled in the art according to standard assays (e.g., Meth. Enzymol. 1981 ; 71 :455-509 and references cited therein). A variety of these compounds are described and referenced below however other HMG-CoA reductase inhibitors will be known to those skilled in the art. U.S. Pat. No. 4,231 ,938 (the disclosure of which is hereby incorporated by reference) discloses certain compounds isolated after cultivation of a microorganism belonging to the genus Aspergillus, such as lovastatin. Also, U.S. Pat. No. 4,444,784 (the disclosure of which is hereby incorporated by reference) discloses synthetic derivatives of the aforementioned compounds, such as simvastatin. Also, U.S. Pat No. 4,739,073 (the disclosure of which is incorporated by reference) discloses certain substituted indoles, such as fluvastatin. Also, U.S. Pat. No. 4,346,227 (the disclosure of which is incorporated by reference) discloses ML-236B derivatives, such as pravastatin. Also, EP-491226A (the disclosure of which is incorporated by reference) discloses certain pyridyldihydroxyheptenoic acids, such as cerivastatin. In addition, U.S. Pat. No.
5,273,995 (the disclosure of which is incorporated by reference) discloses certain 6- [2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones such as atorvastatin and any pharmaceutically acceptable form thereof (i.e. LIPITOR®). Additional HMG-CoA reductase inhibitors include rosuvastatin and pitavastatin. Any PPAR modulator may be used in the combination aspect of this invention. The term 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. It is believed that 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. By virtue of their activity, 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. Hence, these compounds are useful for the treatment and correction of the various dyslipidemias observed to be associated with the development and incidence of atherosclerosis and cardiovascular disease, including hypoalphalipoproteinemia and hypertriglyceridemia. A variety of these compounds are described and referenced below, however, others will be known to those skilled in the art. International Publication Nos. WO 02/064549 and 02/064130 and U.S. patent application 10/720942, filed November 24, 2003 (the disclosures of which are hereby incorporated by reference) disclose certain compounds which are PPARα activators.
Any MTP/Apo B (microsomal triglyceride transfer protein and or apolipoprotein B) secretion inhibitor may be used in the combination aspect of this invention. The term 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). A variety of these compounds are described and referenced below however other MTP/Apo B secretion inhibitors will be known to those skilled in the art, including imputapride (Bayer) and additional compounds such as those disclosed in WO 96/40640 and WO 98/23593, (two exemplary publications).
For example, the following MTP/Apo B secretion inhibitors are particularly useful:
4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1 H-[1 ,2,4,]triazol-3-ylmethyl)- 1 ,2,3,4-tetrahydro-isoquinolin-6-y]]-amide;
4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-acetylamino-ethyl)-1 ,2,3,4- tetrahydro-isoquinolin-6-yl]-amide;
(2-{6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1 H- isoquinolin-2-yl}-ethyl)-carbamic acid methyl ester; 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-imidazol-2-ylmethyl)-
1 ,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;
4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,2-diphenyl-ethyl)-1 ,2,3,4- tetrahydro-isoquinolin-6-yl]-amide; and 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-ethoxy-ethyl)-1 ,2,3,4- tetrahydro-isoquinolin-6-yl]-amide.
Any HMG-CoA synthase inhibitor may be used in the combination aspect of this invention. The term 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 (the disclosure of which is hereby incorporated by reference) discloses certain beta-lactam derivatives. U.S. Pat. No. 5,064,856 (the disclosure of which is hereby incorporated by reference) discloses certain spiro-lactone derivatives prepared by culturing a microorganism (MF5253). U.S. Pat. No. 4,847,271 (the disclosure of which is hereby incorporated by reference) 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. Such regulation is readily determined by those skilled in the art according to standard assays (Meth. Enzymol. 1985; 110:9- 19). Several compounds are described and referenced below, however other inhibitors of HMG-CoA reductase gene expression will be known to those skilled in the art. U.S. Pat. No. 5,041 ,432 (the disclosure of which is incorporated by reference) 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).
Any squalene synthetase inhibitor may be used in the combination aspect of this invention. The term 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. 5,026,554 (the disclosure of which is incorporated by reference) discloses fermentation products of the microorganism MF5465 (ATCC 74011) including zaragozic acid. A summary of other patented squalene synthetase inhibitors has been compiled (Curr. Op. Ther. Patents (1993) 861-4). Any squalene epoxidase inhibitor may be used in the combination aspect of this invention. The term squalene epoxidase inhibitor refers to compounds which inhibit the bioconversion of squalene and molecular oxygen into squalene-2,3- epoxide, catalyzed by the enzyme squalene epoxidase. Such inhibition is readily determined by those skilled in the art according to standard assays (Biochim. Biophys. Acta 1984; 794:466-471 ). A variety of these compounds are described and referenced below, however other squalene epoxidase inhibitors will be known to those skilled in the art. U.S. Pat. Nos. 5,011 ,859 and 5,064,864 (the disclosures of which are incorporated by reference) disclose certain fluoro analogs of squalene. EP publication 395,768 A (the disclosure of which is incorporated by reference) discloses certain substituted allylamine derivatives. PCT publication WO 9312069 A (the disclosure of which is hereby incorporated by reference) discloses certain amino alcohol derivatives. U.S. Pat. No. 5,051 ,534 (the disclosure of which is hereby incorporated by reference) discloses certain cyclopropyloxy-squalene derivatives.
Any squalene cyclase inhibitor may be used as the second component in the combination aspect of this invention. The term 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.). In addition, 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 (the disclosure of which is hereby incorporated by reference) 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. French patent publication 2697250 (the disclosure of which is hereby incorporated by reference) discloses certain beta, beta-dimethyl-4-piperidine ethanol derivatives such as 1 -(1 ,5,9-trimethyldecyl)-beta,beta-dimethyl-4-piperidineethanol
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. Thus, inhibition by combined squalene epoxidase/squalene cyclase inhibitors is readily determined by those skilled in art according to the aforementioned standard assays for squalene cyclase or squalene epoxidase inhibitors. A variety of these compounds are described and referenced below, however other squalene epoxidase/squalene cyclase inhibitors will be known to those skilled in the art. U.S. Pat. Nos. 5,084,461 and 5,278,171 (the disclosures of which are incorporated by reference) disclose certain a∑adecalin derivatives. EP publication 468,434 (the disclosure of which is incorporated by reference) 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 (the disclosure of which is hereby incorporated by reference) discloses certain acyl-piperidines such as 1-(1-oxopentyl-5-phenylthio)-4-(2-hydroxy-1-methyl)- ethyl)piperidine. U.S. Pat. No. 5,102,915 (the disclosure of which is hereby incorporated by reference) 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 ADVICOR™ (Kos Pharmaceuticals Inc.).
Any cholesterol absorption inhibitor can be used as an additional in the combination aspect of the present invention. The term cholesterol absorption inhibition refers to the ability of a compound to prevent cholesterol contained within the lumen of the intestine from entering into the intestinal cells and/or passing from within the intestinal cells into the lymph system and/or into the blood stream. Such cholesterol absorption inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Lipid Res. (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 ™ (ezetimibe) (Schering-Plough/Merck). Any ACAT inhibitor may be used in the combination therapy aspect of the present invention. The term 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.). Under normal physiological conditions, 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. Following further deacylation, the lipase-fatty acid intermediate is cleaved, resulting in free lipase, a glyceride and fatty acid. In the intestine, 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. Such 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. Because 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. Such 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).
A variety of gastric and/or pancreatic lipase inhibitors are known to one of ordinary skill in the art. Preferred 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. The pancreatic lipase inhibitors lipstatin, (2S, 3S, 5S, 7Z, 10Z)-5-[(S)-2-formamido-4- methyl-valeryloxy]-2-hexyl-3-hydroxy-7,10-hexadecanoic acid lactone, and tetrahydrolipstatin (orlistat), (2S, 3S, 5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]- 2-hexyl-3-hydroxy-hexadecanoic 1 ,3 acid lactone, and the variously substituted N- formylleucine derivatives and stereoisomers thereof, are disclosed in U.S. Patent No. 4,598,089. For example, 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. The 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). The pancreatic lipase inhibitors, ebelactone A and ebelactone B, and 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.
Other compounds that are marketed for hyperlipidemia, including hypercholesterolemia and which are intended to help prevent or treat atherosclerosis include bile acid sequestrants, such as Welchol®, Colestid®, LoCholest® and Questran®; and 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. This includes the classes of anti-diabetic agents (and specific agents) described herein. Any glycogen phosphorylase inhibitor can be used as the second agent in combination with a compound of the present invention. The term glycogen phosphorylase inhibitor refers to compounds that inhibit the bioconversion of glycogen to glucose-1 -phosphate which is catalyzed by the enzyme glycogen phosphorylase. Such glycogen phosphorylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Med. Chem. 41 (1998) 2934-2938). A variety of glycogen phosphorylase inhibitors are known to those skilled in the art including those described in WO 96/39384 and WO 96/39385. Any aldose reductase inhibitor can be used in combination with a compound of the present invention. The term 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.
Any sorbitol dehydrogenase inhibitor can be used in combination with a compound of the present invention. The term sorbitol dehydrogenase inhibitor refers to compounds that inhibit the bioconversion of sorbitol to fructose which is catalyzed by the enzyme sorbitol dehydrogenase. Such 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. 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. Additionally, it is known chyme remaining in the stomach promotes the production of gastric juice, which initiates or favors the development of gastritis or duodenal ulcers. Accordingly, 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. Such 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.
A variety of 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. The glucosidase inhibitor, MDL-25637, 2,6-dideoxy-7-0-β- 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]-α-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.
A variety of 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, PPARβ 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). Other examples would include PKC-β inhibitors and AGE breakers.
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, β3 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, galanin antagonists, lipase inhibitors (e.g., tetrahydrolipstatin, i.e. orlistat), bombesin agonists, anorectic agents (e.g., a bombesin agonist), Neuropeptide-Y antagonists, thyroxine, thyromimetic agents, dehydroepiandrosterones or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide- 1 receptor agonists, ciliary neurotrophic factors (e.g.,
Axokine™), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists, and the like.
Any thyromimetic can be used as the second agent in combination with a compound of the present invention. Such 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®. 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. In the U.S., 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.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
Those skilled in the art will recognize that anti-resorptive agents (for example progestins, polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists, estrogen, estrogen/progestin combinations, Premarin®, estrone, estriol or 17α- or 17β-ethynyl estradiol) may be used in conjunction with the compounds of the present invention.
Exemplary 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 acetate, norethynodrel, norgestimate, norgestomet, norgestrel, oxogestone phenpropionate, progesterone, quingestanol acetate, quingestrone, and tigestol.
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.
Other preferred 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, pentane-5-amino-1-hydroxy-1 ,1- diphosphonic acid, hexane-6-amino-1-hydroxy-1 ,1-diphosphonic acid and pharmaceutically acceptable esters and salts thereof.
In particular, 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. In particular, 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. Such activities are readily determined by those skilled in the art of standard assays including estrogen receptor binding assays, standard bone histomorphometric and densitometer methods, and Eriksen E.F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S.J. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31(1):50-62; Wahner H.W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). A variety of these compounds are described and referenced below.
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-
424 (Wyeth-Ayerst Laboratories) and arazoxifene.
Other preferred 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;
(-)-c/s-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro- naphthalene-2-ol (also known as lasofoxifene); c/s-6-phenyl-5-(4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro- naphthalene-2-ol; c/s-1-(6'-pyrrolodinoethoxy-3'-pyridyl)-2-phenyl-6-hydroxy-1 ,2,3,4- tetrahydronaphthalene;
1-(4'-pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl)-6-hydroxy-1 , 2,3,4- tetrahydroisoquinoline; c/s-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-elhoxy)-phenyl)-5,6,7,8- tetrahydro-naphthalene-2-ol; and
1 -(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1 ,2,3,4- tetrahydroisoquinoline. Other estrogen agonist/antagonists are described in U.S. patent 4,133,814
(the disclosure of which is incorporated herein by reference). U.S. patent 4,133,814 discloses derivatives of 2-phenyl-3-aroyl-benzothiophene and 2-phenyl-3- aroylbenzothiophene-1 -oxide.
Other 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. 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. Examples of 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
02/00617, WO 02/16310, U.S. Patent Application Publication No. US 2002/0099096, U.S. Patent Application Publication No. US 2003/0022868, WO 03/011302 and WO 03/011824. All of the above refences are hereby incorporated by reference herein. The starting materials and reagents for the above described compounds, are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein, are related to, or are derived from compounds in which there is a large scientific interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.
Some of the compounds of 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. Also, 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. Also, some of the compounds of this invention are atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
More specifically, 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
Chiralcel™ AD or OD (obtained from Chiral Technologies, Exton, Pennsylvania)) with 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.
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.
In addition, when 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. Thus, the compounds of this invention elevate plasma HDL cholesterol, its associated components, and the functions performed by them in mammals, particularly humans. By virtue of their activity, these agents also reduce plasma levels of triglycerides, VLDL cholesterol, Apo-B, LDL cholesterol and their associated components in mammals, particularly humans. Moreover, these compounds are useful in equalizing LDL cholesterol and HDL cholesterol. Hence, 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.
Further, introduction of a functional CETP gene into an animal lacking CETP (mouse) results in reduced HDL levels (Agellon, L.B., et al: J. Biol. Chem. (1991) 266: 10796-10801.) and increased susceptibility to atherosclerosis.(Marotti, K.R., et al: Nature (1993) 364: 73-75.). Also, inhibition of CETP activity with an inhibitory antibody raises HDL-cholesterol in hamster (Evans, G.F., et al: J. of Lipid Research (1994) 35: 1634-1645.) and rabbit (Whitlock, M.E., et al: J. Clin. Invest. (1989) 84: 129-137). Suppression of increased plasma CETP by intravenous injection with antisense oligodeoxynucleotides against CETP mRNA reduced atherosclerosis in cholesterol-fed rabbits (Sugano, M., et al: J. of Biol. Chem. (1998) 273: 5033-5036.) Importantly, human subjects deficient in plasma CETP, due to a genetic mutation possess markedly elevated plasma HDL-cholesterol levels and apolipoprotein A-l, the major apoprotein component of HDL. In addition, most demonstrate markedly decreased plasma LDL cholesterol and apolipoprotein B (the major apolipoprotein component of LDL. (Inazu, A., Brown, M.L., Hesler, C.B., et al.: N. Engl. J. Med. (1990) 323: 1234-1238.)
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. These include 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, atherosclerosis associated with organ transplantation, cerebrovascular disease, 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.
Because of the beneficial effects widely associated with elevated HDL levels, 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.
Thus, given the ability of the compounds of this invention, their prodrugs and the salts of such compounds and prodrugs to alter lipoprotein composition via inhibition of cholesterol ester transfer, they are of use in the treatment of vascular complications associated with diabetes, lipoprotein abnormalities associated with diabetes and sexual dysfunction associated with diabetes and vascular disease. Hyperlipidemia is present in most subjects with diabetes mellitus (Howard, B.V. 1987. J. Lipid Res. 28, 613). Even in the presence of normal lipid levels, diabetic subjects experience a greater risk of cardiovascular disease (Kannel, W.B. and McGee, D.L. 1979. Diabetes Care 2, 120). 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.
The described agents are useful in the treatment of obesity and elevated cardiovascular risk associated with obesity. In both humans (Radeau, T., Lau, P., Robb, M., McDonnell, M., Ailhaud, G. and McPherson, R., 1995. Journal of Lipid Research. 36 (12):2552-61) and nonhuman primates (Quinet, E., Tall, A., Ramakrishnan, R. and Rudel, L., 1991. Journal of Clinical Investigation. 87 (5): 1559- 66) 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
McPherson, R., 1993. Journal of Lipid Research. 34 (3):437-46), and is translated into functional transfer protein and through secretion contributes significantly to plasma CETP levels. In human adipocytes the bulk of cholesterol is provided by plasma LDL and HDL (Fong, B. S., and Angel, A., 1989. Biochimica et Biophysica Acta. 1004 (1 ):53-60). The uptake of HDL cholesteryl ester is dependent in large part on CETP (Benoist, F., Lau, P., McDonnell, M., Doelle, H., Milne, R. and McPherson, R., 1997. Journal of Biological Chemistry. 272 (38):23572-7). This ability of CETP to stimulate HDL cholesteryl uptake, coupled with the enhanced binding of HDL to adipocytes in obese subjects (Jimenez, J. G., Fong, B., Julien, P., Despres, J. P., Rotstein, L, and Angel, A., 1989. International Journal of Obesity. 13 (5):699- 709), suggests a role for CETP, not only in generating the low HDL phenotype for these subjects, but in the development of obesity itself by promoting cholesterol accumulation. Inhibitors of CETP activity that block this process therefore serve as useful adjuvants to dietary therapy in causing weight reduction. CETP inhibitors are useful in the treatment of inflammation due to Gram- negative sepsis and septic shock. For example, the systemic toxicity of Gram- negative sepsis is in large part due to endotoxin, a lipopolysaccharide (LPS) released from the outer surface of the bacteria, which causes an extensive inflammatory response. Lipopolysaccharide can form complexes with lipoproteins (Ulevitch, R.J., Johnston, A.R., and Weinstein, D.B., 1981. J. Clin. Invest. 67, 827- 37). In vitro studies have demonstrated that binding of LPS to HDL substantially reduces the production and release of mediators of inflammation (Ulevitch, R.J., Johhston, A.R., 1978. J. Clin. Invest. 62, 1313-24). In vivo studies show that transgenic mice expressing human apo-AI and elevated HDL levels are protected from septic shock (Levine, D.M., Parker, T.S., Donnelly, T.M., Walsh, A.M., and Rubin, A.L. 1993. Proc. Natl. Acad. Sci. 90, 12040-44). Importantly, administration of reconstituted HDL to humans challenged with endotoxin resulted in a decreased inflammatory response (Pajkrt, D., Doran, J.E., Koster, F., Lerch, P.G., Arnet, B., van der Poll, T., ten Cate, J.W., and van Deventer, S.J.H. 1996. J. Exp. Med. 184, 1601-08). The 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 (e.g. humans, male or female) 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 (with appropriate modifications within the skill in the art) 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 3H-labeled cholesteryl oleate (CO) from exogenous tracer HDL or LDL to the nonHDL or HDL lipoprotein fraction in human plasma, respectively, or from 3H- labeled LDL to the HDL fraction in animal plasma. 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 3H-CO from phospholipid liposomes to all the lipoprotein fractions in plasma. 3H-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.
For the 97% or whole plasma activity assay, 3H-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. Introducing varying quantities of the compounds of this invention as a solution in dimethylsulfoxide into human plasma, before addition of the radiolabeled cholesteryl oleate, and comparing the amounts of radiolabel transferred compared to incubations containing no inhibitor compounds allows the cholesteryl ester transfer inhibitory activities to be determined.
When a more sensitive assay is desirable, an in vitro assay using diluted human plasma is utilized. For this assay, 3H-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. Introducing varying quantities of the compounds of this invention as a solution in dimethylsulfoxide into diluted human plasma, before addition of the radiolabeled cholesteryl oleate, and comparing the amounts of radiolabel transferred compared to incubations containing no inhibitor compounds allows the cholesteryl ester transfer inhibitory activities to be determined. This assay has been adapted to run in microtiter plate format with liquid scintillation counting accomplished using a Wallac plate reader.
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 (Charles River, Boston, MA) 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. At various times after dosing, ranging from 4h to 24h, the animals are sacrificed, blood obtained by heart puncture, and lipid parameters measured, including total cholesterol, HDL and LDL cholesterol, and triglycerides. CETP activity is determined by a method similar to that described above except that 3H-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).
IN VIVO ATHEROSCLEROSIS ASSAY 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. After 3-5 months, 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/m2. 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. IN VIVO SEPSIS ASSAY
In vivo studies show that transgenic mice expressing human apo-AI and elevated HDL levels are protected from septic shock. Thus the ability of CETP inhibitors to protect from septic shock can be demonstrated in transgenic mice expressing both human apo-AI and human CETP transgenes (Levine, D. M., Parker, T.S., Donnelly, T. M., Walsh, A. M. and Rubin, A.L., 1993. Proc. Natl. Acad. Sci. 90, 12040-44). LPS derived from E. coli is administered at 30mg/kg by i.p. injection to animals which have been administered a CETP inhibitor at an appropriate dose to result in elevation of HDL. The number of surviving mice is determined at times up to 48h after LPS injection and compared to those mice administered vehicle (minus CETP inhibitor) only.
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.
In general an amount of a compound of this invention is used that is sufficient to achieve the therapeutic effect desired (e.g., HDL elevation).
In general 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. For example, typically an effective dosage for HMG-CoA reductase inhibitors is in the range of 0.01 to 100 mg/kg/day. In general 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. Thus, the compounds of this invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form. For oral administration 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.
Additionally, 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, Miglyol™; or mono- or diglycerides such as those marketed under the name, Capmul™, for example, in a soft gelatin capsule. Antioxidants may be added to prevent long-term degradation as appropriate. When aqueous suspensions and/or elixirs are desired for oral administration, 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. For purposes of parenteral administration, 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. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
For purposes of transdermal (e.g..topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.
Methods of preparing various pharmaceutical composi l' ions with a certain amount of active ingredient are known, or will be apparent in ght of this disclosure, to those skilled in this art. For examples of methods of prepari ni g pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).
Pharmaceutical compositions according to the invention may contain 0.1%- 95% of the compound(s) of this invention, preferably 1%-70%. In any event, 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.
Since the present invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, a prodrug thereof or a salt of 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. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician. 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. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide 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. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, ...etc.... Second Week, Monday, Tuesday,..." etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day.
Also, 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.
In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is 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.
The compounds of this invention either alone or in combination with each other or other compounds generally will be administered in a convenient formulation. The following formulation examples only are illustrative and are not intended to limit the scope of the present invention.
In the formulations which follow, "active ingredient" means a compound of this invention. Formulation 1 : Gelatin Capsules
Hard gelatin capsules are prepared using the following: Ingredient Quantity (mg/capsule)
Active ingredient 0.25-100
Starch, NF 0-650
Starch flowable powder 0-50
Silicone fluid 350 centistokes 0-15
A tablet formulation is prepared using the ingredients below: Formulation 2: Tablets
Ingredient Quantity (mg/tablet)
Active ingredient 0.25-100
Cellulose, microcrystalline 200-650
Silicon dioxide, fumed 10-650
Stearate acid 5-15
The components are blended and compressed to form tablets. Alternatively, tablets each containing 0.25-100 mg of active ingredients are made up as follows: Formulation 3: Tablets
Ingredient Quantity (mg/tablet)
Active ingredient 0.25-100
Starch 45
Cellulose, microcrystalline 35
Polyvinylpyrrolidone (as 10% solution in water) 4
Sodium carboxymethyl cellulose 4.5
Magnesium stearate 0.5
Talc 1
The active ingredients, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50° - 60°C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose are made as follows:
Formulation 4: Suspensions
Ingredient Quantity (mg/5 ml)
Active ingredient 0.25-100 mg
Sodium carboxymethyl cellulose 50 mg
Syrup 1.25 mg
Benzoic acid solution 0.10 mL
Flavor q.v.
Color q.v.
Purified Water to 5 mL
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.
An aerosol solution is prepared containing the following ingredients: Formulation 5: Aerosol
Ingredient Quantity (% by weight)
Active ingredient 0.25
Ethanol 25.75
Propellant 22 (Chlorodifluoromethane) 70.00
The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30°C, and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container. Suppositories are prepared as follows: Formulation 6: Suppositories
Ingredient Quantity (mg/suppository)
Active ingredient 250
Saturated fatty acid glycerides 2,000
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
Ingredient Quantity
Active ingredient dissolved in ethanol 1% 20 mg
Intralipid™ emulsion 1 ,000 mL
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
Ingredient Quantity (mg/capsule)
Active ingredient 10-500
Olive Oil or Miglyol™ Oil 500-1000
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. Concentration in vacuo means that a rotary evaporator was used. The names for the compounds of the invention were created by the Autonom 2.0 PC-batch version from Beilstein Informationssysteme GmbH (ISBN 3-89536-976-4). The chemical structures depicted may be only exemplary of the general structure or of limited isomers, and not include specific stereochemistry as recited in the chemical name.
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 (δ) 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. Where the intensity of chlorine- or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for 35CI/37CI-containing ions and 1 :1 for 79Br/81Br-containing ions) and the position of only the lower mass ion is given.
Column chromatography was performed with either Baker Silica Gel (40 μm) (J.T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (40-63 μm)(EM Sciences, Gibbstown, N.J.). Flash chromatography was performed using a Flash 12 or Flash 40 column (Biotage, Dyar Corp., Charlottesville, VA). Preparative HPLC purification was performed on a Shimadzu 10A preparative HPLC system (Shimadzu Corporation, Kyoto, Japan) using a model SIL-10A autosampler and model 8A HPLC pumps. 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. In acidic mode, typical columns used include Waters Symmetry C8, 5μm, 19x50mm or 30x50mm, Waters XTerra C18, 5μm, 50x50 (Waters Corp, Milford, MA) or Phenomenex Synergi Max-RP 4μm, 50x50mm (Phenomenex Inc., Torrance, CA). In basic mode, the Phenomenex Synergi Max-RP 4μm, 21.2x50mm or 30x50mm columns (Phenomenex Inc., Torrance, CA) were used.
Optical rotations were determined using a Jasco P-1020 Polarimeter Jasco Inc., Easton, MD)
Dimethylformamide, tetrahydrofuran, toluene and dichloromethane were the anhydrous grade supplied by Aldrich Chemical Company (Milwaukee, Wl). Unless otherwise specified, reagents were used as obtained from commercial sources. The terms "concentrated" 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 "μl" or "μL" stand for microliters.
Preparation 1 (R,S)-2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Method 1 ) To a solution of (R,S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (1294gm, 4.09mol, prepared according to the procedure described in WO 0140190) in glacial acetic acid (3882ml) was added a solution of sodium nitrite (582gm, 8.18mol) in water (1618ml), maintaining a temperature of 20 to 25°C. 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.
Preparation 2 (RS)-2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of (R,S)-2-ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (1208gm, 3.81 mol) in methylene chloride (4663ml) was added 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), free radical (6.1gm, 0.038mol), and a solution of potassium bromide (45.8gm, 0.381 mol) dissolved in water (191 ml). 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).
1H-NMR (DMSO-d6) δ 8.03 (m, 2H), 7.91 (dd, J=9.12, 2.49Hz, 1 H), 4.79 (m, 1 H), 4.23 (q, J=7.05Hz, 2H), 3.25 (dd, J=17.42, 5.81 Hz, 1 H), 2.61 (dd, J=17.42, 1.66Hz, 1 H), 1.42 (m, 2H), 1.25 (t, J=7.05Hz, 3H), 0.76 (t, J=7.05Hz, 3H). Preparations 3 and 4
(R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (3) and (S)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (4) (RS)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester was resolved by chiral chromatography on a 10cm x 25cm column packed with Chiralcel OD (Chiral Technologies Inc., Exton, PA). The racemic ketone (300mg) in methanol (0.84mL) was injected onto the column and eluted with heptane: isopropanol 99:1 at a flow rate of 275mL/min to give the title compounds:
