WO2007108968A2 - Ophthalmic compositions for treating ocular hypertension - Google Patents

Ophthalmic compositions for treating ocular hypertension Download PDF

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Publication number
WO2007108968A2
WO2007108968A2 PCT/US2007/006109 US2007006109W WO2007108968A2 WO 2007108968 A2 WO2007108968 A2 WO 2007108968A2 US 2007006109 W US2007006109 W US 2007006109W WO 2007108968 A2 WO2007108968 A2 WO 2007108968A2
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WIPO (PCT)
Prior art keywords
methoxy
oxoquinolin
acetamide
butyl
cyclopentyl
Prior art date
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PCT/US2007/006109
Other languages
French (fr)
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WO2007108968A3 (en
Inventor
James B. Doherty
Min Shu
Dong-Ming Shen
Fengqi Zhang
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Merck & Co., Inc.
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Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002644716A priority Critical patent/CA2644716A1/en
Priority to JP2009500400A priority patent/JP2009533326A/en
Priority to EP07752786A priority patent/EP2004193A2/en
Priority to AU2007227664A priority patent/AU2007227664A1/en
Priority to US12/225,026 priority patent/US20090062280A1/en
Publication of WO2007108968A2 publication Critical patent/WO2007108968A2/en
Publication of WO2007108968A3 publication Critical patent/WO2007108968A3/en

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    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • 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
    • C07D215/20—Oxygen atoms
    • 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
    • C07D241/44—Benzopyrazines 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 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
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.
  • This invention relates to the use of potent quinoli-2(lH)-one derivatives and their aza analogues as potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular pressure in the eye of a patient.
  • This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans. More particularly this invention relates to the treatment of glaucoma and/or ocular hypertension (elevated intraocular pressure) using novel quinoli-2(lH)-one derivatives and their aza analogues having the structural formula I:
  • Z 5 Z] 3 Z 2 , and Z3 independently represent CH or N;
  • R and RY independently represent hydrogen, or Ci_6 alkyl
  • Rl represents hydrogen or C ⁇ - ⁇ alkyl, CF3, (CH2) n C3-l 0 cycloalkyl, (CH 2 ) n C6_io aryl, -(CH 2 ) n C5-i0 heteroaryl, C ⁇ . ⁇ alkoxy, OH, COR C , said alkyl, cycloalkyl, aryl, heteroaryl, and alkoxy optionally substituted with 1-3 groups selected from Rb;
  • X represents -(CHR7) p -, -(CHR7) p C(O)-;
  • Q represents N, CRy * or O, wherein R2 is absent when Q is O;
  • R2 represents hydrogen, Ci_jo alkyl, C2-10 hydroxylalkyl, C].6 alkylSR, -(CH2)nO(CH2) m OR, (CH 2 )m0R, -(CH2)n(CHR 7 )s(CH2)mCl-6 alkoxy, -(CH2)n(CHR7)(CH 2 ) m C3-8 cycloalkyl, - (CH2)n(CHR7) s (CH2) m C3-10 heterocyclyl, -(CH2) n C5-io heteroaryl, -N(R)2, -COOR, or - (CH2)n(CHR7)s(CH2)mC6-10 3 T ⁇ sa 'd alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups selected from Ra;
  • R3 represents hydrogen, Ci-io alkyl, C2-6 alkenyl, -(CH2) n (CHR7) s (CH2)mC3-8 cycloalkyl, - (CH2)n(CHR7)s(CH2) m C3-10 heterocyclyl, -(CH 2 )n(CHR7)(CH2) m C5-10 heteroaryl, - (CH2)n(CHR7)s(CH 2 ) m COOR, -(CH2)n(CHR 7 ) s (CH2)rnC6-l0 aryl, -(CH2) n (CHR7)s(CH 2 )mNHR8 3 - (CH2)n(CHR 7 ) s (CH2) m N(R)2, -(CH2)n(CHR7)s(CH 2 )mN(R8)2, -(CH2)n(CHR7) s (CH 2 )mNHCOOR, - (CH2)n(CHR7)s(CH2) m N(R
  • R2 and R3 taken together with the intervening CRy form a 4-10 membered carbocyclic or heterocyclic aromatic ring or fused ring optionally interrupted by 1-2 atoms of O, S 5 C(O) or NR, and optionally having 1-5 double bonds, and optionally substituted by 1-3 groups selected from Ra;
  • R4 represents hydrogen, Cj -6 alkoxy, halogen, cyano, OH, Ci_6 alkyl, COOR, SO3H, Ci_ 6 alkylcarbonyl, S(O)qRy, -O(CH2) n N(R)2, -O(CH2) n CO 2 R, -OPO(OH)2, CF 3 , -N(R)2, nitro, or Ci-6 alkylamino;
  • R7 represents hydrogen, C ⁇ -6 alkyl, -(CH2) n COOR or -(CH2) n N(R)2,
  • R8 represents -(CH2) n C3_8 cycloalkyl, -(CH2)n 3-10 heterocyclyl, Ci-6 alkoxy or -(CH2)nC5-iO heteroaryl, -(CH2)nC6-10 aryl said heterocyclyl, cycloalkyl, aryl orheteroaryl optionally substituted with 1-3 groups selected from R a ;
  • Ra represents F, Cl, Br, I, CF 3 , N(R) 2 , NO 2 , CN, -(CKk) n CORs, -(CH ⁇ nCONHRg, -
  • K independently represents CH, CH 2 or NH
  • R w represents H, C]_ 6 alkyl, -C(O)C]_ 6 alkyl, -C(O)OCi_ 6 alkyl, -SO2N(R)2, -SO2C1-6 alkyl, -SO2C 6 _ 10 aryl, NO 2 , CN or -C(O)N(R) 2 ;
  • Rb represents Ci -6 alkyl, -COOR, -SO3R, CN, (CH2) n OR, C(O)O(CH2) n C(O)R, -OPO(OH)2, - (CH2) n C6-10 aryl, or -(CH2) n C5-i0 heteroaryl;
  • Rc represents hydrogen, C 1-6 alkyl, or -(CH2)nC6-10 ar yl
  • the present invention is directed to novel potassium channel blockers of Formula I. It also relates to a method for decreasing elevated intraocular pressure or treating glaucoma by administration, preferably topical or intra-camaral administration, of a composition containing a potassium channel blocker of Formula I described hereinabove and a pharmaceutically acceptable carrier.
  • Still another embodiment of this invention is realized when Q is N and all other variables are as originally described.
  • Still another embodiment of this invention is realized when Q is CH or CCH 3 and all other variables are as originally described.
  • R w is selected from H, Ci _6 alkyl, -C(O)Ci -6 alkyl and - C(O)N(R) 2 .
  • a sub-embodiment of this invention is realized when QR2R3 is a dialkylamine or hydroxylarnine and all other variables are as originally described..
  • Still another embodiment of this invention is realized when Ri is C] -6 alkyl, Z is N, Zi, Z2, and Z3 are each CH, and QR2R3 is a dialkylamine or hydroxyldialkylamine and all other variables are as originally described.
  • R7 is hydrogen or Ci-g alkyl, and all other variables are as originally described.
  • R a is selected from F, Cl 5 Br, I, CF 3 , N(R) 2 , NO 2 , CN, -CONHR8, -CON(RS)2, -O(CH2) n COOR, -NH(CEk) n OR, -COOR 1 - OCF3, -NHCOR, -SO2R, -SO2NR2, -SR 5 (C 1 -C 6 alkyl)O-, -(CH2) n O(CH2) ra OR, -(CH2) n Ci-6 alkoxy, (aryl)O-, -OH, (C 1 -C 6 alkyl)S(O) m -, H 2 N-C(NH)-, (C 1 -C 6 alkyl)C(O)-, (C 1 -C 6 alkyl)OC(O)NH
  • Still another embodiment of this invention is realized when R2 and R3 are taken together with the intervening N atom form a 4-10 membered heterocyclic carbon ring optionally interrupted by 1- 2 atoms of O, S, C(O) or NR, and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from R a .
  • heterocyclic groups are:
  • Still another embodiment of this invention is realized when Q equals CRY, and R2 and R3 taken together with the intervening CRy form a 4-10 membered carbocyclic or heterocyclic aromatic ring or fused ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-5 double bonds, and optionally substituted by 1-3 groups selected from R a .
  • groups are phenyl, pyridinyl, adamantyl, [l.l .l]bicyclopentyl, and the like.
  • Rl represents hydrogen or Ci_6 alkyl, (CH2)nC3-lO cycloalkyl, (CH2)nC6-10 aryl, -(CH2) n C5_io heteroaryl, C] _ ⁇ alkoxy, said alkyl, cycloalkyl, aryl and alkoxy optionally substituted with 1-3 groups selected from Rb;
  • R2 represents hydrogen, Ci_io alkyl, C2-10 hydroxylalkyl, (CH2) m OR, -(CH2)n(CHR7)s(CH2) m Ci-6 alkoxy, -(CH2)n(CHR7) s (CH2) m C3-8 cycloalkyl, -(CH2)n(CHR 7 ) s (CH2) m C3-10 heterocyclyl, - (CH2)nC5-io heteroaryl, or -(CH2)n(CHR7) s (CH2)mC6-10 ⁇ yU said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups selected from R a ;
  • R3 represents hydrogen, C] .10 alkyl, -(CH2)n(CHR7) s (CH2)mC3-8 cycloalkyl, - (CH2)n(CHR7) s (CH2)mC3-10 heterocyclyl, -(CH2)n(CHR7) s (CH2)rnC5-10 heteroaryl, or - (CH2)n(CHR7) s (CH2)mC6-10 3 W ⁇ sa *d alkyl, cycloalkyl, alkoxy, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups of R a ; and all other variables are as described herein.
  • a sub-embodiment of the compounds of formula EL is realized when Ri is C ⁇ -6 alkyl, optionally substituted with 1 to 3 groups of Rb.
  • Examples of C ⁇ . ⁇ alkyls are t-butyl, ethyl, isopropyl, methyl and the like.
  • Another sub-embodiment of the compounds of formula II is realized when Rl is hydrogen.
  • Still another sub-embodiment of the compounds of formula II is realized when Ri is (CH2)nC6-l 0 aryU optionally substituted with 1 to 3 groups of Rb.
  • Yet another sub-embodiment of the compounds of formula H is realized when Ri is (CH2)nC3-10 cycloalkyl, optionally substituted with 1 to
  • R2 and R3 are independently Ci-io alkyl, -(CH2) n (CHR7) s (CH2) m C6- 10 aryl, (CH2)n(CHR 7 ) s (CH2)rnC3_io heterocyclyl, said alkyl, heterocyclyl, aryl optionally substituted with 1-3 groups selected from R a .
  • R2 and R3 are independently hydrogen, Ci_io alkyl, said alkyl, optionally substituted with 1-3 groups selected from R a .
  • the compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E.L. Eliel and S.H. Wile ⁇ Stereochemistry of Carbon Compounds (John Wiley and Sons, New York 1994), in particular pages 1119-1190)
  • any variable e.g. aryl, heterocycle, Ri, R4 etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • R a When R a is -O- and attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.
  • a nitrogen e.g., nitrogen atom on a pyridyl group
  • sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl cyclopentyl and cyclohexyl. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group”.
  • Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, unless otherwise defined, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings, which can be fused. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkenyl is C2-C6 alkenyl.
  • Alkoxy refers to an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, with the alkyl group optionally substituted as described herein.
  • Said groups are those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond.
  • Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
  • Halogen refers to chlorine, fluorine, iodine or bromine.
  • Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like.
  • An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms.
  • aryl groups are phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl and phenanthrenyl, preferably phenyl, naphthyl or phenanthrenyl.
  • Aryl groups may likewise be substituted as defined.
  • Preferred substituted aryls include phenyl and naphthyl.
  • heterocyclyl or heterocyclic represents a stable 3- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O 5 and S 5 and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • heterocycle or heterocyclic includes heteroaryl moieties.
  • heterocyclic elements include, but are not limited to, azepinyl, benz ⁇ midazolyl, benzisoxazolyl, benzofurazanyl, benz ⁇ pyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydropyrrolyl, 1,3- dioxolanyl, furyl, imidazolidinyl, imidazoiinyl, imidazolyl, indolinyl, indolyl, isochxomanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazoHdinyl, mo ⁇
  • heterocycle is selected from 2-azepinonyl, benzimidazolyl, 2-diazapinonyl, dihydroimidazolyl, dihydropyrrolyl, imidazolyl, 2-imidazolidinonyl, indolyl, isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidinyl, 2-piperidinonyl, 2-pyrimidinonyl, 2-pyrollidinonyl, quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.
  • heteroatom means O, S or N, selected on an independent basis.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S 3 and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein.
  • heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolin
  • This invention is also concerned with compositions and methods of treating ocular hypertension or glaucoma by administering to a patient in need thereof one of the compounds of formula I in combination with one or more of a ⁇ -adrenergic blocking agent such as timolol, betaxolol, levobetaxolol, carteolol, levobunolol, a parasympathomimetic agent such as epinephrine, iopidine, brimonidine, clonidine, para-aminoclonidine, carbonic anhydrase inhibitor such as dorzolamide, acetazolamide, metazolamide or brinzolamide, an EP4 agonist (such as those disclosed in WO 02/24647, WO 02/42268, EP 1114816, WO 01/46140 and WO 01/72268), a prostaglandin such as latanoprost, travaprost, unoprostone, rescula, S 1033 (
  • hypotensive lipid (the carboxylic acid group on the D-chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents) is that in which the carboxylic acid group is replaced with a Cj_6 alkoxy group such as OCH3 (PGF2 a I-OCH3), or a ammalia group (PGF2 a 1-OH).
  • Preferred potassium channel blockers are calcium activated potassium channel blockers. More preferred potassium channel blockers are high conductance, calcium activated potassium (Maxi-K) channel blockers. Maxi-K channels are a family of ion channels that are prevalent in neuronal, smooth muscle and epithelial tissues and which are gated by membrane potential and intracellular Ca2+.