(R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (3), retention time 7.82 min, [α] = -139.81° (c=0.438, chloroform).
(S)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (4), retention time 8.93 min, [α]D = +139.7° (c=0.41 , chloroform). Preparation 5
4-Hydrazono-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A mixture of 6,7-dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester (1.00gm, 3.41 mmol, prepared according to the procedure described in German Patent DE 2461050), hydrazine hydrate (330μl, 6.80mmol) and ethanol ( .5mL) were heated together in a crimp-topped vial at 150°C for 30 min in a microwave oven (Emrys Optimizer, Personal Chemistry, Uppsala, Sweden). The solvent was removed under vacuum, the residue dissolved in ethanol (4.5mL), hydrazine hydrate (330μl, 6.80mmol) added and the solution was heated as before at 150°C for 30 min. The solvent was evaporated under vacuum to give the title compound as a pale yellow solid. MS: 308.2 [M+H]+ found
1H-NMR (CDCI3) δ 7.39 (s, 1 H), 7.03 (brs, 1 H), 5.21 (s, 2H), 5.04 (m, 1H), 4.27 (m, 1 H), 4.15 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.61 (dd, J=17, 5.81 Hz, 1H), 2.53 (dd, J=17, 1.66Hz, 1 H), 1.28 (t, J=7.47Hz, 3H), 1.08 (d, J = 6.64Hz, 3H).
Preparation 6 (R)-2-Ethyl-4-hydrazono-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester A mixture of (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester (Preparation 3, 1.13gm, 3.58mmol), hydrazine hydrate
(348μl, 7.16mmol) and ethanol (10mL) were heated in a Dean-Stark apparatus under conditions allowing for slow distillation of the solvent. After 5h approximately 5mL of distillate had been collected. The solution was diluted with an equal volume of toluene and the solvent was evaporated under vacuum to give a pale green solid which was triturated and rinsed with a little hexanes to give the title compound as a nearly colorless solid (1.07g).
MS: 330.2 [M+H]+ found 1H-NMR (CDCI3) δ 8.23 (s, 1 H), 7.62 (brd, J=8.30Hz, 1 H), 7.46 (dd, J=8.30,
1.66Hz, 1 H), 5.45 (brs, 2H), 4.82 (m, 1 H), 4.28 (m, 1 H), 4.24 (m, 1H), 2.64 (m, 2H), 1.36 (m, 2H), 1.31 (t, J=7.47Hz, 3H), 0.84 (t, J = 7.47Hz, 3H).
Preparation 7 4-Diazo-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
To a solution of 4-hydrazono-6,7-dimethoxy-2-methyl-3,4-dihydro-2H- quinoIine-1 -carboxylic acid ethyl ester (Preparation 5, 200mg, 0.65mmol) in diethyl ether (20mL) was added manganese (IV) oxide (400mg, activated, -85%, Aldrich Chemical Company, Milwaukee, Wl). The suspension was stirred at ambient temperature under nitrogen in the dark for 30 min then the solid removed by filtration through Celite® to give the title compound as a fuchsia colored solution which was typically used immediately.
Preparation 8 (R)-4-Diazo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
To a solution of (R)-2-ethyl-4-hydrazono-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (Preparation 6, 317mg, 0.962mmol) in diethyl ether (6mL) was added manganese (IV) oxide (1.1g, activated, -85%, Aldrich Chemical Company, Milwaukee, Wl). The suspension was stirred at ambient temperature under nitrogen in the dark for 1.5 h then the solid removed by filtration through Celite®. The filtrate was diluted with toluene (15mL) prior to evaporation to a final volume of approximately 10mL (never to dryness) to give the title compound as a fuchsia colored solution which was typically used immediately.
Preparations 9 and 10 (R)-4-Chloro-2-ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (9) and (R)-2-ethyl-4- methoxycarbonecarbonyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester
(10) To a solution of (R)-4-diazo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1 -carboxylic acid ethyl ester (Preparation 8) prepared from Preparation 6 (317mg, 0.962mmol) as a solution in toluene as described above was added N,N- diisopropylethylamine (335μl, 1.92mmoi) followed, dropwise, by methyl chlorooxoacetate (0.962mmol, 88.4μl). The mixture was allowed to stir at room temperature under nitrogen. Gas evolution was observed and the fuchsia color changed to yellow-orange within about 10 min. The solution was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution then water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed on silica eluting with a hexanes:ethyl acetate gradient from 19:1 to 4:1 to give the title compounds:
(R)-4-Chloro-2-ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1 -carboxylic acid ethyl ester (earlier eluting diastereoisomer, 82mg)
MS: 422.0 [M+Hf found 1H-NMR (CDCI3) δ 7.72 (d, J=9.13Hz, 1H), 7.58 (m, 1 H), 7.54 (s. 1 H), 4.57
(m, 1 H), 4.27 (m, 1 H), 4.25 (m, 1H), 3.95 (s, 3H), 2.85 (dd, J=14.11 , 6.64Hz, 1H), 2.77 (dd, J=14.11 , 6.92Hz, 1H), 1.61 (m, 1H), 1.52 (m, 1 H), 1.30 (t, J=7.47Hz, 3H), 0.87 (t, J = 7.47Hz, 3H).
(R)-4-Chloro-2-ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1 -carboxylic acid ethyl ester (later eluting diastereoisomer, 73mg)
MS: 422.0 [M+Hf found H-NMR (CDCI3) δ 7.88 (s, 1H), 7.60 (m, 2H), 7.54 (s. 1 H), 4.57 (m, 1 H), 4.22 (m, 1 H), 4.20 (m, 1H), 3.73 (s, 3H), 3.26 (dd, J=13.8, 7.47 Hz, 1 H), 2.23 (dd, J=13.8, 6.75 Hz, 1 H), 1.65 (m, 1 H), 1.53 (m, 1H), 1.27 (t, J=7.47 Hz, 3H), 0.89 (t, J = 7.47 Hz, 3H).
(R)-2-Ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-2H-quinoline-1- carboxylic acid ethyl ester, 133mg
MS: 384.1 [M-H]" found
1H-NMR (CDCI3) δ 8.27 (s, 1H), 7.71 (brd, J=8.30Hz, 1 H), 7.56 (dd, J=8.30, 1.66Hz, 1 H), 7.20 (d, J=6.64Hz, 1 H), 5.21 (m, 1 H), 4.28 (m, 2H), 3.95 (s, 3H), 1.57 (m, 1 H), 1.41 (m, 1 H), 1.32 (t, J=7.47Hz, 3H), 0.91 (t, J = 7.47Hz, 3H). Preparation 11 2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Method 2) To a solution of 2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester (0.89gm, 2.83mmol) in methanol (20mL) was added solid sodium borohydride (102mg, 2.8mmol). After 10 min acetone was added to quench the reaction and the mixture was stirred for 2h before evaporating the solvent under vacuum. The residue was dissolved in methylene chloride and the solution was washed with 0.05N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, diluted with toluene and evaporated to dryness to give the title compound as a mixture of diastereoisomers which were carried forward unseparated.
MS: 318.0 [M+H]+ found
(trans isomer- minor) 1H-NMR (CDCI3) δ 7.80 (d, J=8.30Hz, 1H), 7.69 (s, 1H), 7.49 (dd, J=8.30, 1.66Hz, 1 H), 4.86 (m, 1 H), 4.58 (m, 1 H), 4.25 (m, 2H), 2.16 (m, 2H), 1.60 (m, 1 H), 1.50 (m, 1 H), 1.32 (t, J=7.47Hz, 3H), 0.90 (t, J=7.47Hz, 3H). MS: 318.0 [M+H]+ found
(cis isomer- major) H-NMR (CDCI3) δ 7.73 (s, 1 H), 7.58 (d, J=9.13Hz, 1 H), 7.50 (dd, J=9.13, 1.66Hz, 1 H), 4.55 (m, 1 H), 4.41 (m, 1H), 4.24 (m, 2H), 2.52 (ddd, J=13.28, 7.47, 4.98Hz, 1 H), 1.67 (m, 1H), 1.60 (m, 1 H), 1.48 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 0.85 (t, J=7.47Hz, 3H).
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 (245μl, 3.16mmol) were added. After 2h, a further aliquot of triethylamine (1.OmL, 7.17mmol) was added, and the mixture stirred at ambient temperature for 15h then washed with water containing 2N hydrochloric acid (10mL). The organic layer was dried over anhydrous sodium sulfate, evaporated to dryness and purified by chromatography on silica eluting with hexanes:acetone 25:1 to give title compound as an unequal mixture of diastereoisomers (590mg) which typically were carried forward unseparated. Diastereoisomer 1 (Major) MS: 336.0 [M+Hf found
1H-NMR (CDCI3) δ 7.69 (d, J=8.29Hz, 1 H), 7.60 (s, 1H), 7.63 (d, J=8.29Hz, 1H), 5.12 (dd, J=6.64, 4.98Hz, 1 H), 4.60 (m, 1 H), 4.27 (m, 2H), 2.60 (ddd, J=14.11 , 6.64, 6.64Hz, 1 H), 2.13 (ddd, J=14.11 , 6.64, 4.98Hz, 1 H), 1.64 (m, 1 H), 1.54 (m, 1H), 1.31 (t, J=7.47Hz, 3H), 0.89 (t, J=7.47Hz, 3H). Diastereoisomer 2 (Minor) MS: 336.0 [M+Hf found
1H-NMR (CDCI3) δ 7.82 (s, 1H), 7.68 (d, J=8.30Hz, 1 H), 7.51 (dd, J=8.30, 1.66Hz, 1 H), 5.08 (dd, J=5.81 , 5.81 Hz, 1H), 4.55 (m, 1 H), 4.25 (m, 2H), 2.71 (ddd, J=14.11 , 5.81 , 5.81Hz, 1 H), 2.18 (ddd, J=14.11 , 5.81 , 5.81 Hz, 1H), 1.74 (m, 1 H), 1.60 (m, 1 H), 1.31 (t, J=7.47Hz, 3H), 0.91 (t, J=7.47Hz, 3H).
Preparation 13 (R, S)-2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Method 3)
To a solution of (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester (1.1gm, 3.49mmol) in anhydrous tetrahydrofuran at 0°C under nitrogen was added potassium triisobutylborohydride (K-Selectride®, 1 M in tetrahydrofuran, 8.0mL, δmmol). After 1.5h the mixture was allowed to warm to ambient temperature, stirred for 16h then an additional aliquot of K-Selectride®
(3.49mL, 3.49mmol) was added. After 1.5h the solvent was removed under vacuum, the residue was dissolved in ethyl acetate (50mL) and this solution was washed with 2N sodium hydroxide solution (20mL) followed by hydrogen peroxide (30%, 15mL), dried over anhydrous magnesium sulfate and concentrated to low volume. The residue was taken up in acetonitrile and evaporated to dryness (x3) to remove residual water to give the title compound (100%), identical to the cis isomer of the product described above (Preparation 11 ).
Preparation 14 (R)-4-Chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Method 2)
(R, S)-2-ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester (Preparation 13, 1.1 gm, 3.47mmol) was dissolved in thionyl chloride (20mL) at ambient temperature under nitrogen. After 1h N,N- dimethylformamide (2 drops) was added and the mixture allowed to stir at ambient temperature for 15h. The solvent was removed under reduced pressure and the residue was chromatographed on silica eluting with ethyl acetate-hexanes 50:1 to give the title compound as a yellow oil (405mg) with a proton NMR spectrum very similar to that obtained for Preparation 12 except that the major and minor components of the mixture were reversed.
Example 1
Figure imgf000102_0001
4-(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-2H-quinoline-1 -carboxylic acid ethyl ester A solution of 4-diazo-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 - carboxylic acid ethyl ester (Preparation 7, 0.65mmol) prepared as a solution in diethyl ether as described above was added to a solution of 3,5-bistrifluoromethylbenzoyl chloride (180mg, 0.65mmol) and N,N-diisopropylethylamine (120μl, 0.65mmol) in diethyl ether (15mL) and allowed to stir at room temperature under nitrogen in the dark for 15h. The solvent was removed under vacuum and the residue was chromatographed on silica eluting with hexanes:ethyl acetate 3:1 to give a partially purified product which was further purified by reverse phase chromatography (linear acetonitrile:water gradient, 55% to 100% acetonitrile, both phases containing 0.1% formic acid) to give the title compound as a lemon yellow solid (90mg). MS: 518.1 [M+Hf found
1H-NMR (CDCI3) δ 8.26 (s, 2H), 8.07 (s, 1 H), 7.25 (brs, 1 H), 7.04 (s, 1H), 6.32 (d, J=6.64Hz, 1 H), 5.31 (m, 1 H), 4.33 (m, 1 H), 4.23 (m, 1 H), 3.91 (s, 3H), 3.80 (s, 3H), 1.33 (t, J=7.47Hz, 3H), 1.20 (d, J=6.64Hz, 3H). Example 2
Figure imgf000103_0001
(R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester A solution of 3,5-bis(trifluoromethylphenyl)magnesium bromide was prepared by dropwise addition of a solution of 3,5-bistrifluoromethylbromobenzene (0.818mL, 4.74mmol) in anhydrous tetrahydrofuran (0.7mL) to a stirred suspension of magnesium powder (116mg, 4.74mmol) in anhydrous tetrahydrofuran (4.7mL) at 35°C. The mixture was then heated under reflux for 1 h to give a dark colored solution. A portion of this solution (1.5mL) was added dropwise to a solution of (R)- 2-ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester (Preparation 10, 133mg, 0.345mmol) in anhydrous tetrahydrofuran (4mL) at -78°C. After 30 min the mixture was warmed to 0°C and poured into water and extracted with ethyl acetate, adding a few drops of 2N hydrochloric acid to facilitate separation of the layers. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. This procedure was repeated in an exactly similar manner using (R)-2-ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-2H-quinoline- 1-carboxylic acid ethyl ester (Preparation 10, 235mg, 0.609mmol) in anhydrous tetrahydrofuran (5mL) and adding the solution of 3,5- bis(trifluoromethylphenyl)magnesium bromide (2mL). The combined crude product was chromatographed on silica eluting with an ethyl acetate-hexanes gradient from 5% to 30% to give the title compound as a mixture of diastereoisomers (463mg) which were carried forward unseparated. MS: 597.9 [M-H]~ found Diastereoisomer 1 : 1H-NMR (CDCI3) δ 7.92 (s, 2H), 7.75 (s, 1H), 7.67 (s, 1H),
7.65 (d, J=8.30Hz, 1 H), 7.34 (dd, J=8.30, 1.66Hz, 1H), 5.97 (d, J=6.64Hz, 1 H), 5.04 (m, 1 H), 4.53 (s, 1 H), 4.27 (m, 2H), 3.87 (s, 3H), 1.47 (m, 1H), 1.35 (m, 1H), 1.28 (t, J=7.47Hz, 3H), 0.85 (d, J=6.64Hz, 3H).
MS: 597.9 [M-H]" found
Diastereoisomer 2: 1H-NMR (CDCI3) δ 8.16 (s, 2H), 7.90 (s, 1 H), 7.65 (d, J=8.30, 1H), 7.63 (s, 1 H), 7.45 (dd, J=8.30, 1.66Hz, 1 H), 5.82 (d, J=6.42Hz, 1 H), 4.96 (m, 1H), 4.34 (s, 1H), 4.27 (m, 2H), 3.78 (s, 3H), 1.47 (m, 1 H), 1.35 (m, 1 H), 1.33 (t, J=7.47Hz, 3H), 0.83 (d, J=7.47Hz, 3H).
Examples 3 and 4
Figure imgf000104_0001
(R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000104_0002
(R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of (R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl- methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester (Example 2, 125mg, 0.208mmol) and 2,6-di-tert-butyl-4-methylpyridine (256mg, 1.248mmol) in chloroform (7mL) was added thionyl chloride (30.4μl, 0.417mmol). After stirring for 18h at ambient temperature the mixture was diluted with methylene chloride, washed with water and dried over anhydrous sodium sulfate. After removal of the solvent under vacuum the residue was chromatographed on silica eluting with an ethyl acetate-hexanes gradient from 0% to 40% to give 4-[(3,5-bis-trifluoromethyl-phenyl)-chloro-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester as a mixture of diastereoisomers. This material (128mg) was dissolved in a mixture of tetrahydrofuran (2mL) and acetic acid (2mL). Zinc dust (200mg, 3.05mmol) was added followed by 2N hydrochloric acid (1.5mL). The suspension was stirred at ambient temperature for 3h then diluted with methylene chloride and washed with water. The organic layer was dried with anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was chromatographed on silica eluting with a methylene chloride-hexanes gradient from 60% to 80% to give the title compounds:
Diastereoisomer 1 : 44mg
MS: 584.0 [M+Hf found H-NMR (CDCI3) δ 7.79 (s, 1 H), 7.76 (s, 2H), 7.74 (d, J=8.30Hz, 1 H), 7.47 (d, J=8.30Hz, 1 H), 7.41 (s, 1H), 6.02 (d, J=6.64Hz, 1 H), 5.12 (s, 1 H), 5.01 (m, 1 H), 4.26 (m, 2H), 3.82 (s, 3H), 1.53 (m, 1H), 1.40 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 0.87 (d, J=7.47Hz, 3H).
Diastereoisomer 2: 16mg
MS: 584.0 [M+Hf found
1H-NMR (CDCI3) δ 7.88 (s, 2H), 7.87 (s, 1 H), 7.77 (d, J=8.30Hz, 1 H), 7.49 (d, J=8.30Hz, 1 H), 7.33 (s, 1 H), 5.96 (d, J=5.81 Hz, 1 H), 5.07 (s, 1 H), 5.00 (m, 1H), 4.29 (m, 2H), 3.74 (s, 3H), 1.47 (m, 1 H), 1.36 (m, 1 H), 1.34 (t, J=7.47Hz, 3H), 0.84 (d, J=7.47Hz, 3H).
Examples 5 and 6
Figure imgf000105_0001
(RS, SR, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000106_0001
(RS, SR, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of 4-chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester (Preparation 12, 275mg, 0.82mmol) and 3,5- bis(trifluoromethylphenyl)acetic acid methyl ester (286mg, 1 mmol) in anhydrous dimethylformamide (2mL) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU, ~100mg). The mixture was stirred at ambient temperature for 24h then at 50°C for 15h. The mixture was poured into water, acidified by the addition of a little 2N hydrochloric acid and extracted with methylene chloride (x3). The extract was dried over anhydrous sodium sulfate, evaporated to dryness and the residue purified initially by reverse phase chromatography and finally by chromatography on silica eluting with hexanes-ethyl acetate 6:1 to give the title compounds.
(RS, SR, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (13.8mg, first eluting diastereoisomer)
MS: 586.0 [M+Hf found
1H-NMR (CDCI3) δ 7.90 (s, 2H), 7.87 (s, 1 H), 7.59 (d, J=8.30Hz, 1H), 7.62 (d, J=8.30Hz, 1H), 7.61 (s, 1 H), 4.39-4.27 (m, 2H), 4.27-4.18 (m, 1 H), 3.78 (d, J=11.61Hz, 1H), 3.59 (m, 1 H), 3.48 (s, 3H), 1.76 (ddd, J=14.10, 8.30, 3.30Hz, 1 H), 1.61-1.55 (m, 1 H),1.57-1.50 (m, 1 H), 1.48-1.40 (m, 1 H), 1.35 (t, J=7.47Hz, 3H), 0.73 (t, J=7.47Hz, 3H).
(RS, SR, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (33.7mg, second eluting diastereoisomer) MS: 586.0 [M+Hf found
1H-NMR (CDCI3) δ 7.66 (s, 1 H), 7.42 (d, J=8.30Hz, 1H), 7.40 (s, 2H), 7.33 (dd, J=8.30, 1.66Hz, 1 H), 6.47 (d, J=1.66Hz, 1H), 4.55-4.47 (m, 1 H), 4.34 (m, 1 H), .32 (m,1H), 3.83 (d, J=11.61 Hz, 1 H), 3.80 (s, 3H), 3.43 (ddd, J=11.61 , 4.98, 2.49Hz, 1H), 2.44 (ddd, J=14.11 , 8.30, 2.49Hz, 1H), 1.81 (ddd, J=14.10, 8.30, 4.98Hz, 1 H), 1.67 (m, 1H),1.51 (m, 1H), 1.33 (t, J=7.47Hz, 3H), 0.85 (t, J=7.47Hz, 3H).
Examples 7 and 8
Figure imgf000107_0001
(RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000107_0002
(2S, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
A mixture of (RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester and (RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester (prepared by a procedure exactly similar to that described for Examples 3 and 4 with the exception that racemic starting material was used and the mixture of diastereoisomers produced were not separated) (20mg, 0.0342mmol) in ethanol (5mL) containing palladium hydroxide (20% on carbon, 20mg) was hydrogenated in a Parr shaker (Parr Instrument Company, Moline, Illinois) at 40psi for 5h. 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.
(RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (first eluting diastereoisomer, 8mg) MS: 586.0 [M+Hf found
1H-NMR (CDCI3) δ 7.89 (s, 1 H), 7.88 (s, 2H), 7.53 (m, 2H), 7.39 (s, 1 H), 4.55- 4.47 (m, 1 H), 4.34-4.24 (m, 2H), 4.24-4.18 (m, 1H), 4.03 (d, J=11.62Hz, 1 H), 3.77 (s, 3H), 3.38 (m, 1 H), 1.75 (m, 1 H), 1.49 (m, 1 H), 1.38 (m, 1 H), 1.31 (t, J=7.47Hz, 3H), 0.96 (m, 1 H), 0.71 (t, J=7.47Hz, 3H).
(RS, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (second eluting diastereoisomer, 5mg) MS: 586.0 [M+Hf found
1H-NMR (CDCI3) δ 7.93 (s, 2H), 7.84 (s, 1 H), 7.53 (d, J=8.29Hz, 1 H), 7.43 (dd, J=8.29Hz, 1 H), 7.07 (s, 1 H), 4.42 (m, 1 H), 4.27 (d, J=9.96Hz, 1 H), 4.26 (m, 2H), 4.32 (m,1 H), 3.76 (s, 3H), 3.28 (m, 1 H), 2.36 (m, 1H), 1.65 (m, 1 H), 1.62 (m, 1 H),1.45 (m, 1 H), 1.31 (t, J=7.47Hz, 3H), 0.84 (t, J=7.47Hz, 3H). Examples 9 and 10
Figure imgf000108_0001
(R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000109_0001
(R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester Sodium hydride (60% dispersion in mineral oil, 34mg, 0.85mmol) was added to a solution of 3,5-bis(trifluoromethylphenyl)acetonitrile (212mg, 0.84mmol) in anhydrous dimethylformamide (1.5mL). After stirring under nitrogen for 30 min at ambient temperature a solution of (R)-4-chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1 -carboxylic acid ethyl ester (Preparation 14, 188mg, 0.56mmol) in anhydrous dimethylformamide (2mL) was added. The mixture was stirred at ambient temperature for 16h then poured into water (20mL) and extracted with diethyl ether (3x20mL). The extract was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. This material was purified by chromatography on silica eluting initially with ethyl acetate - hexanes (1:19) to obtain one diastereoisomer of the desired compound in an impure form which was further purified by reverse phase chromatography to obtain the title compound Example 9 as a clear oil (69mg).
Further elution of the silica column with ethyl acetate - hexanes (1 :4) provided the title compound of Example 10 as a yellow oil (54mg).
(R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester MS: 553 [M+Hf found
1H-NMR (CDCI3) δ 7.80 (s, 1 H), 7.60 (d, J=8.30Hz, 1 H), 7.49 (dd, J=8.30, 1.66Hz, 1 H), 7.40 (s, 2H), 6.60 (d, J=1.66Hz, 1 H), 4.59 (m, 1H), 4.33 (m, 2H), 4.06 (d, J=9.96, 1 H), 3.20 (m, 1 H), 2.78 (m, 1 H), 1.89 (m, 1 H), 1.65 (m, 1H), 1.53 (m, 1H), 1.34 (t, J=7.47Hz, 3H), 0.96 (m, 1 H), 0.88 (t, J=7.47Hz, 3H). (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester MS: 553 [M+Hf found 1H-NMR (CDCI3) δ 7.89 (s, 1 H), 7.62 (s, 2H), 7.62 (d, J=8.30Hz, 1H), 7.55 (d, J=8.30Hz, 1H), 7.38 (s, 1 H), 4.41 (m, 1H), 4.24 (m, 2H), 4.16 (m, 1 H), 4.15 (d, J=8.30Hz, 1 H), 3.48 (m, 1 H), 2.01 (m, 1H), 1.95 (m, 1H), 1.48 (m, 1 H), 1.41 (m, 1 H), 1.29 (t, J=7.47Hz, 3H), 0.77 (t, J=7.47Hz, 3H). Preparation 15
Figure imgf000110_0001
[(R, S), (S, R)] and [(R, R), (S, S)]-4-Cyano-6,7-dimethoxy-2-methyl-4- trimethylsilanyloxy-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester
[(RS)]-6,7-Dimethoxy-2-methyl-4-oxo-3,4-dihydro-2 -/-quinoline-1-carboxylic acid ethyl ester (8.02gm, 27.3mmol, 1 eq) and zinc iodide (0.43gm, 1.37mmol, 0.05 eq) were added to a dry round bottomed flask equipped with a magnetic stir bar and reflux condenser under a nitrogen atmosphere. Toluene (20mL) was added to the flask followed by trimethylsilyl cyanide (4.40mL, 33.0mmol, 1.2 eq). The reaction was heated to 80 °C. After 5 hr, the reaction mixture was concentrated to dryness to afford the title compounds (10.7gm, 27.2mmol, 100% yield) that were used without further purification.
LCMS (ESI+): 393 (MH+).
Preparation 16
Figure imgf000110_0002
(RS) -4-Cyano-6,7-dimethoxy-2-methyl-2H-quinoline-1 -carboxylic acid ethyl ester [(R, S), (S, R)] and [(R, R), (S, S)]-4-cyano-6,7-dimethoxy-2-methyl-4- trimethylsilanylqxy-3,4-dihydro-2/- -quinoline-1 -carboxylic acid ethyl ester (10.7gm, 27.37mmol) was placed in a 100mL round bottomed flask and dissolved in ethanol (25 mL). Hydrochloric acid in dioxane (21.OmL of a 4.0 M solution) was added to the mixture. After 12 hr at room temperature, the reaction mixture was concentrated, quenched with a saturated aqueous sodium hydrogen carbonate solution and extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. Flash chromatography eluting with 80/20 hexanes/ethyl acetate the title compounds (5.49gm, 18.1mmol, 67% yield).
LCMS (ESI+): 303 (MH+). 1H-NMR (CDCI3): δ 1.13 (d, 3H), 1.33 (t, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 4.30
(m, 2H), 5.25 (m, 1H), 6.65 (d, 1H), 6.91 (s, 1 H), 7.24 (br s, 1 H).
Preparations 17 and 18
Figure imgf000111_0001
[(R, S), ((S, R)] and [(R, R), (S, S)]-4-Cyano-6,7-dimethoxy-2-methyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester
(RS) -4-Cyano-6,7-dimethoxy-2-methyl-2 - -quinoline-1 -carboxylic acid ethyl ester (4.99gm, 16.5mmol) was placed in a round bottomed flask equipped with a magnetic stir bar, dissolved in 47mL of ethanol, and was combined with sodium borohydride (3.18gm, 84.3mmol, 5.1 eq). After 45 min of heating at reflux, the mixture was concentrated to dryness, quenched with water, and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and concentrated to afford the title compounds (4.91 gm, 16.1mmol, 98% yield). cis isomer: LCMS (ESI+): 305 (MH+).
(R, S) and (S, R) 1H-NMR (CDCI3): δ 1.23 (d, 3H), 1.29 (t, 3H), 1.78 (m, 1H), 2.65 (m, 1 H), 3.74 (m, 1H), 3.86 (s, 3H), 3.90 (s, 3H), 4.22 (m, 2H), 4.61 (m, 1 H), 6.92 (s, 1 H), 7.10 (s, 1H). trans isomer: LCMS (ESI+): 305 (MH+).
(R, R) and (S, S) 1H-NMR (CDCI3): δ 1.16 (d, 3H), 1.32 (t, 3H), 2.03 (m, 1H), 2.42 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 3.94 (m, 1 H), 4.26 (m, 2H), 4.86 (m, 1 H), 6.77 (s, 1 H), 7.30 (s, 1 H).
Preparations 19 and 20
Figure imgf000112_0001
[(ft S), (S, R)] and [(R, R), (S, S)]-4-Carbamoyl-6,7-dimethoxy-2-methyl-3,4-dihydro- 2 --quinoline-1 -carboxylic acid ethyl ester [(ft S), (S, R)] and [(ft R), (S, S)]-4-cyano-6,7-dimethoxy-2-methyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (2.22gm, 7.32mmol, 1 eq) was dissolved in concentrated sulfuric acid (12mL) and water (0.66mL, 36.6mmol, 5 eq). After 12 hr at ambient temperature the reaction was quenched into solid sodium bicarbonate, dissolved in water and extracted 3 times with ethyl acetate. Organic layers were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compounds (2.25gm, 6.98mmol, 95% yield). LCMS (ESI+): 323 (MH+).
[(ft S), (S, R)]: 1H-NMR (CDCI3): δ 1.20 (d, 3H), 1.30 (t, 3H), 1.89 (m, 1 H), 2.41 (m, 1 H), 3.37 (m, 1 H), 3.84 (s, 3H), 3.86 (s, 3H), 4.22 (m, 2H), 4.55 (m, 1 H), 5.70 (s, 1H), 5.80 (s, 1 H), 6.70 (s, 1H), 7.21 (s, 1H). LCMS (ESI÷): 323 (MH+).
[(ft R), (S, S)]: 1H-NMR (CDCI3): δ 1.17 (d, 3H), 1.30 (t, 3H), 1.74 (m, 1 H), 2.67 (m, 1 H), 3.55 (m, 1 H), 3.86 (s, 3H), 3.87 (s, 3H), 4.21 (m, 2H), 4.58 (m, 1 H), 5.36 (s, 1 H), 5.49 (s, 1 H), 6.65 (s, 1H), 7.15 (s, 1 H).
Preparations 21 and 22
Figure imgf000112_0002
[(ft S), (S, R)] and [(ft R), (S, S)]-6,7-Dimethoxy-2-methyl-3, 4-dihydro-2H- quinoline-1 ,4-dicarboxylic acid-1 -ethyl ester- -methyl ester [(ft S), ((S, R)] and [(ft R), (S, S)]-4-Carbamoyl-6,7-dimethoxy-2-methyl-3,4- dihydro-2r-/-quinoline-1 -carboxylic acid ethyl ester (2.24gm, 6.95mmol, 1 eq) was placed in a 10OmL round bottomed flask equipped with a stir bar and was dissolved in methylene chloride (56.5mL). 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+).
[(ft S) (S, R)] 1H-NMR (CDCI3): δ 1.17 (d, 3H), 1.29 (t, 3H), 1.81 (m, 1H), 2.46 (m, 1H), 3.56 (m, 1 H), 3 .81 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 4.21 (m, 2H), 4.55 (m, 1 H), 6.60 (s, 1 H), 7.11 (s, 1 H).
LCMS (ESI+): 338 (MH+).
[(ft R) (S, S)]: 1H-NMR (CDCI3): δ 1.13 (d, 3H), 1.29 (t, 3H), 1.78 (m, 1 H), 2.54 (m, 1 H), 3.67 (s, 3H), 3.71 (m, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 4.21 (m, 2H), 4.74 (m, 1 H), 6.66 (s, 1 H), 7.13 (s, 1H).
Preparations 23 and 24
Figure imgf000113_0001
[(ft S), (S, R)] and [(ft R), (S, S)]-6,7-Dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-
1 ,4-dicarboxylic acid-1 -ethyl ester [(ft S), (S, R)] and [(ft R), (S, S)]-6,7-Dimethoxy-2-methyl-3,4-dihydro-2H- quinoline-1 ,4-carboxylic acid ethyl ester-4-methyl ester (0.62gm, 1.73mmol, 1 eq) was dissolved in dioxane (12mL) and water (12mL) in round bottomed flask with a magnetic stir bar. Sodium hydroxide (0.13gm, 3.48mmol, 2 eq) was added and stirred at room temperature. After 12 hr, the reaction mixture was concentrated 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 ether. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated to provide the title compounds (0.536gm, 1.65mmol, 90% yield) as a mixture of diastereoisomers. LCMS (ESI+): 324 (MH+). [(ft S), (S, R)]: 1H-NMR (CDCI3): δ 1.18 (d, 3H), 1.30 (t, 3H), 1.89 (m, 1H), 2.48 (m, 1H), 3.61 (m, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 4.21 (m, 2H), 4.60 (m, 1H), 6.75 (s, 1 H), 7.15 (s, 1H).
LCMS (ESI+): 324 (MH+).
[(ft R), (S, S)]: H-NMR (CDCI3): δ 1.14 (d, 3H), 1.29 (t, 3H), 1.83 (m, 1 H), 2.56 (m, 1H), 3.74 (m, 1H), 3.85 (s, 6H), 4.21 (m, 2H), 4.76 (m, 1 H), 6.70 (s, 1H), 7.14 (s, 1 H).
Examples 11 and 12
Figure imgf000114_0001
[(R, S), (S, R)] and [(ft R), (S, S)]-4-(3,5-Bis-trifluoromethyl-benzylcarbamoyl)-6,7- dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
[(ft S), (S, R)] and [(ft R), (S, S)]-6,7-Dimethoxy-2-methyl-3,4-dihydro-2H- quinoline-1 ,4-dicarboxylic acid-1-ethyl ester (0.229gm, 0.710mmol) was placed in a
25mL round bottomed flask equipped with a stir bar. Methylene chloride (7.0mL) was added followed by the addition of 3,5-bis(trifluoromethyl)benzylamine (0.519gm,
2.14mmol, 3.0 eq). To this reaction, 1-hydroxybenzotriazole hydrate (0.022gm,
0.146mmol, 0.2 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(0.232gm, 1.21mmol, 1.7 eq) were added. The reaction mixture was stirred at room temperature. After 12 hr, the reaction was quenched with water and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered, concentrated to provide the title compounds (0.1225gm, 0.223mmol,
58% yield) as a mixture of diastereoisomers.
LCMS (ESI+): 549 (MH+).
1H NMR [(ft R), (S, S) and (ft S) (S, R)] (CDCI3): δ 1.16 (d, 3H), 1.24 (t, 3H), 1.80 (m, 1H), 2.66 (m, 1H), 3.64 (m, 1 H), 3.81 (s, 3H), 3.86 (s, 3H), 4.11 (m, 2H),
4.29 (m, 1H), 4.56 (m, 2H), 4.70 (m, 2H), 6.05 (m, 1H), 6.40 (m, 1 H), 6.65 (s, 1H),
6.60 (s, 1 H), 7.13 (s, 1 H), 7.66 (s, 2H), 7.75 (s, 1 H), 7.80 (s, 1H). LCMS (ESI+):
549 (MH+). Preparations 25 and 26 [(R, S), (S, R)] and [(R, R), (S, S)]-6,7-Dimethoxy-4-(methoxymethyl-carbamoyl)-2- methyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester [(ft S), (S, R)] and [(ft R), (S, S)]-6,7-Dimethoxy-2-methyl-3,4-dihydro-2H- quinoline-1 ,4-dicarboxylic acid-1 -ethyl ester (0.536gm, 1.55mmol) was placed in a 25mL round bottomed flask equipped with a stir bar and dissolved in methylene chloride (10mL). The 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. LCMS (ESI+): 367 (MH+).
[(ft R), (S, S)] 1H-NMR (CDCI3): δ 1.10 (d, 3H), 1.28 (t, 3H), 1.83 (m, 1H), 2.41 (m, 1 H), 3.16 (s, 3H), 3.38 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 4.06 (m, 1 H), 4.21 (m, 2H), 4.84 (m 1H), 6.55 (s, 1 H), 7.16 (s, 1 H). LCMS (ESI+): 367 (MH+). [(ft S), (S, R)] 1H-NMR (CDCI3): δ 1.32 (d, 3H), 1.65 (t, 3H), 1.75 (m, 1 H),
2.39 (m, 1H), 3.16 (s, 3H), 3.35 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 4.06 (m, 1H), 4.21 (m, 2H), 4.84 (m 1 H), 6.45 (s, 1 H), 7.05 (s, 1 H).
Examples 13 and 14
Figure imgf000115_0001
[(ft S), (S, R)] and [(ft R), (S, S)]-4-(3,5-Bis-trifiuoromethyl-benzoyl)-6,7-dimethoxy- 2-methyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester [(ft S), (S, R)] and [(ft R), (S, S)]-6,7-Dimethoxy-4-(methoxy-methyl- carbamoyl)-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.56gm, 1.45mmol, 1 eq) was dissolved in tetrahydrofuran (12mL) in a round bottomed flask equipped with a magnetic stir bar. The reaction was cooled to 0 °C. 3,5- Bis(trifluoromethyl)phenyl magnesium bromide (13.6mL of 0.5 M solution) was added drop wise, and the reaction mixture was stirred at room temperature. After 12 hr, the reaction mixture was quenched with aqueous ammonium chloride, further saturated with NaCl and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and concentrated to dryness. Flash chromatography eluting with 90/10 hexanes/ethyl acetate provided the title compounds (0.556gm, 1.07mmol, 73% yield).
LCMS (ESI÷): 520 (MH+).
[(ft S), (S, R)]: 1H NMR (CDCI3): δ 1.24 (d, 3H), 1.35 (t, 3H), 1.81 (m, 1 H), 2.52 (m, 1 H), 3.63 (s, 3H), 3.88 (s, 3H), 4.29 (m, 2H), 4.42 (m, 1 H), 4.57 (m, 1 H), 6.21 (s, 1H), 7.15 (s, 1 H), 8.13 (s, 1 H), 8.45 (s, 2H).
LCMS (ESI+): 520 (MH+).
[(ft R), (S, S)] 1H NMR (CDCI3): δ 1.18 (d, 3H), 1.28 (t, 3H), 1.88 (m, 1H), 2.67 (m, 1H), 3.79 (s, 3H), 3.84 (s, 3H), 4.21 (m, 2H), 4.45 (t, 1 H), 4.88 (m, 1 H), 6.59 (s, 1H), 7.07 (s, 1H), 7.97 (s, 1 H), 8.25 (s, 2H).
Example 15
Figure imgf000116_0001
[(ft R), (S, S)]- 4-(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-methyl-5,6- dimethoxy-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester [(ft R), (S, S)]-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-6,7-dimethoxy-3,4- dihydro-2/--quinoline-1 -carboxylic acid ethyl ester (0.062gm, 0.120mmol) was dissolved in methylene chloride (0.25mL) in a vial equipped with a magnetic stir bar. [Bis(2-methoxyethyl)amino]sulfur trifluoride (0.22mL, 1.20mmol, 10 eq) was added to this solution and the reaction mixture was stirred at room temperature. After 12 hr, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted 3 times with ethyl acetate. The organic layers were collected, dried over magnesium sulfate, filtered, concentrated and purified by chromatography on silica eluting with 90/10 hexanes/ethyl acetate to provide the title compound (0.045gm, O.Oδmmol, 66% yield).
LCMS (ESI+): 542 (MH+).
[(ft R), (S, S)]: 1H NMR (CDCI3): δ 1.10 (d, 3H), 1.22 (t, 3H), 1.95 (m, 1 H), 2.45 (m, 1 H), 3.55 (m, 1 H), 3.75 (s, 3H), 3.87 (s, 3H), 4.00 (m, 1 H), 4.19 (m, 1 H), 4.60 (m, 1 H), 6.45 (s, 1 H), 6.99 (s, 1 H), 7.6 (s, 2H), 7.90 (s, 1H).
Examples 16 and 17
Figure imgf000117_0001
[(ft ft R), (S, S, S)] and [(ft ft S), (S, S, R)]-4-[(3,5-Bis-trifluoromethyl-phenyl)- hydroxy-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester
[(ft R), (S, S)]-4-(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4- dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester (0.302gm, 0.58mmol, 1 eq) was placed in a round bottomed flask equipped with a magnetic stir bar. Methanol (12mL) was added followed by the addition of sodium borohydride (0.131gm, 3.48mmol, 6 eq) at room temperature. After 1 hour, the reaction mixture was quenched with a brine solution, extracted 3 times with ethyl acetate and dried over sodium sulfate.
The material was purified by flash chromatography eluting with 75/25 hexanes/ethyl acetate to provide the title compounds (0.271 gm, 0.52mmol, 89% yield). Diastereoisomer 1 (29% yield)
LCMS (ESI÷): 522 (MH+).
1H NMR (CDCI3): δ 1.12 (d, 3H), 1.29 (t, 3H), 1.39 (m, 1 H), 2.52 (m, 1 H), 2.81
(br s, 1 H), 2.94 (m, 1H), 3.65 (s, 3H), 3.83 (s, 3H), 4.21 (m, 2H), 4.67 (m, 1 H), 5.04
(d, 1 H), 6.18 (s, 1 H), 7.02 (s, 1 H), 7.64 (s, 2H), 7.72 (s, 1 H). Diastereoisomer 2 (60% yield)
LCMS (ESI+): 522 (MH+).
1H NMR (CDCI3): δ 1.14 (d, 3H), 1.34 (t, 3H), 1.56 (m, 1 H), 1.86 (m, 1 H), 2.97
(m, 1 H), 3.87 (s, 3H), 3.88 (s, 3H), 4.26 (m, 2H), 4.49 (m, 1H), 4.77 (d, 1H), 6.70 (s,
1 H), 7.09 (s, 1 H), 7.84 (s, 3H). Examples 18 and 19
Figure imgf000118_0001
[(ft ft R), (S, S, S) and (R, ft S), (S, S, R)]-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro- methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester
[(ft ft R), (S, S, S) and (R, ft S), (S, S, R)]-4-[(3,5-Bis-trifluoromethyl- phenyl)-hydroxy-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester (O.Oδgm, 0.115mmol) was placed in a small round bottomed flask containing a magnetic stir bar and dissolved in dichloromethane
(0.25mL). To this reaction, (diethylamino)sulfur trifluoride (0.152mL) was added dropwise at room temperature. After 2 hr, the reaction was quenched with the addition of aqueous ammonium chloride solution and extracted 3 limes with EtOAc.
Organics were collected, dried over Na2S04, filtered and concentrated to afford the title compounds in 40% isolated yield (0.024gm, 0.046mrnol).
LCMS (ESI+): 524 (MH+).
1H NMR (CDCI3): δ 1.19 (d, 3H), 1.30 (t, 3H), 2.02 (m, 1H), 2.95 (m, 1 H), 3.95
(s, 3H), 3.97 (s, 3H), 4.26 (m, 2H), 4.49 (m, 1H), 6.40 (s, 1H), 6.9 (s, 1 H), 7.1 (s, 1 H),
7.8 (s, 3H), 7.95 (s, 1 H).
Preparation 27
Figure imgf000118_0002
[(ft S) and (ft R)]-4-Chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 ,4- dicarboxylic acid-1 -ethyl ester-4-methyl ester (R)-2-Ethyl-4-hydrazono-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester (Preparation 6, 1.22gm, 3.70mmol) was placed in a 250mL round bottomed flask equipped with a stir bar. Diethyl ether (100mL) was added followed by the addition of Mn0 (22.2mmol, 6 eq). The reaction was protected from light and stirred at room temperature for 90 min. The solution was filtered through Celite® and concentrated to a final volume of 30mL. Additional toluene (100mL) was added and concentrated to 40mL. To this solution was added of di-iso-propylethylamine (3.25mL, 18.5mmol), followed by the addition of 20% phosgene solution in toluene (7.5mL). The reaction mixture was stirred for 45 min before anhydrous methanol (10mL) was added. After 2 hr, the reaction was concentrated down to 20mL, extracted into methylene chloride and washed with 0.1 N HCI. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated to dryness to obtain the title compound (1.43gm, 3.66mmol, 98% yield).
LCMS (ESI+): 394 (MH+).
(ft S), (R, R): 1H NMR (CDCI3): δ 0.95 (t, 3H), 1.25 (m, 2H), 1.30 (t, 3H), 2.60
(dd, 1 H), 2.79 (dd, 1 H), 3.99 (s, 3H), 4.23 (m, 2H), 4.62 (m, H), 7.61 (d, 1H), 7.70 (d,
1 H).
Preparation 28 and 29
Figure imgf000119_0001
Preparation of [(R, S) and (R, R)]-2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-
1 ,4-dicarboxylic acid-1 -ethyl ester-4-methyl ester [(R, S) and (ft R)]-4-Chloro-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 ,4-dicarboxylic acid-1 -ethyl ester-4 methyl ester (1.40 grams, 3.56 mmol) was dissolved in 30 mL of methanol before
0.15 grams of 10% Pd/C was added and the mixture was hydrogenated at 45 psi on the par shaker for 2 hours. The reaction mixture was filtered through Celite and concentrated. The crude mixture was then dissolved in dichloromethane and the organics were collected, dried over magnesium sulfate and concentrated. The product was isolated after purification by column chromatography eluting with a solution of 90:10 hexane-acetone to yield 83% (2.98 mmol) of the title compound.
(ft S): 1H NMR (CDCI3): δ? 0.84 (t, 3H), 1.30 (t, 3H), 1.40 (m, 2H), 1.95 (m, 1 H),
2.47 (m, 1H), 3.61 (m, 1 H), 3.80 (s, 3 H), 4.3 (m, 2H), 4.42 (m, 1 H), 7.40 (s, 1H), 7.60
(d, 1 H), 7.70 (d, 1 H).
LCMS (ESI+): 360 (MH+) (ft R): 1H NMR (CDCI3): δ? 0.86 (t, 3H), 1.28 (t, 3H), 1.38 (m, 2H), 2.1 (m, 1 H), 2.56 (m, 1 H), 3.69 (s, 3H), 3.90 (t, 1H), 4.30 (m, 2H), 4.58 (m, 1 H). 7.46 (s, 1H), 7.50 (d, 1 H), 7.70 (d, 1 H) LCMS (ESI+): 360 (MH+)
Preparation 30
Figure imgf000120_0001
[(ft S) and (ft R)]-2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 ,4-dicarboxylic acid-1 -ethyl ester
[(R, S) and (ft R)]-2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 ,4- dicarboxylic acid-1 -ethyl ester-4-methyl ester (Preparation 28 and 29, 0.070gm, 0.195mmol, 1 eq) was dissolved in a round bottomed flask with magnetic stir bar containing dioxane (1.5mL) and water (1.5mL). Sodium hydroxide (0.016gm, 0.409mmol, 2.1 eq) was added and stirred at room temperature. After 12 hr, the 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).
LCMS (ESI+): 346 (MH+).
[(ft S), (ft R)]: 1H-NMR (CDCI3): δ 0.84 (t, 3H), 1.23 (t, 3H), 1.39 (m, 2H), 1.94 (m, 1 H), 2.59 (m, 1 H), 3.84 (t, 1 H), 4.19 (m, 2H), 4.62 (m, H), 7.49 (m, 2H), 7.63 ( , 1H).
Preparation 31
Figure imgf000120_0002
[(R, S) and (ft R)]-2-Ethyl-4-(methoxy-methyl-carbamoyl)-6-trifluoromethyl-3,4- dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester [(R, S) and (ft R)]-2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 ,4- dicarboxylic acid-1 -ethyl ester (0.066gm, 0.239mmol) was placed in a 5mL round bottomed flask equipped with stir bar. Methylene chloride (3mL) was added. The reaction mixture was cooled to 0 °C. Di-iso-propylethylamine (0.032gm, 0.248mmol, 1.3 eq) was added followed by addition of Λ/.O-dimethylhydroxylamine HCI salt
(0.239mmol), 4-dimethylaminopyridine (0.019mmol) and 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (0.210mmol). The reaction was stirred at room temperature. After 12 hr, the reaction was quenched with water and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered, concentrated to provide the title compounds (0.065gm, 0.167mmol, 88% yield).
LCMS (ESI+): 389 (MH+).
[(ft S), (ft R)]: 1H-NMR (CDCI3): δ 0.90 (t, 3H), 1.33 (t, 3H), 1.39 (m, 2H), 2.0 (m, 1H), 2.55 (m, 1 H), 3.20 (s, 3H), 3.40 (s, 3H), 4.19 (m, 2H), 4.62 (m, 1H), 7.21 (s, 1 H), 7.40 (s, 2H), 7.62 (d, 2H).
Examples 20 and 21
Figure imgf000121_0001
[(R, S)] and [(R, R)]-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester [(R, S), (ft R)]-2-Ethyl-4-(methoxy-methyl-carbamoyl)-6-trifluoromethyl-3,4- dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester (0.564gm 1.45mmol, 1 eq) was dissolved in tetrahydrofuran (12mL) in a round bottomed flask equipped with a stir bar. The reaction was cooled to 0 °C. 3,5-Bis(trifluoromethyl)phenyl magnesium bromide (13.6mL of 0.5M solution) was added dropwise, and the reaction mixture was stirred at room temperature. After 12 hr, the reaction mixture was quenched with aqueous ammonium chloride solution, further saturated with NaCl and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and concentrated to dryness. Flash chromatography eluting with 90/10 hexanes/ethyl acetate provided the title compounds (0.556gm, 1.02mmol, 70% yield). trans isomer:
LCMS (ESI+): 542 (MH+).
(ft R): 1H-NMR (CDCI3): δ 0.98 (t, 3H), 1.29 (t, 3H), 1.52 (m, 2H), 2.05 (m, 1H), 2.64 (m, 1 H), 4.24 (m, 2H), 4.66 (m, 2H), 7.40 (s, 1H), 7.55 (d, 1 H), 7.60 (d, 1H), 8.05 (s, 2H), 8.24 (s, 1 H). cis isomer:
LCMS (ESI+): 542 (MH+).
(ft S): 1H-NMR (CDCI3): δ 0.91 (t, 3H), 1.39 (t, 3H), 1.43 (m, 2H), 1.78 (m, 1 H), 1.99 (m, 1 H), 2.60 (m, 1 H), 4.34 (m, 2H), 4.56 (m, 2H), 7.05 (s, 1H), 7.55 (d, 1H), 7.65 (d, 1 H), 8.20 (s, 1H), 8.44 (s, 2H).
Examples 22, 23, 24 and 25
Figure imgf000122_0001
Figure imgf000122_0002
[(ft ft R)], [(ft ft S)], [(ft S, S)], and [(ft S, R)]-4-(3,5-bis-trifluoromethyl-phenyl)- hyd roxy-methyl]-2-ethyl-6-trif I uoromethyl-3 ,4-d i hyd ro-2 - -q u i nol i ne- 1 -carboxyl ic acid ethyl ester [(ft S)] and [(ft R)]-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.182gm, 0.34mmol, 1 eq) was placed in a round bottomed flask equipped with a magnetic stir bar. Methanol (6.8mL) was added followed by the addition of (0.077gm, 2.05mmol, 6 eq) sodium borohydride at room temperature. After 1 hour, the reaction mixture was quenched with brine solution, extracted 3 times with ethyl acetate and dried over sodium sulfate. The material was purified by flash chromatography eluting with 90/10 hexanes/ethyl acetate to provide the title compounds in three fractions. (R.S.R):
LCMS (ESI+): 544 (MH+).
1H-NMR (CDCI3): δ 0.81 (t, 3H), 1.27 (t, 3H), 2.04 (m, 1 H), 4.22 (m, 3H), 7.86 (s, 1H), 7.90 (s, 1 H). (R.S.S): LCMS (ESI+): 544 (MH+).
1H-NMR (CDCI3): δ 0.73 (t, 3H), 1.09 (m, 1 H), 1.27 (t, 3H), 1.43 (m, 2H), 1.67 (m, 1 H), 2.44 (d, 1H), 2.87 (m, 1 H), 4.24 (m, 3H), 5.17 (dd, 1H), 7.26 (s, 1H), 7.50 (m, 2H), 7.90 (s, 2H), 7.92 (s, 1 H).
(R,R,R) and (R,R,S): This mixture was separated on a 10 cm by 50 cm, Chiralpak AD column eluting in heptane/IPA 9S//2 at a flow rate of 275 mL/min.
(R.R.R): 1H-NMR (CDCI3): δ 0.77 (t, 3H), 1.31 (t, 3H), 1.41 (m, 2H), 2.21 (d, 1 H), 3.19 (m, 1 H), 4.23 (m, 2H), 4.37 (m, 1 H), 4,83 (d, 1 H), 7.65 (s, 2H), 7.79 (s, 1H). LCMS (ESI+): 544 (MH+).
(R.R.S): 1H-NMR (CDCI3): δ 0.81 (t, 3H), 1.33 (t, 3H), 1.6 (m, 2H), 2.22 (d, 1 H), 3.05 (m, 1 H), 4.30 (m, 2H), 4.62 (m, 1 H), 5.19 (d, 1 H), 7.01 (s, 1H), 7.40 (s, 2H), 7.85 (s, 1 H).
LCMS (ESI+): 544 (MH+).
Preparations 32 and 33 [(ft R), (S, S)] and [(S, R), (ft S)]-4-Aminomethyl-6,7-dimethoxy-2-methyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Sodium borohydride (0.828gm, 21.9mmol) was suspended in tetrahydrofuran (13.5mL) in a dry 50mL round-bottomed flask equipped with stir bar. In another flask trifluoroacetic acid (1.68mL, 21.8mmol) was dissolved in tetrahydrofuran (5mL). The 50mL reaction flask was cooled to 0°C and the trifluoroacetic acid solution was added slowly. The reaction was allowed to stir at room temperature. After 30 min, [(ft R), (S, S)] and [(S, R), (R, S)]-4-cyano-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline- 1 -carboxylic acid ethyl ester (1.33gm, 4.37mmol) in tetrahydrofuran (5mL) was added drop wise to the reaction. After 12 hr, the reaction was cooled back to 0 °C and carefully quenched with water. The aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography eluting with 97/2/1 methylene chloride/methanol/triethylamine to afford the title compounds (0.982gm, 3.18mmol, 73% yield).
LCMS (ESI+): 309 (MH+).
[(ft S), (S, R)] 1H-NMR (CDCI3): δ 1.18 (d, 3H), 1.27 (t, 3H), 2.47 (m, 2H), 2.92 (m, 1H), 3.29 (m, 1 H), 3.84 (s, 3H), 3.86 (s, 3H), 4.19 (m, 2H), 4.47 (m, 1 H), 6.69 (s, 1H), 7.02 (s, 1 H).
LCMS (ESI+): 309 (MH+).
[(ft R), (S, S)] 1H-NMR (CDCI3): δ1.15 (d, 3H), 1.31 (t, 3H), 1.76 (m, 1 H), 2.18 (m, 1 H), 2.94 (m, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 4.22 (m, 2H), 4.61 (m, 1 H), 6.69 (s, 1 H), 7.12 (s, 1 H).
Example 26
Figure imgf000124_0001
[(ft S), (ft R)] and [(S, S), (S, R)]-4-[(3,5-Dϊfiuoro-benzoylamino)-methyl]-6,7- dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
To a solution of [(R, S), (R, R)] and [(S, S), (S, R)]-4-aminomethyl-6,7- dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.012gm, 0.039mmol) in methylene chloride (1.OmL) was added 3,5-difluorobenzoic acid (0.0065gm, 0.041 mmol, 1.0 eq) followed by 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.012gm, 0.065mmol, 1.6 eq) and 1- hydroxybenzotriazole hydrate (O.OOδgm, 0.039mmol, 1 eq). The reaction was stirred at ambient temperature for 12 hr. The mixture was concentrated, dissolved in dimethylsulfoxide and purified by HPLC to provide the title compound (O.OOδgm, 0.019mmol).
LCMS (ESI+): 449 (MH+). [( ?, S), (R, R)] and [(S, S), (S, R)]: 1H-NMR (CDCI3): δ 1.15 (d, 3H), 1.30 (t, 3H), 1.79 (m, 1 H), 2.16 (m, 1H), 3.16 (m, 1 H), 3.63 (m, 2H), 3.82 (s, 3H), 3.87 (s, 3H), 4.22 (m, 2H), 4.63 (m, 1 H), 6.13 (m, 1H), 6.63 (s, 1 H), 6.92 (m, 1 H), 7.13 (s, 1H), 7.19 (m, 2H).
Examples 27 and 28
Figure imgf000125_0001
[(ft S), (S, R)] and [(ft R), (S, S)]-4-[(3,5-Bis-trifluoromethyl-benzylamino)-methyl]- 6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester [(ft S), (S, R)] and [(S, S), (R, R)]-4-Aminomethyl-6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.131gm, 0.428mmol) was dissolved in dichloroethane (2. OmL) in a 10mL round bottomed flask equipped with a stir bar. To this solution, 3,5-bis(trifluoromethyl)benzaldehyde (0.071 mL, 0.431 mmol) was added followed by sodium triacetoxyborohydride (0.272gm, 1.28mmol). After stirring at ambient temperature for 12 hr, the reaction mixture was quenched with a 1.0 N aqueous sodium hydroxide solution and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography eluting with 80/20 hexanes/ethyl acetate provided the title compounds (0.063gm, 0.12mmol, 28% yield). LCMS (ESI+): 535 (MH+).
[(ft S) (S, R)] 1H-NMR (CDCI3): δ 1.09 (m, 1H), 1.17 (d, 3H), 1.28 (t, 3H), 2.47 (m, 1 H), 2.61 (m, 1 H), 2.83 (m, 1 H), 3.16 (m, 1 H), 3.83 (s, 3H), 3.84 (s, 3H), 4.02 (s, 2H), 4.20 (m, 2H), 4.47 (m, 1 H), 6.81 (s, 1 H), 7.01 (s, 1 H), 7.82 (s, 1 H), 7.87 (s, 2H). LCMS (ESI+): 535 (MH+).
[(ft R) (S, S)] 1H-NMR (CDCI3): δ 1.14 (d, 3H), 1.28 (t, 3H), 1.74 (m, 1H), 2.21 (m, 1 H), 2.79 (m, 2H), 2.93 (m, 1 H), 3.83 (s, 3H), 3.84 (s, 3H), 3.88 (s, 2H), 4.20 (m, 2H), 4.56 (s, 1 H), 6.69 (s, 1 H), 7.11 (s, 1H), 7.75 (s, 1 H), 7.79 (s, 2H). Examples 29 and 30
Figure imgf000126_0001
[(ft S), (S, R)] and [(ft R), (S, S)]-4-[(3,5-Bis-trifluoromethyl-benzyl)- methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2/-/-quinoline-1- carboxylic acid ethyl ester
[(ft S), (S, R)] and [(S, S), (R, R)]-4-[(3,5-Bis-trifluoromethyl-benzylamino)- methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester (0.020gm, 0.037mmol) was dissolved in tetrahydrofuran (2.0mL) in a 10mL round bottomed flask equipped with a stir bar. To this solution, potassium carbonate (0.134gm, 0.972mmol) was added followed by the addition of methyl chloroformate
(0.030mL, 0.388mmol). The reaction mixture was stirred at room temperature. After
12 hr, the reaction mixture was quenched with 1.0 N aqueous sodium hydroxide and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography eluting with 65/35 hexanes/ethyl acetate provided the title compounds (O.OOSgm,
O.OOδmmol, 30% yield).
LCMS (ESI+): 593 (MH+).
(ft S) (S, R)] 1H-NMR (CDCI3): δ 1.17 (d, 3H), 1.29 (t, 3H), 2.30 (m, 1H),
2.75 (m, 1 H), 3.60 (m, 1 H), 3.78 (s, 3H), 3.δ3 (s, 3H), 3.65 (s, 3H), 4.22 (m, 2H), 4.39 (m, 1 H), 7.03 (s, 1 H).
LCMS (ESI+): 593 (MH+).
[(ft R) (S, S)] 1H-NMR (CDCI3): δ 1.15 (d, 3H), 1.24 (m, 3H), 1.63 (m, 1H),
2.15 (m, 1 H), 3.78 (s, 3H), 3.83 (s, 3H), 3.86 (s, 3H), 4.17 (m, 2H), 4.53 (m, 1 H),
7.06 (s, 1H). The following examples were prepared from analogous starting materials using methods analogous to those described in the examples above:
Example 31
Figure imgf000127_0001
[(ft S), (S, R)]-4-[(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester 1H-NMR (CDCI3): δ 1.2 (d, 3H), 1.35 (t, 3H), 1.95 (m, 1H), 2.55 (m, 1H), 3.60 (s, 3H), 3.97 (s, 3H), 4.20 (m, 1H), 4.22 (m, 1H), 4.40 (m, 1H), 4.62 (m, 1H), 6.2 (s, 1H), 7.1 (s, 1H) 8.19 (s, 1H), δ.45 (s, 2H). LCMS (ESI+): 522 (MH+).
Example 32
Figure imgf000127_0002
[(ft S, S), (S, R, R), (ft S, R), (S, R, S)]-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy- methyl]-6,7-dimethoxy-2-rnethyl-3,4-dihydro-2 -quinoline-1 -carboxylic acid ethyl ester
1H-NMR (CDCI3): δ 1.13 (d, 3H), 1.34 (t, 3H), (m, 1H), 2.97 (m, 1H), 3.87 (s,
3H), 3.δδ (s, 3H), 4.26 (m, 2H), 4.40 (m,1H), 5.05 (d, 1H), 6.89 (s,1H), 6.99 (s,
1H), 7.84 (s,3H).
LCMS (ESI+): 522 (MH+).
Example 33
Figure imgf000127_0003
(R, S)-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (R, S)]- cis: 1H-NMR (CDCI3): δ 0.91 (t, 3H), 1.39 (t, 3H), 1.43 (m, 2H), 1.78 (m, 1 H), 1.99 (m, 1H), 2.60 (m, 1H), 4.34 (m, 2H), 4.56 (m, 2H), 7.05 (s, 1H), 7.55 (d, 1 H), 7.65 (d, 1H), 8.20 (s, 1 H), 8.44 (s, 2H). LCMS (ESI+): 542 (MH+).
Example 34
Figure imgf000128_0001
[(R, ft S), (S, S, R), (ft R, R), (S, S, S)]-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)- methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
1H-NMR (CDCI3): δ 1.10 (d, 3H), 1.29 (t, 3H), 1.62 (m, 1 H), 1.87 (m, 1 H),
2.00 (s, 3H), 3.22 (m, 1 H), 3.84 (s, 3H), 3.86 (s, 3H), 4.21 (m, 2H), 4.47 (m, 1 H),
5.89 (d, 1 H), 6.62 (s, 1 H), 7.03 (s, 1 H), 7.66 (s, 2H), 7.80 (s, 1 H).
LCMS (ESI+): 564 (MH+).
Example 35
Figure imgf000128_0002
[(R.R.R) (S.S.S) and (R.R.S) and (S,S,R)]-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro- methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
1H-NMR (CDCI3): δ 1.19 (d, 3H), 1.30 (t, 3H), 2.02 (m, 1 H), 2.95 (m, 1H), 3.95 (s, 3H), 3.97 (s, 3H), 4.26 (m, 2H), 4.49 (m, 1 H), 6.40 (s, 1 H), 6.9 (s, 1 H), 7.1 (s, 1 H), 7.8 (s, 3H), 7.95 (s, 1 H).
LCMS (ESI+): 524 (MH+).
Figure imgf000129_0001
[(ft R), (S, S), (ft S), (S, R)]-4-(Hydroxy-diphenyl-methyl)-6,7-dimethoxy-2-methyl-
3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
1H-NMR (CDCI3): δ 1.0 (d, 3H), 1.32 (t, 3H), 2.2 (m, 1H), 3.90 (s, 3H), 3.95 (s,
3H), 4.26 (m, 2H), 4.6 (m, 1 H), 6.60 (s, 1 H), 6.9 (s, 1H), 7.0 (s, 1H), 7.2-7.4 (m,
10H).
LCMS (ESI+): 444 (MH+) (minus 17 OH group).
Example 37
Figure imgf000129_0002
[(R, R), (S, S)-4-benzoyl-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester
1H-NMR (CDCI3): δ 1.19 (d, 3H), 1.25 (t, 3H), 2.4 (m, 1 H), 3.75 (s, 3H), 3.85
(s, 3H), 4.30 (m, 2H), 4.6 (m, 1 H), 4.9 (m, 1H), 6.50 (s, 1H), 7.2 (s, 1 H), 7.4 (m, 2H),
7.5 (t, 1 H), 7.9 (d, 2H).
LCMS (ESI+): 384 (MH+).
Example 38
Figure imgf000129_0003
[(ft S, S), (ft S, R), (S, ft R), (S, R, S)] 4-(Hydroxy-phenyl-methyl)-6,7- dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester LCMS (ESI+): 386(MH+) Examples 39-169 in Table A were prepared as racemic mixtures using analogous methods as described above from the appropriate starting materials and have the following structure:
Figure imgf000130_0001
Table A
Figure imgf000130_0002
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Preparation 34 3-Ethyl-6,7-dimethyl-3,4-dihydro-1H-quinoxalin-2-one
A mixture of 5,6-dimethyl phenylenediamine (22.45gm, 165mmol, 1eq), 2- ketobutyric acid (16.83gm, 165mmol, 1eq) and ethanol (75mL) were irradiated in the Milestone microwave (Milestone Laboratories, Sorisole, Italy) for 5 min at 180°C. The solid product upon cooling was filtered and washed with ethanol. Concentration of the filtrate and further crystallization provided the desired quinoxalin-2-one (18.45gm, 55.2%).
1H-NMR (dmso-d6): δ 1.17 (t, J=7.05Hz, 3H), 2.25 (s, 3H), 2.26 (s, 3H), 2.74 (q, J=7.05Hz, 2H), 7.00 (s, 1 H), 7.48 (s, 1 H), 12.15 (brs, 1 H).
ESI-MS: 203 (MH+). Preparation 35 3-Chloro-2-ethyl-6,7-dimethyl-1 ,2-dihydro-quinoxaline 3-Ethyl-6,7-dimethyl-3,4-dihydro-1 H-quinoxalin-2-one (18.45g, 91.2mmol) was dissolved in 180mL phosphorus oxychloride and the mixture was heated overnight at 110°C under a drying tube charged with potassium hydroxide and Drierite®. After cooling, the phosphorus (V) oxychloride was carefully distilled off, and residue was carefully quenched with ice, followed by saturated sodium hydrogen carbonate. The aqueous suspension was extracted several times with methylene chloride. The combined organics were washed 1 time with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the title compound (19.3gm, 81%), which was carried forward without further purification.
1H-NMR (dmso-d6): δ 1.30 (t, J=7.47Hz, 3H), 3.04 (q, J=7.47Hz, 2H), 7.74, (s, 1 H), 7.83 (s, 1H).
Preparation 36 2-Ethyl-6,7-dimethyl-1 ,2,3,4-tetrahydro-quinoxarme The residue containing 3-chloro-2-ethyl-6,7-dimethyl-1 ,2-dihydro-quinoxaline was dissolved in 200mL acetic acid and 18.2g sodium acetate was added (222mmol, 3eq). After flushing with nitrogen, the vessel was charged with palladium on carbon (10%, 7.86gm, 0.1 eq Pd, 7.39mmol). The reaction was subjected to hydrogenation at 45psi for 5 hr whereupon hydrogen uptake ceased. The reaction was filtered through Celite® and evaporated. The residue was azeotroped 3 times with heptane to remove further acetic acid. The residue was then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was washed 3 times with saturated aqueous sodium hydrogen carbonate, 1 time with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Flash chromatography eluting with a 20-50% ethyl acetate /hexanes gradient provided the desired quinoxaline (10.56gm, 63% yield.) as a fluffy pinkish solid. 1H-NMR (dmso-d6): δ 0.89 (I, J=7.46Hz, 3H), 1.35 (m, 2H), 1.89, (s, 3H), 1.94
(s, 3H), 2.75 (m, 1H), 2.96 (m, 1 H), 3.14 (m, 1H), 6.12, (s, 1 H), 6.17 (s, 1 H).
Preparation 37 3-Ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid tert-butyl ester 2-Ethyl-6,7-dimethyl-1 ,2,3,4-tetrahydro-quinoxaline (10.56g, 55.6mmol, 1eq) was dissolved in anhydrous methylene chloride and cooled to -30°C in an ethylene glycol/dry ice bath. A solution of di-tert-butyl dicarbonate (12.13gm, 55.6mmol, 1eq) in methylene chloride (50mL) was added dropwise, and the reaction was allowed to slowly warm to room temperature overnight. The reaction was evaporated to dryness and repartitioned between ethyl acetate and 0.1 M HCI. The organic layer was washed 3 times with 0.1 M HCI, 1 time with saturated sodium hydrogen carbonate, 1 time with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Silica chromatography eluting with 10% ethyl acetate /hexane provided the desired compound (10.35g, 64%).
1H-NMR (dmso-d6): δ 0.90 (t, J=7.47Hz, 3H), 1.34 (m, 2H), 1.41 (s, 9H), 2.02 (s, 6H), 3.09 (m, 1 H), 3.24 (m, 1 H), 3.58 (m, 1 H), 5.74 (s, 1 H), 6.34 (s, 1 H), 7.05 (brs, 1 H).
ESI-MS: 290 (M+), 235 (MH+ - isobutylene). Preparation 38 2-Ethyl-6,7-dimethyl-2,3-dihydro-quinoxaline-1 ,4-dicarboxylic acid 4-tert-butyl ester
1 -ethyl ester A solution of 3-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid tert-butyl ester (10.35gm, 35.7mmol, 1eq) and 4-dimethylaminopyridine (436mg, 3.57mmol , 0.1 eq) in anhydrous pyridine (250mL) was cooled to 0°C and ethyl chloroformate (17.0mL, 178.3mmol, 5eq) was added dropwise. The reaction was allowed to warm to room temperature overnight. The solvents were evaporated under vacuum and azeotroped 3 times with heptanes. The residue, after drying under vacuum, was partitioned between ethyl acetate and 0.1 M HCI. The organic layer was extracted with 0.1 M HCI until the extracts were acidic, then was washed 1 time with saturated aqueous sodium hydrogen carbonate, 1 time with water, 1 time with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to provide the desired compound (100%). 1H-NMR (dmso-d6): δ 0.77 (t, J=7.05Hz, 3H), 1.20 (t, J=7.05Hz, 3H), 1.25 (m,
2H), 1.44 (s, 9H), 2.13 (s, 6H), 3.55 (dd, J=13.35, 4.98Hz, 1H), 3.78 (dd, J=13.1 , 3.32Hz, 1 H), 4.12 (m, 2H), 4.39 (m, 1H), 7.41 (s, 1 H), 7.44 (s, 1 H). ESI-MS: 307 (MH+-isobutylene), 263 (MH+ - boc).
Preparation 39 2-Ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester:
To 2-Ethyl-6,7-dimethyl-2,3-dihydro-quinoxaline-1 ,4-dicarboxylic acid 4-tert- butyl ester 1 -ethyl ester (12.93g) was added trifluoroacetic acid (200mL), the mixture was stirred until a solution had formed and then evaporated to dryness under vacuum. The residue was azeotroped 3 times with heptane and dried under vacuum. The residual oil was then partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The aqueous layer was extracted 3 times with methylene chloride. The combined methylene chloride extracts were dried over anhydrous sodium sulfate, filtered and evaporated, giving the desired quinoxaline (100%). 1H-NMR (dmso-d6): δ 0.77 (t, J=7.47Hz, 3H), 1.19 (t, J=7.05Hz, 3H), 1.24 (m,
2H), 2.02 (s, 6H), 3.14 (m, 2H), 4.08 (m, 2H), 4.24 (m, 1 H), 5.72 (m, 1H), 7.11 (brs, 1 H).
ESI-MS: 263 (MH+). This racemic quinoxaline was subjected to preparative chiral separations using a ChiralcelOD 10x25cm chiral preparative column. The eluentwas 5% ethanol in heptane, at a flow rate of 275mL/min, observing at 300nm. The sample was loaded on the column using 2:1 methanol/dichloromethane. Retention time of the S- enantiomer was 16min, the R-enantiomer was 22min. A 25g sample was subjected to these conditions, resulting in 10g of the R-enantiomer, 99.4%ee, and 11g of the S- enantiomer, 95.1%ee.
Examples 170, 171 , 172 and 173
Figure imgf000156_0001
(R,R, R,S, S,R and S,S) -4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl- methyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester Method A: 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, 1.1eq, 2.74mmol) and 2,6-lutidine (0.87mL, 3eq, 7.47mmol) in dimethylformamide (3mL) were heated at 140°C for 20 min by microwave irradiation in an Emrys Optimizer (Personal Chemistry, Uppsala, Sweden). The mixture was partitioned between methylene chloride and water, and the phases were separated. The aqueous phase was extracted 3 times with methylene chloride, 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 10% ethyl acetate in hexanes as eluant provided the title compounds as a mixture of two diastereoisomers (900mg, 66%).
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 aqueous phase was extracted 3 times with methylene chloride, 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 10% ethyl acetate in hexanes as eluant provided the title compounds as a mixture of two diastereoisomers (900mg, 66%).
Diastereoisomer 1 1H-NMR (CDCI3): δ 0.71 (t, J=7.57Hz, 3H), 1.30 (t, J=7.05Hz, 3H), 1.46 (m, 2H), 2.18 (s, 3H), 2.20 (s, 3H), 2.77 (dd, J=9.54, 2.08Hz,1 H), 3.37 (dd, J=11.38, 3.32Hz, 1H) 3.82 (s, 3H), 4.20 (m, 2H), 4.26 (m, 1 H), 5.82 (s, 1H), 6.58 (s,1H), 7.49 (brs, 1H) 7.75 (s,2H), 7.88 (s,1 H). LCMS (ESI+): 547 (MH+)
Diastereoisomer 2: 1H-NMR (CDCI3): δ 0.87 (t, J=7.47Hz, 3H), 1.28 (t, J=6.64Hz, 3H), 1.43 (m, 2H), 2.18 (s, 3H), 3.11 (dd, J=11.35, 4.98Hz, 1 H), 3.22 (dd, J=10.79, 1.66Hz, 1 H), 3.83 (s, 3H), 4.19 (m, 2H), 4.44 (m, 1 H), 5.66 (s, 1 H), 6.41 (s, 1 H), 7.28 (brs, 1 H), 7.73 (s, 2H), 7.86 (s, 1 H). LCMS (ESI+): 547 (MH+).
This racemic mixture of diastereoisomers could be further resolved by chiral HPLC on a Pirkle Covalent (S,S)Whelk-0 1 column (Regis Technologies, Inc., Morton Grove, IL) (5 x 25cm) eluting at 100mL/min with 5% ethanol/heptane to provide three fractions:
Isomer 1 , Retention time =18min Isomers 2 and 3, Retention time =25min Isomer 4, Retention time =37min
Examples 174 and 175
Figure imgf000157_0001
Preparation of 4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid methyl ester This compound was prepared using the procedure as described above for 4- [(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6,7-dimethyl-3,4- dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester, but using methyl chloroformate in the place of ethyl chloroformate. Diastereoisomer 1 1H-NMR (CDCI3): δ 0.86 (t, J=7.47Hz, 3H), 1.43 (m, 2H),
2.18 (s, 6H), 3.10 (dd, J=11.48, 4.98Hz, 1 H), 3.22 (dd, J=11.17Hz 1.66Hz, 1H), 3.75 (s, 3H), 4.43 (m, 1 H), 3.82 (s, 3H), 5.66 (s, 1 H), 6.41 (s, 1 H), 7.22 (brs, 1 H), 7.72 (s, 2H), 7.86 (s, 1H).
LCMS (ESI+): 532 (M+). Diastereoisomer 2 1H-NMR (CDCI3): δ 0.71 (t, J=7.47Hz, 3H), 1.19 (m, 1 H),
1.43 (m, 1H), 2.19 (s, 3H), 2.20 (s, 3H), 2.77 (dd, J=11.47, 1.65Hz, 1H), 3.38 (dd, J=11.30, 3.74Hz, 1 H), 3.77 (s, 3H), 3.81 (s, 3H), 4.38 (m, 1 H), 5.83 (s, 1 H), 6.58 (s, 1 H), 7.37 (s, 1 H), 7.75 (s, 2H), 7.88 (s, 1 H). LCMS (ESI+): 532 (M+). Examples 176 and 177
Figure imgf000158_0001
Preparation of 4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester This compound was prepared using the procedure as described above for compound 4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6,7- dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester, but using isopropyl chloroformate in the place of ethyl chloroformate.
Diastereoisomer 1 1H-NMR (CDCI3): δ 0.86 (t, J=7.47Hz, 3H), 1.16 (dd, J=6.22, 6.22Hz, 3H), 1.26 (dd, J=15.07, 6.22Hz, 3H), 1.50 (m, 2H), 2.17, (s, 6H), 3.10, (m, 1H), 3.2 (m, 1 H), 3.82 (s, 3H), 4.42 (m, 1H), 5.00 (m, 1H), 5.65 (s, 1 H), 6.40 (s, 1 H), 7.31 (brs, 1 H), 7.64 (s, 1H), 7.74 (s, 1H). ). LCMS (ESI+): 560 (M+). Diastereoisomer 2 1H-NMR (CDCI3): δ 0.71 (t, J=7.47, 3H), 1.16 (m, 1 H), 1.26 (d, J=6.23Hz), 1.29 (d, J=5.81 Hz), 1.44 (m, 1H), 2.18 (s, 3H), 2.20 (s, 3H), 2.76 (dd, J=11.52, 2.07Hz, 1 H), 3.37 (dd, J=11.52, 3.32Hz), 3.82 (s, 3H), 4.38 (m, 1 H), 5.01 (m, 1 H), 5.82 (s, 1 H), 6.58 (s, 1H), 7.47 (brs, 1H), 7.75 (s, 2H), 7.88 (s, 1H). LCMS (ESI+): 561 (MH+).
Preparation 40 (3,5-Bis-trifluoromethyl-phenyl)-bromo-acetonitrile To a solution of (3,5-bis-trifluoromethyl-phenyl)-acetonitrile (2.0g, 7.9mmol) in carbon tetrachloride (20mL) was added dibenzoyl peroxide (0,076g, 0.3mmol) and N- bromosucinnimide (1.4g, 7.9mmol). This reaction mixture was refluxed for 24h then diluted with methylene chloride and washed with brine. The organic layer was dried and concentrated to afford the crude product which was purified by silica gel chromatography using 2% ethyl acetate in hexanes as eluant to afford the title compound (2.0g, 75%). LCMS (ESI+): 333 (MH+).
Example 178
Figure imgf000159_0001
4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl-3,4-dihydro- 2H-quinoxaline-1 -carboxylic acid ethyl ester Method A: A mixture of 2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 - carboxylic acid ethyl ester (1g, 1eq, 3.81mmol), 3,5-bis-(trifluoromethyl-phenyl)- bromo-acetonitrile (Preparation 40, 1.27gm, 1eq, 3.81 mmol) and potassium carbonate (1.58gm, 3eq, 11.43mmol) in acetonitrile (5mL) was subjected to microwave irradiation in the Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) at 140°C for 20 min. 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 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%). LCMS (ESI+): 514 (MH+)
Example 179
Figure imgf000160_0001
Preparation of 4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6,7- dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester To a solution of the 4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl- methyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester (0.14g, 0.26mmol) in tetrahydrofuran (5mL) at -78°C was added a solution of lithium aluminum hydride (1M in tetrahydrofuran, 0.16mL) dropwise. This solution was slowly warmed to room temperature over 3 h. The reaction mixture was quenched with sodium sulfate hexahydrate (2gm) and the mixture was stirred for 30 min. The reaction mixture was filtered and concentrated to afford the crude product (mixture of diastereoisomers) which was purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to give the title compound (0.08g, 70%).
1H-NMR (CDCI3): δ 0.71 (t, J=7.57Hz, 3H), 0.95 (t, J=7.05Hz, 3H), 1.26 (m, 2H), 2.20 (bs, 6H), 2.97 (dd, 1H), 3.25 (m, 1H), 3.37 (m, 1 H), 3.85 (m, 2H), 4.15 (m, 3H), 4.5 (bm, 1H), 4.62(m, 1 H), 4.70 (m, 1 H), 5.82 (s, 1 H), 6.58 (s, 1H), 7.49 (brs, 1 H) 7.75 (s, 2H), 7.88 (s, 1 H).
LCMS (ESI+): 518 (MH+)
Example 180
Figure imgf000161_0001
Preparation of 4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6,7- dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester To a solution of 4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester (0.044gm, 0.13mmol) in anhydrous dimethylformamide (93mL), was added sodium hydride (60% suspension, O.OOSgm, 0.27mmol) and the mixture was stirred for 20 min.
Excess of methyl iodide was added and the reaction was stirred for 1 h and quenched with saturated ammonium chloride. The mixture was extracted with ether (3x20mL) and concentrated. Silica gel chromatography of the crude product using a gradient of 10-30% ethyl acetate in hexanes as eluant provided the desired product as an oil (0.015gm, 35%).
1H-NMR (CDCI3): δ 0.71 (t, J=7.57Hz, 3H), 1.30 (t, J=7.05Hz, 3H), 1.46 (m, 2H), 2.20 (brs, 6H), 2.97 (dd, 1 H), 3.25 (m, 1 H), 3.37 (m, 1H), 3.4 (s, 3H), 3.85 (m, 2H), 4.26 (m, 1 H), 4.5 (bm, 1 H), 4.62(m, 1H), 4.70 (m, 1H), 5.82 (s, 1 H), 6.58 (s, 1 H), 7.49 (brs, 1H), 7.75 (s,2H), 7.88 (s,1 H). LCMS (ESI+): 532 (MH+). Example 181
Figure imgf000162_0001
Preparation of 4-[2-Acetoxy-1 -(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6,7- dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester 4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6,7-dimethyl-3,4- dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester was dissolved in a 1 :1 mixture of acetic anhydride and pyridine (4mL) and the mixture was stirred at ambient temperature for 10h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to afford the desired acetate (25 mg, 58%; mixture of diastereoisomers)
1H-NMR (CDCI3): δ 0.71 (t, J=7.57Hz, 3H), 1.30 (t, J=7.05Hz, 3H), 1.46 (m, 2H), 1.98 (s, 3H) 2.18 (s, 3H), 2.20 (s, 3H), 2.77 (dd, 1H), 3.05 (m, 1 H), 3.37 (m, 1 H), 4.20 (m, 2H), 4.26 (m, 1 H), 4.5 (m, 1 H), 4.62(m, 1 H), 4.70 (m, 1H), 5.82 (s, 1H), 6.58 (s, 1 H), 7.49 (brs, 1 H), 7.75 (s,2H), 7.88 (s,1 H). LCMS (ESI+): 560 (MH+)
Example 182
Figure imgf000162_0002
Preparation of 4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro- 2H-quinoxaline-1 -carboxylic acid ethyl ester A room-temperature solution of 2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester (0.1 gm, 1eq, 0.38mmol) in 5mL methylene chloride was treated with the acid chloride formed by combination of 3,5-bis- (trifluoromethyl)benzoic acid (147mg, 1.5eq, 0.57mmol), oxalyl chloride (0.05mL, 1.5eq, 0.57mmol) and a drop of anhydrous dimethylformamide. The reaction was allowed to stir overnight at room temperature, at which time the reaction was quenched with saturated sodium hydrogen carbonate and extracted 3 times with methylene chloride. The combined organic extracts were washed 1 time with 1 M HCI, 1 time with saturated sodium hydrogen carbonate, 1 time with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Chromatography on silica gel using a 10-20% ethyl acetate in hexanes gradient provided 4-(3,5-Bis-trifluoromethyl- benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester (130mg, 68%).
1H-NMR (CDCI3): δ 0.91 (t, J=7.47Hz, 3H), 1.30 (t, J=7.04Hz, 3H), 1.50 (m, 1 H), 1.60 (m, 1 H), 1.94 (s, 3H), 2.20 (s, 3H), 3.39 (m, 1 H), 4.26 (q, J=6.22Hz, 2H), 4.68 (m, 2H), 6.29 (brs, 1H), 7.41 (brs, 1 H), 7.78 (s, 2H), 7.85 (s, 1 H). FIA-MS (APCI+): 503 (MH+).
Preparation 41 6-Trifluoromethyl-1 ,2,3,4-tetrahydro-quinoxaline This desired quinoxaline was prepared using the method described by V.
Krchnak etal. (Tetrahedron Lett. 42, 2443-2446 (2001)), using 3-(R)-amino-pentan-1- ol and 2-fluoro-5-trifluoromethyl-nitrobenzene.
1H-NMR (dmso-d6): δ 1.06 (t, J=7.48Hz, 3H), 1.73 (m, J=7.90Hz, 2H), 3.19 (dd, J=9.96Hz, 1 H), 3.68 (dd, J=9.55Hz, 1 H), 3.71 (m, 1 H), 6.98 (d, J=8.3Hz, 1 H), 7.25 (dd, 1 H), 7.43 (s, 1 H). ESI-MS: 231 (MH+).
Example 183
Figure imgf000164_0001
4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester A solution of 6-trifluoromethyl-1 ,2,3,4-tetrahydro-quinoxaline (Preparation 41 ,
.01 g, 0.04mmol, 1eq), 3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl bromide (0.017g, 0.044mmol, 1.1eq), and 2,6-lutidine (.014g, 0.12mmol 3eq) in dimethylformamide (0.5mL) were irradiated in the Milestone microwave (Milestone Laboratories, Sorisole, Italy) for 10 min at 140°C. The solvent was removed under reduced pressure to yield a dark oil which was used without further purification. ESI-MS: 542 (MH+).
This residue was combined with 2,6-lutidine (0.018g, 0.16mmol, 2eq) and ethyl chloroformate (0.0175g, 0.16mmol, 2eq) in dimethylformamide (0.5mL) and heated at 140°C for 10 min by irradiation in a Milestone microwave (Milestone Laboratories, Sorisole, Italy). The solution was purified by preparative HPLC eluting with water 0.1%NH4OH, 70 - 0% with acetonitrile, 0.1%NH4OH, 6min gradient time, andδmin run time to yield the title compound. ESI-MS: 587 (MH+)