  • the present invention is based upon the finding that maxi-K channels, if blocked, inhibit aqueous humor production by inhibiting net solute and H2O efflux and therefore lower IOP.
  • maxi-K channel blockers are useful for treating other ophthamological dysfunctions such as macular edema and macular degeneration. It is known that lowering IOP promotes blood flow to the retina and optic nerve. Accordingly, the compounds of this invention are useful for treating macular edema and/or macular degeneration.
  • maxi-K channel blockers which lower IOP are useful for providing a neuroprotective effect. They are also believed to be effective for increasing retinal and optic nerve head blood velocity and increasing retinal and optic nerve oxygen by lowering 1OP 3 which when coupled together benefits optic nerve health. As a result, this invention further relates to a method for increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension as well as providing a neuroprotective effect or a combination thereof.
  • a number of marketed drugs function as potassium channel antagonists. The most important of these include the compounds Glyburide, Glipizide and Tolbutamide. These potassium channel antagonists are useful as antidiabetic agents.
  • the compounds of this invention may be combined with one or more of these compounds to treat diabetes.
  • Potassium channel antagonists are also utilized as Class 3 antiarrhythmic agents and to treat acute infarctions in humans.
  • a number of naturally ammalian toxins are known to block potassium channels including Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, and ⁇ -Bungarotoxin ( ⁇ -BTX).
  • the compounds of this invention may be combined with one or more of these compounds to treat arrhythmias.
  • Depression is related to a decrease in neurotransmitter release.
  • Current treatments of depression include blockers of neurotransmitter uptake, and inhibitors of enzymes involved in neurotransmitter degradation which act to prolong the lifetime of neurotransmitters.
  • Alzheimer's disease is also characterized by a diminished neurotransmitter release.
  • Three classes of drugs are being investigated for the treatment of Alzheimer's disease cholinergic potentiators such as the anticholinesterase drugs (e.g., physostigmine (eserine), and Tacrine (tetrahydroaminocridine)), nootropics that affect neuron metabolism with little effect elsewhere (e.g., Piracetam, Oxiracetam; and those drugs that affect brain vasculature such as a mixture of ergoloid mesylates amd calcium channel blocking drugs including Nimodipine.
  • anticholinesterase drugs e.g., physostigmine (eserine), and Tacrine (tetrahydroaminocridine)
  • nootropics that affect neuron metabolism with little effect elsewhere
  • Piracetam, Oxiracetam e.g., Piracetam, Oxiracetam
  • those drugs that affect brain vasculature such
  • Selegiline a monoamine oxidase B inhibitor which increases brain dopamine and norepinephrine has reportedly caused mild improvement in some Alzheimer's patients.
  • Aluminum chelating agents have been of interest to those who believe Alzheimer's disease is due to aluminum toxicity.
  • Drugs that affect behavior, including neuroleptics, and anxiolytics have been employed.
  • Anxiolytics, which are mild tranquilizers, are less effective than neuroleptics
  • the present invention is related to novel compounds which are useful as potassium channel antagonists.
  • the compounds within the scope of the present invention exhibit potassium channel antagonist activity and thus are useful in disorders associated with potassium channel malfunction.
  • a number of cognitive disorders such as Alzheimer's Disease, memory loss or depression may benefit from enhanced release of neurotransmitters such as serotonin, dopamine or acetylcholine and the like.
  • Blockage of Maxi-K channels maintains cellular depolarization and therefore enhances secretion of these vital neurotransmitters.
  • the compounds of this invention may be combined with anticholinesterase drugs such as physostigmine (eserine) and Tacrine (tetrahydroaminocridine), nootropics such as Piracetam, Oxiracetam, ergoloid mesylates, selective calcium channel blockers such as Nimodipine, or monoamine oxidase B inhibitors such as Selegiline, in the treatment of Alzheimer's disease.
  • anticholinesterase drugs such as physostigmine (eserine) and Tacrine (tetrahydroaminocridine)
  • nootropics such as Piracetam, Oxiracetam, ergoloid mesylates
  • selective calcium channel blockers such as Nimodipine
  • monoamine oxidase B inhibitors such as Selegiline
  • the compounds of this invention may also be combined with Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, ⁇ -Bungarotoxin ( ⁇ -BTX) or a combination thereof in treating arrythmias.
  • the compounds of this invention may further be combined with Glyburide, Glipizide, Tolbutamide or a combination thereof to treat diabetes.
  • each of the claimed compounds are potassium channel antagonists and are thus useful in the decribed neurological disorders in which it is desirable to maintain the cell in a depolarized state to achieve maximal neurotransmitter release.
  • the compounds produced in the present invention are readily combined with suitable and known pharmaceutically acceptable excipients to produce compositions which may be administered to mammals, including humans, to achieve effective potassium channel blockage.
  • salts of the compounds of formula I will be.pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted, amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, NjN'-dibenzylethylenediami ⁇ e, diethylamin, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as argin
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethion ⁇ c, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
  • composition is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.
  • maxi-K channel blockers used can be administered in a therapeutically effective amount intravaneously, subcutaneously, topically, transdermally, parenterally or any other method known to those skilled in the art.
  • Ophthalmic pharmaceutical compositions are preferably adapted for topical administration to the eye in the form of solutions, suspensions, ointments, creams or as a solid insert.
  • Ophthalmic formulations of this compound may contain from 0.01 ppm to 1% and especially 0.1 ppm to 1% of medicament. Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in reducing intraocular pressure, treating glaucoma, increasing blood flow velocity or oxygen tension.
  • For a single dose from between 1 ng to 500ug, preferably 1 ng to 500 ug, of the compound can be applied to the human eye.
  • the pharmaceutical preparation which contains the compound may be conveniently admixed with a non-toxic pharmaceutical organic carrier, or with a non-toxic pharmaceutical inorganic carrier.
  • a non-toxic pharmaceutical organic carrier or with a non-toxic pharmaceutical inorganic carrier.
  • pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethyl-cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers.
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and the like.
  • auxiliary substances such as e
  • suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like.
  • the pharmaceutical preparation may also be in the form of a microparticle formulation.
  • the pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament.
  • the polymer used to form the insert may be any water soluble non-toxic polymer, for example, cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, (hydroxyloweralkyl cellulose), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; acrylates such as polyacrylic acid salts, ethylacrylates, polyactylamides; natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia; the starch derivatives such as starch acetate, hydroxymethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrol idone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum, gellan gum, and mixtures of said polymer.
  • cellulose derivatives such as methylcellulose, sodium carboxy
  • Suitable subjects for the administration of the formulation of the present invention include primates, man and other animals, particularly man and domesticated animals such as cats and dogs.
  • the pharmaceutical preparation may contain non-toxic auxiliary substances such as antibacterial components which are non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenylethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethyl enediamine tetraacetic acid, and the like.
  • auxiliary substances such as antibacterial components which are non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenylethanol
  • buffering ingredients such as sodium chloride, sodium borate, sodium acetate,
  • the ophthalmic solution or suspension may be administered as often as necessary to maintain an acceptable IOP level in the eye. It is contemplated that administration to the ammalian eye will be about once or twice daily.
  • novel formulations of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of the active component or some multiple thereof in the case of a combination therapy.
  • AIBN 2,2'-azobisisobutyronitrile, DCM - Dichloromethane, mCPBA — meta-Chloroperbenzoic acid,
  • the core heterocycle of.l,6-naphthy ⁇ din-2(lH)-one 1 can be prepared as shown in Scheme 8.
  • Substituted analogues could be prepared from a more elaborated starting material or obtained by further transformation of the un-substituted heterocycle using the method depicted in Scheme 9.
  • Step D Ethyl 2-[(2-amino-4-methoxyphenyl)(hydroxy)methyl]-3,3-dimethylbutanoate
  • Steps B and C (7-Methoxy-2-oxoquinolin-l(2H)-yl)acetic acid
  • the title compound was prepared using the procedure described in Steps F-G of Preparative Example 1 and starting with 7-methoxyquinolin- 2(lH)-one from the Step A above.
  • N-butyl-3,3-dimethylbutanamide was prepared from n-butylamine, t-butylacetyl chloride, and DIEA.
  • the crude amide was reduced in refluxing benzene with 1.5 molar equiv. of LAH in 2 hours.
  • the excess LAH was quenched with MeOH and 1 ⁇ KOH after cooling.
  • the resulting mixture was filtered and the solid washed with ether.
  • the residue from the organic layer was dissolved in ether and treated with 1 ⁇ HCl in ether to precipitate the title compound.
  • Step B 4-[(3 3 3-Dimethylbutyl)amino]-2-methylbutan-2-ol
  • the title compound of Step C can also be obtained as follows. A mixture of 50 mg methyl N-(6- methoxy-3- ⁇ itropyridin-2-yI)glycinate, 37 mg 3,3-dimethyl-2-oxobutanoic acid, 48 mg HOBt, and 41.7 mg DIEA in 1 mL dry DMF was treated with 79.8 mg EDC. The title compound was isolated on RP- HPLC. Similar result was obtained using PyBOP instead of EDC.
  • Step D (2-ter/-Butyl-6-methoxy-3-oxo ⁇ yrido[2,3- ⁇ ]pyrazin-4(3H)-yl)acetic acid
  • Step A tert-Butyl N-(6-methoxy-3-nitropyridin-2-yl)glycinate
  • Step B tert-Butyl (2-fer/-butyl-6-methoxy-3-oxo ⁇ yrido[2,3-6]pyrazin-4(3H)-yl)acetate
  • the title compound was prepared from 4-methoxybenzene-l,2-diamine and 3,3-dimethyl-2- oxobutanoic acid in ⁇ OAc at 48 ⁇ 49°C overnight as described in Preparative Example 50 Step C. It was separated from isomeric side-product 3-rer/-butyl-6-methoxyquinoxalin-2(lH)-one by SGC.
  • Step B Methyl (3-ter ⁇ butyl-7-methoxy ⁇ 2-oxoquinoxalin-l(2H)-yl)acetate
  • Step B ⁇ ert-Butyl (3-rer/'-butyl-7-methoxy-2-oxoquinoxalin-l(2i ⁇ )-yl)acetate
  • Step A N-Butyl-3-hydroxy-2,2-dimethylpropanamide
  • a mixture of 4.54 g 3-hydroxy-2,2- dimethylpropanoic acid, 4.21 g n-butylamine, 7.78 g HOBt 5 and 14.89 g DEEA in 100 mL DMF was treated with 18.4 g EDC overnight at room temperature.
  • Solvent was removed under reduced pressure and residue was diluted with saturated NH 4 Cl solution and extracted with EtOAc. The combined extract was washed with water and saturated brine and concentrated to give the title compound.
  • Step A 5-Methoxy-N-(4-methoxybenzyl)-2-nitroaniline
  • the title compound was prepared from 3-fluoro- 4-nitrophenol 5 methyl iodide, and 4-methoxybenzylamine using the procedure described in Preparative Example 51 Method B Step A.
  • Step B Methyl ⁇ 4-[3-(acetyIoxy)propyl]phenyl ⁇ (oxo)acetate
  • a solution of 5 g 3-phenyl propylacetate and 4.1 g methyl oxalyl chloride in 20 mL DCM was added slowly to a mixture of 8.2 g anhydrous aluminum chloride in 30 mL DCM at 0 0 C.
  • the reaction mixture is then allowed to warm up to room temperature overnight.
  • Aqueous work-up with saturated NHjCl and EtOAc followed by SGC using 3:1 hexanes and EtOAc afforded the title compound as clear oil.
  • Step C 4-Methoxy-N 2 -(4-methoxybenzyl)benzene-l,2-diamine
  • Step D 3 - ⁇ 4-[6-Methoxy-4-(4-methoxybenzyl)-3 -oxo-3,4-dihydroquinoxalin-2-yI]phenyl ⁇ propyl acetate
  • the title compound was prepared from 4-methoxy-iV 2 -(4-methoxybenzyl)-benzene-l,2-diamine and methyl ⁇ 4-[3-(acetyloxy)propyl] ⁇ henyl ⁇ (oxo)acetate in HOAc at 45°C in 6 hours. Similar reaction in THF was very slow. SGC purification using hexanes-EtOAc afforded pure title compound. LC-MS: 3.97 min. (m/Z 473.1).
  • Step E 3-[4-(6-Methoxy-3-oxo-3,4-dihydroquinoxalin-2-yl)phenyl]propyl acetate
  • Step F 3-[4-(3-Hydroxypropyl)phenyl]-7-methoxyquinoxalin-2(lH)-one
  • Step G Methyl [3-[4-(3-hydroxypropyl)phenyl]-7-methoxy-2-oxoquinoxalin-l(2H)-yl]acetate
  • Step B Methyl ⁇ 4-[(acetyloxy)methyl]phenyl ⁇ (oxo)acetate
  • Step C 4-[6-Methoxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydroquinoxalin-2-yl]benzyl acetate
  • the title compound was prepared from methyl ⁇ 4-[(acetyloxy)methyl]phenyl ⁇ (oxo)acetate and 4- methoxy-N 2 -(4-methoxybenzyl)benzene-l,2-diamine using method described in Preparative Example 57 Step D.
  • the title compound was prepared from 4,4-dimethylcyclohexane-l 5 3-dione using the method of Langley et al. (J. Chem. Soc. 1962, 2972). It was obtained as a 6:5 mixture of 3,3-dimethyl-2- oxohexanedioic acid and 2,2-dimethylpentanedioic acid based on 1 H NMR and was used in the next step without purification.