General procedure for parallel synthesis of amides: The required benzoic acids (0.06mmol, 1eq) were combined with PS-PPh3
(115mg, 1.51mmol/g, 3eq, 0.18mmol) (Argonaut Technologies, Inc., Foster City, CA) in septum-capped 2 dram vials. To this solid mixture was added dichloroethane (1mL) via a Tecan US (Research Triangle Park, NC) liquid handler. To this suspension was added via the Tecan a solution of trichloroacetonitrile (0.0072mL, 1.2eq, 0.07mmol) in dichloroethane (1 mL) and the reactions were gently agitated by means of an orbital shaker for 3h. To this solution was added PS-DIPAM (56mg, 3.2mmol/g, 3eq, 0.1δmmol)(Polymer Laboratories, Amherst, MA) and a solution of 2- ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester (15mg, 0.06mmol, 1.0eq) in dichloroethane (1mL) was added via the Tecan. The reactions were agitated overnight. The reactions were filtered through filter tubes using the Tecan liquid handler, and the resins were washed 3 times with dichloroethane. 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) δ 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).
Using the appropriate starting materials, Examples 1 δ4-409 were made as racemic mixtures in an analogous manner to Example 183:
Example 184
Figure imgf000165_0001
4-(5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 427 (MH+). Example 185
Figure imgf000166_0001
2-Ethyl-4-[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-6,7-dimethyl-3,4-dihydro-
2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): (MH+).
Example 166
Figure imgf000166_0002
-(2-Difluoromethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 476 (MH+).
Example 167
Figure imgf000167_0001
-(3-Difluoromethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 433 (MH+).
Example 18δ
Figure imgf000167_0002
-Ethyl-6,7-dimethyl-4-(2-trifluoromethyl-[1 ,8]naphthyridine-3-carbonyl)-3,4-dihydro- 2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 487 (MH+).
Example 189
Figure imgf000167_0003
-Ethyl-6,7-dimethyl-4-(2-trifluoromethyl-[1 ,6]naphthyridine-3-carbonyl)-3,4-dihydro- 2H-quinoxaline-1 -carboxylic acid ethyl ester :-MS (ESI+): 487 (MH+).
Example : 190<
Figure imgf000168_0001
2-Ethyl-6,7-dimethyl-4-(5-trifluoromethyl-thieno[3,2-b]pyridine-6- carbonyl)-3,4- dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 492 (MH+).
Example 191
Figure imgf000168_0002
-Ethyl-6,7-dimethyl-4-(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-3,4-dihydro- 2H-quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 502 (MH+).
Example 192
Figure imgf000169_0001
-(4-Dipropylsulfamoyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 530 (MH+).
Example 193
Figure imgf000169_0002
4-(2,3-Dihydro-benzofuran-7-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 409 (MH+).
Example 194
Figure imgf000169_0003
-(3-Bromo-4-chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 480 (MH+).
Example 195
Figure imgf000170_0001
-(2-Chloro-3-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 415 (MH+).
Example 196
Figure imgf000170_0002
4-(2-Chloro-4-methanesulfonyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 479 (MH+).
Example 197
Figure imgf000171_0001
4-(2,6-Dichloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 436 (MH+). Example 198
Figure imgf000171_0002
-Ethyl-4-(4-methoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 397 (MH+). Example 199
Figure imgf000171_0003
-Ethyl-4-(2-methoxy-pyridine-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+): 398 (MH+).
Example 200
Figure imgf000172_0001
2-Ethyl-6,7-dimethyl-4-(1-phenyl-5-trifluoromethyl-1 H-pyrazole-4-carbonyl)-3,4- dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 501 (MH+).
Example 201
Figure imgf000172_0002
-Ethyl-6,7-dimethyl-4-(3-methyl-benzofuran-2-carbonyl)-3,4-dihydro-2H-quinoxaline- 1 -carboxylic acid ethyl ester
LC-MS (ESI+): 421 (MH+).
Example 202
Figure imgf000173_0001
-Ethyl-4-(2-methanesulfonyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 445 (MH+).
Example 203
Figure imgf000173_0002
2-Ethyl-4-(9H-fluorene-4-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 455 (MH+).
Figure imgf000174_0001
-Ethyl-6,7-dimethyl-4-(2,3,6-trifluoro-benzoyl)-3,4-dihydro-2H- quinoxaline-1 - carboxylic acid ethyl ester LC-MS (ESI+): 421 (MH+).
Example 205
Figure imgf000174_0002
-(4,5-Dichloro-isothiazole-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 443 (MH+).
Example 206
Figure imgf000175_0001
-Ethyl-6,7-dimethyl-4-(5-methyl-2-phenyl-2H[1 ,2,3]triazole-4-carbonyl)-3,4-dihydro- 2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 44δ (MH+).
Example 207
Figure imgf000175_0002
2-Ethyl-6,7-dimethyl-4-(2-phenoxymethyl-benzoyl)-3,4-dihydro-2H-quinoxaline- carboxylic acid ethyl ester LC-MS (ESI+): 473 (MH+).
Example 203
Figure imgf000176_0001
-(3-Chloro-benzo[b]thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 457 (MH+).
Example 209
Figure imgf000176_0002
-(3-Chloro-4-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 415 (MH+).
Example 210
Figure imgf000177_0001
4-(3-Bromo-2,6-dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro- 2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 506 (MH+). Example 211
Figure imgf000177_0002
-(2-Chloro-3,4-dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+): 461 (MH+). Example 212
Figure imgf000177_0003
-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1 H-pyrazole-4-carbonyl]-2-ethyl-6,7-dimethyl- 3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 535 (MH+).
Example 213
Figure imgf000178_0001
-(3-Ethoxy-thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+): 417 (MH+).
Example 214
Figure imgf000178_0002
4-(5-Chloro-4-methoxy-thiophene-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 437 (MH+).
Example 215
Figure imgf000178_0003
-[2-(2,3-Dihydro-benzo[1 ,4]dioxin-2-yl)-thiazole-4-carbonyl]-2-ethyl-6,7-dimethyl-3,4- dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 50δ (MH+). Example 216
Figure imgf000179_0001
4-(3-Cyclopentyloxy-4-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 431 (MH+).
Example 217
Figure imgf000179_0002
-Ethyl-4-(4-methoxy-3-propoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 455 (MH+).
Example 21 δ
Figure imgf000179_0003
-Ethyl-4-(3-isopropoxy-4-methoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+): 455 (MH+).
Example 219
Figure imgf000180_0001
-(3-Butoxy-4-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 469 (MH+).
Example 220
Figure imgf000180_0002
2-Ethyl-4-(5-methoxycarbonyl-pyridine-2-carbonyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 426 (MH+).
Example 221
Figure imgf000181_0001
2-Ethyl-6,7-dimethyl-4-(4-trifluoromethyl-pyridine-3-carbonyl)-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 436 (MH+).
Example 222
Figure imgf000181_0002
-Ethyl-6,7-dimethyl-4-[6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):466 (MH+).
Example 223
Figure imgf000181_0003
-Ethyl-4-[5-methoxy-2-(2,2,2-trifluoro-ethoxy)-benzoyl]-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):495 (MH+). Example 224
Figure imgf000182_0001
2-Ethyl-6,7-dimethyl-4-(2-methyl-5-phenyl-furan-3-carbonyl)-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 447 (MH+).
Example 225
Figure imgf000182_0002
-Ethyl-6,7-dimethyl-4-(5-methyl-2-trifluoromethyl-furan-3-carbonyl)-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 439 (MH+).
Example 226
Figure imgf000182_0003
2-Ethyl-4-(2-ethyl-5-methyl-2H-pyrazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 399 (MH+). Example 227
Figure imgf000183_0001
-(2-tert-Butyl-5-methyl-2H-pyrazole-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 427 (MH+).
Example 228
Figure imgf000183_0002
2-Ethyl-4-[2-(4-ethyl-benzoyl)-benzoyl]-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 499 (MH+).
Example 229
Figure imgf000183_0003
4-(2-Ethoxy-naphthalene-1-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 461 (MH+).
Example 230
Figure imgf000184_0001
-(5-Bromo-2,3-dihydro-benzofuran-7-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 48δ (MH+).
Example 231
Figure imgf000184_0002
4-[2-(4-Chloro-phenoxy)-pyridine-3-carbonyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester
- LC-MS (ESI+): 494 (MH+).
Example 232
Figure imgf000185_0001
-Ethyl-6,7-dimethyl-4-(2-p-tolyloxy-pyridine-3-carbonyl)-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+): 474 (MH+).
Example 233
Figure imgf000185_0002
-Ethyl-4-(5-isobutyl-isoxazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+):414 (MH+). Example 234
Figure imgf000185_0003
-Ethyl-4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzoyl}-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 440 (MH+). Example 235
Figure imgf000186_0001
4-(3,5-Dimethyl-1 H-indole-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 434 (MH+).
Example 236
Figure imgf000186_0002
-Ethyl-4-[4-(5-ethyl-[1 ,2,4]oxadiazol-3-yl)-benzoyl]-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 463 (MH+).
Example 237
Figure imgf000186_0003
-Ethyl-6,7-dimethyl-4-[3-(5-methyl-[1 ,2,4]oxadiazol-3-yl)-benzoyl]-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 449 (MH+).
Example 236
Figure imgf000187_0001
-Ethyl-6,7-dimethyl-4-(5-propyl-isoxazole-3-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+)400 (MH+).
Example 239
Figure imgf000187_0002
-Ethyl-4-(5-isobutyl-2-methyl-2H-pyrazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 427 (MH+).
Example 240
Figure imgf000188_0001
2-Ethyl-4-(5-methoxymethyl-furan-2-carbonyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 401 (MH+).
Example 241
Figure imgf000188_0002
2-Ethyl-4-(5-isopropyl-2H-pyrazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 399 (MH+). Example 242
Figure imgf000188_0003
-Ethyl-6,7-dimethyl-4-(4-morpholin-4-yl-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 452 (MH+). -137-
Example 243
Figure imgf000189_0001
4-(5-Chloro-3-methyl-1H-indole-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 454 (MH+).
Example 244
Figure imgf000189_0002
4-(3,5-Dimethyl-1 H-pyrrole-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 364 (MH+).
Example 245
Figure imgf000189_0003
-Ethyl-6,7-dimethyl-4-(6,7,δ,9-tetrahydro-5H-carbazole-3-carbonyl)-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+).
Example 246
Figure imgf000190_0001
4-[4-(2,5-Dimethoxy-benzoyl)-benzoyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 531 (MH+).
Example 247
Figure imgf000190_0002
-Ethyl-6,7-dimethyl-4-(2-methyl-thiazole-4-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+):38δ (MH+).
Example 24δ
4-[3-(3,5-Dimethyl-pyrazol-1-yl)-benzoyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 461 (MH+).
Example 249
Figure imgf000191_0002
-Ethyl-6,7-dimethyl-4-(2-p-tolyl-quinoline-4-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 508 (MH+).
Example 250
Figure imgf000191_0003
-Ethyl-6,7-dimethyl-4-(5-methyl-1 ,3-diphenyl-1 H-pyrazole-4-carbonyl)-3,4-dihydro- 2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 523 (MH+).
Example 251
Figure imgf000192_0001
2 -Ethyl-6,7-dimethyl-4-(4-piperidin-1-yl-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 450 (MH+). Example 252
Figure imgf000192_0002
-[3-(3,5-Dimethyl-pyrazol-1-ylmethyl)-benzoyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 475 (MH+). Example 253
Figure imgf000192_0003
-Ethyl-6,7-dimethyl-4-(quinoline-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 418 (MH+). Example 254
Figure imgf000193_0001
-Ethyl-4-(furan-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 357 (MH+).
Example 255
Figure imgf000193_0002
-(5-Bromo-2-chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+).
Example 256
Figure imgf000193_0003
-(4-Acetyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 409 (MH+). Example 257
Figure imgf000194_0001
-(2-Chloro-6-fluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 419 (MH+).
Example 25δ
Figure imgf000194_0002
2-Ethyl-6,7-dimethyl-4-(naphthalene-2-carbonyl)-3,4-dihydro-2H-quinoxaline- carboxylic acid ethyl ester LC-MS (ESI+): 417 (MH+).
Example 259
Figure imgf000194_0003
-(3-Bromo-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 446 (MH+).
Example 260
Figure imgf000195_0001
2-Ethyl-6,7-dimethyl-4-(2,3,4-trimethoxy-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 457 (MH+).
Example 261
Figure imgf000195_0002
-Ethyl-4-(4-ethyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+):395 (MH+).
Example 262
Figure imgf000196_0001
-Ethyl-6,7-dimethyl-4-(2-phenyl-quinoline-4-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 494 (MH+).
Example 263
Figure imgf000196_0002
2-Ethyl-6,7-dimethyl-4-(2-trifluoromethyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 435 (MH+).
Example 264
Figure imgf000196_0003
2-Ethyl-6,7-dimethyl-4-(4-trifluoromethyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 435 (MH+).
Example 265
Figure imgf000197_0001
-[2-(4-Chloro-benzoyl)-benzoyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 506 (MH+).
Example 266
Figure imgf000197_0002
4-(3,4-Diethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 455 (MH+).
Example 267
Figure imgf000198_0001
4-(2-Chloro-5-methylsulfanyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 443 (MH+). Example 26δ
Figure imgf000198_0002
-Ethyl-6,7-dimethyl-4-(3-methyl-thiophene-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 387 (MH+). Example 269
Figure imgf000198_0003
4-(2,5-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 427 (MH+). Example 270
Figure imgf000199_0001
-(2,4-Difluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 403 (MH+).
Example 271
Figure imgf000199_0002
-(3,4-Difluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):403 (MH+).
Example 272
Figure imgf000199_0003
4-(3-Bromo-4-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+). Example 273
Figure imgf000200_0001
-Ethyl-4-(4-isopropyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 409 (MH+).
Example 274
Figure imgf000200_0002
2-Ethyl-4-(2-methoxy-4-methylsulfanyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):443 (MH+).
Example 275
Figure imgf000200_0003
-(3,5-Difluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 403 (MH+). Example 276
Figure imgf000201_0001
4-(2-Chloro-4-fluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):419 (MH+).
Example 277
Figure imgf000201_0002
-Ethyl-6,7-dimethyl-4-(9-oxo-9H-fluorene-1-carbonyl)-3,4-dihydro-2H-quinoxaline- carboxylic acid ethyl ester LC-MS (ESI+): 469 (MH+).
Example 278
Figure imgf000201_0003
4-(Benzofuran-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 407 (MH+).
Example 279
Figure imgf000202_0001
-Ethyl-4-(2-methoxycarbonyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 425 (MH+).
Example 280
Figure imgf000202_0002
2-Ethyl-6,7-dimethyl-4-(2,4,5-trifluoro-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 421 (MH+).
Example 281
Figure imgf000203_0001
-Ethyl-6,7-dimethyl-4-(4-propyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 409 (MH+).
Example 232
Figure imgf000203_0002
2-Ethyl-6,7-dimethyl-4-(2,3,4-trifluoro-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 421 (MH+).
Example 283
Figure imgf000203_0003
2-Ethyl-4-(2-fluoro-3-trifluoromethyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 453 (MH+). Example 284
Figure imgf000204_0001
-Ethyl-6,7-dimethyl-4-[2-(4-methyl-benzoyl)-benzoyl]-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 485 (MH+).
Example 285
Figure imgf000204_0002
2-Ethyl-6,7-dimethyl-4-(4,-trifluoromethyl-biphenyl-2-carbonyl)-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):511 (MH+).
Example 286
Figure imgf000205_0001
-Ethyl-4-(3-fluoro-4-methoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):415 (MH+).
Example 287
Figure imgf000205_0002
2-Ethyl-4-(4-isopropoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 425 (MH+). Example 288
Figure imgf000205_0003
2-Ethyl-6,7-dimethyl-4-(4-propoxy-benzoyl)-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 425 (MH+). Example 289
Figure imgf000206_0001
4-(3-Chloro-4-fluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):419 (MH+).
Example 290
Figure imgf000206_0002
-(2,4-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 503 (MH+).
Example 291
Figure imgf000206_0003
4-(2,6-Dimethoxy-pyridine-3-carbonyl)-2-ethyl -6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 428 (MH+).
Example 292
Figure imgf000207_0001
-(2-Bromo-5-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 476 (MH+).
Example 293
Figure imgf000207_0002
2-Ethyl-4-(2-fluoro-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 385 (MH+).
Example 294
Figure imgf000208_0001
-(2,5-Dimethyl-furan-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 385 (MH+).
Example 295
Figure imgf000208_0002
2-Ethyl-4-(4-fluoro-3-trifluoromethyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ES1+): 453 (MH+).
Example 296
Figure imgf000208_0003
-(2-Benzoyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 471 (MH+). Example 297
Figure imgf000209_0001
4-(4-Benzoyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 471 (MH+).
Example 298
Figure imgf000209_0002
4-(Biphenyl-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 443 (MH+).
Example 299
Figure imgf000209_0003
4-(Biphenyl-4-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 443 (MH+).
Example 300
Figure imgf000210_0001
-(3-Chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+):401 (MH+).
Example 301
Figure imgf000210_0002
-(4-Cyano-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+):392 (MH+).
Example 302
Figure imgf000210_0003
4-(2,3-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 427 (MH+).
Example 303
Figure imgf000211_0001
-(2,4-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):427 (MH+).
Example 304
Figure imgf000211_0002
-(3,4-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 427 (MH+).
Example 305
Figure imgf000211_0003
-(3,5-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 427 (MH+).
Example 306
Figure imgf000212_0001
4-(3,4-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):395 (MH+).
Example 307
Figure imgf000212_0002
4-(3,5-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 395 (MH+).
Example 308
Figure imgf000212_0003
-Ethyl-4-(3-fluoro-4-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 399 (MH+).
Figure imgf000213_0001
-Ethyl-4-(furan-2-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 357 (MH+).
Example 310
Figure imgf000213_0002
-Ethyl-4-(3-fluoro-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester LC-MS (ESI+): 385 (MH+).
Example 311
Figure imgf000213_0003
-Ethyl-4-(3-methoxy-4-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1 - carboxylic acid ethyl ester LC-MS (ESI+): 411 (MH+). Example 312
Figure imgf000214_0001
-Ethyl-6,7-dimethyl-4-(5-methyl-thiophene-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 387 (MH+).
Example 313
Figure imgf000214_0002
2- -Ethyl-6,7-dimethyl-4- (naphthalene-1-carbonyl)-3,4-dihydrθ' -2H- -quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+):417 τ (MH+).
Example 314
Figure imgf000214_0003
-Ethyl-6,7-dimethyl-4-(6-methyl-pyridine-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):382 (MH+). Example 315
Figure imgf000215_0001
-Ethyl-6,7-dimethyl-4-(2,4,6-trimethoxy-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ES1+): 457 (MH+).
Example 316
Figure imgf000215_0002
-[3-(2-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-ethyl-6,7-dimethyl-3,4- dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 482 (MH+).
Example 317
Figure imgf000215_0003
-(2-Bromo-5-chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 480 (MH+). Example 318
Figure imgf000216_0001
-(3-Bromo-4-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):476 (MH+).
Example 319
Figure imgf000216_0002
4-(4-Benzyloxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):473 (MH+).
Example 320
Figure imgf000216_0003
2-Ethyl-6,7-dimethyl-4-(thiophene-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):373 (MH+).
Example 321
Figure imgf000217_0001
-Ethyl-6,7-dimethyl-4-(2-methyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 381 (MH+).
Example 322
Figure imgf000217_0002
-Ethyl-6,7-dimethyl-4-(3-methyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 381 (MH+).
Example 323
Figure imgf000217_0003
-Ethyl-6,7-dimethyl-4-(4-methyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): (MH+).
Example 324
Figure imgf000218_0001
-Ethyl-6,7-dimethyl-4-(3,4,5-trimethoxy-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 457 (MH+).
Example 325
Figure imgf000218_0002
-Ethyl-4-(isoquinoline-1-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 418 (MH+).
Example 326
Figure imgf000218_0003
4-(2,6-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 395 (MH+).
Example 327
Figure imgf000219_0001
-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 503 (MH+).
Example 328
Figure imgf000219_0002
4-Benzoyl-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 367 (MH+).
Example 329
Figure imgf000220_0001
4-(5-Chloro-3-phenyl-1 H-indole-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 517 (MH+).
Example 330
Figure imgf000220_0002
-Ethyl-4-(4'-fluoro-biphenyl-4-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):461 (MH+).
Example 331
Figure imgf000220_0003
-Ethyl-4-(3'-fluoro-biphenyl-4-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 461 (MH+).
Example 332
Figure imgf000221_0001
-Ethyl-4-(2'-fluoro-biphenyl-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):461 (MH+).
Example 333
Figure imgf000221_0002
-Ethyl-4-(3'-fluoro-biphenyl-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):461 (MH+).
Example 334
Figure imgf000221_0003
-Ethyl-4-(4'-fluoro-biphenyl-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 461 (MH+). Example 335
Figure imgf000222_0001
-Ethyl-6,7-dimethyl-4-([1 ,2,5]thiadiazole-3-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):375 (MH+).
Example 336
Figure imgf000222_0002
2-Ethyl-6,7-dimethyl-4-(2-pyrazol-1-yl-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 433 (MH+).
Example 337
Figure imgf000222_0003
2-Ethyl-6,7-dimethyl-4-(4-pyrazol-1-yl-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 433 (MH+).
Figure imgf000223_0001
-Ethyl-6,7-dimethyl-4-(3-phenyl-isoxazole-5-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 434 (MH+).
Example 339
Figure imgf000223_0002
2-Ethyl-4-[5-(4-methoxy-phenyl)-furan-2-carbonyl]-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 463 (MH+).
Example 340
Figure imgf000223_0003
-Ethyl-6,7-dimethyl-4-(2-methyl-5-propyl-2H-pyrazole-3-carbonyl)- 3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 413(MH+).
Example 341
Figure imgf000224_0001
-Ethyl-4-(5-ethyl-2-methyl-2H-pyrazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):399 (MH+).
Example 342
Figure imgf000224_0002
2-Ethyl-6,7-dimethyl-4-(pyrazolo[1 ,5-a]quinoline-2-carbonyl)-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 457 (MH+).
Example 343
Figure imgf000225_0001
-Ethyl-6,7-dimethyl-4-(3-phenyl-1H-indole-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):482 (MH+). Example 344
Figure imgf000225_0002
-Ethyl-4-[5-(4-methoxy-phenyl)-thiophene-2-carbonyl]-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):479 (MH+). Example 345
Figure imgf000225_0003
4-(5-Bromo-2-methoxy-pyridine-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 477 (MH+). Example 346
Figure imgf000226_0001
2-Ethyl-4-(3-methoxy-benzoyl)-6,7-dimethyl-3,4-dity 'dro-2H quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 397 (MH+).
Example 347
Figure imgf000226_0002
-Ethyl-4-(4-fluoro-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 385 (MH+). Example 348
Figure imgf000226_0003
-Ethyl-6,7-dimethyl-4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 448 (MH+). Example 349
Figure imgf000227_0001
-(2-Chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 401 (MH+).
Example 350
Figure imgf000227_0002
-(4-Chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+):401 (MH+). Example 351
Figure imgf000227_0003
-Ethyl-4-[2-(4-fluoro-benzoyl)-benzoyl]-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 489 (MH+). Example 352
Figure imgf000228_0001
4-(2-Bromo-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2B -quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 446 (MH+).
Example 353
Figure imgf000228_0002
-(2,4-Dichloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 436 (MH+). Example 354
Figure imgf000228_0003
-(3,4-Dichloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 436 (MH+). Example 355
Figure imgf000229_0001
-(4-Ethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 411 (MH+).
Example 356
Figure imgf000229_0002
2-Ethyl-6,7-dimethyl-4-(4-methylsulfanyl-benzoyl)-3,4-dihydro-2H- quinoxaline-1 - carboxylic acid ethyl ester LC-MS (ESI+): 413 (MH+).
Example 357
Figure imgf000229_0003
-(4-Chloro-2-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 431 (MH+). Example 358
Figure imgf000230_0001
4-(2-Ethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 411 (MH+).
Example 359
Figure imgf000230_0002
-(2,3-Dichloro-benzoyl)-2-ethyl-6,/f-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 436 (MH+).
Example 360
Figure imgf000230_0003
2-Ethyl-6,7-dimethyl-4-(thiophene-3-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 373 (MH+). Example 361
Figure imgf000231_0001
-(2,3-Difluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 403 (MH+).
Example 362
Figure imgf000231_0002
-Ethyl-4-(4-fluoro-naphthalene-1-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+): 435 (MH+).
Example 363
Figure imgf000231_0003
2-Ethyl-6,7-dimethyl-4-(4-trifluoromethoxy-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 451 (MH+).
Example 364
Figure imgf000232_0001
2-Ethyl-4-(2-fluoro-4-trifluoromethyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 453 (MH+).
Example 365
Figure imgf000232_0002
-(2,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 503 (MH+).
Example 366
Figure imgf000233_0001
2-Ethyl-4-(2-fluoro-6-trifluoromethyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester
LC-MS (ESI+): 453 (MH+).
Example 367
Figure imgf000233_0002
2-Ethyl-4-(3-fluoro-2-methyl-ben∑oyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 399 (MH+). Example 368
Figure imgf000233_0003
-(2,4-Dichloro-5-fluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 454 (MH+). Example 369
Figure imgf000234_0001
2- -Ethyl-6,7 -dimethyl-4- (2,4,6-trifluoro-benzoyl)-3,4-dihydro -2H -quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 421 (MH+).
Example 370
Figure imgf000234_0002
-Ethyl-4-(5-fluoro-2-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 399 (MH+).
Example 371
Figure imgf000234_0003
-Ethyl-4-(2-fluoro-5-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-=quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 399 (MH+).
Example 372
Figure imgf000235_0001
-(5-Bromo-thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 452 (MH+).
Example 373
Figure imgf000235_0002
4-(4-Difluoromethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):433 (MH+).
Example 374
Figure imgf000235_0003
4-(2,6-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 427 (MH+). Example 375
Figure imgf000236_0001
2-Ethyl-6,7-dimethyl-4-(4-methyl-naphthalene-1-carbonyl)-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 431 (MH+).
Example 376
Figure imgf000236_0002
-(3-Chloro-2,6-dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+):461 (MH+).
Example 377
Figure imgf000236_0003
4-(3-Chloro-2-fluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 419 (MH+).
Example 378
Figure imgf000237_0001
-(3-Chloro-thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 407 (MH+).
Example 379
Figure imgf000237_0002
2-Ethyl-6,7-dimethyl-4-(2-trifluoromethoxy-benzoyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+):451 (MH+).
Example 380
Figure imgf000238_0001
-Ethyl-6,7-dimethyl-4-(5-methyl-isoxazole-3-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 372 (MH+).
Example 381
Figure imgf000238_0002
2-Ethyl-6,7-dimethyl-4-(3-methyl-furan-2-carbonyl)-3,4-dihydro -2H -quinoxaline-1 carboxylic acid ethyl ester
LC-MS (ESI+): 371 (MH+).
Example 382
Figure imgf000238_0003
4-(4-Bromo-2-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+). Example 383
Figure imgf000239_0001
4-(4-Bromo-2-chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 480 (MH+).
Example 384
Figure imgf000239_0002
4-(4-Bromo-3-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+).
Example 385
Figure imgf000239_0003
-(5-Chloro-thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 407 (MH+). Example 386
Figure imgf000240_0001
-(3-Benzyloxy-4-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+): 503 (MH+).
Example 387
Figure imgf000240_0002
-(3,5-Dimethoxy-4-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+): 441 (MH+).
Example 388
Figure imgf000240_0003
-(Benzo[b]thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 423 (MH+).
Example 389
Figure imgf000241_0001
-(4-Chloro-3-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 415 (MH+).
Example 390
Figure imgf000241_0002
-(2-Bromo-4-chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 480 (MH+).
Example 391
Figure imgf000242_0001
-(2-Bromo-3-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+).
Example 392
Figure imgf000242_0002
-(2-Bromo-5-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-uinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+).
Example 393
Figure imgf000242_0003
-(3-Bromo-2-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+).
Example 394
Figure imgf000243_0001
-(2-Chloro-4,5-dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
•1 -carboxylic acid ethyl ester LC-MS (ESI+):461 (MH+).
Example 395
Figure imgf000243_0002
-(7-Ethoxy-benzofuran-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-
1 -carboxylic acid ethyl ester LC-MS (ESI+): 451 (MH+).
Example 396
Figure imgf000243_0003
2-Ethyl-6,7-dimethyl-4-[2-(1-phenyl-ethylcarbamoyl)-benzoyl]-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 514 (MH+).
Example 397
Figure imgf000244_0001
-(Benzo[1 ,3]dioxole-5-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 411 (MH+).
Example 398
Figure imgf000244_0002
-(4-tert-Butyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):423 (MH+).
Example 399
Figure imgf000245_0001
2-Ethyl-6,7-dimethyl-4-(2-phenoxy-benzoyl)-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 459 (MH+).
Example 400
Figure imgf000245_0002
-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 503 (MH+).
Example 401
Figure imgf000245_0003
-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 503 (MH+).
Example 402
Figure imgf000246_0001
-Ethyl-6,7-dimethyl-4-(1-methyl-1 H-indole-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 420 (MH+).
Example 403
Figure imgf000246_0002
-(Benzo[b]thiophene-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester
LC-MS (ESI+): 423 (MH+).
Example 404
Figure imgf000247_0001
2-Ethyl-4-(2-methoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):3977 (MH+).
Example 405
Figure imgf000247_0002
-(2,3-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):395 (MH+).
Example 406
Figure imgf000247_0003
-246-
4-(2,4-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+):395 (MH+).
Example 407
Figure imgf000248_0001
4-(2,5-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 395 (MH+).
Example 408
Figure imgf000248_0002
-Ethyl-4-(4-methoxy-3-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- carboxylic acid ethyl ester LC-MS (ESI+):411 (MH+).
Example 409
Figure imgf000248_0003
Preparation of 4-(3,5-Bis-trifluoromethyl-benzyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester
A solution of 2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester (0.05g, 1eq, 0.19mmol), 3,5-bis-(trifluoromethyl)benzyl bromide (0.038mL, 2.2eq, 0.42mmol) and triethylamine (0.062mL, 3eq, 0.57mmol) in acetonitrile (2mL) was treated with catalytic potassium iodide and subjected to two ten minute cycles on the Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) chemical microwave at 180°C. The reaction was evaporated to dryness and purified on the Shimadzu Corporation (Kyoto, Japan) preparative HPLC system using a 40- 100% acetonitrile/water 6 min gradient, 8min total run time to provide the title compound (0.0045mg, 5%).
1HNMR (CDCI3): δ 0.90 (t, J=7.47Hz, 3H), 1.31 (t, J=7.05Hz, 3H), 1.46 (m, 2H), 2.11 (s, 3H), 2.16 (s, 3H), 3.17 (dd, J=11.28, 1.24Hz, 1 H), 3.49 (dd, J=11.16, 4.15Hz, 1H), 4.19 (m, 1 H), 4.28 (m, 1H), 4.46 (d, J=17.43Hz), 4.52 (m, 1 H), 4.66 (d, J=17.01Hz, 1 H), 6.31 (s, 1 H), 7.29 (brs, 1 H), 7.71 (s, 2H), 7.78 (s, 1 H).
LCMS (ESI+): 489 (MH+).
The prophetic examples 410-427 may be prepared in optically enriched form by resolution of the corresponding racemate indicated, or an intermediate in its synthesis, using methods analogous to those described herein:
Example 410 (Stereo-lsomers of Example 2)
Figure imgf000249_0001
(R, f?)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(S, f?)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; or (S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 411 (Stereo-lsomers of Examples 3 and 4)
Figure imgf000250_0001
(S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; or
(S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 412 (Stereo-lsomers of Examples 5, 6, 7 and 8)
Figure imgf000250_0002
(R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, f?)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S, S, f?)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or
(S, R, f?)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 413 (Stereo-lsomers of Examples 9 and 10)
Figure imgf000251_0001
(R, R, f?)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, f?)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (S, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl-2H- quinoline-1 -carboxylic acid ethyl ester;
( ,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; (R, ?)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(S, )-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; or
(S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 414 (Stereo-lsomers of Examples 13 and 14)
Figure imgf000252_0001
(R,S)-4-[(3,5-bis-trifluoromethyl-benzoyl)]-6,7-dimethoxy-2-methyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-benzoyl)]-6,7-dimethoxy-2-methyl-3,4- dihydro-2/7-quinoline-1 -carboxylic acid ethyl ester; (S,R)-4-[(3,5-bis-trifluoromethyl-benzoyl)]-6,7-dimethoxy-2-methyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or