  • Step B 4- ⁇ 4- [6-Methoxy-4-(4-methoxy benzy l)-3-oxo-3 ,4-dihydroquinoxal in-2-y l]phenyl ⁇ -4- methylpentanoic acid
  • Step C 4-[4-(6 ⁇ Methoxy-3-oxo-3,4-dihydroquinoxalin-2-yl)phenyl]-4-methylpentanoic acid
  • Step D 3-[4-(4-Hydroxy- 1 , 1 -dimethylbutyl)phenyl]-7-methoxyquinoxalin-2( 1 H)-one
  • Step E Methyl [3-(4-hydroxy-l,l-dimethylbutyI)-7-methoxy-2-oxoquinoxal ⁇ n-l(2H)-yl]acetate
  • Step F [3-(4-Hydroxy-l,l-dimethylbutyI)-7-methoxy-2-oxoquinoxalin-l(2H)-yl]acetic acid
  • Step B.3-ter/-Butyl-l,8-naphthyridin-2(lH)-one The title compound was prepared from 5.9 g methyl 2- [ ⁇ 2-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl ⁇ (hydroxy)methyI]-3,3-dimethylbutanoate in 20 mL dioxane and 35 mL 4 N HCl in dioxane by heating at 170 0 C in a microwave reactor for 2 hours in three portions. The solvent was removed from the combined reaction mixture under reduced pressure and the residue was suspended in water and EtOAc after being neutralized to p ⁇ 7. The title compound was obtained by filtration.
  • Step C 3-/ert-Butyl-l,8-naphthyridin-2(lH)-one 8-oxide
  • the title compound was prepared by heating a solution of 2.05 g 3-ter/-butyl ⁇ l,8-naphthyridin-2(lH)-one in 20 mL 35% peracetic acid in acetic acid at 50 0 C overnight. Aqueous work-up with EtOAc afforded the title compound.
  • Step D 3-ter/-Butyl-7-methoxy-l,8-naphthyridin-2(lH)-one
  • the title compound was prepared from 3-/er/-butyl-l,8-naphthyridin-2(lH)-one 8-oxide using a modified method of ⁇ ayashida etal. ( ⁇ eterocycles, 31 (7), 1325, 1990) with 10 equiv. of pTsCI and 20 equiv. OfEt 3 N.
  • Step E Methyl (3-fer/-butyl-7-methoxy-2-oxo-l,8- ⁇ aphthyridin-l(2i7)-yl)acetate
  • the title compound was prepared from 3-tert-butyl-7-methoxy-l,8-naphthyridin-2(lH)-one and methyl bromoacetate using the method described in Preparative Example 57 Step G. It was separated from the faster-el uting isomeric methyl [(3-t ⁇ r/-butyl-7-methoxy-l,8-naphthyridin-2-yl)oxy]acetate on RP- ⁇ PLC. LC-MS: 3.54 min. (m/Z 305.1).
  • the title compound was prepared from methyl (3-.”erf-butyl-7-methoxy-2-oxo-l,8-naphthyridin-l(2H)-yl)acetate using the method described in Preparative Example 57 Step ⁇ .
  • Example 2 Utilizing the method described in Example 1 using (3-?er/-butyl-7-methoxy-2-oxoquinolin- l(2H)-yl)acetic acid and the amine listed in Table 4 below Examples 2 through 47 in Table 4 were prepared. In Examples 32-36, PyBOP and HOAt were used instead of EDC and HOBt.
  • the title compound was prepared from 50 mg 3-ter/-butylquinolin-2(lH)-one (Preparative Example 1, Step E), 55 mg l-bromo-3,3-dimethylbutane, and 143 mg cesium carbonate in 1 mL DMF at 55°C for 12 hours. It was separated from less polar side-product 3-ter*-butyl-2-(3,3-dimethylbutoxy)-7- methoxyquinoline using RP- ⁇ PLC. The isomers were identified by comparison of NMR with isomers in Preparative Example 1, Step F.
  • the title compound was prepared from 50 mg 3-/er/-butylquinolin-2(lH)-one (Preparative Example 1, Step E), 50 mg l-bromo-3,3-dimethylbutane, and 143 mg cesium carbonate in 1 mL DMF at 55°C for 12 hours. It was separated purified from less polar side-product 3-ter/-butyl-2-(3- methylbutoxy)-7-methoxyquinoline using ⁇ PLC.
  • the title compound was prepared from (3-isopr ⁇ yl-2-oxoquinolin-l(2H)-yl)acetic acid from Preparative Example 2, EDC, ⁇ OBt, and DIEA using the method in Example 1, purified on ⁇ PLC, and re-crystallized from EtOAc-hexanes to give colorless crystals.
  • LC-MS 4.17 min. (m/Z 437.1).
  • the title compound was prepared from (3-cyclohexyl-2-oxoquinolin-l(2H)-yl)acetic acid from Preparative Example 3, EDC, ⁇ OBt, and DIEA using the method in Example 1, purified on ⁇ PLC, and re-crystallized from EtOAc-hexanes to give colorless crystals.
  • Example 124 PyBOP and HO At were used instead of EDC and HOBt.
  • the title compound was prepared from (2-oxo-3-phenylquinolin-l(2H)-yl)acetic acid from Preparative Example 4, EDC, HOBt, and DDBA using the method in Example 1 , purified on HPLC, and re-crystallized from EtOAc-hexanes to give colorless crystals.
  • Example 287 was obtained as the side-product during the preparation of Example 286.
  • Step A Di-tert-butyl 3-[(3,3-dimethylbutyl)amino]-2,2-dimethylpropyl phosphate Treat a solution of 100 mg 3-[(3,3-dimethylbutyl)amino)-2,2-dimethylpropan-l-ol and 156 mg di-Zert-butyl diethylamidophosphite in 0.6 mL anhydrous DCM with 3.5 mL of 0.45 M tetrazole in MeCN at room temperature overnight. Cool half of this mixture to -40 0 C and add a solution of 140 mg 72% mCPBA in 2.5 mL DCM. Remove the cooling bath and let the reaction mixture warm up to room temperature.
  • Step C 2-[[(3-terr-Butyl-7-methoxy-2-oxoquinoxalin-l(2H)-y0 acet yl](3,3-dimethylbutyl)amino]-l,l- dimethylethyl dihydrogen phosphate
  • Examples 295-301 in Table 15 were prepared using the same method described in Example 294. Some of the bromoketones used were prepared using the method of Gaudry and Marguet (Org. Syn. Coll. Vol. 6, 193).
  • Step A tert-Butyl [3-(4-cyanophenyl)-7-methoxy-2-oxoquinoxalin-l(2H)-yI]acetate
  • the title compound was prepared from tert-buty] iV-(5-methoxy-2-nitrophenyI)gIycinate and ethyl (4- cyanophenyl)(oxo)acetate using method described in Preparative Example 51 Method B
  • Step B LC-MS: 3.75 min. (m/Z 392.0).
  • Example 342 The following compounds in Table 20 were prepared using the method described in Example 1 using (3-ter/-Butyl-7-methoxy-2-oxo-l,8-naphthyridin-l(2H)-yl)acetic acid and the amine listed in Table 20.
  • Step A.3-/er/-Buryl-7-chloro-l,8-naphthyridin-2(lH)-one The title compound was prepared by treating 14.5 mg 3-.eri-butyl-l,8-naphthyridin-2(lH)-one 8-oxide with 1 mL thionyl chloride at room temperature overnight. It was separated from its 7-hydroxy and 4-chloro derivatives on RP- ⁇ PLC. LC- MS: 3.21 min. (m/Z 237.1). 1 H NMR (CDCl 3 , 500 MHz) ⁇ : 7.85 (d, 8.0 Hz 3 IH), 7.64 (s, IH), 7.22 (d, 8.0 Hz 5 IH) 3 1.45 (s, 9H)
  • Step A 3-/erf-Butyl-7-chloro-l-(3 3 3-dimethyl-2-oxobutyl)-l,8-naphthyr ⁇ di ⁇ -2(lH)-one
  • Step A Methyl 2-[ ⁇ 4-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl ⁇ (hydroxy)methyI]-3,3- dimethylbutanoate
  • the title compound was prepared from N-(3-formylpyridin-4-yl)-2,2- dimethylpropanamide and methyl 3-methylbutanoate using the method of Turner (J. Org. Chem. 55, 4744, 1990).
  • Step B 3-t ⁇ r/-Butyl-l,6-naphthyridin-2(l//)-one
  • the title compound was prepared from methyl 2-[ ⁇ 4- [(2,2-dimethylpropanoyl)amino]pyridin-3-yl ⁇ (hydroxy )methyl]-3,3-dimethylbutanoate using the method described in Preparative Example 60 Step B by heating in a microwave reactor at 160 0 C for 2 hours.
  • LC- MS 1.75 min. (m/Z 203.1).
  • Step C Methyl (3-te/"/-butyl-2-oxo-t,6-naphthyridin-l(2H)-yl)acetate
  • the title compound was prepared from 3-t ⁇ rr-butyl-l,6-naphthyridin-2(lH)-one and methyl bromoacetate using the method described in Preparative Example 57 Step G. It was separated from the slower-eluting isomeric methyl [(3-ter/-buryl-l,6-naphthyridin-2-yl)oxy]acetate on RP- ⁇ PLC.
  • LC-MS 2.18 min. (m/Z 275.1 ).
  • Step D (3-ter/'-Butyl-2-oxo-l,6-naphthyridin-l(2H)-yl)acetic acid
  • the title compound was prepared from methyl (3-tert-butyl-2-oxo-l,6-naphthyridin-l(2H)-yl)acetate using the method described in Preparative Example 57 Step ⁇ .
  • Step E N,iV-Dibutyl-2-(3-ferir-butyl-2-oxo- 1 ,6-naphthyridin- 1 (2H)-yI)acetamide
  • the identification of inhibitors of the Maxi-K channel can be accomplished using Aurora Biosciences technology, and is based on the ability of expressed Maxi-K channels to set cellular resting potential after transient transfection of both ⁇ and ⁇ subunits of the channel in TsA-201 cells.
  • cells display a hyperpolarized membrane potential, negative inside, close to E ⁇ (-80 mV) which is a consequence of the activity of the Maxi-K channel.
  • Blockade of the Maxi-K channel will cause cell depolarization. Changes in membrane potential can be determined with voltage-sensitive fluorescence resonance energy transfer (FRET) dye pairs that use two components, a donor coumarin (CC 2 DMPE) and an acceptor oxanol (DiSBAC 2 (3)).
  • FRET voltage-sensitive fluorescence resonance energy transfer
  • Oxanol is a lipophilic anion and distributes across the membrane according to membrane potential. Under normal conditions, when the inside of the cell is negative with respect to the outside, oxanol is accumulated at the outer leaflet of the membrane and excitation of coumarin will cause FRET to occur. Conditions that lead to membrane depolarization will cause the oxanol to redistribute to the inside of the cell, and, as a consequence, to a decrease in FRET. Thus, the ratio change (donor/acceptor) increases after membrane depolarization.
  • Transient transfection of the Maxi-K channel in TsA-201 cells can be carried out as previously described (Hanner et al. (1998) J. Biol. Chem. 273, 16289-16296) using FUGENE6TM as the transfection reagent. Twenty four hours after transfection, cells are collected in Ca 2+ -Mg 2+ -free Dulbecco's phosphate-buffered saline (D-PBS), subjected to centrifugation, plated onto 96-well poly-'d- lysine coated plates at a density of 60,000 cells/well, and incubated overnight.
  • D-PBS Ca 2+ -Mg 2+ -free Dulbecco's phosphate-buffered saline
  • the cells are then washed Ix with D-PBS, and loaded with 100 ⁇ l of 4 ⁇ M CC 2 DMPE-0.02% pluronic-127 in D-PBS. Cells are incubated at room temperature for 30 min in the dark. Afterwards, cells are washed 2x with D-PBS and loaded with 100 ⁇ l of 6 ⁇ M DiSBAC 2 (3) in (mM): 140 NaCl 5 0.1 KCl, 2 CaCl 2 , 1 MgCl 2 , 20 Hepes- NaOH, pH 7.4, 10 glucose. Test compounds are diluted into this solution, and added at the same time. Cells are incubated at room temperature for 30 min in the dark.
  • the compounds of this invention were found to cause concentration-dependent inhibition of the fluorescence ratio with IC 5 o's in the range of about 5 nM to about 500 ⁇ M, more preferably from about 5 nM to about 20 nM.
  • IC 5 o's concentration-dependent inhibition of the fluorescence ratio with IC 5 o's in the range of about 5 nM to about 500 ⁇ M, more preferably from about 5 nM to about 20 nM.
  • maxi-K channels The activity of high-conductance calcium-activated potassium (maxi-K) channels in human non-pigmented ciliary epithelial cells was determined using electrophysiological methods. Currents through maxi-K channels were recorded in the inside-out configuration of the patch clamp technique, where the pipette solution faces the extracellular side of the channel and the bath solution faces the intracellular side. Excised patches contained one to about fifty maxi-K channels. Maxi-K channels were identified by their large single channel conductance (250-300 pS), and by sensitivity of channel gating to membrane potential and intracellular calcium concentration. Membrane currents were recorded using standard electrophysiological techniques.
  • the bath (intracellular) solution was identical, except, in some cases, calcium was removed, 1 mM EGTA was added and 20 mM KCl was replaced with 20 mM KF to eliminate calcium to test for calcium sensitivity of channel gating. Drugs were applied to the intracellular side of the channel by bath perfusion.
  • Human non-pigmented ciliary epithelial cells were grown in tissue culture as described (Martin-Vasallo, P., Ghosh, S., and Coca-Prados, M., 1989, J. Cell. Physiol. HL, 243-252), and plated onto glass cover slips prior to use. High resistance seals (>1 Gohm) were formed between the pipette and cell surface, and inside out patches were excised. Maxi-K channels in the patch were identified by their gating properties; channel open probability increased in response to membrane depolarization and elevated intracellular calcium. In patches used for pharmacological analysis, removing intracellular calcium eliminated voltage-gated currents. Maxi-K currents were measured after depolarizing voltage steps or ramps that caused channel opening.
  • the compounds of this invention were applied to the intracellular side of the channel in appropriate concentrations (0.001 to 100 ⁇ M).
  • the compounds reduced channel open probability, and this effect was reversed upon washout of compounds from the experimental chamber.
  • the IC50 for block of maxi-K channels under these conditions for the compounds of this invention ranged from about 0.2 nM to about 100 ⁇ M.

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Abstract

This invention relates to the use of potent potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which leads to elevated intraoccular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans.

Description

TITLE OF THE INVENTION
OPHTHALMIC COMPOSITIONS FOR TREATING OCULAR HYPERTENSION
This invention claims the benefit of US Provisional application 60/781,904 filed on March 13, 2006.
BACKGROUND OF THE INVENTION
Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.
There are several current therapies for treating glaucoma and elevated intraocular pressure (e.g., pilocarpine, beta blockers (e.g,, timolol), carbonic anhydrase inhibitors (e.g., dorzolamide, brinzolamide) and prostaglandins (e.g., latanoprost), but the efficacy and the side effect profiles of these agents are not ideal. Recently potassium channel blockers were found to reduce intraocular pressure in the eye and therefore provide yet one more approach to the treatment of ocular hypertension and the degenerative ocular conditions related thereto. Blockage of potassium channels can diminish fluid secretion, and under some circumstances, increase smooth muscle contraction and would be expected to lower IOP and have neuroprotective effects in the eye. (see US Patent Nos. 5,573,758 and 5,925,342; Moore, et al., Invest. Ophthalmol. Vis. Sci 38, 1997; WO 89/10757, WO94/28900, and WO 96/33719).
SUMMARY OF THE INVENTION
This invention relates to the use of potent quinoli-2(lH)-one derivatives and their aza analogues as potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans. More particularly this invention relates to the treatment of glaucoma and/or ocular hypertension (elevated intraocular pressure) using novel quinoli-2(lH)-one derivatives and their aza analogues having the structural formula I:
Figure imgf000002_0001
Formula I
- I - or a pharmaceutically acceptable salt, ester including phosphate, enantiomer, diastereomer or mixture thereof: wherein,
Z5 Z]3 Z2, and Z3 independently represent CH or N;
R and RY independently represent hydrogen, or Ci_6 alkyl;
Rl represents hydrogen or C\-β alkyl, CF3, (CH2)nC3-l 0 cycloalkyl, (CH2)nC6_io aryl, -(CH2)nC5-i0 heteroaryl, C\.β alkoxy, OH, CORC, said alkyl, cycloalkyl, aryl, heteroaryl, and alkoxy optionally substituted with 1-3 groups selected from Rb;
X represents -(CHR7)p-, -(CHR7)pC(O)-;
Q represents N, CRy* or O, wherein R2 is absent when Q is O;
R2 represents hydrogen, Ci_jo alkyl, C2-10 hydroxylalkyl, C].6 alkylSR, -(CH2)nO(CH2)mOR, (CH2)m0R, -(CH2)n(CHR7)s(CH2)mCl-6 alkoxy, -(CH2)n(CHR7)(CH2)mC3-8 cycloalkyl, - (CH2)n(CHR7)s(CH2)mC3-10 heterocyclyl, -(CH2)nC5-io heteroaryl, -N(R)2, -COOR, or - (CH2)n(CHR7)s(CH2)mC6-10 3T^ sa'd alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups selected from Ra;
R3 represents hydrogen, Ci-io alkyl, C2-6 alkenyl, -(CH2)n(CHR7)s(CH2)mC3-8 cycloalkyl, - (CH2)n(CHR7)s(CH2)mC3-10 heterocyclyl, -(CH2)n(CHR7)(CH2)mC5-10 heteroaryl, - (CH2)n(CHR7)s(CH2)mCOOR, -(CH2)n(CHR7)s(CH2)rnC6-l0 aryl, -(CH2)n(CHR7)s(CH2)mNHR83 - (CH2)n(CHR7)s(CH2)mN(R)2, -(CH2)n(CHR7)s(CH2)mN(R8)2, -(CH2)n(CHR7)s(CH2)mNHCOOR, - (CH2)n(CHR7)s(CH2)mN(R8)CO2R, -(CH2)n(CHR7)s(CH2)mN(R8)COR, - (CH2)n(CHR7)s(CH2)mNHCOR, -(CH2)n(CHR7)s(CH2)mCONH(R8), aryl, - (CH2)n(CHR7)s(CH2)mOR, -(CH2)nC(R7)2(CH2)mOR, CF3, -(CH2)n(CHR7)s(CH2)mSθ2Rs - (CH2)n(CHR7)s(CH2)mSθ2N(R)2, -(CH2)n(CHR7)s(CH2)mCON(R)2, -
(CH2)H(CHR7)S(CH2)HICONHC(R)35 -(CH2)HCONHC(R)2CO2R, -(CH2)n(CHR7)s(CH2)mCOR8, nitro, cyano or halogen, said alkyl, cycloalkyl, alkoxy, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups of Ra; or, when Q is N3 R.2 and R3 taken together with the intervening N atom form a 4-10 membered heterocyclic ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from Ra-,
or, when Q equals CRY, R2 and R3 taken together with the intervening CRy form a 4-10 membered carbocyclic or heterocyclic aromatic ring or fused ring optionally interrupted by 1-2 atoms of O, S5 C(O) or NR, and optionally having 1-5 double bonds, and optionally substituted by 1-3 groups selected from Ra;
R4 represents hydrogen, Cj -6 alkoxy, halogen, cyano, OH, Ci_6 alkyl, COOR, SO3H, Ci_6 alkylcarbonyl, S(O)qRy, -O(CH2)nN(R)2, -O(CH2)nCO2R, -OPO(OH)2, CF3, -N(R)2, nitro, or Ci-6 alkylamino;
R7 represents hydrogen, Cχ-6 alkyl, -(CH2)nCOOR or -(CH2)nN(R)2,
R8 represents -(CH2)nC3_8 cycloalkyl, -(CH2)n 3-10 heterocyclyl, Ci-6 alkoxy or -(CH2)nC5-iO heteroaryl, -(CH2)nC6-10 aryl said heterocyclyl, cycloalkyl, aryl orheteroaryl optionally substituted with 1-3 groups selected from Ra;
Ra represents F, Cl, Br, I, CF3, N(R)2, NO2, CN, -(CKk)nCORs, -(CH^nCONHRg, -
(CH2)nCON(R8)2> -O(CH2)nCOOR, -NH(CH2)nOR, -COOR, -OCF3, -O-, -NHCOR, -SO2R, - %O2NR2, -SR, (C1-C6 alkyQO-, -(CH2)nO(CH2)mOR, -(CH2)nCl-6 alkoxy, (aryl)O-, -OH, (C1-C6 alkyl)S(O)m-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)NH-, -(C1-C6 alkyl)NRw(CH2)nC3_io heterocyclyl-Rw, -(C1-C6 alkyl)0(CH2)nC3_ιo heterocyclyl-Rw, -(C1-C6 alkyl)S(CH2)nC3-10 heterocyclyl-Rw, -(Cj-C6 alkyl)-C3-io heterocyclyl-Rw, -(CH2)n-K-C(=K)N(R)2, - (C2-6 alkenyl)NRw(CH2)nC3-10 heterocyclyl-Rw, -(C2-6 alkenyl)O(CH2)nC3-10 heterocyc]yl-Rw, -(C2- 6 alkenyl)S(CH2)nC3-lO heterocyclyl-Rw, -(C2-6 alkenyl)-C3_io heterocydyI-Rw, -(C2-6 a!kenyI)-K- C(^K)N(R)2, -(CH2)nSO2R, -(CH2)nSO3H, -(CH2)nPO(OR)2, -(CH2)nOPO(OR)2, cyclohexyl, cyclopentyl, moφholinyl, piperidyl, pyrroHdinyl, thiophenyl, phenyl, pyridyl, imidazolyl, oxazojyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl, C2-6 alkenyl, and C1-C1Q alkyl, said alkyl, alkenyl, alkoxy, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, and isothiazolyl optionally substituted with 1-3 groups selected from C1-C6 alkyl, and COOR;
K independently represents CH, CH2 or NH;
Rw represents H, C]_6 alkyl, -C(O)C]_6 alkyl, -C(O)OCi_6 alkyl, -SO2N(R)2, -SO2C1-6 alkyl, -SO2C6_ 10 aryl, NO2, CN or -C(O)N(R)2; Rb represents Ci -6 alkyl, -COOR, -SO3R, CN, (CH2)nOR, C(O)O(CH2)nC(O)R, -OPO(OH)2, - (CH2)nC6-10 aryl, or -(CH2)nC5-i0 heteroaryl;
Rc represents hydrogen, C 1-6 alkyl, or -(CH2)nC6-10 aryl
m is 0-3; n is 0-3; q is 0-2; s is θ-l;and p is 0-2.
This and other aspects of the invention will be realized upon inspection of the invention as a whole.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to novel potassium channel blockers of Formula I. It also relates to a method for decreasing elevated intraocular pressure or treating glaucoma by administration, preferably topical or intra-camaral administration, of a composition containing a potassium channel blocker of Formula I described hereinabove and a pharmaceutically acceptable carrier.
In an embodiment of the instant invention are the compounds wherein X represents CHR7CO.
Still another embodiment of this invention is realized when Q is N and all other variables are as originally described.
Still another embodiment of this invention is realized when Q is CH or CCH3 and all other variables are as originally described.
In another embodiment Rw is selected from H, Ci _6 alkyl, -C(O)Ci -6 alkyl and - C(O)N(R)2.
Another embodiment of this invention is realized when Z=N, and Z\, IQ., and Z3 are each CH and all other variables are as originally described. A sub-embodiment of this invention is realized when QR2R3 is a dialkylamine or hydroxylarnine and all other variables are as originally described..
Still another embodiment of this invention is realized when Ri is C] -6 alkyl, Z is N, Zi, Z2, and Z3 are each CH, and QR2R3 is a dialkylamine or hydroxyldialkylamine and all other variables are as originally described..
Yet another embodiment of this invention is realized when R7 is hydrogen or Ci-g alkyl, and all other variables are as originally described. Another embodiment of the instant invention is realized when Ra is selected from F, Cl5 Br, I, CF3, N(R)2, NO2, CN, -CONHR8, -CON(RS)2, -O(CH2)nCOOR, -NH(CEk)nOR, -COOR1 - OCF3, -NHCOR, -SO2R, -SO2NR2, -SR5 (C1-C6 alkyl)O-, -(CH2)nO(CH2)raOR, -(CH2)nCi-6 alkoxy, (aryl)O-, -OH, (C1-C6 alkyl)S(O)m-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)NH-, -(C1- C6 alkyl)NRw(CH2)nC3-10 heterocyclyl-Rw, -(CH2)n-K-C(=K)N(R)2, -(C2-6 alkenyl)NRw(CH2)nC3-10 heterocyclyl-Rw,-(C2-6 alkenyl)-K-C(=K)N(R)2,-(CH2)nSO2R, -(CH2)nSO3H, -(CH2)nPO(OR)2, C2-6 alkenyl, and C1-C1Q alkyl, said alkyl and alkenyl, optionally substituted with 1 -3 groups selected from
C1-C6 alkyl, and COOR;
Still another embodiment of this invention is realized when R2 and R3 are taken together with the intervening N atom form a 4-10 membered heterocyclic carbon ring optionally interrupted by 1- 2 atoms of O, S, C(O) or NR, and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from Ra. Examples of said heterocyclic groups are:
Figure imgf000006_0001
and the like.
Still another embodiment of this invention is realized when Q equals CRY, and R2 and R3 taken together with the intervening CRy form a 4-10 membered carbocyclic or heterocyclic aromatic ring or fused ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-5 double bonds, and optionally substituted by 1-3 groups selected from Ra. Examples of said groups are phenyl, pyridinyl, adamantyl, [l.l .l]bicyclopentyl, and the like.
Another embodiment of this invention is realized by structural formula II:
Figure imgf000006_0002
π or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof: wherein,
Q is N;
Z=CH or N; Rl represents hydrogen or Ci_6 alkyl, (CH2)nC3-lO cycloalkyl, (CH2)nC6-10 aryl, -(CH2)nC5_io heteroaryl, C] _β alkoxy, said alkyl, cycloalkyl, aryl and alkoxy optionally substituted with 1-3 groups selected from Rb;
R2 represents hydrogen, Ci_io alkyl, C2-10 hydroxylalkyl, (CH2)mOR, -(CH2)n(CHR7)s(CH2)mCi-6 alkoxy, -(CH2)n(CHR7)s(CH2)mC3-8 cycloalkyl, -(CH2)n(CHR7)s(CH2)mC3-10 heterocyclyl, - (CH2)nC5-io heteroaryl, or -(CH2)n(CHR7)s(CH2)mC6-10 ∞yU said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups selected from Ra;
R3 represents hydrogen, C] .10 alkyl, -(CH2)n(CHR7)s(CH2)mC3-8 cycloalkyl, - (CH2)n(CHR7)s(CH2)mC3-10 heterocyclyl, -(CH2)n(CHR7)s(CH2)rnC5-10 heteroaryl, or - (CH2)n(CHR7)s(CH2)mC6-10 3W^ sa*d alkyl, cycloalkyl, alkoxy, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups of Ra; and all other variables are as described herein.
A sub-embodiment of the compounds of formula EL is realized when Ri is C\-6 alkyl, optionally substituted with 1 to 3 groups of Rb. Examples of C\.β alkyls are t-butyl, ethyl, isopropyl, methyl and the like. Another sub-embodiment of the compounds of formula II is realized when Rl is hydrogen. Still another sub-embodiment of the compounds of formula II is realized when Ri is (CH2)nC6-l 0 aryU optionally substituted with 1 to 3 groups of Rb. Yet another sub-embodiment of the compounds of formula H is realized when Ri is (CH2)nC3-10 cycloalkyl, optionally substituted with 1 to
3 groups of Rb.
Another sub-embodiment of the compounds of formula II is realized when R2 and R3 are independently Ci-io alkyl, -(CH2)n(CHR7)s(CH2)mC6- 10 aryl, (CH2)n(CHR7)s(CH2)rnC3_io heterocyclyl, said alkyl, heterocyclyl, aryl optionally substituted with 1-3 groups selected from Ra.
Another sub-embodiment of the compounds of formula II is realized when R2 and R3 are independently hydrogen, Ci_io alkyl, said alkyl, optionally substituted with 1-3 groups selected from Ra.