(S,S)-4-[(3,5-Bis-trifluoromethyl-benzoyl)]-6,7-dimethoxy-2-methyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt thereof.
Example 415 (Stereo-lsomers of Examples 18, 19 and 35)
Figure imgf000253_0001
(f?,R,f?)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2f/-quinoline-1 -carboxylic acid ethyl ester;
(/?,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
( ?,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or
(S,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-fiuoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 416 (Stereo-lsomers of Examples 20 and 21)
Figure imgf000254_0001
(S,R)-4-[(3,5-bis-trifluoromethyl-benzoyl)]-2-ethyl-6-trifluoromethyl-3,4- dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester; or
(S,S)-4-[(3,5-bis-trifluoromethyl-benzoyl)]-2-ethyi-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 417 (Stereo-lsomers of Examples 16 and 17)
Figure imgf000254_0002
(R,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2/- -quinoline-1 -carboxylic acid ethyl ester;
(R.R^H-KS.S-bis-trifluoromethyl-pheny -hydroxy-methy -ej-dimethoxy^- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2r-/-quinoline-1 -carboxylic acid ethyl ester;
(S,RJS)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2fY-quinoline-1 -carboxylic acid ethyl ester; or (S,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 418 (Stereo-lsomers of Example 34)
Figure imgf000255_0001
(R,S,S)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]- •6,7-dimethoxy-2- methyl ■3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,R,S)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]- -6,7-dimethoxy-2- methyl ■3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S,R)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]- ■6,7-dimethoxy-2- methyl ■3,4-dihydro-2/- -quinoline-1 -carboxylic acid ethyl ester; (R,R,R)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]- -6,7-dimethoxy-2- methyl ■3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (S,S,S)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]- 6,7-dimethoxy-2- methyl ■3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (S,R,S)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]- •6,7-dimethoxy-2- methyl ■3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (S,S,R)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]- •6,7-dimethoxy-2- methy ■3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester; or (S,R,R)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]- ■6,7-dimethoxy-2- methyl ■3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. Example 419 (Stereo-lsomers of Examples 22, 23, 24 and 25)
Figure imgf000256_0001
(R,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester;
(R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester;
(R,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester;
(S,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (S,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or
(S,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. Example 420
Figure imgf000256_0002
4-[(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or
(S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. Example 421 (Stereo-lsomers of Example 15)
Figure imgf000257_0001
(R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-methyl-6,7- dimethoxy-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-methyl-6,7- dimethoxy-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-methyl-6,7- dimethoxy-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or
(S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-methyl-6,7- dimethoxy-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 422 (Stereo-lsomers of Example 182)
Figure imgf000257_0002
(R)-4-[(3,5-Bis-trifluoromethyl-benzoyl)]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester; or
(S)-4-[(3,5-Bis-trifluoromethyl-benzoyl)]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 423 (Stereo-lsomers of Example 178)
Figure imgf000258_0001
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl- 3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; (R,s5)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl-
3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester;
(S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl- 3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; or
(S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl- 3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 424 (Stereo-lsomers of Examples 170, 171 , 172, and 173)
Figure imgf000259_0001
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- , 7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester;
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- ,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester;
(S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- , 7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; or
(S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- ,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
Example 425 (Stereo-lsomers of Examples 174 and 175)
Figure imgf000260_0001
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- ,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid methyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- , 7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid methyl ester;
(S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- , 7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid methyl ester; or
(S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- ,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid methyl ester; or a pharmaceutically acceptable salt of said compound.
Example 426 (Stereo-lsomers of Examples 176 and 177)
Figure imgf000260_0002
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- ,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester;
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- ,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester;
(S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- ,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester; or (S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester; or a pharmaceutically acceptable salt of said compound. Example 427 (Stereo-lsomers of Example 183)
Figure imgf000261_0001
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester;
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; (S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; or
(S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. Examples 428 and 429
Figure imgf000261_0002
(R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl-3,4- dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester and (R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl-3,4- dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester A mixture of 2-ethyl-6,7-dimethyl-3,4-dihydro-2(R)-H-quinoxaline-1 -carboxylic acid ethyl ester (1g, 1eq, 3.81mmol), 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 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 diastereoisomers (1.5:1) (1.0g. and 0.7g, 60%). Isomer 1 :
LCMS (ESI+): 514 (MH+) 1H-NMR (CDCI3) δ 0.88 (t, J=7.5Hz, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.49 (m,
2H), 2.21 (s, 3H), 2.22 (s, 3H), 3.03 (dd, J^H .OHz, J2=2.9Hz, 1 H), 3.19 (dd, J.|=11.0Hz, J2=5.4Hz, 1 H), 4.19 (m, 1H), 4.27 (m, 1 H), 4.50 (brm, 1 H), 6.05 (s, 1 H), 6.59 (s, 1 H), 7.33 (brs, 1 H), 7.94 (s, 1 H), 7.97 (s, 2H). lsomer2: LCMS (ESI+): 514 (MH+)
1H-NMR (CDCI3) δ 0.76 (t, J=7.48 Hz, 3H), 1.31 (t, J=7.06Hz, 3H), 1.52 (m, 2H), 2.21 (s, 3H), 2.23 (s, 3H), 2.75 (dd, ^=11.0Hz, J2=2.1 Hz, 1 H), 3.29 (dd, J2=3.73Hz, 1 H), 4.19-4.30 (m, 2H), 4.52 (brm, 1H), 6.19 (s, 1 H), 6.70 (s,1 H), 7.47 (brs, 1 H), 7.96 (s, 1 H), 8.00 (s, 2H). Preparation 42
Figure imgf000262_0001
(R)-2-Ethyl-4-iodo-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester The title compound was prepared using the general procedure described by D.H.R. Barton et al. (Tetrahedron Letters 1983 24, 1605). To a solution of iodine (3.0gm, 9.1 mmol) in anhydrous tetrahydrofuran (30mL) under nitrogen was slowly added a solution of 1 ,1 ,3,3-tetramethylguanidine (63.7mmol, 8mL) in anhydrous tetrahydrofuran (30mL). The mixture was stirred at room temperature for 10min before addition of (R)-2-ethyl-4-hydrazono-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester (Preparation 6, 9.1 mmol, 3gm) in anhydrous tetrahydrofuran (30mL). After 15min the solvent was removed under vacuum and the residue heated under nitrogen at 85°C for 90min. The residue was dissolved in ethyl acetate, washed with 2N hydrochloric acid, aqueous sodium sulfite solution (2.5%), saturated sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The crude product was purified by chromatography on silica gel eluting with hexanes/ethyl acetate from 19:1 to 85:15 to give the title compound as a yellow solid (2.8gm, 72%).
MS: 426.3 [M+H]+ found.
1H-NMR (CDCI3) δ 7.69 (brs, 1H), 7.61 (brd, J = 8.14Hz, 1H), 7.49 (brd, J = 8.14Hz, 1 H), 6.85 (d, J = 6.64Hz, 1H), 4.87 (m, 1H), 4.27 (m, 2H), 4.15 (m, 1 H), 1.50 (m, 1H), 1.38 (m, 1 H), 1.32 (t, J=7.47Hz, 3H), 0.87 (t, J=7.47Hz, 3H).
Example 430
Figure imgf000263_0001
(RS, RS) and (RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester
To a solution of (RS)-2-ethyl-4-iodo-6-trifluoromethyl-2H-quinoline-1- carboxylic acid ethyl ester (814mg, 1.91 mmol, prepared as described above for the (R) isomer except that racemic starting material was used) in anhydrous tetrahydrofuran (4mL) under nitrogen at -78°C was added dropwise n-butyllithium (2.5M in hexanes, 2.87mmol, 1.15mL). After 5min 3,5- bis(trifluoromethyl)benzaldehyde (6.06mmol, 1 mL) was added dropwise. After 45min at -78°C the mixture was allowed to warm to room temperature and after 1hr water was added. The mixture was acidified by addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate from 9:1 to 4:1 then further purified by chromatography on silica gel eluting with dichloromethane to give the title compounds as a mixture of diastereoisomers (60mg). MS: 540.3 [M-Hf found.
Example 431
Figure imgf000264_0001
(RS, RS) and (RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxy-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of the diastereoisomeric mixture (RS, RS) and (RS, SR)-4-[(3,5- bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1- carboxylic acid ethyl ester (Example 430, 32mg, 0.059mmol) in dimethylsulfoxide (3mL) under nitrogen was added powdered potassium hydroxide (0.236mmol, 13mg) followed immediately by iodomethane (0.118mmol, 7.4μL). The mixture was stirred at room temperature for 2hr then diluted with 2N hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under vacuum. The crude product was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 then 85:15 to give the title compound (13mg) as a mixture of diastereoisomers.
Example 432
Figure imgf000265_0001
(RS)-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-2H-quinoline-1- carboxylic acid ethyl ester To a solution of the diastereoisomeric mixture (RS, RS) and (RS, SR)-4-[(3,5- bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1- carboxylic acid ethyl ester (Example 430, 11mg, 0.020mmol) in anhydrous diethyl ether (1mL) was added manganese (IV) oxide (22mg, activated, -85%, Aldrich Chemical Company, Milwaukee, Wl). The suspension was stirred at ambient temperature for 90 min. A second aliquot of manganese (IV) oxide (20mg) was added and stirring was continued for a further 1 hr before a third aliquot of manganese (IV) oxide (30mg) was added. After 10min the solid was removed by filtration through Celite®, the solvent was removed under vacuum and the residue was chromatographed on Baker Silica Gel (1gm, 40 μm) (J.T. Baker, Phillipsburg, N.J.) eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 then 85:15 then 4:1 to give the title compound (6.6mg). MS: 540.3 [M+H]+ found.
1H-NMR (CDCI3) δ 8.27 (s, 2H), 8.11 (s, 1 H), 7.79 (brd, J=8.3Hz, 1H), 7.77 (brs, 1H), 7.57 (brd, J=8.3Hz, 1H), 6.56 (d, J=6.64Hz, 1 H), 5.18 (m, 1H), 4.31 (m, 2H), 1.64 (m, 1 H), 1.55 (m, 1H), 1.33 (t, J=7.47Hz, 3H), 0.96 (t, J=7.47Hz, 3H). Examples 433 and 434
Figure imgf000266_0001
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000266_0002
(S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
(Example 7) was resolved on a Pirkle Covalent (S,S)Whelk-O 1 column (Regis Technologies, Inc., Morton Grove, IL) (5 x 25cm) eluting at 100mL/min with 5% ethanol/heptane to provide two fractions:
First eluting: (S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; MS: 585.8 [M+H]+ found.
Second eluting: (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)- methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester;
MS: 586.2 [M+H]+ found. Examples 435 and 436
Figure imgf000267_0001
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000267_0002
(R, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester A mixture of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 433, 98mg, 0.167mmol), aqueous sodium hydroxide (1 N, 1mL,
1 mmol) and anhydrous tetrahydrofuran (2.4mL) was stirred at room temperature for 5 days before adding 2N hydrochloric acid to acid pH. The mixture was extracted with ethyl acetate, the organic solution washed with water (x3) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue chromatographed on Baker Silica Gel (1gm, 40 μm) (J.T. Baker, Phillipsburg, N.J.) eluting with a hexanes-ethyl acetate gradient from 0% to 80% ethyl acetate to give the title compounds:
First eluting: (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (67mg); MS: 572.4 [M+Hf found.
1H-NMR (CDCI3) δ 7.90 (s, 1 H), 7.89 (s, 2H), 7.54 (m, 2H), 7.46 (brs, 1H), 4.28 (m, 2H), 4.22 (m, 1 H), 4.08 (d, J=11.2Hz, 1H), 3.37 (m, 1 H), 1.76 (m, 1 H), 1.48 (m, 1 H), 1.38 (m, 1H), 1.31 (t, J=7.05Hz, 3H), 0.95 (m, 1H), 0.70 (t, J=7.47Hz, 3H). Second eluting: (R, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-
2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (29.5mg)
MS: 572.3 [M+H]+ found 1H-NMR (CDCI3) δ 7.94 (s, 2H), 7.83 (s, 1 H), 7.50 (d, J=8.14Hz, 1H), 7.41 (brd, J=8.14Hz, 1H), 7.01 (brs, 1 H), 4.42 (m, 1 H), 4.22 (m, 2H), 4.21 (m, 1 H), 3.32 (m,1 H), 2.45 (m, 1 H), 1.58 (m, 1 H), 1.41 (m, 1 H), 1.41 (m, 1H), 1.28 (t, J=7.47Hz, 3H), 0.79 (t, J=7.47Hz, 3H).
Example 437
Figure imgf000268_0001
(R, R) and (R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of (R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester and (R, S)- 4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl- 2H-quinoline-1 -carboxylic acid ethyl ester (Examples 3 and 4, used as the mixture obtained prior to separation, 329mg, 0.563mmol) in anhydrous tetrahydrofuran (6mL) under nitrogen at -40°C was added dropwise a solution of lithium aluminum hydride (1M in tetrahydrofuran, 845μL, 0.845mmol). After 30min an excess of ethyl acetate was added to quench the reaction and the mixture was allowed to warm to room temperature. The mixture was shaken with water/ethyl acetate, the organic layer washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum. The crude product was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 9:1 then 4:1 then 7:3 to give the title compounds as a mixture of diastereoisomers (243mg). MS: 556.3 [M+H]+ found.
Example 438
Figure imgf000269_0001
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester A mixture of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxy-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 435, 1 lOmg, 0.193mrnol) and thionyl chloride (1mL) was stirred at room temperature under nitrogen for 3 days then the excess thionyl chloride was removed under vacuum. To the residue was added a solution of ammonia in dioxane (0.5M, 6mL, 3mmol). After 12hr the mixture was diluted with ethyl acetate, washed with water (x2) and the organic layer was dried over anhydrous sodium sulfate then evaporated to dryness under vacuum. The crude product was purified by chromatography on silica gel eluting with dichloromethane/ethyl acetate 39:1 then 19:1 to give the title compound (103mg). MS: 571.3 [M+H]+ found.
1H-NMR (CDCI3) δ7.88 (s,1 H), 7.88 (s, 2H), 7.51 (m, 2H), 7.46 (brs, 1H), 5.80 (brs, 1 H), 5.53 (brs, 1 H), 4.26 (m, 1 H), 4.26 (m, 1H), 4.19 (m, 1H), 3.82 (d,
J=10.79Hz, 1H), 3.45 (m, 1 H), 1.68 (m, 1 H), 1.49 (m, 1 H), 1.39 (m, 1 H), 1.29 (t, J=7.06Hz, 3H), 0.95 (m, 1H), 0.70 (t, J=7.47Hz, 3H).
The two following compounds were prepared by an analogous procedure utilizing, respectively, methylamine and dimethylamine in place of ammonia: Example 439
Figure imgf000270_0001
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methylcarbamoyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester MS: 585.3 [M+H]+ found.
Example 440
Figure imgf000270_0002
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-dimethylcarbamoyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester MS: 599.3 [M+H]+ found.
Examples 441 and 442
Figure imgf000271_0001
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000271_0002
(R, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carbamoyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 438, 30mg, 0.053mmol) in anhydrous dichloromethane (1mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess reagent, 37mg, 0.157mmol). The mixture was stirred at room temperature for 72hr under nitrogen then evaporated under vacuum. The crude product was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 to give the title compounds: First eluting compound: (R, R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (8mg);
MS: 553.3 [M+H]+ found; 1H-NMR (CDCI3) δ 7.96 (s, 1H), 7.90 (s, 2H), 7.60 (m, 2H), 7.56 (brs, 1H), 4.88 (d, J=3.32Hz, 1H), 4.28 (m, 1H), 4.22 (m, 1 H), 4.22 (m, 1H), 2.93 (m, 1 H), 2.22 (m, 1 H), 1.63 (m, 1H), 1.62 (m, 1 H), 1.51 (m, 1H), 1.27 (t, J=7.47Hz, 3H), 0.83 (t, J=7.47Hz, 3H). Second eluting compound: (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (20mg);
MS: 553.3 [M+H]+ found;
1H-NMR (CDCI3) δ 7.96 (s, 1 H), 7.92 (s, 2H), 7.59 (brs, 1 H), 7.57 (m, 2H), 4.36 (m, 1 H), 4.30 (m, 1 H), 4.27 (d, J=8.3Hz, 1 H), 4.22 (m, 1 H), 3.23 (m, 1 H), 2.08 (m, 1H), 1.55 (m, 1H), 1.43 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 1.27 (m, 1H), 0.79 (t, J=7.47Hz, 3H).
Preparation 43 (R)-4-Bromo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester
To a solution of (R, S)-2-ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (Preparation 13, 3.29gm, 10.37mmol) in dichloromethane (25mL) at ambient temperature under nitrogen was added pyridine (1.58mL) followed dropwise by a solution of phosphorus (III) bromide (1.1 mL) in dichloromethane (10mL). The mixture was allowed to stir at ambient temperature for 15h then partitioned between water and dichloromethane. The organic layer was washed with saturated sodium hydrogen carbonate solution (2 x 15mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound as a yellow oil (3.79gm) containing an approximately 5:1 mixture of diastereoisomers and a variable amount of (R)-2-ethyl-6-trifluoromethyl- 2H-quinoline-1 -carboxylic acid ethyl ester formed by elimination of hydrogen bromide. The crude bromide was used directly without further purification or stored in the refrigerator to arrest further decomposition. MS: 379, 381 [M].+ found (GC-MS). Examples 443 and 444
Figure imgf000273_0001
(R, R, R)-4-[Cyano-(3,5-dichloro-phenyl)-methyl]-2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000273_0002
(R, R, S)-4-[Cyano-(3,5-dichloro-phenyl)-methyl]-2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of 3,5-dichlorophenylacetonitrile (134mg, 0.72mmol, prepared according to the procedure described in WOOO/58292) in anhydrous N,N- dimethylformamide (1mL) was added sodium hydride (60% mineral oil dispersion, 0.925mmol, 37mg) and the mixture was stirred at room temperature for 30min. A solution of (R)-4-bromo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic acid ethyl ester (Preparation 43, 250mg, mixture of isomers as prepared above) in anhydrous N,N-dimethylformamide (1.5mL) was added and the mixture was stirred at room temperature for 5min. Water was added and the mixture was extracted with diethyl ether (3 x 20mL) and the organic extract was diluted with heptane and evaporated to dryness to give the crude product as a yellow oil (~400mg). Initial purification was achieved by purified by chromatography on silica gel eluting with hexanes/ethyl acetate 9:1. Fractions containing the title compounds were further purified using radial chromatography (Chromatron model 7924T, Harrison Research, Palo Alto, CA) with a 2mm silica gel rotor eluting with hexanes/ethyl acetate 9:1 to give the title compounds:
First eluting compound:
(R, R, R)-4-[cyano-(3,5-dichloro-phenyl)-methyl]-2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (14mg);
1H-NMR (CDCI3) δ 7.59 (s, 2H), 7.54 (s, 1 H), 7.43 (t, J=1.95Hz, 1 H), 7.35 (d, J=1.95Hz, 2H), 4.69 (d, J=3.52Hz, 1 H), 4.28 (m, 1 H), 4.22 (m, 1H), 4.22 (m, 1H), 2.90 (m, 1 H), 2.27 (m, 1H), 1.61 (m, 1H), 1.50 (m, 1 H), 1.49 (m, 1H), 1.29 (t, J=7.03Hz, 3H), 0.84 (t, J=7.42Hz, 3H).
Second eluting compound:
(R, R, S)-4-[cyano-(3,5-dichloro-phenyl)-methyl]-2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (5mg);
MS: 485.2 [M+Hf found;
1H-NMR (CDCI3) δ 7.59 (s, 1 H), 7.55 (s, 2H), 7.42 (t, J=1.66Hz, 1 H), 7.33 (d, J=1.66Hz, 2H), 4.34 (m, 1 H), 4.27 (m, 1H), 4.22 (m, 1 H), 4.01 (d, J=9.13Hz, 1 H), 3.13 (m, 1 H), 2.07 (m, 1 H), 1.53 (m, 1 H), 1.42 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 1.16 (m, 1 H), 0.78 (t, J=7.47Hz, 3H).
Example 445
Figure imgf000274_0001
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-ethoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester A solution of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxy-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 435, 33mg, 0.058mmol) in anhydrous ethanol (5mL) containing concentrated sulfuric acid (4 drops) was heated under reflux for 18hr then the solvent was evaporated under vacuum. The residue was partitioned between water and ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel eluting with hexanes then a hexanes/ethyl acetate gradient from 9:1 to 4:6 to give the title compound (17.5mg) as a gum. MS: 600.6 [M+Hf found.
1H-NMR (CDCI3) δ 7.88 (s, 2H), 7.88 (s, 1 H), 7.53 (m, 2H), 7.44 (brs, 1H), 4.35 (m, 1 H), 4.27 (m, 2H), 4.22 (m, 1 H), 4.06 (m, 1 H), 4.01 (d, J=11.62Hz, 1 H), 3.37 (m, 1 H), 1.73 (m, 1H), 1.48 (m, 1 H), 1.38 (m, 1 H), 1.30 (t, J=7.06Hz, 3H), 1.27 (t, J=7.06Hz, 3H), 0.94 (m, 1H), 0.70 (t, J=7.47Hz, 3H). Example 446
Figure imgf000275_0001
(R)-4-(3,5-Bis-trifluoromethyl-benzyl)-2-ethyl-6-trifluoromethyl-2H-quinoline-1- carboxylic acid ethyl ester To a solution of (R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester and (R, S)- 4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl- 2H-quinoline-1 -carboxylic acid ethyl ester (Examples 3 and 4, used as the mixture obtained prior to separation, 148mg, 0.253mmol) in tetrahydrofuran (3mL) under nitrogen was added aqueous sodium hydroxide solution (1 M, 250μL, 0.25mmol). After stirring at room temperature for 72hr an additional aliquot of aqueous sodium hydroxide solution (1M, 100μL, 0.1 mmol) was added. After 72hr the mixture was acidified by addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under vacuum and the residue was purified by chromatography on silica gel eluting with dichloromethane/hexanes 1:1 then 3:1 followed by dichloromethane then dichloromethane/methanol 9:1 then a hexanes/ethyl acetate gradient from 9:1 to 4:6 to give the title compound (4.5mg).
MS: 526.3 [M+Hf found.
1H-NMR (CDCIs) δ 7.76 (s, 1H), 7.74 (m, 1H), 7.68 (s, 2H), 7.48 (m, 1H), 7.42 (brs, 1H), 5.76 (d, J=5.81Hz, 1H), 4.93 (m, 1 H), 4.27 (m, 2H), 3.92 (m, 1H), 3.88(m, 1H), 1.48 (m, 1H), 1.38 (m, 1H), 1.32 (t, J=7.47Hz, 3H), 0.85 (t, J=7.47Hz, 3H).
Example 447
Figure imgf000276_0001
(R, R, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
To a solution of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxy-methyl]- 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 435, 67mg, 0.117mmol) in tetrahydrofuran (1mL) under nitrogen was added borane-dimβthylsulfide complex (22.2μL, 0.234mmol). After 24hr aqueous sodium hydroxide (1 M, 4 drops) was added to quench the reaction and the mixture was allowed to stir for 1 hr. The mixture was acidified by addition of 2N hydrochloric acid, stirred for 10min and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated under vacuum. The crude product was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 then 4:1 then 3:7 and finally 2:3 to give the title compound (54mg). MS: 558.3 [M+Hf found.
1H-NMR (CDCI3) δ 7.83 (s, 1H), 7.80 (s, 2H), 7.60 (brs, 1H), 7.52 (m, 2H), 4.27 (m, 1 H), 4.24 (m, 2H), 4.20 (m, 1H), 4.00 (m, 1H), 3.54 (m, 1H), 2.84 (m, 1H), 1.82 (m, 1 H), 1.63 (brs, 1 H), 1.46 (m, 1 H), 1.32 (m, 1 H), 1.31 (t, J=7.05Hz, 3H), 0.87 (m, 1H), 0.69 (t, J=7.47Hz, 3H). Preparation 44 Methyl (3,5-dichloro)-phenylacetate A mixture of 3,5-dichlorophenylacetonitrile (2gm, prepared according to the procedure described in WO00/58292), ethanol (25mL), potassium hydroxide (3.95gm) and water (1 OmL) was heated under reflux for 4hr then evaporated to dryness under vacuum. The residue was partitioned between water (20mL) and diethyl ether and the aqueous layer was acidified to pH1 by addition of concentrated hydrochloric acid. The mixture was extracted with diethyl ether (3 x 25mL), the organic layer dried over anhydrous sodium sulfate and evaporated under vacuum. The carboxylic acid was dissolved in methanol (20mL) and trimethylsilyldiazomethane (2M solution in hexanes, 30mL, Aldrich Chemical Company, Milwaukee, Wl) was added slowly. After 1 hr the solvent was removed under vacuum, the residue dissolved in diethyl ether, washed with aqueous sodium carbonate solution (2M), dried over anhydrous sodium sulfate and evaporated to dryness to give the title compound (2.1gm).
1H-NMR (CDCI3) δ 7.27 (s,1 H), 7.17 (s, 2H), 3.71 (s, 3H), 3.57 (s, 2H). Examples 448, 449, 450 and 451
Figure imgf000277_0001
(R, S, R)-4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000278_0001
(R, R, S)-4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000278_0002
(R, S, S)-4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000278_0003
(R, R, R)-4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of methyl (3,5-dichloro)-phenylacetate (311 mg, 1.42mmol) in anhydrous N,N-dimethylformamide (3mL) was added sodium hydride (60% mineral oil dispersion, 1.93mmol, 77mg) and the mixture was stirred at room temperature for 30min. A solution of (R)-4-bromo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1 -carboxylic acid ethyl ester (490mg, mixture of isomers, Preparation 43) in anhydrous N,N-dimethylformamide (5mL) was added and the mixture was stirred at room temperature for 5min. Water was added and the mixture was extracted with diethyl ether (3 x 20mL) and the organic extract was diluted with heptane and evaporated to dryness to give the crude product as a yellow oil (~460mg). Purification was achieved using radial chromatography (Chromatron model 7924T, Harrison Research, Palo Alto, CA) with a 4mm silica gel rotor eluting with hexanes/ethyl acetate 9:1 and subsequently rechromatographing appropriate fractions eluting with dichloromethane/hexanes 45:55 to give the title compounds:
(R, S, R)-4-[(3,5-dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (1 Omg);
MS: 518.3 [M+Hf found;
1H-NMR (CDCI3) δ 7.55 (brd, J=8.30Hz, 1 H), 7.49 (brd, J=8.30Hz, 1H), 7.48 (brs, 1 H), 7.33 (m, 2H), 7.33 (m, 1 H), 4.33 (m, 1 H), 4.31 (m, 1 H), 4.24 (m, 1 H), 3.56 (d, J=11.62Hz, 1 H), 3.52 (m, 1 H), 3.46 (s, 3H), 1.86 (m, 1 H), 1.53 (m, 1 H), 1.47 (m, 2H), 1.34 (t, J=7.47Hz, 3H), 0.74 (t, J=7.47Hz, 3H).
(R, R, S)-4-[(3,5-dichloro-phenyl)-methoxycarbonyl-methyi]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (24mg);
MS: 518.3 [M+Hf found;
1H-NMR (CDCI3) δ 7.52 (m, 1H), 7.50 (m, 1 H), 7.35 (t, J=1.66Hz, 1 H), 7.32 (brs, 1 H), 7.30 (d, J=1.66Hz, 2H), 4.30 (m, 1 H), 4.27 (m, 1 H), 4,20 (m, 1 H), 3.78 (d, J=11.61Hz, 1 H), 3.74 (s, 3H), 3.28 (m, 1 H), 1.85 (m, 1 H), 1.49 (m, 1 H), 1.39 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 0.91 (m, 1H), 0.72 (t, J=7.47Hz, 3H).
(R, S, S)-4-[(3,5-dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (29mg); MS: 518.3 [M+Hf found;
1H-NMR (CDCI3) δ 7.43 (d, J=8.30Hz, 1 H), 7.36 (dd, J=8.30, 1.66Hz, 1 H), 7.15 (t, J=1.66, 1 H), 6.88 (d, J=1.66Hz, 2H), 6.69 (brs, 1 H), 4.45 (m, 1 H), 4.32 (m, 1 H), 4.31 (m, 1H), 3.75 (s, 3H), 3.62 (d, J=10.79Hz, 1 H), 3.40 (m, 1 H), 2.88 (m, 1H), 1.75 (m, 1H), 1.64 (m, 1H),1.48 (m, 1H), 1.34 (t, J=7.47Hz, 3H), 0.83 (t, J=7.47Hz, 3H).
(R, R, R)-4-[(3,5-dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (18mg);
MS: 518.3 [M+Hf found; 1H-NMR (CDCI3) δ 7.51 (brd, J=8.59Hz, 1H), 7.43 (brd, J=8.59Hz, 1H), 7.33 (m, 2H), 7.31 (m, 1H), 7.10 (brs, 1 H), 4.40 (m, 1 H), 4.28 (m, 1H), 4.23 (m, 1 H), 4.06 (d, J=10.15Hz, 1 H), 3.74 (s, 3H), 3.24 (m, 1H), 2.32 (m, 1 H), 1.64 (m, 1H), 1.47 (m, 1 H),1.37 (m, 1 H), 1.32 (t, J=7.02Hz, 3H), 0.83 (t, J=7.47Hz, 3H). Example 452
Figure imgf000280_0001
(R, R, S)-4-[(3,4-Dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of methyl (3,4-dichloro)-phenylacetate (1.22gm, 5.57mmol) in anhydrous N,N-dimethylformamide (5mL) was added sodium hydride (60% mineral oil dispersion, 7mmol, 280mg) and the mixture was stirred at room temperature for 5min. A solution of (R)-4-bromo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester (798mg, mixture of isomers, Preparation 43) in anhydrous N,N-dimethylformamide (4mL) was added and the mixture was stirred at room temperature for 15min. Water was added and the mixture was acidified by addition of 2N hydrochloric acid then extracted with dichloromethane (x 3) and the organic extract was dried over anhydrous sodium sulfate and evaporated to dryness to give a yellow oil. This was dissolved in tetrahydrofuran (10mL) and water (5mL) and aqueous sodium hydroxide (2N, 10mL) was added. The mixture was stirred at room temperature for 24hr then partitioned between hydrochloric acid (0.1 N) and dichloromethane. The organic extract was dried over anhydrous sodium sulfate and evaporated to dryness to give a mixture of carboxylic acids. This material was purified by chromatography on silica gel eluting with hexanes/ethyl acetate 5:1 then 4:1. Fractions containing the first carboxylic acid to elute (with the desired R, R, S stereochemistry) were combined, evaporated to dryness under vacuum and dissolved in methanol (25mL). Trimethylsilyldiazomethane (2M solution in hexanes, Aldrich Chemical Company, Milwaukee, Wl) was added slowly until effervescence ceased and a yellow color persisted. This was discharged by addition of a small amount of acetic acid then the solvent was removed under vacuum and the residue was purified by chromatography on silica gel eluting with a hexanes/dichloromethane gradient from 2:1 to 1 :2. Final purification was achieved using reverse phase HPLC 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) 8 min run, 6 min gradient, 25mL/min, UV triggered collection, observing at 210nm. The product-containing fractions were evaporated to dryness to give the title compound (75mg). MS: 518.3 [M+Hf found. 1H-NMR (CDCI3) δ 7.52 (m, 1H), 7.51 (m, 1H), 7.50 (m, 1 H), 7.47 (d, J=8.3Hz,
1 H), 7.34 (brs, 1H), 7.25 (dd, J=8.3, 2.49Hz, 1H), 4.28 (m, 1 H), 4.27 (m, 1 H), 4.20 (m, 1 H), 3.80 (d, J=11.62Hz, 1 H), 3.73 (s, 3H), 3.29 (m, 1 H), 1.86 (m, 1H), 1.50 (m, 1 H), 1.37 (m, 1 H), 1.30 (t, J=7.47Hz, 3H), 0.90 (m, 1 H), 0.71 (t, J=7.47Hz, 3H).
Example 453
Figure imgf000281_0001
(R, S) and (R, R)-4-[2-Acetoxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of the diastereoisomeric mixture (R, R) and (R, S)-4-[1-(3,5-bis- trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1- carboxylic acid ethyl ester (Example 437, 57mg, 0.102mmol) in dichloromethane
(1mL) under nitrogen was added triethylamine (43μL, 0.306mmol) followed by acetyl chloride (9μL, 0.132mmol). After 3hr the mixture was partitioned between water and dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 then 4:1 then 3:7 and finally 2:3 to give the title compound as a mixture of diastereoisomers (51 mg). MS: 598.3 [M+Hf found.
Example 454
Figure imgf000282_0001
(R, R, S)-4-[2-Acetoxy-1 -(3,5-bis-trif luoromethyl-phenyl)-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
To a solution of (R, R, S)-4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy- ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 447, 50mg, 0.0896mmol) in dichloromethane (1 mL) under nitrogen was added triethylamine (37μL, 0.269mmol) followed by acetyl chloride (8.3μL, 0.116mmol). After 30min the mixture was partitioned between water and dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 then 4:1 to give the title compound (41 mg). MS: 600.4 [M+Hf found.
1H-NMR (CDCI3) δ 7.88 (s, 1 H), 7.85 (s, 1 H), 7.73 (s, 2H), 7.64 (m, 1 H), 7.62 (m, 1 H), 4.80 (dd, J=11.62, 4.15Hz, 1 H), 4.29 (m, 1H), 4.25 (m, 1H), 4.23 (m, 1 H), 4.20 (m, 1 H), 3.72 (ddd, J=9.13, 9.13, 3.32Hz, 1H), 2.79 (m, 1 H), 1.97 (s, 3H), 1.84 (m, 1 H), 1.46 (m, 1 H), 1.32 (m, 1H), 1.31 (t, J=7.47Hz, 3H), 0.87 (m, 1H), 0.69 (t, J=7.47Hz, 3H).
Example 455
Figure imgf000283_0001
(R, R, S)-4-[1 -(3,5-Bis-trif luoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of (R, R, S)-4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy- ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 447, 20mg, 0.035mmol) in tetrahydrofuran (1mL) under nitrogen was added sodium hydride (60% mineral oil dispersion, 0.043mmol, 1.7mg) followed after 5min by iodomethane (2 drops). After stirring for 16hr additional aliquots of sodium hydride (2mg) and iodomethane (3 drops) were added. The mixture was stirred at room temperature for 48hr then diluted with ethyl acetate. The mixture was washed with water, the organic layer separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The crude product was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 to give the title compound (19mg). MS: 572.5 [M+Hf found.
1H-NMR (CDCI3) δ 7.81 (s, 1H), 7.76 (s, 2H), 7.61 (brs, 1H), 7.52 (m, 2H), 4.27 (m, 1 H), 4.24 (m, 1 H), 4.21 (m, 1 H), 3.89 (dd, J=9.96, 3.32Hz, 1H), 3.74 (dd, J=9.13, 7.47Hz, 1 H), 3.55 (m, 1 H), 3.29 (s, 3H), 2.85 (m, 1 H), 1.80 (m, 1 H), 1.47 (m, 1 H), 1.32 (m, 1 H), 1.31 (t, J=7.47Hz, 3H), 0.87 (m, 1 H), 0.69 (t, J=7.47Hz, 3H). Example 456