Examples of compounds to be used in this invention are:
ΛyV-Dibutyl-2-(3-te/-^-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide,
2-(3-rer?-butyI-7-methoxy-2-oxoquinolin-l(2H)-yl)-Nr?V-bis(3-methylbutyI)acetamide,
2-(3-7e/-f-butyl-7-methoxy-2-oxoquinolin-l(2H)-yI)-N-(cycIopropylmethyl)-N-propyIacetamide,
2-(3-7'err-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N^v*-diisobutylacetamide,
2-(3-re?-/-butyl-7-methoxy-2-oxoquinolin-l(2/ϊ)-yl)-N-(3,3-dimethylbutyl)-iV-ethylacetamide,
2-(3-re^-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-propylacetamide,
2-(3-rer/-butyl-7-methoxy-2-oxoquinolin-l(2//)-yl)-N-(2,2-dimethyIpropyl)-N-ethylacetamide,
2-(3-rβ^-butyl-7-methoxy-2-oxoquinolin-l (2H)-yl)-N-ethyl-iV-(3-methylbutyl)acetamide,
2-(3-rerf-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iv'-(3-methyIbutyl)-N-propylacetamide, N-Butyl-2-(3-terf-butyl-7-rnethoxy-2-oxoquinoIin-l(2H)-yl)-N-(3-methylbutyl)acetamide,
2-(3-re^butyl-7-me1hoxy-2-oxoquinolin-l(2H)-yl)-N-(2-hydroxyethyl)-N-(3-methylbutyl)acetamide,
2-(3-7er/-butyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-N-isobutyl-Λ'-propylacetamide,
N-butyl-2-(3-ter/-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)--V-isobutylacetamide,
2-(3-rer/-butyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-N-(3-hydroxy-2,2-dimethylpropyl)-N-(3- methylbutyl)acetamide,
2-(3-rer/-butyI-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-(5-hydroxy-4,4-dimethylpentyI)-7Sr-(3- methylbutyl)acetamide,
2-(3-rert-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-ΛT-(353-dimethy]butyl)-N-(3-hydroxy-2,2- dimethylpropyl)acetamide,
2-(3-Je7-/-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethyIbutyl)-N-(2-hydroxy-2- methylpropyl)acetamide,
2-(3-rer/-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(5-hydroxypentyl)-N-(3-methylbutyl)acetamide,
2-(3-rert-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-(5- hydroxypentyl)acetamide,
2-(3-rert-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-(2-hydroxy-l,l- dimethylethyl)acetamide,
3-re/-r-butyl-l-(3,3-dimethyl-2-oxobutyl)-7-methoxyquinolin-2(lH)-one5
N,iV-Dibutyl-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide,
NyN-Diisobutyl-2-(3-isopropyI-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide,
Figure imgf000008_0001
N-(3,3-Dimethylbuty!)-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-propylacetamide,
2-(3-Isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-octyl-iV-pentylacetamide,
N-Ethyl-2-C3-isopropyl-7-methoxy-2-oxoquinolin-l (2B)-yl)-N- 1 ,3-thiazol-2-ylacetamide, (±)-3-Isopropyl-7-methoxy-l-{2-[trans-octahydroisoquinolin-2(lH)-yl]-2-oxoethyl}quinolin-2(lH)-one,
N^V-Bis(2,2-dimethylpropyl)-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide,
2-(3-Isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3-methylbutyl)-N-propylacetamide,
N-ButyI-2-(3 -isopropy l-7-methoxy-2-oxoquinolin- 1 (2H)-yl)-7V-(3-methylbuty l)acetamide,
N-Isobutyl-2-(3-isopropyl-7-methoxy-2-oxoquinoIin-l(2H)-yI)-N-propylacetamideJ
N-Butyl-N-isobutyl-2-(3-isopropyI-7-methoxy-2-oxoquinoIin-l(2H)-yl)acetamide,
N-(5-Ηydroxy-4;,4-dimethylpentyI)-2-(3-isopropyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-JV-(3- methylbutyl)acetamide,
N-(3,3-Dimethylbutyl).-N-(5-hydroxypentyl)-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2H)- yl)acetamide,
N,N-Dibutyl-2-(3-cyclohex.yI-7-methoxy-2-oxoquinoΗn-l(2H)-yl)acetamide>
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N,7V-dipropylacetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoqu inolin- 1 (2H)-yl)-JV-(cycloproρy ImethyI)-N-propy!acetamide,
N-Cyclohexyl-2-(3-cyclohexyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-iV-ethylacetamide,
- 1 - 2-(3 -Cyclohexy l-7-methoxy-2-oxoquinolin- 1 (2H)-yl)-N^V-diisobuty lacetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-y])-Nr/V-bis(3-methylbutyl)acetamide,
2-(3 -Cyclohexyl-J-methoxy-^-oxoq uinolin- 1 <2H)-y l)-N-ethyl-jV-(3 -methy Ibutyl)acetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-(3,3-dimethylbutyl)-N-ethylacetamide,
2-(3-CyclohexyI-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethylbutyI)-N-propylacetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yI)-N-(2,2-dimethylpropyl)-N-ethylacetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N'-(3-methylbutyl)-N-propylacetamide,
N-Butyl-2-(3-cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3-methylbutyl)acetarnideJ
2-(3-Cyclohexyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-JV'-methyl-iV-(3-methyIbutyl)acetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(2-hydroxyethyl)-N-(3-methylbutyl)acetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-ethyl-N-isobutylacetamide:>
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-isobutyl-N-propylacetamide:,
N-Butyl-2-(3-cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yI)-N-isobutyIacetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinoliπ-l(2H)-yl)-N-(3-hydroxy-2,2-dimethylpropyl)-N-(3- methylbutyl)acetamide,
N-(353-Dimethylbutyl)-2-(7-methoxy-2-oxo-3-phenylquinoIin-l(2H)-yl)-N-propylacetainide
ΛyV-Dibutyl-2-(7-methoxy-2-oxo-3-phenyIquinolin-l(2H)-yl)acetamide,
N-(CycIopropylmethyl)-2-(7-methoxy-2-oxo-3-phenylquinolin-l(2H)-yl)-N-propyIacetamide,
ΛyV-Diisobutyl-2-(7-methoxy-2-oxo-3-phenylquinolin-l(2/Z)-yl)acetamide,
2-(7-Methoxy-2-oxo-3-phenylquinolin-](2H)-yl)-N,iV-bis(3-methylbutyl)acetaniide, iV-Ethyl-2-(7-methoxy-2-oxo-3-phenylquinoI in- 1 (2H)-yl)-N-(3-methylbutyl)acetamide,
N-(3,3-Dimethylbutyl)-N-ethyl-2-(7-methoxy-2-oxo-3-phenylquinoIin-l(2H)-yl)acetamide,
N-(2,2-Dimethylpropyl)-N-ethyl-2-(7-methoxy-2-oxo-3-phenylquinolin-l(2H)-yl)acetamide5
2-(3-Ethyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-N^V-bis(3-methyIbutyl)acetatnide,
N-(3,3-Dimethylbutyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-propylacetamide,
ΛζN-Bis(3,3-dimethylbutyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide,
ΛζN-Bis(252-dimethylpropyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yI)acetamide,
N-Butyl-iV-(2,2-dimethylpropyl)-2-(3-ethyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)acetamide,
N-(2:i2-DimethylpropyI)-2-(3-ethyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-iV-pentylacetamide,
N-(2,2-Dimethylpropyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3-methylbutyI)acetamide,
N-Cyc!opentyl-iV-(2,2-dimethylpropyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide3
N-(3,3-Dimethylbutyl)-N-(2,2-dimethyIpropyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yI)acetamide,
N-ButyI-N'-(3,3-dimethylbutyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide,
N-(3,3-Dimethylbutyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-pentylacetamide,
N-Cyclopentyl-iV'-(353-dimethylbutyl)-2-C3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yI)acetarnide,
N-Butyl-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3-methylbutyl)acetamide.
ΛζN-Dibutyl-2-(3-cyclopentyl-7-πiethoxy-2-oxoquinoliπ-l(2H)-yl)acetamide, 2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-7vr,N-dipropylacetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(cyclopropylmethyl)-N-propylacetamide,
N-Cyclohexyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-ethylacetamide,
N-Butyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-ethylacetamide:>
2-(3-CycIopentyl-7-methoxy-2-oxoquinolin-](2H)-yI)-NJN-diisobutylacetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoqu inolin- 1 (2H)-yl)-ΛζN-bis(3-methylbutyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-ethyl-N'-(3-methylbutyl)acetamide,
N-Butyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-ρroρylacetamide,
2-(3-Cyclopen(yl-7-methoxy-2-oxoquinolin-l(2J^-yl)-N-(3,3-dimethylbutyl)-N-ethylacetarnide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-(353-dimethylbutyI)-N-propylacetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-Λ'"-(2,2-dimethylpropyl)-Λr-ethylacetarnide,
N-Cyclohexyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yI)-iV-isopropylacetamide,
2-(3-Cyclopentyl-7-methoxy-2-oXoquinolin-l(2H)-yl)-N,N-bis(3,3-dimethylbutyl)acetamide5
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-octyl-N-pentylacetamide,
N-(sec-Butyl)-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-propylacetamide,
2-(3-Cyc1opentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-ethyl-N-I,3-thiazol-2-ylacetamide,
(±)-3-Cyclopentyl-7-methoxy-l-{2-trans-octahydroisoquinolin-2(lH)-yl]-2-oxoβthyl}quinolin-2(IH)-one,
N-Butyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(2,2-dimethylpropyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-7V-(2,2-dimethylpropyl)-N-pentylacetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(2,2-dimethylpropyl)-N-(3- methylbutyl)acetamide,
N-Cyclopentyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(2,2-dimethylpropyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin- 1 (2H)-yl)-iV-(3 ,3-dimethylbutyl)-N-(2,2- d imethy lpropyl)acetamide,
N-Butyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-N-(3,3-dimethylbutyl)acetamideJ
2-(3-CyclopentyI-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-(353-dimethylbutyl)-N-pentyIacetamide,
N-Cyclopentyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3:)3-dimethylbutyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-(3- methylbutyOacetamide,
2-(3-Cyclopentyl-7-rnethoxy-2-oxoquinolin-l(2H)-yl)-iV-(3--nethylbutyl)-N-propylacetaπiide>
N-Butyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3-methylbutyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-methyl-N-(3-methylbutyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-N-(2-hydroxyethyl)-N-(3-methyIbutyl)acetamide:)
2-(3-CycIopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-ethyl-N-isobutylacetamide,
2-(3-Cyclopen<yl-7-methoxy-2-oxoquinolin-l(2H)-yl)--V-isobutyl--V-propylacetamide,
N-Butyl-2-(3-cyclopentyl-7-raethoxy-2-oxoquinolin-l(2H)-yl)-N-isobutylacetamide,
Figure imgf000011_0001
Figure imgf000012_0001
The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E.L. Eliel and S.H. Wileπ Stereochemistry of Carbon Compounds (John Wiley and Sons, New York 1994), in particular pages 1119-1190)
When any variable (e.g. aryl, heterocycle, Ri, R4 etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
When Ra is -O- and attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.
The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl cyclopentyl and cyclohexyl. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group".
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, unless otherwise defined, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings, which can be fused. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Alkenyl is C2-C6 alkenyl.
Alkoxy refers to an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, with the alkyl group optionally substituted as described herein. Said groups are those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
Halogen (halo) refers to chlorine, fluorine, iodine or bromine.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Examples of aryl groups are phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl and phenanthrenyl, preferably phenyl, naphthyl or phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl. The term heterocyclyl or heterocyclic, as used herein, represents a stable 3- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O5 and S5 and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. The term heterocycle or heterocyclic includes heteroaryl moieties. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzϊmidazolyl, benzisoxazolyl, benzofurazanyl, benzόpyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydropyrrolyl, 1,3- dioxolanyl, furyl, imidazolidinyl, imidazoiinyl, imidazolyl, indolinyl, indolyl, isochxomanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazoHdinyl, moφholinyl, naphthyridinyl, oxadiazolyl, 2- oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl. tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamoφholinyl sulfoxide, thiazolyl, thtazolinyl, thienofuryl, thienothienyl, and thienyl. Preferably, heterocycle is selected from 2-azepinonyl, benzimidazolyl, 2-diazapinonyl, dihydroimidazolyl, dihydropyrrolyl, imidazolyl, 2-imidazolidinonyl, indolyl, isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidinyl, 2-piperidinonyl, 2-pyrimidinonyl, 2-pyrollidinonyl, quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.
The term "heteroatom" means O, S or N, selected on an independent basis.
The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S3 and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, thienyl and triazolyl. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole. In addition, the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted. For example, any claim to compound A below is understood to include tautomeric structure B, and vice versa, as well as mixtures thereof.
Figure imgf000015_0001
B
This invention is also concerned with compositions and methods of treating ocular hypertension or glaucoma by administering to a patient in need thereof one of the compounds of formula I in combination with one or more of a β-adrenergic blocking agent such as timolol, betaxolol, levobetaxolol, carteolol, levobunolol, a parasympathomimetic agent such as epinephrine, iopidine, brimonidine, clonidine, para-aminoclonidine, carbonic anhydrase inhibitor such as dorzolamide, acetazolamide, metazolamide or brinzolamide, an EP4 agonist (such as those disclosed in WO 02/24647, WO 02/42268, EP 1114816, WO 01/46140 and WO 01/72268), a prostaglandin such as latanoprost, travaprost, unoprostone, rescula, S 1033 (compounds set forth in US Patent Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444); a hypotensive lipid such as lumigan and the compounds set forth in US Patent No. 5,352,708; a neuroprotectant disclosed in US Patent No. 4,690,931, particularly eliprodil and R- eliprodil as set forth in WO 94/13275, including memantine; or an agonist of 5-HT2 receptors as set forth in PCT/USOO/31247, particularly ]-(2-aminopropyl)-3-methyl-lH-imdazol-6-ol fumarate and 2-(3- chloro-6-methoxy-indazol-l-yl)-l-methyl-ethylamine. An example of a hypotensive lipid (the carboxylic acid group on the D-chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents) is that in which the carboxylic acid group is replaced with a Cj_6 alkoxy group such as OCH3 (PGF2a I-OCH3), or a ammalia group (PGF2a 1-OH). •
Preferred potassium channel blockers are calcium activated potassium channel blockers. More preferred potassium channel blockers are high conductance, calcium activated potassium (Maxi-K) channel blockers. Maxi-K channels are a family of ion channels that are prevalent in neuronal, smooth muscle and epithelial tissues and which are gated by membrane potential and intracellular Ca2+.
The present invention is based upon the finding that maxi-K channels, if blocked, inhibit aqueous humor production by inhibiting net solute and H2O efflux and therefore lower IOP. This finding suggests that maxi-K channel blockers are useful for treating other ophthamological dysfunctions such as macular edema and macular degeneration. It is known that lowering IOP promotes blood flow to the retina and optic nerve. Accordingly, the compounds of this invention are useful for treating macular edema and/or macular degeneration.
It is believed that maxi-K channel blockers which lower IOP are useful for providing a neuroprotective effect. They are also believed to be effective for increasing retinal and optic nerve head blood velocity and increasing retinal and optic nerve oxygen by lowering 1OP3 which when coupled together benefits optic nerve health. As a result, this invention further relates to a method for increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension as well as providing a neuroprotective effect or a combination thereof.
A number of marketed drugs function as potassium channel antagonists. The most important of these include the compounds Glyburide, Glipizide and Tolbutamide. These potassium channel antagonists are useful as antidiabetic agents. The compounds of this invention may be combined with one or more of these compounds to treat diabetes.
Potassium channel antagonists are also utilized as Class 3 antiarrhythmic agents and to treat acute infarctions in humans. A number of naturally ammalian toxins are known to block potassium channels including Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, and β-Bungarotoxin (β-BTX). The compounds of this invention may be combined with one or more of these compounds to treat arrhythmias.
Depression is related to a decrease in neurotransmitter release. Current treatments of depression include blockers of neurotransmitter uptake, and inhibitors of enzymes involved in neurotransmitter degradation which act to prolong the lifetime of neurotransmitters.
Alzheimer's disease is also characterized by a diminished neurotransmitter release. Three classes of drugs are being investigated for the treatment of Alzheimer's disease cholinergic potentiators such as the anticholinesterase drugs (e.g., physostigmine (eserine), and Tacrine (tetrahydroaminocridine)), nootropics that affect neuron metabolism with little effect elsewhere (e.g., Piracetam, Oxiracetam; and those drugs that affect brain vasculature such as a mixture of ergoloid mesylates amd calcium channel blocking drugs including Nimodipine. Selegiline, a monoamine oxidase B inhibitor which increases brain dopamine and norepinephrine has reportedly caused mild improvement in some Alzheimer's patients. Aluminum chelating agents have been of interest to those who believe Alzheimer's disease is due to aluminum toxicity. Drugs that affect behavior, including neuroleptics, and anxiolytics have been employed. Anxiolytics, which are mild tranquilizers, are less effective than neuroleptics The present invention is related to novel compounds which are useful as potassium channel antagonists.
The compounds within the scope of the present invention exhibit potassium channel antagonist activity and thus are useful in disorders associated with potassium channel malfunction. A number of cognitive disorders such as Alzheimer's Disease, memory loss or depression may benefit from enhanced release of neurotransmitters such as serotonin, dopamine or acetylcholine and the like. Blockage of Maxi-K channels maintains cellular depolarization and therefore enhances secretion of these vital neurotransmitters.
The compounds of this invention may be combined with anticholinesterase drugs such as physostigmine (eserine) and Tacrine (tetrahydroaminocridine), nootropics such as Piracetam, Oxiracetam, ergoloid mesylates, selective calcium channel blockers such as Nimodipine, or monoamine oxidase B inhibitors such as Selegiline, in the treatment of Alzheimer's disease. The compounds of this invention may also be combined with Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, β-Bungarotoxin (β-BTX) or a combination thereof in treating arrythmias. The compounds of this invention may further be combined with Glyburide, Glipizide, Tolbutamide or a combination thereof to treat diabetes.
The herein examples illustrate but do not limit the claimed invention. Each of the claimed compounds are potassium channel antagonists and are thus useful in the decribed neurological disorders in which it is desirable to maintain the cell in a depolarized state to achieve maximal neurotransmitter release. The compounds produced in the present invention are readily combined with suitable and known pharmaceutically acceptable excipients to produce compositions which may be administered to mammals, including humans, to achieve effective potassium channel blockage.
For use in medicine, the salts of the compounds of formula I will be.pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted, amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, NjN'-dibenzylethylenediamiπe, diethylamin, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionϊc, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977:66:1-19. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.
The maxi-K channel blockers used can be administered in a therapeutically effective amount intravaneously, subcutaneously, topically, transdermally, parenterally or any other method known to those skilled in the art.
Ophthalmic pharmaceutical compositions are preferably adapted for topical administration to the eye in the form of solutions, suspensions, ointments, creams or as a solid insert. Ophthalmic formulations of this compound may contain from 0.01 ppm to 1% and especially 0.1 ppm to 1% of medicament. Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in reducing intraocular pressure, treating glaucoma, increasing blood flow velocity or oxygen tension. For a single dose, from between 1 ng to 500ug, preferably 1 ng to 500 ug, of the compound can be applied to the human eye.
The pharmaceutical preparation which contains the compound may be conveniently admixed with a non-toxic pharmaceutical organic carrier, or with a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethyl-cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and the like. Additionally, suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like. The pharmaceutical preparation may also be in the form of a microparticle formulation. The pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament. The polymer used to form the insert may be any water soluble non-toxic polymer, for example, cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, (hydroxyloweralkyl cellulose), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; acrylates such as polyacrylic acid salts, ethylacrylates, polyactylamides; natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia; the starch derivatives such as starch acetate, hydroxymethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrol idone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum, gellan gum, and mixtures of said polymer.
Suitable subjects for the administration of the formulation of the present invention include primates, man and other animals, particularly man and domesticated animals such as cats and dogs.
The pharmaceutical preparation may contain non-toxic auxiliary substances such as antibacterial components which are non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenylethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethyl enediamine tetraacetic acid, and the like.
The ophthalmic solution or suspension may be administered as often as necessary to maintain an acceptable IOP level in the eye. It is contemplated that administration to the ammalian eye will be about once or twice daily.
For topical ocular administration the novel formulations of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of the active component or some multiple thereof in the case of a combination therapy.
Definitions of the terms used in the examples are as follows: SM - Starting material, DMSO - dimethyl sulfoxide, TLC — thin layer chromatography, SGC — silica gel chromatography, PhMgBr - phenylmagnesiumbromide h = hr = hour, THF — tetrahydrofuran, DMF — dimethylformamide, min — minute,
JLC/MS — liquid chromatography/mass spectrometry, HPLC - high performance liquid chromatography,
PyBOP — Benzotriazol-1-yloxytris-pyrrolidino-phosphonium hexafluorophosphate, equiv = eq = equivalent, NBS — N-Bromosuccinamide,
AIBN — 2,2'-azobisisobutyronitrile, DCM - Dichloromethane, mCPBA — meta-Chloroperbenzoic acid,
TFA - Trifluoroacetic acid,
DIEA - N1N-Di isopropylethylamine,
HOBt - 1-Hydroxybenzotriazole hydrate,
EDC - N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, and
HOAt - l-Hydroxy~7-azabenzotriazole.
The following examples given by way of illustration are demonstrative of the present invention.
Several methods are known in the literature for the preparation of the core structure of quinoli-2(lH)-one. For example, Turner (J. Org. Chem. 1990, 55, 4744) and Nielsen et al. (J. Amer. Chem. Soc. 2002, 124, 3254) have both published approaches to the core structure of quinoli-2(lH)-one and some of the aza derivatives. The reaction sequence shown in Scheme 1 uses the method of Turner for the preparation of the quinoli-2(lH)-one core. The substituted benzaldehyde A was prepared by standard method. It was converted to substituted quinoli-2(lH)-one B using the method of Turner. Subsequent alkylation with bromo-ketones gave two isomeric products, which can be separated either on silica gel or using RP-HPLC. Analoguous alkylation of B using bromo-esters also afforded two isomeric products which can be separated using the same methods. Following hydrolysis of the esters to acid, standard amide formation reactions can be applied to provide amides.
SCHEME l
Figure imgf000021_0001
Two isomeric 4-aza-quinoli-2(lH)-ones can be synthesized by the reaction of an α-keto- acid with o-phenylenediamine (Scheme T). The two isomers were separated on silica gel. Similar transformations as in Scheme 1 provide ketone or amide derivatives of interest.
SCHEME 2
-NH, t-BuCOCO2H
NH, HOAc, 48°C
Figure imgf000022_0001
Figure imgf000022_0002
A similar method as in Scheme 2 can be used to prepare substituted pyrido[2,3- έ]pyrazin-3(4H)-one (Scheme 3). An alternative method is shown in Scheme 4.
SCHEME 3
Figure imgf000023_0001
or HOAc, 48°C
Figure imgf000023_0002
SCHEME 4
Figure imgf000023_0003
Using the modified method of Turner, the core heterocycle of l,8-naphthyridin-2(lH)- one can be prepared as shown in Scheme 5. Substituted analogues could be prepared from a more elaborated starting material or obtained by further transformation of the un-substituted heterocycle using the method depicted in Schemes 6 and 7.
Figure imgf000024_0001
SCHEME 7
λv° POC|3 »
Figure imgf000025_0001
Similarly, the core heterocycle of.l,6-naphthyπdin-2(lH)-one 1 can be prepared as shown in Scheme 8. Substituted analogues could be prepared from a more elaborated starting material or obtained by further transformation of the un-substituted heterocycle using the method depicted in Scheme 9.
SCHEME 8
(4:I) m>=rowave, 16O0C, 2 hr
Figure imgf000025_0002
Figure imgf000025_0003
Figure imgf000025_0004
Figure imgf000025_0005
SCHEME 9
Figure imgf000026_0001
Preparation of phosphates of hydroxyl amides are illustrated in Schemes 10 and 11.
SCHEME 10
1) tetrazole in MeCN O0°H +
Figure imgf000026_0002
2) m-CPBA in CH2CI2
Figure imgf000026_0003
Figure imgf000026_0004
SCHEME 1 1
Figure imgf000026_0005
Figure imgf000027_0001
(3-Terϊ-butyl-7-methoxy-2-oxoquinolin-l(2H)-yI)acetic acid Step A. l-(DibromomethyI)-4-methoxy-2-nitrobenzene
The title compound was prepared from 4-methoxy-l-methyl-2-nitrobenzene using the method of Suvorov, N. N.; et al.; J Gen Chem USSR (Engl Transl) 1960, 30, 3118 and purified using silica gel column with 100:7 hexanes and ethyl acetate. 1HMMR in CDCl3 at 500 MHz: 7.57 (d, 2.5Hz, IH), 7.48 (d, 9.0Hz, IH), 7.15(dd, 9 Hz, 2.5 Hz, IH), 4.82 (s, 2H), 3.91 (s, 3H).
Step B: 4-Methoxy-2-nitrobenzaldehyde
The title compound was prepared from ]-(dibromomethyl)-4-methoxy-2-nitrobenzene using the method of Suvorov, N. N.; et al.; J Gen Chem USSR (Engl Transl) 1960, 30, 3118 and purified using silica gel column with 5:1 hexanes and ethyl acetate followed by methylene chloride. 1H NMR in CDCI3 at 500 MHz: 10.32 (s, IH), 8.01 (d, 8.5 Hz, IH), 7.54 (d, 2.5 Hz, IH), 7.26 (dd, 8.5 Hz, 2.5 Hz, IH), 3.99 (s, 3H).
Step C: Ethyl 2-[hydroxy(4-methoxy-2-nitrophenyl)methyl]-3,3-dimethylbutanoate
A 2 M solution of LDA in heptane/THF/ethylbenzene (15.2 mL) was added to a mixture of 4.0 g ethyl 3,3-dimethyIbutanoate in 100 mL anhydrous THF at -78 0C. 4-methoxy-2-nitrobenzaldehyde (5.0 g) from the step above was added to the reaction mixture. The resulting mixture was stirred for 2 hours and was allowed to warm to room temperature. The reaction was quenched by addition of 2 mL water. Solvents were removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic extract was washed with 1 N HCl and NaHCO3. The resulting crude product was purified on silica gel using 100:15 hexanes and EtOAc to give two diastereomeric isomers of the title compound. 1H NMR in CDCl3 at 500 MHz of the less polar pair of isomers: 7.56 (d, 9 Hz, IH), 7.52 (d, 2.5 Hz, IH), 7.16 ( dd, 9 Hz, 2.5 Hz, IH), 5.73 ( d, 8.5 Hz, IH), 4,84 (d, 9.5 Hz, IH), 4.10-3.95 ( m, 2H), 3.88 ( s, 3H), 2.64 (d, 2 Hz, IH), 1.20 (s, 9H), 1.09 (t, 7 Hz, 3H)
Step D: Ethyl 2-[(2-amino-4-methoxyphenyl)(hydroxy)methyl]-3,3-dimethylbutanoate
A solution of 2.5 g ethyl 2-[hydroxy(4-methoxy-2-nitrophenyl)methyI]-3,3-dimethylbutanoate from the step above in 100 mL ethanol was treated with a catalytic amount of 10% Pd/C and a hydrogen balloon overnight. The reaction mixture was then filtered and concentrated under reduced pressure to give title compound.
Figure imgf000028_0001
(3-Isopropyl-2-oxoquinolin-l(2H)-yl)acetic acid The title compound was prepared using the procedure described in Steps C~G of Preparative Example 1 and starting with methyl 3-methylbutanoate and 4-methoxy-2-nitrobenzaldehyde. LC-MS: 3.15 min. (m/Z 217.1). 1H NMR in DMSO-d6 at 500 MHz: 7.69 (s, IH), 7.63 (d, 8.5 Hz, IH), 6.87 (dd, 8.5 Hz, 2 Hz, IH), 6.79 (d, 2 Hz, IH), 5.00 (s, 2H), 3.83 (s, 3H), 3.09-3.04 (m, IH), 1.16 (d, 7 Hz, 6H).