Figure imgf000284_0001
(R, R, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-fluoro-ethyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
To a solution of (R, R, S)-4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy- ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 447, 20mg, 0.035mmol) in dichloromethane (1mL) under nitrogen was added diethylaminosulfur trifluoride (47μL, 0.358mmol). The mixture was stirred at room temperature for 3hr then a further aliquot of diethylaminosulfur trifluoride (47μL, 0.358mmol) was added. After 1 hr the mixture was partitioned between water and dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was initially purified by chromatography on silica gel eluting with hexanes/ethyl acetate 19:1 then 19:1 then 9:1 and finally purified by reverse phase hplc 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) 8 min run, 6 min gradient, 25mL/min, UV triggered collection, observing at 210nm. The product-containing fractions were evaporated to dryness to give the title compound (3mg).
MS: 560.3 [M+Hf found.
1H-NMR (CDCI3) δ 7.86 (s, 1 H), 7.80 (s, 2H), 7.55 (m, 2H), 7.54 (s, 1 H), 4.93 (ddd, J=46.47, 9.96, 4.14Hz, 1H), 4.82 (ddd, J=46.47, 9.96, 6.64Hz, 1H), 4.28 (m, 1H), 4.27 (m, 1H), 4.23 (m, 1H), 3.72 (m, 1H), 2.91 (m, 1H), 1.88 (m, 1H), 1.48 (m, 1 H), 1.34 (m, 1H), 1.32 (t, J=7.47Hz, 3H), 0.92 (m, 1 H), 0.71 (t, J=7.47Hz, 3H).
Example 457
Figure imgf000285_0001
(R, R, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-amino-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carbamoyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 438, 25mg, 0.0438mmol) in tetrahydrofuran (3mL) under nitrogen was added borane-dimethylsulfide complex (8.3μL, 0.0876mmol). The mixture was heated at 70°C for 48hr then water (2.5mL) and saturated aqueous sodium carbonate solution (1 mL) was added. The mixture was heated at 70°C for 1 hr then partitioned between water and dichloromethane. The organic layer was evaporated to dryness under vacuum and the residue dissolved in diethyl ether (5mL) and 2N hydrochloric acid (1mL) added. After 24hr the mixture was diluted with water, sodium carbonate solution added and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under vacuum. The crude product was purified by chromatography on silica gel eluting with hexanes/ethyl acetate 3:1 then ethyl acetate give the title compound (18.5mg). MS: 557.4 [M+Hf found.
1H-NMR (CDCI3) δ 7.84 (s, 1 H), 7.77 (s, 2H), 7.58 (brs, 1 H), 7.52 (m, 2H), 4.27 (m, 1H), 4.23 (m, 1H), 4.22 (m, 1H), 3.44 (dd, J=13.28, 3.32Hz, 1H), 3.35 (m, 1H), 3.09 (dd, J=13.28, 9.13Hz, 1 H), 2.76 (m, 1H), 1.76 (m, 1 H), 1.45 (m, 1 H), 1.34 (m, 1 H), 1.31 (t, J=7.47Hz, 3H), 0.84 (m, 1H), 0.69 (t, J=7.47Hz, 3H).
Examples 458, 459, 460 and 461
Figure imgf000286_0001
[(R, S, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000286_0002
[(R, R, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000286_0003
[(R, R, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000286_0004
[(R, S, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester These compounds (previously prepared in Examples 22, 23, 24 and 25) were prepared in optically enriched form by resolution of the corresponding racemate indicated, or an intermediate in its synthesis, using methods analogous to those described herein. Examples 462, 463, 464 and 465
Figure imgf000287_0001
Preparation of [(R, R, R)], [(R, R, S)], [(R, S, S)], and [(R, S, R)]-4-[Amino-(3,5-bis- trifluoromethyl-phenyl)-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2 - -quinoline-1- carboxylic acid ethyl ester General procedure to make amine compounds: [(R, R, R)]-4-(3,5-bis- trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (0.527 grams, 0.971 mmol, 1 eq) was placed in a round bottomed flask equipped with a magnetic stir bar. Methylene chloride (20 mL) was added followed by the addition of triethylamine (0.456 mL, 3.37 mmol, 3.37 eq) and mesyl chloride (0.150 mL, 1.94 mmol, 2.0 eq) at room temperature and the reaction mixture was stirred overnight. The reaction mixture was quenched with water, extracted 4 times with ethyl acetate. The organic layer was washed with 0.1 M HCI, followed by saturated bicarbonate solution and dried over sodium sulfate. The solution was filtered, concentrated and dried on the high vacuum to provide [(R, R, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-methanesulfonyloxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.599 grams, 99% yield) as a white solid, MS (ES+) m/z=622 (M+1).
[(R, R, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-methanesulfonyloxy-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.313 grams, 0.504 mmol, 1 eq) was placed in a round bottomed flask equipped with a magnetic stir bar. DMF (12 mL) was added followed by the addition of sodium azide (0.201 grams, 0.3.10 mmol, 6.1 eq). The reaction mixture was heated to 70°C for 12 hours. The reaction mixture was cooled to room temperature, diluted into 200 mL of EtOAc and washed 4 times with brine and water. The EtOAc was collected, dried over sodium sulfate, filtered and concentrated. The material was purified on a Biotage flash 40s to provide [(R, R, S)]-4-[Azido-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester 0.202 grams, 71 % yield) MS (ES+) m/z=569 (M+1 ).
[(R, R, S)]-4-[Azido-(3,5-bis-trifluoromethyl-phenyl)-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2 --quinoline-1 -carboxylic acid ethyl ester ( 0.202 grams, 0.356 mol, 1 eq) was placed in a round bottomed flask and equipped with a magnetic stir bar and reflux condenser. NH4CO2H (0.226 grams, 3.58 mol, 10.1 eq) and Pd/C (0.113 grams, 0.107 mol, 0.30 eq) was added followed by the addition of a 2:1 solution of methanol and ethyl acetate (8.80 mL). The reaction mixture was refluxed for 2 hours and then filtered through Celite®. The titrate was concentrated but not to dryness and partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The crude material was purified on Biotage Flash 40 M to provide the desired compound, [(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 (0.162 grams, 83% yield) MS (ES+) m/z=543 (M+1).
1H NMR (CDCI3): δ 0.82 (t, 3H), 1.32 (t, 3H), 1.34-1.57 (m, 3H), 2.53 (m, 1 H), 3.00 (m, 1 H), 4,28 (q, 2H), 4.50 (d, 1 H), 4.54 (m, 1H), 7.03 (s, 1 H), 7.42 (d, 1 H), 7.60 (d, 1 H), 7.66 (s, 2H), 7.72 (s, 1 H). MS (ES+) m/z=543 (M+1).
These additional compounds were prepared using analogous procedures to those described herein:
Figure imgf000288_0001
[(R, S, S)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester: 1H NMR (CDCI3): δ 0.71 (t, 3H), 1.00 (m, 1H), 1.29 (t, 3H), 1.33-1.52 (m, 2H), 1.67 (m, 1H & H2O), 2.70 (m, 1H), 4.15-4.31 (m, 3H), 4.47 (d, 1H), 7.51 (m, 2H), 7.84 (s, 1H), 7.89 (s, 2H), 7.91 (s, 1H);
MS (ES+) m/z=543 (M+1).
Figure imgf000289_0001
[(R, R, /?)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester:
HNMR (CDCI3): δ 0.75 (t, 3H), 1.33 (t, 3H), 1.37-1.62 (m, 3H), 1.82 (m, 1H), 2.98 (m, 1 H), 4.17-4.36 (m, 4H), 7.51 (s, 1 H), 7.53-7.61 (m, 2H), 7.83 (s, 1 H), 7.86 (s, 2H);
MS (ES+) m/z=543 (M+1).
Figure imgf000289_0002
[(R, S, R)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-ethyl-6-2- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester:
HNMR (CDCI3): δ 0.82 (t, 3H), 1.27 (t, 3H), 1.40-1.64 (m, 3H), 2.07 (m, 1 H), 2.76 (m, 1 H), 4.09-4.27 (m, 3H), 5.07 (m, 1 H), 7.55 (q, 2H), 7.66 (s, 1H), 7.83 (s, 1 H), 7.96 (s, 2H);
MS (ES+) m/z=543 (M+1).
Example 466, 467, 468 and 469 The following compounds were prepared from starting materials and procedures analogous to those described above, particularly in Examples 18, 19, and 456.
Figure imgf000290_0001
[(R, S, R)]-4-(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
1H-NMR (CDCI3): δ 7.92 (s, 1H), 7.83 (s, 2H), 7.67 (s, 1H), 7.57 (s, 2H), 6.5 (d, 1H), 4.24 (m, 3H), 2.91 (dd, 1 H), 2.08 (m, 1 H), 1.51 (m, 3H), 1.27 (t, 3H), 0.80 (t, 3H);
MS: 546.3 [M+H]+ found.
Figure imgf000290_0002
[(R, S, S)]-4-(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
1 H-NMR (CDCI3): δ 7.96 (s, 1 H), 7.88 (s, 2H), 7.76 (s, 1H), 7.55 (s, t, 2H), 5.86 (dd, J=9.13 Hz, 1 H), 4.25 (m, 3H), 3.10 (m, 1 H), 1.75 (m, 1 H), 1.47 (m, 2H), 1.29 (t, 3H), 1.18 (t , 3H), 0.77 (t, 3H);
MS: 546.4 [M+H]+ found.
Figure imgf000290_0003
[(R, R, S)]-4-(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester 1H-NMR (CDCI3): δ 7.8 (s, 1H), 7.59 (d, 1 H), 7.47 (d, 1 H), 7.43 (s, 2H), 6.86 (s, 1H), 5.65 (dd, J=7.88 Hz, 1H), 4.60 (m, 1 H), 4.28 (m, 2H), 3.21 (m, 1H), 2.65 (m, 3H), 1.74 (m, 1H), 1.41-1.62 (m, 2H), 1.31 (t, 3H), 0.86 (t, 3H);
MS: 546.3 [M+H]+ found
Figure imgf000291_0001
[( ?, R, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
1H-NMR (CDCI3): δ 7.88 (s, 1H), 7.63 (s, d, 3H), 7.52 (d, 1H), 7.41 (s, 1 H), 5.58 (dd, J=7.47 Hz, 1H), 4.42 (m, 1H), 4.24 (m, 2H), 3.40 (m, 1 H), 1.97 (m, 1 H), 1.74 (m, 1 H), 1.41 (m, 2H), 1.27 (t, 3H), 0.79 (t , 3H); MS: 546.3 [M+H]+ found.
Examples 470, 471 , 472 and 473 The following compounds were prepared from starting materials and procedures analogous to those described above, as shown in Scheme 2 whereby the addition of a suitable organometallic derivative such as magnesium or lithium derivative, prepared from a compound alkyl-Hal, wherein Hal represents a chlorine, bromine or iodine atom to XXV produced compounds shown in examples 470, 471 , 472 and 473.
[(R,R), (S,S)]-4-[(3,5-Bis-trifluoromethyl-benzoyl)]-6,-trifluoromethyl -2-ethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.015 grams, 0.028 mmol) was placed in a small round bottomed flask containing a magnetic stir bar and dissolved in 0.50 mL of tetrathydrofuran. Methyl magnesium bromide solution (0.028 mL of 3.0 M in diethylether) was added to the reaction mixture at room temperature and stirred for 2 hours. The reaction mixture was then quenched with saturated ammonium chloride solution and extracted into ethyl acetate. The organic layer was washed with water, dried over magnesium sulafte, filtered and concentrated to provide the desired products as an crude oil. The alcohol diastereomers were separated by silica gel chromatography to provide [(R, R, R)],-4-[(3,5-bis- trifluoromethyl-phenyl)-1-hydroxyl- ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester and [(R, R, S)]-4-[(3,5-bis-trifluoromethyl- phenyl)-1 -hydroxyl- ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- carboxylic acid ethyl ester.
Figure imgf000292_0001
[(R, R, R)], (R, R, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-1 -hydroxyl- ethyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2 - -quinoline-1 -carboxylic acid ethyl ester
First eluting compound: 1H-NMR (CDCI3): δ 7.86 (s, 2H), 7.80 (s, 1 H), 7.53 (dd, 2H), 7.34 (s, 1H), 4.3 (m, 2H), 4.18 (m, 1 H), 3.18 (m, 1 H), 1.95 (m, 1 H), 1.80 (s, 1H), 1.5-1.63 (m, 4H), 1.24 - 1.45 (m, 5H), 0.70 (t, 3H);
MS: 588.3 [M+H]+ found.
Second eluting compound:1H-NMR (CDCI3): δ 7.76 (m, 3H), 7.53 (d, 1 H), 7.42 (d, 1 H), 7.06 (s, 1 H), 4.41 (m, 1 H), 4.2 (q, 2H), 3.18 (m, 1 H), 2.30 (m, 1H), 1.91 (br s, 1 H), 1.62-1.74 (m, 4H), 1.24 - 1.43 (m, 5H), 0.77 (t, 3H);
MS: 588.3 [M+H]+ found.
Figure imgf000292_0002
[( ?, S, R)], (R, S, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-1 -hydroxyl- ethyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester
First eluting compound: 1H-NMR (CDCI3): δ 7.86 (s, 1 H), 7.80 (s, 1 H), 7.70 (s, 1 H), 7.55 (m ,2H), 7.35 (s, 1H), 4.3 (m, 2H), 4.19 (m, 1 H), 3.20 (m, 1 H), 1.91 (m, 1 H), 1.60 (s, 3H), 1.30 (t, 3H), 0.70 (t, 3H);
MS: 556.2 [M-H]" found. Second eluting compound:1H-NMR (CDCI3): δ 8.0 (s, 2H), 7.80 (s, 1H), 7.50 (brs, 1 H), 7.40 (dd, 2H), 4.4 (br m, 1 H), 4.20 (m, 2H), 3.05 (d, 1 H), 2.55 (br m, 1 H), 1.74 (s, 3H), 1.63 (m, 1 H), 1.43 (m, 2H), 1.30 (t, 3H), 0.90 (t, 3H); MS: 558.3 [M+Hf found.
Example 474 and 475 The following compounds were prepared from starting materials and procedures analogous to those described in Scheme 1 above, particularly in Example 2.
Figure imgf000293_0001
[(R, R)], (R, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-1-hydroxyl- methoxycarbonyl-methyl]- 6,7-dimethoxy-2-methyl-2H-quinoline-1 -carboxylic acid ethyl ester
Diastereomer 1 : 1H-NMR (CDCI3): δ 7.92 (s, 2H), 7.73 (s, 1 H), 6.81 (s, 1 H), 5.80 (d, 1H), 5.20 (br m, 1 H), 4.40 (brs, 1H), 4.30 (m, 1 H), 4.20 (br m, 1 H), 3.84 (s, 3H), 3.80 (s, 3H), 3.50 (s, 3H), 1.34 (m, 4H), 1.09 (d, 3H); MS: 578.5 [M+H]+ found.
Diastereomer 2: 1H-NMR (CDCI3): δ 8.18 (s, 2H), 7.87 (s, 1 H), 6.67 (s, 1 H), 5.65 (br s, 1 H), 5.15 (br s, 1 H), 4.31 (brm, 1H), 4.20 (br m, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.58 (s, 3H), 1.33 (t, 3H), 1.09 (d, 3H); MS: 578.6 [M+H]+ found.
(Examples 476 and 477 The following compounds were prepared from starting materials and procedures analogous to those described in Scheme 1 above, particularly in Examples 7 and 8.
Figure imgf000294_0001
[(R, S, R), (R, S, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl- methoxycarbonyl- methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester
First Eluting: 1H NMR (CDCI3): δ 8.18 (s, 2H), 7.88 (s, 1 H), 7.03 (br s, 1 H), 6.73 (s, 1H), 4.31 (m, 1H), 4.20 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.81 (s, 3H), 3.30 (d, 1 H), 1.70 (m, 2H), 1.21 -1.30 (t, m, 4H), 1.09 (d, 3H);
MS: 580.6 [M+H]+ found.
Second Eluting: 1H NMR (CDCI3): δ 8.25 (s, 2H), 7.84 (s, 1H), 6.92 (br s, 1 H), 6.30 (s, 1 H), 4.55 (m, 1 H), 4.30 (m, 1H), 4.20 (m, 1H), 3.88 (s, 3H), 3.80 (s, 3H) 3.60 (d, 1H), 3.40 (s, 3H), 2.03 (m, 2H), 1.55 (m, 1H), 1.32 (t, 3H) 1.09 (d, 3H);
MS: 580.5 [M+H]+ found.
Examples 478 and 479
The following compounds were prepared from starting materials and procedures analogous to those described above, particularly in Examples 448, 449, 450 and 451.
[(R, R, R)], (R, R, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl- methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000294_0002
1H NMR (CDCI3): δ 7.97 (s, 2H), 7.83 (s, 1H), 7.0 (brs, 1 H), 6.20 (s, 1H), 4.50 (m, 1 H), 4.30 (m, 1 H), 4.30 (m, 1 H), 4.19 (m, 1 H), 4.17 (d, 1 H), 3.80 (s, 3H), 3.74 (s, 3H), 3.51 (s, 3H), 3.32 (m, 1H), 2.30 (m, 1H), 1.31 (t, 3H), 1.20 (d, 3H);
MS: 564.5 [M+H]+ found.
Figure imgf000295_0001
1H NMR (CDCI3): δ 7.87 (s, 3H), 7.03 (br s, 1 H), 6.72 (s, 1 H), 4.31 (m, 2H), 4.20 (m, 1 H), 3.98 (d, 1H), 3.86 (s, 6H), 3.75 (s, 3H), 3.32 (t, 1 H), 1.70 (m, 1 H), 1.30 (t, 3H), 1.07 (d, 3H), 0.80 (m, 1 H); MS: 564.4 [M+H]+ found. Example 480
The following compound was prepared from starting materials and procedures analogous to those described above, particularly in Examples 470, 471 , 472 and 473.
[(R, R, R)], (R, R, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-1 -hydroxyl- ethyl]- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.079 grams, 0.142 mmol) was placed in a small round bottomed flask containing a magnetic stir bar and dissolved in 1.5 mL of anhydrous chloroform. To this reaction solution, 2,6-di-t-butyl-4-methylpyridine (0.117 grams, 0.568 mmol) and thionyl chloride (0.051 grams, 0.425 mmol) was added and allowed to stir at room temperature for four hours. The reaction mixture was quenched with water and extracted into methylene chloride. The organic layers was washed with 0.1 N HCI, dried over magnesium sulfate, filtered and concentrated to provide [(R, R, R)], (R, R, S)]-4-[1-(3,5-bis-trifluoromethyl-phenyl)-1-chloro-ethyl]-2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester as an oil which was used without further purification. [(R, R, R)], (R, R, S)]-4-[1-(3,5-bis-trifluoromethyl-phenyl)-1- chloro-ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.085 grams, 0.142 mmol) was placed in a small round bottomed flask containing a magnetic stir bar and dissolved in 0.48 mL THF. This solution was added glacial acetic acid (0.48 mmol), HCI (0.80 mmol), and zinc dust ((0.093 grams, 1.42 mmol). The reaction mixture was stirred at room temperature for three hours. The reaction mixture was quenched with water and extracted three times with ethyl actetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated to provide [(R, R)-4-[1-(3,5-bis-trifluoromethyl-phenyl)-vinyl]- 2-ethyl-6-trifluoromethyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester as an oil.
[(R,R ^-[1-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (15 mg) was placed in a small round bottomed flask and dissolved in 10 mL of methanol. To this solution was added 10 mg of 10% Pd/C. The reaction mixture was hydrogenated at 45 psi for 12 hours. The reaction mixture was then filtered through Celite® and washed with methanol. The filtrate was concentrated to an oil and purified by silica gel chromatography to provide [(R, R, R)], (R, R, S)]-4-[1-(3,5-bis-trifluoromethyl- phenyl)-ethyl]- 6,7-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester in 66% yield.
Figure imgf000296_0001
[(R, S, R)], (R, S, S)]-4-[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl- 6,7- trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
1H NMR (CDCI3): δ 7.78 (s, 1 H), 7.65 (s, 2H), 7.59 (dd, 2H), 7.41 (s, 1H), 4.30 (m, 1H), 4.20 (m, 2H), 2.95 (m, 2H), 1.80 (m, 1 H), 1.58 (m, 2H), 1.40 (m, 1 H), 1.30 (t, 3H), 1.20 (d, 3H), 0.72 (t, 3H); MS: 542.3 [M+H]+ found. Example 481 (Stereo-lsomers of Examples 462, 463, 464 and 465)
Figure imgf000297_0001
[(S, R, S)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
[(S, S, S)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
[(S, R, R)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester;
[(S, S, R)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
The above stereo-isomers of examples 462, 463, 464 and 465 are prophetic and may be prepared in optically enriched form by resolution of the corresponding racemate indicated, or an intermediate in its synthesis, using methods analogous to those described herein. Examples 482 and 483
Figure imgf000297_0002
(R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester The mixture of two diastereoisomers (Example 2, 1.0g) was chromatographed on silica (Flash 40M column, Biotage, Dyar Corp., Chariottesville, VA) eluting with a methylene chloride -hexanes gradient from 2:3 to 4:1 to give the title compounds as white solids.
First eluting diastereoisomer (4a stereochemistry not determined):
MS: 597.9 [M-H]" found 1H-NMR (CDCI3) δ 7.92 (s, 2H), 7.75 (s, 1 H), 7.67 (s, 1H), 7.65 (d, J=8.30Hz,
1 H), 7.34 (dd, J=8.30, 1.66Hz, 1H), 5.97 (d, J=6.64Hz, 1 H), 5.04 (m, 1H), 4.53 (s, 1 H), 4.27 (m, 2H), 3.87 (s, 3H), 1.47 (m, 1 H), 1.35 (m, 1H), 1.28 (t, J=7.47Hz, 3H), 0.85 (d, J=6.64Hz, 3H).
Second eluting diastereoisomer (4a stereochemistry not determined): MS: 597.9 [M-H]" found
1H-NMR (CDCI3) δ 8.16 (s, 2H), 7.90 (s, 1 H), 7.65 (d, J=8.30, 1 H), 7.63 (s, 1 H), 7.45 (dd, J=8.30, 1.66Hz, 1 H), 5.82 (d, J=6.42Hz, 1H), 4.96 (m, 1H), 4.34 (s, 1 H), 4.27 (m, 2H), 3.78 (s, 3H), 1.47 (m, 1 H), 1.35 (m, 1H), 1.33 (t, J=7.47Hz, 3H), 0.83 (d, J=7.47Hz, 3H).
Example 484
Figure imgf000298_0001
(R, R)- 4-(3,5-bis-trifluoromethyl-benzyl)-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester.
[(R, R, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-methanesulfonyloxy-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.045 mmol, 0.0278 g) was placed in a 5 mL reaction flask. To this 1.3 mL of DMF followed by sodium borohydride (0.526 mmol, 0.019 g) was added. The reaction was heated to 85 °C for twelve hours. The reaction mixture was then diluted with ethyl actetate and washed with an aqueous brine solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to dryness. The crude reaction mixture was purified on silica gel chromatography to provide 18.5 mg of the desired product (R, R)- 4-(3,5-bis-trifluoromethyl-benzyl)-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester in 78% yield.
1H NMR (CDCI3): 0.80 ppm (t, 3H), 1.10 (m, 1H), 1.29 (t, 3H), 1.41-1.62 (m, 2H & H2O), 2.16 (m, 1H), 2.76-2.87 (m, 2H), 3.64 (d, 1H), 4.15-4.32 (m, 3H), 7.47 (s, 1H), 7.51-7.57 (m, 2H), 7.70 (s, 2H), 7.80 (s, 1 H). MS (ES+) m/z=528 (M+1).
Example 485
Figure imgf000299_0001
(R, R, S) 4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester.
(R, R, S) 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)-methyl]-2-ethyl-6- trifluoromethyl-3, 4-dihydro-2/-/-quinoline-1-carboxylic acid ethyl ester (0.193 g, 0.357 mmol) was placed in a sealed tube that contained 7 mL of ethyl formate. The tube was sealed and heated for twelve hours at 100 °C. The reaction mixture was then concentrated and purified on silica gel chromatography to provide 0.165 g of the formamide in 81% yield. This product was then placed in a round bottomed flask equipped with a magnetic stir bar and dissolved in 7.3 mL of toluene. To this solution, 2.92 mL of borane methyl sulfide complex in toluene (2.0 M) was added. A reflux condenser was attached to the flask and the reaction was heated to 74 °C for twelve hours. The reaction mixture was then quenched with methanol and a few drops of HCI. This mixture was then heated for 1 hour. After cooling to room temperature, the mixture was quenched with aqueous NaHCO3 and extracted 3 times with ethyl acetate. The organics were collected, dried over sodium sulfate and concentrated to dryness. The crude oil was purified on silica gel chromatography to provide (R, R, S) 4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester in 41% yield. 1H NMR (CDCI3): 0.81 ppm (t, 3H), 1.33 (t, 3H), 1.36-1.52 (m, 3H), 2.25 (s, 3H), 2.52 (m, 1 H), 2.97 (m, 1 H), 3.99 (d, 1 H), 4.28 (m, 2H), 4.52 (m, 1H), 7.04 (s, 1H), 7.41 (m, 1 H), 7.59-7.61 (m, 3H), 7.72 (s, 1H). MS (ES+) m/z=557 (M+1).
Examples 486 - 499 These compounds were prepared from appropriate starting materials procedures analogous to those described in Examples 9, 10, 433, 434, 438, 443, 444, 452, 454, 457 and described generally in Scheme 2. The appropriately substituted bromo intermediates designated as Formula XVII in Scheme 2, were prepared using procedures described by Matsugi in Tetrahedron Lett 2000, 41, 8523 and Hardy in U.S. patent 6,288,075.
Example 486
Figure imgf000300_0001
(RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6-fluoro-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester GCMS (El): 535 (M+)
1H-NMR (CDCI3): δ 0.87 (m, 1 H), 1.04 (d, 3H), 1.25 (m, 3H), 1.32 (d, 3H), 1.69 (m, 1 H), 3.33 (m, 1H), 3.76 (s, 3H), 3.92 (d, 1 H), 4.29 (m, 1H), 5.03 (m, 1H), 6.81 (dd, 1 H), 6.87 (m, 1H), 7.38 (bs, 1 H), 7.85 (s, 2H), 7.87 (s, 1 H).
Example 487
Figure imgf000300_0002
(R, R, S)-4- ,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6-fluoro-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester GCMS (El): 535 (M+)
1H-NMR (CDCI3): δ 0.83 (m, 1 H), 1.04 (d, 3H), 1.26 (d, 3H), 1.32 (d, 3H), 1.72 (m, 1H), 3.33 (m, 1 H), 3.77 (s, 3H), 3.91 (d, 1H), 4.28 (m, 1 H), 5.03 (m, 1 H), 6.82 (dd, 1H), 6.95 (m, 1H), 7.38 (bs, 1 H), 7.84 (s, 2H), 7.87 (s, 1H).
Example 488
Figure imgf000301_0001
(S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6-fluoro-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester
GCMS (El): 535 (M+)
1H-NMR (CDCI3): δ 0.83 (m, 1H), 1.04 (d, 3H), 1.26 (d, 3H), 1.32 (d, 3H), 1.69 (m, 1H), 3.33 (m, 1H), 3.77 (s, 3H), 3.91 (d, 1H), 4.28 (m, 1H), 5.03 (m, 1 H), 6.82 (dd, 1 H), 6.95 (m, 1H), 7.38 (bs, 1 H), 7.84 (s, 2H), 7.87 (s, 1H). Example 489
Figure imgf000301_0002
(RS, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6-fluoro-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester GCMS (El): 535 (M+) 1 H-NMR (CDCIa): δ 0.87 (m, 1H), 1.17 (d, 3H), 1.26 (m, 3H), 1.32 (d, 3H), 2.31 (m, 1H), 3.28 (m, 1H), 3.74 (s, 3H), 4.17 (d, 1H), 4.46 (m, 1H), 5.04 (m, 1H), 6.44 (dd, 1H), 6.87 (m, 1 H), 7.38 (m, 1H), 7.84 (s, 1 H), 7.89 (s, 2H).
Example 490
Figure imgf000302_0001
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-6-fluoro-2-methyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester GCMS (El): 520 (M+)
1H-NMR (CDCI3): δ 0.85 (m, 1 H), 1.05 (d, 3H), 1.25 (d, 3H), 1.30 (d, 3H), 1.64 (m, 1H), 3.38 (m, 1 H), 3.71 (d, 1 H), 4.26 (m, 1 H), 5.01 (m, 1H), 5.53 (bs, 1H), 5.78 (bs, 1H), 6.93 (m, 2H), 7.37 (m, 1 H), 7.85 (s, 2H), 7.87 (s, 1 H).
Example 491
Figure imgf000302_0002
(RS, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-6-fluoro-2-methyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester
LCMS (ESI+): 503 (MH+)
1H-NMR (CDCI3): δ 1.19 (d, 3H), 1.24 (d, 3H), 1.28 (d, 3H), 1.45 (m, 1H), 2.18 (m, 1 H), 2.87 (m, 1 H), 4.31 (m, 1 H), 4.77 (d, 1H), 4.99 (m, 1H), 7.04 (bs, 1 H), 7.06 (bs, 1 H), 7.45 (m, 1 H), 7.90 (s, 2H), 7.96 (s, 1 H).
Figure imgf000303_0001
(RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-methyl- 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester GCMS (El): 585 (M+)
1H-NMR (CDCI3): δ 0.91 (m, 1 H), 1.09 (d, 3H), 1.29 (d, 3H), 1.34 (d, 3H), 1.75 (m, 1 H), 3.38 (t, 1 H), 3.77 (s, 3H), 4.02 (d, 1H), 4.31 (m, 1H), 5.06 (m, 1H), 7.38 (s, 1H), 7.55 (m, 2H), 7.88 (bs, 3H).
Example 493
Figure imgf000303_0002
(RS, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-methyl- 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 585 (M+)
1H-NMR (CDCI3): δ 1.22 (d, 3H), 1.28 (d, 3H), 1.33 (d, 3H), 1.39 (m, 1 H), 2.36 (m, 1 H), 3.27 (m, 1 H), 3.76 (s, 3H), 4.27 (d, 1H), 4.46 (m, 1H), 5.06 (m, 1H), 7.08 (s, 1 H), 7.43 (d, 1 H), 7.57 (d, 1H), 7.85 (s, 1 H), 7.93 (s, 2H).
Example 494
Figure imgf000304_0001
(RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-2-methyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 571 (MH+)
1H-NMR (CDCI3): δ 0.91 (m, 1 H), 1.09 (d, 3H), 1.27 (d, 3H), 1.33 (d, 3H), 1.68 (m, 1 H), 3.46 (t, 1 H), 3.81 (d, 1 H), 4.28 (m, 1H), 5.04 (m,1 H), 5.54 (bs, 1H), 5.82 (bs, 1 H), 7.46 (s, 1 H), 7.50 (d, 1H), 7.56 (d, 1H), 7.88 (s, 3H).
Example 495
Figure imgf000304_0002
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-2-methyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 571 (MH+)
1H-NMR (CDCI3): δ 0.87 (m, 1H), 1.09 (d, 3H), 1.26 (d, 3H), 1.33 (d, 3H), 1.69 (m, 1H), 3.45 (t, 1H), 3.83 (d, 1H), 4.27 (m, 1H), 5.03 (m,1H), 5.65 (bs, 1H), 5.99 (bs, 1 H), 7.46 (s, 1 H), 7.49 (d, 1 H), 7.55 (d, 1 H), 7.88 (s, 3H).
Example 496
Figure imgf000305_0001
(S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-2-methyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 571 (MH+)
1H-NMR (CDCI3): δ 0.87 (m, 1 H), 1.08 (d, 3H), 1.26 (d, 3H), 1.32 (d, 3H), 1.68 (m, 1 H), 3.44 (t, 1 H), 3.84 (d, 1H), 4.26 (m, 1H), 5.02 (m,1H), 5.69 (bs, 1H), 6.01 (bs, 1 H), 7.47 (s, 1H), 7.49 (d, 1H), 7.54 (d, 1H), 7.87 (s, 3H).
Example 497
Figure imgf000305_0002
(RS, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-2-methyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 571 (MH+)
1H-NMR (CDCI3): δ 0.87 (m, 1 H), 1.18 (d, 3H), 1.24 (d, 3H), 1.28 (d, 3H), 2.54 (m, 1H), 3.37 (t, 1 H), 4.00 (d, 1 H), 4.48 (m, 1H), 5.04 (m,1 H), 6.02 (bs, 1 H), 6.33 (bs, 1 H), 7.00 (s, 1 H), 7.36 (d, 1 H), 7.55 (d, 1 H), 7.81 (s, 1 H), 7.98 (s, 2H).
Example 498
Figure imgf000306_0001
(RS, RS, SR)-4-[2-Amino-1 -(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 557 (MH+)
1H-NMR (CDCI3): δ 0.80 (m, 1H), 1.04 (d, 3H), 1.28 (d, 3H), 1.34 (d, 3H), 1.76 (m, 1H), 2.75 (t, 1H), 3.11 (m, 1H), 3.35 (m, 1 H), 3.46 (m,1H), 4.26 (m, 1 H), 5.06 (m, 1H), 7.54 (m, 3H), 7.77 (s, 2H), 7.84 (s, 1H).
Example 499
Figure imgf000306_0002
(RS, RS, SR)-4-[2-Acetylamino-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 599 (MH+)
1H-NMR (CDCI3): δ 0.78 (m, 1H), 1.04 (d, 3H), 1.28 (d, 3H), 1.34 (d, 3H), 1.76 (m, 1 H), 1.93 (s, 3H), 2.68 (s, 1H), 3.01 (m, 1 H), 3.72 (m, 1 H), 4.26 (m, 1H), 4.37 (m, 1 H), 5.06 (m, 1 H), 5.40 (m, 1 H), 7.53 (s, 2H), 7.70 (s, 2H), 7.85 (s, 1 H), 8.41 (s, 1 H). Examples 500 and 501
Figure imgf000307_0001
(R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000307_0002
(R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of 3,5-bis(trifluoromethylphenyl)acetic acid methyl ester (1.41g, 4.93rnmol) in anhydrous N,N-dimethylformamide (3mL) was added sodium hydride (60% mineral oil dispersion, 6.55mmol, 262mg) and the mixture was stirred at room temperature for 60min. A solution of (R)-4-chloro-2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1-carboxylic acid ethyl ester (1.10g, 3.28mmol, mixture of isomers, Preparation 14) in anhydrous N,N-dimethylformamide (1.5mL) was added and the mixture was stirred at room temperature for 72hr. Water (20mL) was added and the mixture was extracted with diethyl ether (3 x 50mL) and the organic extract was dried over anhydrous sodium sulfate and the solvent was removed under vacuum to give the crude product as a yellow oil (~2g). Purification was achieved using radial chromatography (Chromatron model 7924T, Harrison Research, Palo Alto, CA) with a 4mm silica gel rotor eluting with hexanes/ethyl acetate 9:1 to give the title compounds: (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (first eluting diastereoisomer)
MS: 586.0 [M+Hf found 1H-NMR (CDCI3) δ 7.90 (s, 2H), 7.87 (s, 1H), 7.59 (d, J=8.30Hz, 1 H), 7.62 (d,
J=8.30Hz, 1H), 7.61 (s, 1H), 4.39-4.27 (m, 2H), 4.27-4.18 (m, 1H), 3.78 (d, J=11.61Hz, 1H), 3.59 (m, 1H), 3.48 (s, 3H), 1.76 (ddd, J=14.10, 8.30, 3.30Hz, 1H), 1.61-1.55 (m, 1H),1.57-1.50 (m, 1H), 1.48-1.40 (m, 1 H), 1.35 (t, J=7.47Hz, 3H), 0.73 (t, J=7.47Hz, 3H). (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-
6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (536mg, second eluting diastereoisomer) MS: 586.0 [M+Hf found 1H-NMR (CDCI3) δ 7.66 (s, 1 H), 7.42 (d, J=8.30Hz, 1 H), 7.40 (s, 2H), 7.33 (dd, J=8.30, 1.66Hz, 1H), 6.47 (d, J=1.66Hz, 1 H), 4.55-4,47 (m, 1H), 4.34 (m, 1H), 4.32 (m,1 H), 3.83 (d, J=11.61 Hz, 1 H), 3.80 (s, 3H), 3.43 (ddd, J=11.61 , 4.98, 2.49Hz, 1 H), 2.44 (ddd, J=14.11 , 8.30, 2.49Hz, 1 H), 1.81 (ddd, J=14.10, 8.30, 4.98Hz, 1H), 1.67 (m, 1 H),1.51 (m, 1H), 1.33 (t, J=7.47Hz, 3H), 0.85 (t, J=7.47Hz, 3H).
Examples 502 and 503
Figure imgf000308_0001
(R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000309_0001
(R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester A mixture of (R, S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 501 , 100mg, 0.171mmol), aqueous sodium hydroxide (2N, 0.512mL, 1.024mmol) and anhydrous tetrahydrofuran (2mL) was stirred at room temperature for 2 days before adding 2N hydrochloric acid (1.5mL). The mixture was diluted with acetonitrile and evaporated to dryness under vacuum to give the crude product as an oil (128mg). Purification was achieved using radial chromatography (Chromatron model 7924T, Harrison Research, Palo Alto, CA) with a 4mm silica gel rotor eluting with hexanes/ethyl acetate 55:45 to give the title compounds:
First eluting: (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (14mg); 1H-NMR (CDCIg) δ 7.88 (s, 1 H), 7.88 (s, 2H), 7.55 (m, 1 H), 7.51 (m, 1 H), 7.49
(m, 1 H), 4.32 (m, 1 H), 4.27 (m, 1H), 4.21 (m, 1 H), 3.80 (d, J=10.79Hz, 1H), 3.57 (m, 1H), 1.78 (m, 1H), 1.55 (m, 2H), 1.43 (m, 1H), 1.32 (t, J=7.47Hz, 3H), 0.71 (t, J=7.47Hz, 3H).
Second eluting: (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]- 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (32mg) 1H-NMR (CDCI3) δ 7.67 (s, 1H), 7.45 (s, 2H), 7.41 (m, 1H), 7.34 (m, 1H), 6.51 (brs, 1H), 4.55 (m, 1H), 4.32 (m, 2H), 3.85 (d, J=10.79Hz, 1H), 3.43 (m, 1H), 2.55 (m, 1H), 1.81 (m, 1 H), 1.63 (m, 1 H), 1.60 (m, 1H), 1.31 (t, J=7.47Hz, 3H), 0.84 (t, J=7.47Hz, 3H). Examples 504 and 505
Figure imgf000310_0001
(R, S, R)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
Figure imgf000310_0002
(R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of (R, S, R)- and (R, S, S)- 4-[(3,5-bis-trifluoromethyl-phenyl)- carboxy-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Examples 502 and 503 as prepared above but isomers not separated, 143mg, 0.25mmol) in tetrahydrofuran (3mL) under nitrogen was added borane- dimethylsulfide complex (2M in tetrahydrofuran, 0.25mL, O.δmmol). After 24hr the mixture was diluted with methanol (1mL) and evaporated to dryness under vacuum. To the residue was added 2N hydrochloric acid (3mL), the mixture was stirred for 10min and then extracted with diethyl ether (3 x 15mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under vacuum to give the crude product as an oil (175mg). Purification was achieved using radial chromatography (Chromatron model 7924T, Harrison Research, Palo Alto, CA) with a 1mm silica gel rotor eluting with a hexanes/ethyl acetate gradient from 4:1 to 7:3 to give the title compounds:
First eluting: (R, S, R)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (9mg) MS: 558.3 [M+Hf found.
1H-NMR (CDCI3) δ 7.83 (s, 1H), 7.79 (s, 2H), 7.60 (m, 1 H), 7.53 (brs, 1 H), 7.52 (m, 1 H), 4.35 (m, 1 H), 4.24 (m, 1H), 4.16 (m, 1 H), 3.71 (m, 2H), 3.34 (m, 1 H), 2.99 (m, 1 H), 1.78 (m, 1 H), 1.57 (m, 2H), 1.57 (m, 1H), 1.45 (m, 1H), 1.33 (t, J=7.47Hz, 3H), 0.71 (t, J=7.47Hz, 3H). Second eluting: (R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy- ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (30mg)
MS: 558.5 [M+Hf found.
1H-NMR (CDCI3) δ 7.63 (s, 1 H), 7.40 (m, 1 H), 7.39 (s, 2H), 7.32 (m, 1H), 6.62 (brs, 1H) 4.48 (m, 1 H), 4,25 (m, 2H), 4.15 (m, 2H), 3.13 (m, 2H), 2.60 (m, 1H), 1.69 (m, 3H), 1.50 (m, 1H), 1.29 (t, J=7.47Hz, 3H), 0.86 (t, J=7.47Hz, 3H).
Example 506
Figure imgf000311_0001
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
[(R, R, S)]- 4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.030 grams, 0.055 mmol, 1 eq) was placed in a round bottomed flask equipped with a magnetic stir bar. DMSO (1.0 mL) was added followed by the addition of (0.012grams0.221 mmol, 4 eq) potassium hydroxide and (0.016 grams, 0.110 mmol, 2 eq) methyl iodide at room temperature. After 1.5 hour, the reaction mixture was quenched with 1N HCI, extracted 3 times with ethyl acetate and dried over sodium sulfate. The crude material was purified on silica gel chromatography to provide the title compound. LCMS (ESI+): 551 (MH+).
1H NMR (CDCI3): δ? 0.95 (t, 3H), 1.31 (t, 3H), 1.41 (m, 1 H), 1.60 (m, 1 H), 2.6 (m, 1H), 2.90 (m, 1 H), 3.20 (s, 3H), 4.33 (m, 2H), 4.45 (m, 1 H), 6.60 (s, 1 H), 7.2- (s, 2H), 7.30 (d, 1 H).7.5 (d, 1 H) 7.70 (s, 1H).
Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application for all purposes.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