Figure imgf000029_0001
(3 -Cyclohexyl-2-oxoquinolin- 1 (2H )-yl)acetic acid
The title compound was prepared using the procedure described in Steps C~G of Preparative Example 1 and starting with methyl 3-methylbutanoate and 4-methoxy-2-nitrobenzaldehyde. 1H NMR in DMSOd6 at 500 MHz: 7.65 (s, IH), 7.62 (d, 9 Hz, IH), 6.86 (dd, 9 Hz, 2.5 Hz, IH), 6.78 ( d, 2 Hz, IH), 4.98 (s, 2H), 3.82 (s, 3H), 2.75-2.7] (m, IH), 3.09-3.04 (m, IH), 1.82-1.69 (m, 5H), 1.39-1.18 (m, 5H).
Figure imgf000029_0002
(2-Oxo-3-phenylquinolin-l(2H)-yI)acetic acid
The title compound was prepared using the procedure described in Steps C~G of Preparative Example 1 and starting with methyl phenyl acetate and 4-methoxy-2-nitrobenzaldehyde. 1H NMR in DMSOd6 at 500 MHz: 8.09 (s, IH), 7.74 (d, 9 Hz, IH), 7.70 (d, 7.5 Hz, 2H), 7.41 (t, 7.5 Hz, 2H), 7.34 ( t, 7.5 Hz, IH), 6.93 (dd, 8.5 Hz, 2 Hz, IH), 6.89 (s, IH), 5.06 (s, 2H), 3.87 (s, 3H).
Figure imgf000029_0003
3,3-Dimethyl-iV-propylbutan-l-amine hydrochloride
A mixture of 25 mL 3,3-dimethylbutyradehyde, 11.77 g (16.4 mL) n-propylamine, and 20 g dry 10-16 mesh 4 A molecular sieve in 200 mL hexanes was heated at 600C for 10 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give sticky oil. The latter was treated with 40 psi hydrogen with catalytic amount of 10% Pd/C in EtOAc for 4 hours. The reaction mixture was filtered. The concentrated filtrate was treated with 1 M HCI/ether to give title compound as a white solid. LC-MS: 2.31 min. (m/Z 144.7). 1H NMR in DMSOd6 at 500 MHz: 2.98-2.89 (m, 4H), 1.99-1.94 (m, 2H), 1.86-1.82 (m, 2H), 1.25 (t, 3.5 Hz3 3H), 0.96 (s, 9H).
Preparative Example 6
\ l H
HCl N-(2,2-dimethylpropyl)-2,2-dimethylpropan- 1-amine hydrochloride
The title compound was prepared using the procedure described in Preparative Example 5 and starting with trimethyl acetaldehyde and 2,2-dimethylpropylamine. LC-MS: 1.95 min. (m/Z 158.2). 1H NMR in DMSOd6 at 500 MHz: 2.98-2.96 (m, 4H), 1.02 (s, 18 H).
Preparative Example 7
Figure imgf000030_0001
N-(3,3-dimethylbutyl)-3,3-dimethylbutan-l -amine hydrochloride
The title compound was prepared using the procedure described in Preparative Example 5 and starting with trimethyl acetaldehyde and 2,2-dimethylpropylamine. LC-MS: 2.74 min. (m/Z 186.3). 1H ΝMR in DMSOd6 at 500 MHz: 2.64-2.61 (m, 4H), 1.43-1.40 (m, 4H), 0.92 (s, 18 H).
Preparative Example 8
Figure imgf000030_0002
(3-Ethyl-7-methoxy-2-oxoquinolin-l (2H)-yl)acetic acid
The title compound was prepared using the procedure described in Steps C~G of Preparative Example 1 and starting with methyl n-butanoate and 4-methoxy-2-nitrobenzaldehyde. 1H ΝMR in DMSOd6 at 500 MHz: 7.69 (s, IH), 7.60 (dd, 8.5 & 2.0 Hz, IH), 6.88 (dd, 8.5 & 2.0 Hz, 1 H), 6.80 (s, IH), 5.01 (s, 2H), 3.83 (s, 3H), 2.48 (q, 7.5 Hz, 2H), 1.47 (t, 7.5 Hz, 3H).
Preparative Example 9
Figure imgf000030_0003
[7-Methoxy-3-(l-methyl-l-phenylethyl)-2-oxoquinolin-l(2H)-yl]acetic acid Step A. 3-Methyl-3-phenylbutanoic acid A 0.5 M ether solution of 2-methyI-2-phenylpropylmagnesium chloride (795 mL) was cooled to - 78 0C and treated with carbon dioxide gas. The reaction mixture was slowly warmed up to room temperature. Work-up with EtOAc and aqueous HCl gave the title compound as sticky oil. 1H NMR in CDCl3 at 500 MHz: 7.41 (d, 8.0 Hz, 2H), 7.36 (t, 8.0 Hz, 2H), 7.24 (dt, 7.5 & 1.0 Hz, IH), 2.69 (s, 2H), 1.51 (s, 6H).
Step B. Methyl 3-methyl-3-phenylbutanoate
3-Methyl-3-phenylbutanoic acid (33 g) from the Step A above and 300 g cesium carbonate was refluxed in 450 mL 3:1 THF and DMF. Methyl iodide (57 mL) was added slowly over 5 hours. The resulting mixture was refluxed for 10 hours. Aqueous EtOAc work-up and silica gel column purification using 10:1 hexanes and EtOAc afforded the title compound as colorless oil. 1H NMR in CDCI3 at 500 MHz: 7.41 (d, 8.0 Hz, 2H)5 7.34 (t, 8.0 Hz, 2H), 7.23 (dt, 7.5 & 1.0 Hz, IH), 3.56 (s, 3H), 2.66 (s, 2H), 1.49 (s, 6H).
Steps C-G. [7-Methoxy-3-(l-methyl-l-phenylethyl)-2-oxoquinolin-l(2H)-yl]acetic acid
The title compound was prepared using the procedure described in Steps C-G of Preparative Example 1 and starting with methyl 3-methyl-3-phenylbutanoate and 4-methoxy-2-nitrobenzaIdehyde. LC-MS: 3.32 min. (m/Z 352.1). 1HNMR in DMSO-d6 at 500 MHz: 7.93 (s, IH), 7.74 (d, 8.5 Hz, IH), 7.20-7.16 (m, 4H), 7.09-7.06 (m, IH), 6.90 (dd, 8.5 & 2.0 Hz, IH), 7.62 (d, 2.0 Hz, IH), 4.85 (s, 2H), 3.84 (s, 3H), 1.62 (s, 6H).
Preparative Example 10
Figure imgf000031_0001
(7-Methoxy-2-oxoquinolin-l (2H)-yl)acetic acid Step A. 7-Methoxyquinolϊn-2(lH)-one
The title compound as isolated as a side-product from Step E of Preparative Example 9. LC-MS: 2.07 min. (m/Z 176.1). 1H NMR in DMSO-d6 at 500 MHz: 7.79 (d, 9.5 Hz, IH), 7.54 (d, 8.5 Hz, IH), 6.79-6.76 (m, 2H), 6.28 (d, 9.5 Hz, IH), 3.79 (s, 3H).
Steps B and C. (7-Methoxy-2-oxoquinolin-l(2H)-yl)acetic acidThe title compound was prepared using the procedure described in Steps F-G of Preparative Example 1 and starting with 7-methoxyquinolin- 2(lH)-one from the Step A above. 1HNMR in DMSO-d6 at 500 MHz: 7.87 (d, 9.5 Hz3 IH), 7.65 (d, 8.5 Hz, IH), 6.90 (dd, 8.0 Hz, 2.0 Hz3 IH), 6.83 (d, 2.0 Hz5 IH), 6.43 (d, 9.0 Hz5 IH), 4.99 (s, 2H), 3.84 (s, 3H). Preparative Example 11
Figure imgf000032_0001
353-Dimethyl-N-(3-methylbutyl)butan-l-amine hydrochloride
The title compound was prepared using the procedure described in Preparative Example 5 and starting with 3-methylbutyraldehyde and 3,3-dimethylbutylamine. LC-MS: 2.40 min. (rn/Z 172.2). 1H KMR in CDCl3 at 500 MHz: 2.91-2.88 (m. 4H), 1.79-1.73 (m, 4H), 1.74-1.66 (m, IH), 0.95 (s, 9H), 0.94 (s, 6H).
Preparative Example 12
Figure imgf000032_0002
N-Butyl-3 ,3 -dimethylbutan- 1 -amine hydrochloride
N-butyl-3,3-dimethylbutanamide was prepared from n-butylamine, t-butylacetyl chloride, and DIEA. The crude amide was reduced in refluxing benzene with 1.5 molar equiv. of LAH in 2 hours. The excess LAH was quenched with MeOH and 1 Ν KOH after cooling. The resulting mixture was filtered and the solid washed with ether. The residue from the organic layer was dissolved in ether and treated with 1 Ν HCl in ether to precipitate the title compound. 1H ΝMR in CD3OD at 500 MHz: 3.03-2.99 (m, 4H), 1.70-1.64 (m, 2H), 1.62-1.58 (m, 2H), 1.47-1.40 (m, 2H), 0.99 (t, 4.5 Hz3 3H), 0.98 (s, 9H).
Preparative Examples 13~26
The following compounds in Table 1 were prepared using the method described in Preparative Example 12. For Preparative Examples 27 the LAH reduction were done in refluxing THF. For Preparative Examples 28~29, they were conducted in boiling dioxane.
Table 1. Preparation of amines
Preparative Compound LC-MS, Example min. (m/Z)
Figure imgf000032_0003
Figure imgf000033_0001
Preparative Example 35
Figure imgf000034_0001
(3-Cyclopentyl-7-rnethoxy-2-oxoqumolin-l(2H)-yl)acetic acid
The title compound was prepared using the procedure described in Steps C-G of Preparative Example 1 and starting with methyl cyclopentylacetate and 4-methoxy-2-nitrobenzaldehyde. 1H NMR in DMSOd6 at 500 MHz: 7.71 (s, IH), 7.62 (d, 9.0 Hz, IH), 6.87 (dd, 8.5 & 1.5 Hz, IH), 6.78 (d, 1.5 Hz, IH), 5.00 (s, 2H), 3.82 ( s, 3H), 3.11 (m, IH), 1.93 (m, 2H), 1.73 (m, 2H), 1.62 (m, 2H), 1.53 (m, 2H).
Preparative Example 36
Figure imgf000034_0002
(7-Methoxy-3-methyl-2-oxoquinolin-lC2H)-yl)acetic acid
The title compound was prepared using the procedure described in Steps C-G of Preparative Example 1 and starting with ethyl propionate and 4-methoxy-2-nitrobenzaldehyde. LC-MS: 2.44 min. (m/Z 248.1). 1H NMR in DMSO-d6 at 500 MHz: 7.74 (s, IH), 7.56 (d, 8.5 Hz, IH), 6.88 (dd, 8.5 Hz, 2.0 Hz, IH), 6.80 (d, 2.0 Hz, IH), 5.00 (s, 2H), 3.83 ( s, 3H), 2.07 (s, 3H).
Preparative Example 37
Figure imgf000034_0003
2-[(3-Methylbutyl)amino]ethanol hydrochloride
To a mixture of 10 g N-isovaleroylglycine in 200 mL dry THF at 00C was added 200 mL 1 M LAH in THF. The resulting mixture was refluxed for 10 hrs. The reaction mixture was cooled, quenched, filtered, and concentrated under vacuum. The residue was treated with 1 M HCl in ether, washed with 1 : 1 hexanes and ether, and dried to give the title compound as a white solid. 1H NMR in CDCI3 at 500 MHz: 3.66 (t, 5.0 Hz, 2H), 2.79 (t, 5.0 Hz, 2H), 2.65 (t, 7.5 Hz, 2H), 1.65 (m, IH), 1.40 (m, 2H), 0.92 (d, 6.0 Hz, 6H).
Preparative Example 38
Figure imgf000034_0004
3-[(2-Cyclohexylethyl)amino]propan-l -ol hydrochloride
Cyclohexylacetic acid (20 g) was coupled with 13.7 g 3-hydroxypropylamine using 54 g EDC in the presence of 28.5 g HOBt and 86 mL DIEA in 200 mL dry DMF at room temperature. The reaction mixture was worked up using aqueous EtOAc. The organic extract was washed with 1 N HCl and NaHCO3. The crude white solid (7.38 g) was dissolved in benzene and treated with 74 mL 1 M LAH at 0 0C followed by refluxing for 10 hours. Usual work-up afforded the crude amine which was precipitated from ether with 1 N HCl in ether to give the title compound. LC-MS: 1.76 min. (m/Z 186.3). 1H NMR in CDCl3 at 500 MHz: 3.82 (t, 5.5 Hz, 2H), 3.11 (br s, 2H), 2.89 (t, 6.0 Hz52H), 2.64 (t, 7.5 Hz, 2H), 1.73- 1.64 (m, 7H), 1.38 (m, 2H), 1.33-1.11 (m, 4H), 0.90 (m, 2H).
Figure imgf000035_0001
3-[(2-CycIopentylethyl)amino]propan-l-ol hydrochloride
The title compound was prepared using the same method as described in Preparative Example 38. LC-MS: 1.56 min. (m/Z 172.2). 1H NMR in CDCl3 at 500 MHz: 3.82 (t, 5.5 Hz, 2H)5 2.89 (t, 5.5 Hz, 2H), 2.63 (t, 7.5 Hz, 2H), 1.81-1.73 (m, 3H), 1.70 (m, 2H), 1.61 (m, 2H), 1.450 (m, 4H), 1.10 (m, 2H).