What is claimed is:
1. A compound according to Formula I
Figure imgf000313_0001
Formula I Wherein
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 is Y, W-X or W-Y1; 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 chain is optionally mono-substituted with Z; and Y1 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 chain is optionally mono-substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one
/ to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C2-C6)alkenyl, (Cι-C6) alkyl, hydroxy, (C C6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino wherein said (C C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (Cι-C6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino, said (C CeJalkyl or (C C6)alkoxy substituent is also optionally substituted with from one to nine fluorines;
R2 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 R2 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 R2 ring is optionally attached through (CrC4)alkyl; wherein said R2 ring is optionally mono-, di- or tri-substituted independently with halo, (C2-C6)alkenyl, (C C6) alkyl, hydroxy, (CrC6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(CrC6)alkylamino wherein said (C C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (CrC6)alkoxy, (C C4)alkylthio, oxo or (C C6)alkyloxycarbonyl;
R3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain having 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 R3 carbon adjacent to C4a; provided that in R3 , when J is carbon, it is other than C4a that is optionally replaced with one heteroatom; and provided that in R3, when J is nitrogen, it is other than C4a that is optionally replaced with a heteroatom and it is other than C4a that is optionally mono-substituted with hydroxy or nitrogen; wherein V is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four 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 R3 group; a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; or a tricyclic ring consisting of three fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said V substituent is optionally mono-, di-, tri-, tetra- or penta-substituted independently with V1, (C1-C6)alkyl-V1, C(O)-V1, O-(C0-C6)alkyl-V1, (C1-C6)alkyl-0-V1, C(O)-mono-N- or di-N,N-(C C6)alkyl- V1, halo, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy, (C C6)alkoxy, (C C4)alkylthio, (C C4)alkylsulfinyl, (C C4)alkylsulfonyl, mono-N- or di-N,N-(Cι-C6)alkylsulfonyl, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C1-C6) alkylcarboxamoyl, carboxy, (CrC6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino, wherein said (C C6)alkyl or (C2-C6)alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C C6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (CrC6)alkyloxycarbonyl, mono-N- or di-N,N-(CrC6)alkylamino, wherein each (CrC6)alkyl, (CrC6)alkoxy, (C C4)alkylthio, (C C4)alkylsulfonyl or (C2- C6)alkenyl substituents are also optionally substituted with from one to nine fluorines; wherein V1 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, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said V1 substituent is optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (C1-C6)alkyl, (C C6)alkoxy, hydroxy, oxo, amino, nitro, cyano, (C1-Ce)alkyloxycarbonyl, mono-N- or di- N,N-(Cι-C6)alkylamino wherein said (CrC6)alkyl substituent is optionally mono- substituted with oxo, said (C C6)alkyl or (C1-C6)alkoxy substituent is also optionally substituted with from one to nine fluorines; and each of R4, R5, R6 and R7are independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T or a partially saturated, fully saturated or fully unsaturated (C C12) straight or branched carbon chain wherein each carbon may optionally be replaced with one or two heteroatoms per carbon chain wherein the heteroatoms are selected independently from oxygen, sulfur and nitrogen, wherein 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 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 optionally mono-substituted with T; wherein T is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said T substituent is optionally mono-, di- or tri-substituted independently with halo, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy, (C1-C6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino wherein said (CrC6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C C6)alkoxy, (CrC4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino, said (CrC6)alkyl or (C C6)alkoxy substituent also optionally has from one to nine fluorines;
R4and R5, R5 and R6, and/or R6 and R7 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 R4 and R5, or R5 and R6, and/or R6 and R7 is optionally mono-, di- or tri-substituted independently with halo, (Cι-C6)alkyl, (CrC4)alkylsulfonyl, (C2-C6)alkenyl, hydroxy, (C C6)alkoxy, (C C )alkylthio, amino, nitro, cyano, oxo, carboxy, (CrC6)alkyloxycarbonyl, mono-N- or di-N,N-(C-ι-C6)alkylamino wherein said (C C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (CrC6)alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (CrC6)alkyloxycarbonyl, mono-N- or di-N,N-(C C6)alkylamino, said (C C6)alkyl substituent also optionally has from one to nine fluorines; or a pharmaceutically acceptable salt or prodrug thereof; with the following provisos: a) when there is a single bond between C3 and J, and R3 is a fully saturated one to six membered straight or branched carbon chain substituted on C4a with V then R1 is other than C(O)-(C C4)alkyl optionally mono-, di- or tri-substituted with halo and R1 is other than C(O)-monocyclicaromatic ring; or b) when there is a single bond between C3 and J, and R3 is -C(O)-O-V, and R2 is phenyl then R1 is other than (C C4)alkyl; and c) when there is a double bond between C3 and J, and R2 is methyl then R3 is other than -CH2-O-V, -CH2-V or -CH2-CH2-V.
2. A compound of claim 1 wherein
J is carbon;
R1 is W-X;
W is carbonyl;
X is -O-Y; Y for each occurrence is independently (C C6)alkyl, said (C C6)alkyl optionally having one to nine fluorines or said (C C6)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 C4)alkyl, (C C4)alkoxy, (C C4)alkylthio, nitro, cyano, oxo, or (CrC4)alkyloxycarbonyl, said (C C4)alkyl or (C C4)alkoxy is optionally substituted with from one to nine fluorines;
R2 is beta and is a partially saturated, fully saturated or fully unsaturated (C C4) straight or branched carbon chain wherein one carbon, other than the connecting carbon, may optionally be replaced with oxygen or sulfur and 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 R2 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 R2 ring is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C1-C6)alkoxy, amino, nitro, (Cι-C4)alkyloxycarbonyl or carboxy; wherein R3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than C4a, may optionally be replaced with one heteroatom selected 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 cyano, 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 optionally mono, di-, or tri-substituted with V at C4a or at the R3 carbon adjacent to C4a; V is a three, four, 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 R3 group; wherein said V ring is optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (Cι-C6)alkyl, hydroxy, (C-ι-C6)alkoxy, (C C6)alkoxycarbonyl, nitro, cyano or oxo, wherein said (C C6)alkyl or (C1-C6)alkoxy substituent optionally has from one to nine fluorines;
R4 is hydrogen;
R5 and R6 are each independently hydrogen, halo, T, (d-C6)alkoxy or (C C6)alkyl, said (C C6)alkoxy or (Cι-C6)alkyl substituent optionally having from one to nine fluorines or said (C C6)alkoxy or (C C6)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, (CrC6)alkyl, hydroxy, (CrC6)alkoxy, (C C4)alkylthio, amino, oxo, carboxy, (C C6)alkyloxycarbonyl, mono-N- or di-N,N-(CrC6)alkylamino wherein said (C C6)alkyl or (C C6)alkoxy substituent optionally has from one to nine fluorines;
R7 is hydrogen; or a pharmaceutically acceptable salt thereof.
3. A compound of claim 2 wherein
Y is methyl, ethyl, 1 -propyl, 2-propyl or tert-butyl;
R2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl;
R3 is -C(O)-V, -C(OH)(C(O)OCH3)(V), -CH(F)(V), -CF2(V), -CH(OCH3)(V), - CH(C(O)OCH3)(V), -CH(CN)(V), -CH(OH)(V), -CH2(V), -CH(NH2)(V), - CH(NH(CH3))(V), -CH(C(O)NH2)(V), -CH(CH2OH)V, -CH(CH2OCH3)V, - CH(CH2OC(O)CH3)V, -CH(CH2F)V, or -CH(CH2NH2)V; and
V is phenyl optionally mono-, di- or tri-substituted independently with halo, nitro, or (C C2)alkyl, wherein said (C C2)alkyl optionally has from one to five fluorines; R5 and R6 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; or a pharmaceutically acceptable salt thereof.
4. A compound of claim 3 wherein Y is ethyl;
R2 is ethyl or methyl;
R3 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)-methylamine-methyl; 1-(3,5-bis- (trifluoromethyl)-phenyl)-2-amino-ethyl; 1-(3,5-bis-(trifluoromethyl)-phenyl)-2-fluoro- ethyl; 1-(3,5-bis-(trifluoromethyl)-phenyl)-2-methoxy-ethyl; 1-(3,5-bis-(trifluoromethyl)- phenyl)-2-hydroxy-ethyl; or 2-acetoxy-1-(3,5-bis-(trifluoromethyl)-phenyl)-ethyl; R5 is methoxy or trifluoromethyl; and R6 is hydrogen or methoxy; or a pharmaceutically acceptable salt thereof.
5. A compound of claim 1 wherein
J is nitrogen; the bond between C3 and J is a single bond;
R1 is W-X; W is carbonyl;
X is -O-Y;
Y for each occurrence is independently (C-ι-C6)alkyl, said (C C6)alkyl optionally having one to nine fluorines or said (C C6)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 C4)alkyl, (C C4)alkoxy, (CrC )alkylthio, nitro, cyano, oxo, or (CrC4)alkyloxycarbonyl, said (CrC4)alkyl or (C-ι-C4)alkoxy optionally substituted with from one to nine fluorines;
R2 is a partially saturated, fully saturated or fully unsaturated (C C4) straight or branched carbon chain wherein one carbon, other than the connecting carbon, may optionally be replaced with oxygen or sulfur and 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 monosubstituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo,; or said R2 is a partially saturated, fully saturated or fully unsaturated three to five membered ring optionally having one heteroatom selected independently from oxygenand sulfur; wherein said R2 ring is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (CrC6)alkoxy, amino, nitro, (C1-C4)alkyloxycarbonyl or carboxy; wherein R3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than C4a or the R3 carbon adjacent to C4a, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon, other than C4a, is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with cyano, 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 optionally mono, di-, or tri-substituted with V at C4a or at the the R3 carbon adjacent to C4a;
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 R3 group; wherein said V ring is optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (C C6)alkyl, hydroxy, (CrC6)alkoxy, (CτC6)alkoxycarbonyl, nitro, cyano or oxo, wherein said (CrC^alkyl or (d-C6)alkoxy substituent optionally has from one to nine fluorines; R4 is hydrogen;
R5 and R6 are each independently hydrogen, halo, T, (C1-C6)alkoxy or (C C6)alkyl, said (CrCeJalkoxy or (C C6)alkyl substituent optionally having from one to nine fluorines or said (C C6)alkoxy or (C C6)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, (Cι-G6)alkyl, hydroxy, (CrC6)alkoxy, (C C4)alkylthio, amino, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(CrC6)alkylamino wherein said (C C6)alkyl or (C C6)alkoxy substituent optionally has from one to nine fluorines;
R7 is hydrogen; or a pharmaceutically acceptable salt thereof.
6. A compound of claim 5 wherein
V is (C C4)alkyl, wherein said (CrC4)alkyl substituent optionally has one to nine fluorines;
R2 is (C C4)alkyl, cyclopropyl or cyclobutyl; R3 is -C(O)-V, -CH(C(O)O(CrC3)alkyl)(V), or -CH(CN)(V);
V is phenyl optionally mono-, di- or tri-substituted independently with halo, (C C6)alkyl, hydroxy, (C1-C6)alkoxy, nitro, cyano or oxo wherein said (Cι-C6)alkyl substituent optionally has from one to nine fluorines; R and R6 are each independently hydrogen, (C C3)alkoxy or (C C6)alkyl, said (C C3)alkoxy optionally having from one to nine fluorines, said (C C6)alkyl optionally having from one to seven fluorines; or a pharmaceutically acceptable salt thereof.
7. A compound of claim 6 wherein
Y is methyl, ethyl, 1-propyl, 2-propyl or tert-butyl;
R2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl;
R3 is 3,5-bis-trifluoromethyl-benzoyl, (3,5-bis-trifluoromethyl-phenyl)-cyano- methyl, or (3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl; R5 is methyl or trifluoromethyl;
R6 is hydrogen or methyl.
8. A compound according to claim 1 , selected from the group consisting of:
(R, R, S)-4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester; (R, S, S)-4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-27-quinoline-1 -carboxylic acid ethyl ester;
(R, R)-4-(3,5-bis-trifluoromethyl-benzyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 6,7-dimethoxy-2-methyl-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S)-4-[(3,5-bis-trifiuoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]-
6, 7-dimethoxy-2-methyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, R)- 4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl- methoxycarbonyl- methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl- methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl- methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl- methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl
(R, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl- methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6,7- dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]- 2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]-
2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[2-Acetoxy-1 -(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[2-Acetoxy-1 -(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-fluoro-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-fluoro-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, R, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-amino-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R, S, S)-4-[1 -(3,5-Bis-trifluoromethyl-phenyl)-2-amino-ethyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6- trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S)-4-(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4- dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4- dihydro-2/- -quinoline-1 -carboxylic acid ethyl ester;
(R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester;
(R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R)-4-(3,5-bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S)-4-(3,5-bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2 --quinoline-1 -carboxylic acid ethyl ester; (R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- methyl-3,4-dihydro-2/-/-quinoline-1 -carboxylic acid ethyl ester;
(R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester;
(R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2 --quinoline-1 -carboxylic acid ethyl ester;
(R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2 -/-quinoline-1 -carboxylic acid ethyl ester;
(R)-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl- 3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl- 3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-
6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid methyl ester;
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6, 7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid methyl ester;
(R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6, 7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester;
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl- 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; and
(R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt or prodrug thereof.
9. 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 any of claims 1 to 8, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
10. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of any of claims 1 to 8, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable vehicle, diluent or carrier.
11. A pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of any of claims 1 to 8, 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.
12. A pharmaceutical combination composition as recited in claim 11 wherein the second compound is an HMG-CoA reductase inhibitor or a PPAR modulator.
13. A pharmaceutical combination composition as recited in claim 12 wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.
14. 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 any of claims 1 to 8, 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.
15. A compound of Formula III
Figure imgf000327_0001
Formula III wherein
C3 is carbon;
J is carbon, wherein the bond between C3 and J is a single or double bond; 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;
R2 is (C C4)alkyl, cyclopropyl or cyclobutyl; R5 is CF3; R6 is hydrogen; R10 is a fully saturated (C C4) straight or branched carbon chain;
R11 is halo, hydroxy, -C(O)(O(C C4)alkyl), -C(O)C(O)(O(C1-C4)alkyl), - C(O)NH(O(C C4)alkyl), or -C(O)N((C1-C4)alkyl)(O(C1-C4)alkyl);
R12 is hydrogen or halo, wherein R11 is not halo when R12 is halo; or R11 and R12 are taken together to form oxo or N2; or a pharmaceutically acceptable salt or prodrug thereof.
PCT/IB2004/000836 2003-03-28 2004-03-15 1,2,4-substituted 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity WO2004085401A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU2004224082A AU2004224082A1 (en) 2003-03-28 2004-03-15 1,2,4-substitute 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as CETP inhibitors for the treatment of atherosclerosis and obesity
CA002520405A CA2520405A1 (en) 2003-03-28 2004-03-15 1,2,4-substituted 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity
EA200501376A EA200501376A1 (en) 2003-03-28 2004-03-15 DERIVATIVES OF 1,2,4-SUBSTITUTED 1,2,3,4-TETRAHYDRO- and 1,2-DIHYDROCHINOLINES AND 1,2,3,4-TETRAHYDROCHINOXALINE AS AN INHIBITORS CETR FOR THE TREATMENT OF ATHEROSCLEROSIS AND FAT
BRPI0408897-2A BRPI0408897A (en) 2003-03-28 2004-03-15 1,2,4-substituted 1,2,3,4-tetrahydro-and 1,2-dihydro-quinoline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity
JP2006506369A JP2006521344A (en) 2003-03-28 2004-03-15 1,2,4-substituted 1,2,3,4-tetrahydro- and 1,2-dihydro-quinoline and 1,2,3,4 as CETP inhibitors for the treatment of atherosclerosis and obesity -Tetrahydro-quinoxaline derivatives
EP04720668A EP1622872A1 (en) 2003-03-28 2004-03-15 1,2,4-substituerte 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity
MXPA05010456A MXPA05010456A (en) 2003-03-28 2004-03-15 1,2,4-substituerte 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity.
IS8021A IS8021A (en) 2004-03-15 2005-09-12 1,2,4-substituted 1,2,3,4-tetrahydro- and 1,2-dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives that CETP inhibits for the treatment of fat degeneration and obesity
TNP2005000243A TNSN05243A1 (en) 2003-03-28 2005-09-28 1,2,4,4-TETRAHYDRO- AND 1,2-DIHYDRO-QUINOLINE AND 1,2,3,4-TETRAHYDRO-QUINOXALINE 1,2,4-SUBSTITUTED DERIVATIVES AS INHIBITORS OF CETP FOR THE TREATMENT OF ATHEROSCLEROSIS AND OBESITY
HR20050859A HRP20050859A2 (en) 2003-03-28 2005-09-28 1,2,4-suptituted 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity
NO20054989A NO20054989L (en) 2003-03-28 2005-10-26 1,2,4-substituted 1,2,3,4-tetrahydro and 1,2, dihydroquinoline and 1,2,3,4-tetrahydroquinoxaline derivatives as CETP inhibitors for the treatment of atherosclerosis and obesity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45827403P 2003-03-28 2003-03-28
US60/458,274 2003-03-28

Publications (2)

Publication Number Publication Date
WO2004085401A1 true WO2004085401A1 (en) 2004-10-07
WO2004085401A8 WO2004085401A8 (en) 2005-12-01

Family

ID=33098266

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2004/000836 WO2004085401A1 (en) 2003-03-28 2004-03-15 1,2,4-substituted 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity

Country Status (25)

Country Link
EP (1) EP1622872A1 (en)
JP (1) JP2006521344A (en)
KR (1) KR100729883B1 (en)
CN (1) CN1795177A (en)
AR (1) AR044507A1 (en)
AU (1) AU2004224082A1 (en)
BR (1) BRPI0408897A (en)
CA (1) CA2520405A1 (en)
CL (1) CL2004000639A1 (en)
EA (1) EA200501376A1 (en)
EC (1) ECSP056040A (en)
GT (1) GT200400050A (en)
HR (1) HRP20050859A2 (en)
MA (1) MA27828A1 (en)
MX (1) MXPA05010456A (en)
NL (1) NL1025839C2 (en)
NO (1) NO20054989L (en)
OA (1) OA13153A (en)
PA (1) PA8598901A1 (en)
PE (1) PE20050389A1 (en)
TN (1) TNSN05243A1 (en)
TW (1) TWI285641B (en)
UY (1) UY28243A1 (en)
WO (1) WO2004085401A1 (en)
ZA (1) ZA200507819B (en)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006033001A1 (en) * 2004-09-23 2006-03-30 Pfizer Products Inc. Quinoline compounds
WO2006033004A1 (en) * 2004-09-23 2006-03-30 Pfizer Products Inc. Quinoline compounds as cetp inhibitors
WO2006057460A1 (en) * 2004-11-29 2006-06-01 Japan Tobacco Inc. Nitrogen-containing fused ring compound and use thereof
WO2007138998A1 (en) * 2006-05-26 2007-12-06 Japan Tobacco Inc. Pharmaceutical composition comprising nitrogenated fused cyclic compound
JP2008001689A (en) * 2006-05-26 2008-01-10 Japan Tobacco Inc Pharmaceutical composition comprising nitrogen-containing fused cyclic compound
WO2008058967A1 (en) * 2006-11-15 2008-05-22 Novartis Ag Organic compounds
JP2009519233A (en) * 2005-11-23 2009-05-14 ブリストル−マイヤーズ スクイブ カンパニー Heterocyclic CETP inhibitor
JP2009524579A (en) * 2006-01-31 2009-07-02 田辺三菱製薬株式会社 Trisubstituted amine compounds
JP2009526004A (en) * 2006-02-07 2009-07-16 エフ．ホフマン−ラ ロシュ アーゲー Benzamide and heteroarene derivatives
WO2010049302A1 (en) * 2008-10-29 2010-05-06 F. Hoffmann-La Roche Ag Novel phenyl amide or pyridil amide derivatives and their use as gpbar1 agonists
US7951950B2 (en) * 2005-02-24 2011-05-31 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
US8084611B2 (en) 2006-03-30 2011-12-27 Mitsubishi Tanabe Pharma Corporation Process for preparing tetrahydroquinoline derivatives
US8232403B2 (en) 2006-05-10 2012-07-31 Novartis Ag Bicyclic derivatives as CETP inhibitors
US8486982B2 (en) 2003-04-11 2013-07-16 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acids
US8729091B2 (en) 2010-01-21 2014-05-20 Hoffmann-La Roche Inc. 4-phenoxy-nicotinamide or 4-phenoxy-pyrimidine-5-carboxamide compounds
US8921399B2 (en) 2007-08-27 2014-12-30 Dart Neuroscience (Cayman) Ltd. Therapeutic isoxazole compounds
WO2015074081A1 (en) 2013-11-18 2015-05-21 Bair Kenneth W Benzopiperazine compositions as bet bromodomain inhibitors
US9873677B2 (en) 2014-03-06 2018-01-23 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10517853B2 (en) 2015-10-30 2019-12-31 Ptc Therapeutics, Inc. Methods for treating epilepsy
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
CN114656406A (en) * 2022-01-25 2022-06-24 阿里生物新材料（常州）有限公司 Synthetic method of 2-fluoropyrimidine-4-carboxylic acid
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8293751B2 (en) 2003-01-14 2012-10-23 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
WO2005007658A2 (en) 2003-07-14 2005-01-27 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
MY148521A (en) 2005-01-10 2013-04-30 Arena Pharm Inc Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto
JP4846769B2 (en) * 2007-07-30 2011-12-28 田辺三菱製薬株式会社 Pharmaceutical composition
CN110452183B (en) * 2019-09-04 2023-03-14 中国科学院上海有机化学研究所 Preparation method of chiral heterocyclic compound
CN111440162A (en) * 2020-04-01 2020-07-24 邱曲真 Thiazole dihydronaphthalene derivative and application thereof in metabolic diseases

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE351464C (en) * 1917-12-18 1922-04-07 Chemische Werke Grenzach Aktie Process for the preparation of derivatives of a hydrogenated 2-phenylquinoline-4-carboxylic acid
WO1996019458A2 (en) * 1994-12-22 1996-06-27 Ligand Pharmaceuticals Incorporated Steroid receptor modulator compounds and methods
WO2000017165A1 (en) * 1998-09-17 2000-03-30 Pfizer Products Inc. 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines as cetp inhibitors
WO2001040190A1 (en) * 1999-11-30 2001-06-07 Pfizer Products Inc. 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoline crystal as cetp inhibitor

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0936866A4 (en) * 1996-10-28 2001-04-11 Dept Of The Army Us Government Compounds, compositions and methods for treating antibiotic-resistant infections
US6103905A (en) * 1997-06-19 2000-08-15 Sepracor, Inc. Quinoline-indole antimicrobial agents, uses and compositions related thereto
EP1051413B1 (en) * 1998-01-26 2003-06-04 SmithKline Beecham plc Quinoline derivatives as antibacterials

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE351464C (en) * 1917-12-18 1922-04-07 Chemische Werke Grenzach Aktie Process for the preparation of derivatives of a hydrogenated 2-phenylquinoline-4-carboxylic acid
WO1996019458A2 (en) * 1994-12-22 1996-06-27 Ligand Pharmaceuticals Incorporated Steroid receptor modulator compounds and methods
WO2000017165A1 (en) * 1998-09-17 2000-03-30 Pfizer Products Inc. 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines as cetp inhibitors
WO2001040190A1 (en) * 1999-11-30 2001-06-07 Pfizer Products Inc. 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoline crystal as cetp inhibitor

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BUNCE ET AL, J. ORG CHEM., vol. 66, no. 8, 2001, pages 2822 - 2827, XP002285107 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 1992, RUSSELL, JAMES R. ET AL: "Model studies related to the cofactor of oxomolybdoenzymes. Part 4. Reduction of the pyrazine ring in quinoxalines and pteridines", XP002285108, retrieved from STN Database accession no. 1992:490239 *
EDWARDS ET AL, BIOORG. MED. CHEM. LETT., vol. 9, no. 7, 1999, pages 1003 - 1008, XP002285105 *
JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY (1972-1999) , (10), 1245-9 CODEN: JCPRB4; ISSN: 0300-922X, 1992 *
MASSACRET ET AL, EUR. J. ORG. CHEM., vol. 1, 1999, pages 129 - 134, XP002285106 *

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10071081B2 (en) 2003-04-11 2018-09-11 Ptc Therapeutics, Inc. Compositions of 1,2,4-oxadiazole benzoic acid compounds and methods for their use
US8975287B2 (en) 2003-04-11 2015-03-10 Ptc Therapeutics, Inc. Methods for using 1,2,4-Oxadiazole benzoic acid compounds
US8486982B2 (en) 2003-04-11 2013-07-16 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acids
US8796322B2 (en) 2003-04-11 2014-08-05 Ptc Therapeutics, Inc. Methods for using 1,2,4-oxadiazole benzoic acid compounds
US9861617B2 (en) 2003-04-11 2018-01-09 Ptc Therapeutics, Inc. Compositions of 1,2,4-oxadiazole benzoic acid compounds and methods for their use
US9205088B2 (en) 2003-04-11 2015-12-08 Ptc Therapeutics, Inc. Compositions of 1,2,4-oxadiazol benzoic acid compounds and methods for their use
WO2006033004A1 (en) * 2004-09-23 2006-03-30 Pfizer Products Inc. Quinoline compounds as cetp inhibitors
WO2006033001A1 (en) * 2004-09-23 2006-03-30 Pfizer Products Inc. Quinoline compounds
WO2006057460A1 (en) * 2004-11-29 2006-06-01 Japan Tobacco Inc. Nitrogen-containing fused ring compound and use thereof
US7951950B2 (en) * 2005-02-24 2011-05-31 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
JP2009519233A (en) * 2005-11-23 2009-05-14 ブリストル−マイヤーズ スクイブ カンパニー Heterocyclic CETP inhibitor
JP2009524579A (en) * 2006-01-31 2009-07-02 田辺三菱製薬株式会社 Trisubstituted amine compounds
JP2012246303A (en) * 2006-02-07 2012-12-13 F Hoffmann La Roche Ag Benzamide and heteroarene derivative
JP2009526004A (en) * 2006-02-07 2009-07-16 エフ．ホフマン−ラ ロシュ アーゲー Benzamide and heteroarene derivatives
US8084611B2 (en) 2006-03-30 2011-12-27 Mitsubishi Tanabe Pharma Corporation Process for preparing tetrahydroquinoline derivatives
US8232403B2 (en) 2006-05-10 2012-07-31 Novartis Ag Bicyclic derivatives as CETP inhibitors
US8410275B2 (en) 2006-05-10 2013-04-02 Novartis Ag Bicyclic derivatives as CETP inhibitors
JP2008001689A (en) * 2006-05-26 2008-01-10 Japan Tobacco Inc Pharmaceutical composition comprising nitrogen-containing fused cyclic compound
WO2007138998A1 (en) * 2006-05-26 2007-12-06 Japan Tobacco Inc. Pharmaceutical composition comprising nitrogenated fused cyclic compound
WO2008058967A1 (en) * 2006-11-15 2008-05-22 Novartis Ag Organic compounds
US8921399B2 (en) 2007-08-27 2014-12-30 Dart Neuroscience (Cayman) Ltd. Therapeutic isoxazole compounds
US10053467B2 (en) 2007-08-27 2018-08-21 Dart Neuroscience (Cayman) Ltd. Therapeutic isoxazole compounds
US9029397B2 (en) 2007-08-27 2015-05-12 Dart Neuroscience (Cayman) Ltd. Therapeutic isoxazole compounds
US9650349B2 (en) 2007-08-27 2017-05-16 Dart Neuroscience (Cayman) Ltd. Therapeutic isoxazole compounds
KR101368097B1 (en) * 2008-10-29 2014-03-06 에프. 호프만-라 로슈 아게 Novel phenyl amide or pyridil amide derivatives and their use as gpbar1 agonists
US8309734B2 (en) 2008-10-29 2012-11-13 Hoffmann-La Roche Inc. Substituted pyridines as GPBAR1 agonists
JP2012506887A (en) * 2008-10-29 2012-03-22 エフ．ホフマン−ラ ロシュ アーゲー Novel phenylamide or pyridylamide derivatives and their use as GPBAR1 agonists
WO2010049302A1 (en) * 2008-10-29 2010-05-06 F. Hoffmann-La Roche Ag Novel phenyl amide or pyridil amide derivatives and their use as gpbar1 agonists
US8729091B2 (en) 2010-01-21 2014-05-20 Hoffmann-La Roche Inc. 4-phenoxy-nicotinamide or 4-phenoxy-pyrimidine-5-carboxamide compounds
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
WO2015074081A1 (en) 2013-11-18 2015-05-21 Bair Kenneth W Benzopiperazine compositions as bet bromodomain inhibitors
RU2720237C2 (en) * 2013-11-18 2020-04-28 Форма Терапеутикс, Инк. Compositions containing benzopiperazine as bromodomain bet inhibitors
EP3071205A4 (en) * 2013-11-18 2017-05-10 Forma Therapeutics, Inc. Benzopiperazine compositions as bet bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US9422281B2 (en) * 2013-11-18 2016-08-23 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US9873677B2 (en) 2014-03-06 2018-01-23 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
US10618877B2 (en) 2014-03-06 2020-04-14 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
US10233161B2 (en) 2014-03-06 2019-03-19 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US10517853B2 (en) 2015-10-30 2019-12-31 Ptc Therapeutics, Inc. Methods for treating epilepsy
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
CN114656406A (en) * 2022-01-25 2022-06-24 阿里生物新材料（常州）有限公司 Synthetic method of 2-fluoropyrimidine-4-carboxylic acid
CN114656406B (en) * 2022-01-25 2023-09-05 阿里生物新材料（常州）有限公司 Synthesis method of 2-fluoropyrimidine-4-carboxylic acid

Also Published As

Publication number Publication date
HRP20050859A2 (en) 2006-02-28
MA27828A1 (en) 2006-04-03
GT200400050A (en) 2005-03-02
ZA200507819B (en) 2007-04-25
PA8598901A1 (en) 2004-11-26
UY28243A1 (en) 2004-11-08
OA13153A (en) 2006-12-13
ECSP056040A (en) 2006-01-27
TW200508222A (en) 2005-03-01
NO20054989D0 (en) 2005-10-26
NL1025839C2 (en) 2006-09-06
WO2004085401A8 (en) 2005-12-01
CL2004000639A1 (en) 2005-02-04
CN1795177A (en) 2006-06-28
PE20050389A1 (en) 2005-05-30
KR100729883B1 (en) 2007-06-18
NL1025839A1 (en) 2004-09-30
CA2520405A1 (en) 2004-10-07
TWI285641B (en) 2007-08-21
TNSN05243A1 (en) 2007-06-11
KR20050115938A (en) 2005-12-08
EP1622872A1 (en) 2006-02-08
BRPI0408897A (en) 2006-04-18
AU2004224082A1 (en) 2004-10-07
JP2006521344A (en) 2006-09-21
NO20054989L (en) 2005-12-16
AR044507A1 (en) 2005-09-14
EA200501376A1 (en) 2006-04-28
MXPA05010456A (en) 2006-03-21

Similar Documents

Publication Publication Date Title
WO2004085401A1 (en) 1,2,4-substituted 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity
US20060122224A1 (en) Quinoline and quinoxaline compounds
KR101059274B1 (en) Dibenzyl Amine Derivatives as CPT inhibitors
US20090239865A1 (en) Dibenzyl amine compounds and derivatives
WO2006032987A1 (en) Indoline compounds and their use in the treatment of arteriosclerosis
US20060063803A1 (en) 4-Amino substituted-2-substituted-1,2,3,4-tetrahydroquinoline compounds
KR101058312B1 (en) Dibenzyl Amine Compounds and Derivatives
WO2006033001A1 (en) Quinoline compounds
US20070149567A1 (en) Quinoline compounds
US20100130784A1 (en) Substituted 1,1,1-trifluoro-3-[(benzyl)-(pyrimidin-2-yl)-amino]-propan-2-ol compounds
WO2009027785A2 (en) 1, 3-oxazole derivatives as cetp inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2004224082

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 4056/DELNP/2005

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 170810

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 542529

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 05096777

Country of ref document: CO

Ref document number: CR2005-008002

Country of ref document: CR

WWE Wipo information: entry into national phase

Ref document number: 1-2005-501735

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 2005/07819

Country of ref document: ZA

Ref document number: 2520405

Country of ref document: CA

Ref document number: 2006506369

Country of ref document: JP

Ref document number: 200507819

Country of ref document: ZA

Ref document number: 200501376

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2005/010456

Country of ref document: MX

Ref document number: 1020057018383

Country of ref document: KR

Ref document number: 8997

Country of ref document: GE

Ref document number: 20050345

Country of ref document: UZ

Ref document number: P20050859A

Country of ref document: HR

ENP Entry into the national phase

Ref document number: 2004224082

Country of ref document: AU

Date of ref document: 20040315

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004224082

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2004720668

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: P-2005/0790

Country of ref document: YU

WWE Wipo information: entry into national phase

Ref document number: 1200501576

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 20048146455

Country of ref document: CN

CFP Corrected version of a pamphlet front page

Free format text: UNDER (54) PUBLISHED TITLE REPLACED BY CORRECT TITLE

WWP Wipo information: published in national office

Ref document number: 1020057018383

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2004720668

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0408897

Country of ref document: BR