Figure imgf000035_0002
2-[(2-Phenylethyl)amino]ethanol
The title compound was prepared using the same method as described in Preparative Example 37 from phenaceturic acid. LC-MS: 0.6
Figure imgf000035_0003
3-[(3-Methylbutyl)amino]propan-l-
The title compound was prepared by heating 30 g l-iodo-3-methylbutane and 13.7 g 3- aminopropan-1-ol in 200 mL DMF at 1000C in the presence of 65 g potassium carbonate for 12 hrs. Work-up and evaporation under vacuum gave the title compound as yellow oil. LC-MS: 0.34 min. (m/Z 146.1). 1H NMR in CDCl3 at 500 MHz: 3.81 (q, 6.0 Hz, 2H), 2.64 (m, 2H), 2.44 (m, 2H)3 1.70 (m, 2H), 1.56 (m, IH), 1.37 (m, 2H), 0.91 (d, 6.0 Hz, 6H).
Preparative Examples 42~46 The following compounds in Table 2 were prepared using the method described in Preparative Example 41. All compounds gave satisfactory 1H NMR.
Table 2. Preparation of hydroxylamines
Preparative Compound LC-MS, min. (m/Z) Example
Figure imgf000036_0001
Preparative Example 47
Figure imgf000036_0002
4-[(3,3-Dimethylbutyl)amino]-2-methylbutan-2-oI Step A. Ethyl N-(353-dimethylbutanoyl)-β-alaninate
Add 3.42 g 60% NaH oil dispersion to a solution of ethyl β-alaninate hydrochloride in 150 mL THF at room temperature and stir for 15 minutes. t-Butylacetyl chloride (10 g) was added to the reaction mixture followed by another portion of 3.42 g NaH. The reaction mixture was worked up with aqueous EtOAc after stirring for 6 hours at room temperature to give the title compound, which was used directly in the next step. LC-MS. 1.37 min (m/Z 188.3). 1H NMR in CD3OD at 500 MHz: 7.83 (br s, IH)5 3.28 (m, 2H), 2.04 (s, 2H), 1.67 (m, 2H), 1.22 (s, 6H), 1.01 (s, 9H).
Step B. 4-[(333-Dimethylbutyl)amino]-2-methylbutan-2-ol
A solution of 6.0 g ethyl N-(3,3-dimethylbutanoyl)-β-alaninate from the Step A above in 100 mL anhydrous THF was cooled to -78 0C and 38 mL 3 M methylmagnesium bromide in diethyl ether was added over one hour. The reaction mixture was allowed to warm up to room temperature and worked up using aqueous EtOAc to give crude hydroxyl amide intermediate. This crude product was dissolved in 100 mL anhydrous THF and reduced with 4 equiv. of LAH under refluxing for 2 hours. After cooling the reaction mixture, it was quenched with 1:1 water and methanol. -The title product was isolated with aqueous EtOAc work-up. LC-MS 0.38 min (m/Z 188.3). 1H NMR in CDCI3 at 500 MHz: 2.91 (t, 5.5 Hz, 2H)3 2.60 (m, 2H), 1.60 (t, 6.0 Hz, 2H), 1.38 (m, 2H)3 1.23 (s, 6H), 0.90 (s, 9H).
Figure imgf000037_0001
Step C. Methyl (2-te^butyl-6-methoxy-3-oxopyrido[2,3-&]pyrazm-4(3H)-yl)acetate
A mixture of about 2.1 g crude methyl iV-(6-tnethoxy-3-nitropyridin-2-yl)glycinate and 1.34 g 3,3-dimethyl-2-oxobutanoic acid in 30 mL acetic acid was heated at 48 0C overnight. Some solid side-product (6-methoxy-3,4-dihydropyrido[2,3-Z>]pyrazin-2(lH)-one) was filtered off and the filtrate was purified on SGC using 7:1 EtOAc and hexanes to give pure title compound. LC-MS: 3.72 min. (m/Z 306.1). 1H NMR (CDCl3, 500 MHz) δ: 8.01 (d, 8.7 Hz3 IH), 6.72 (d, 8.7 Hz, IH), 5.18 (s, 2H), 3.97 (s, 3H), 3.78 (s, 3H), 1.48 (s, 9H). 13C NMR (CDCl3, 125 MHz) 5: 168.73, 163.45, 162.67, 154.69, 141.59, 140.57, 122.68, 107.91, 54.39, 52.82, 42.12, 39.47, 28.02.
The title compound of Step C can also be obtained as follows. A mixture of 50 mg methyl N-(6- methoxy-3-πitropyridin-2-yI)glycinate, 37 mg 3,3-dimethyl-2-oxobutanoic acid, 48 mg HOBt, and 41.7 mg DIEA in 1 mL dry DMF was treated with 79.8 mg EDC. The title compound was isolated on RP- HPLC. Similar result was obtained using PyBOP instead of EDC.
Step D. (2-ter/-Butyl-6-methoxy-3-oxoρyrido[2,3-ά]pyrazin-4(3H)-yl)acetic acid
A mixture of 680 mg methyl (2-ter^butyl-6-methoxy-3-oxopyrido[2,3-δ]pyrazin-4(3H)-yl)acetate in 20 mL MeOH and 2 mL water was treated with 2.2 mL 5 Ν ΝaOΗ solution at room temperature overnight. The mixture was evaporated under vacuum and the residue taken up in 20 mL water and acidified with 6 Ν ΗCI to precipitate the title compound. It was obtained as white solid following filtration and drying. LC-MS: 3.25 min. (m/Z 292.1). 1H ΝMR (CDCl3, 500 MHz) δ: 8.02 (d, 8.7 Hz, IH), 6.74 (d, 8.5 Hz, 2H), 5.22 (s, 2 H), 3.98 (s, 3H), 1.47 (s, 9H).
Method B:
Step A. tert-Butyl N-(6-methoxy-3-nitropyridin-2-yl)glycinate
A mixture of 3.67 g 2-chloro-6-methoxy-3-nitropyridine, 4.9 g glycine t-butyl ester hydrochloride, and 6.3 g DDEA in 150 mL t-BuOH was refluxed overnight. After cooling, the precipitate (DIEA slat) was removed by filtration. The title compound was obtained from the filtrate and wash by evaporation and aqueous work-up. LC-MS: 3.59 min. (m/Z 228.3). 1H ΝMR (CDCl3, 500 MHz) δ: 8.50 (br s, IH), 8.35 (d, 9.2 Hz, IH), 6.13 (d, 9.0 Hz, IH), 4.27 (d, 5.5 Hz, 2H), 3.98 (s, 3H), 1.51 (s, 9H).
Step B. tert-Butyl (2-fer/-butyl-6-methoxy-3-oxoρyrido[2,3-6]pyrazin-4(3H)-yl)acetate
A solution of 0.25 g tert-butyl N-(6-methoxy-3-nitropyridin-2-yl)glyciπate in 5 mL THF was treated with a hydrogen balloon with 89 mg 10% PaVC overnight. LC-MS showed reduction product: 2.34 min. (m/Z 198). The reaction mixture was filtered and the filtrate treated with 172 mg 3,3-dimethyl- 2-oxobutanoic acid at room temperature overnight. After evaporation, the residue was purified on SGC using EtOAc-hexanes to give the title compound. LC-MS: 4.19 min. (m/Z 348.1). 1HNMR (CDCl3, 500 MHz) δ: 8.00 (d, 8.5 Hz, IH), 6.70 (d, 8.7 Hz, IH), 5.07 (s, 2H), 3.99 (s, 3H), 1.48 (s, 9H), 1.46 (s, 9H). Step C. (2-fer/-Butyl-6-methoxy-3-oxopyrido[2,3-6]pyrazin-4(3H)-yl)acetic acid tert-Butyl (2-rer/-butyl-6-methoxy-3-oxopyrido[2,3-έ]pyrazin-4(3H)-yl)acetate (0.10 g) was treated with 1 mL formic acid room temperature overnight. The mixture was evaporated under vacuum to give the title compound identical as that obtained from Method A Step D above.
Preparative Example 51
Figure imgf000039_0001
(3-ter/-Butyl-7-methσxy~2-oxoquinoxalin-l(2H)-yl)acetic acid
Method A.
Step A. 3-ter/-Butyl-7-methoxyquinoxalin-2(lH)-one
The title compound was prepared from 4-methoxybenzene-l,2-diamine and 3,3-dimethyl-2- oxobutanoic acid in ΗOAc at 48~49°C overnight as described in Preparative Example 50 Step C. It was separated from isomeric side-product 3-rer/-butyl-6-methoxyquinoxalin-2(lH)-one by SGC. 3-tert-Buty\- 7-methoxyquinoxalin-2(lH)-one 1H NMR (CD3OD, 500 MHz) δ: 7.67 (d, 8.9 Hz, IH), 6.90 (dd, 2.7 & 9.0 Hz, IH), 6.73 (d, 2.8 Hz3 IH), 3.87 (s, 3H), 1.44 (s, 9H).
Step B. Methyl (3-ter^butyl-7-methoxy~2-oxoquinoxalin-l(2H)-yl)acetate
A solution of 300 mg 3-tørt-butyl-7-methoxyquinoxalin-2(]/ϊ)-one in 10 mJLDMF was treated with 265 mg methyl bromoacetate and 505 mg cesium carbonate at room temperature overnight. It was quenched by adding saturated NΗjCl solution and worked up by water and EtOAc. The slower-eluting title compound was separated from isomeric faster-eluting methyl [(3-terϊ-butyl-7-methoxyquinoxalin-2- yl)oxy]acetate using SGC with 7:1 to 3:1 hexanes and EtOAc. Methyl (3-ter/-butyl-7-methoxy-2- oxoquinoxalin-l(2H)-yl)acetate 1HNMR (CD3OD, 500 MHz) δ: 7.74 (d, 9.0 Hz3 IH), 6.97 (dd, 2.5 & 8.7 Hz, IH)3 6.75 (d3 2.5 Hz, IH)3 5.07 (s32H)3 3.89 (s3 3H)3 3.79 (s, 3H)3 1.44 (s, 9H). Its identity was confirmed by NOE spectroscopy using irradiation of the methylene and showing positive NOE at 6.75 ppm.
Step C. (3-ter/-Butyl-7-methoxy~2-oxoquinoxalin-1(2H)-yl)acetic acid
The title compound was prepared from methyl (3-te/-/-butyl-7-methoxy-2-ox.σquinoxalin-l(2H)- yl)acetate using the procedure described in Step D Method A of Preparative Example 50. LC-MS: 3.23 min. (nVZ 291.1). 1H NMR (CD3OD3 500 MHz) δ: 7.73 (d, 8.9 Hz3 IH)3 6.96 (dd, 2.6 & 9.0 Hz3 IH)3 6.74 (d, 2.3 Hz3 IH)3 5.02 (s, 2H)3 3.90 (s3 3H)3 1.45 (s3 9H).
Method B. Step A. tert-Butyl N-(5-methoxy-2-nitrophenyl)glycinate
A mixture of 20.7 g 3-fluoro-4-nitrophenol and 36.2 g potassium carbonate in 130 mL DMF was heated to 500C for 15 minutes, cooled to 00C, and treated with 37.2 g iodomethane. This mixture was heated at 600C for 2.5 hours at which time LC-MS showed no starting phenol. It was evaporated under reduced pressure to remove any remaining iodomethane. Glycine t-butyl ester hydrochloride (23.8 g) was added to the reaction mixture together with 60 mL DMF and the resulting mixture was allowed to sit at room temperature overnight followed by refluxing for 4 hours. Aqueous work-up with EtOAc afforded the title compound. LC-MS: 3.57 min. (m/Z 283). 1H NMR (CDCl3, 500 MHz) δ: 8.66 (br s, IH)5 8.20 (d, 9.4 Hz, IH), 6.31 (dd, 2.6 & 9.6 Hz, IH), 6.02 (d, 2.5 Hz, IH), 3.98 (d, 5.1 Hz, 2H), 3.88 (s, 3H), 1.51 (s, 9H).
Step B. ϊert-Butyl (3-rer/'-butyl-7-methoxy-2-oxoquinoxalin-l(2iϊ)-yl)acetate
A mixture of 3.05 g ter/-butyl JV-(5-methoxy-2-nitroρhenyl)glycinate and 575 mg 10% Pd/C in 125 mL methanol was hydrogenated with hydrogen balloon at room temperature for 3.5 hours. The reaction mixture was filtered to remove the catalyst and the solvent was removed under reduced pressure without heating and replaced with THF. It was treated with 3,3-dimethyl-2-oxobutanoic acid (2.1 g) at room temperature overnight. After removing solvent under reduced pressure, the residue was purified using SGC with 7:1 to 6:1 hexanes and EtOAc go give the title compound. LC-MS: 4.05 min. (m/Z 347.1, 291.0). 1H NMR (CDCl35 500 MHz) δ: 7.77 (d, 8.7 Hz, IH), 6.90 (dd, 2.3 & 8.7 Hz, IH), 6.48 (d. 2.5 Hz, IH), 4.90 (s, 2H), 3.90 (s, 3H), 1.48 (s, 9H), 1.47 (s, 9H). Step C. (3-/ert-Butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetic acid
A solution of 1.49 g tert-butyl (3-/ert-butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetate in 50 mL formic acid was allowed to reaction at room temperature for 2 days followed by 2 hours at 500C. Removing formic acid and drying under vacuum provided the title compound identical to that from Method A above.
Preparative Example 52
Figure imgf000040_0001
3-Isopropyl-7-methoxyquinoxalin-2(lH)-one
The title compound was prepared from 4-methoxybenzene-l,2-diamine and ethyl 3-methyI-2- oxobutanoate in ΗOAc at room temperature overnight followed by 500C for 1.5 hours as described in Preparative Example 51 Method A Step A. It separated from isomeric 3-isopropyl-6-methoxyquinoxalin- 2(lH)-one using SGC with 3: 1 to 1 : 1 hexanes and EtOAc. LC-MS: 2.79 min. (m/Z 219). 1H NMR (CD3OD, 500 MHz) δ: 7.69 (d, 8.9 Hz, IH), 6.93 (dd, 2.8 & 9.0 Hz, IH), 6.75 (d, 2.8 Hz, IH), 3.88 (s, 3H), 3.46-3.51 (m, IH)5 1.28 (d, 6.9 Hz5 6H).
Preparative Example 53
Figure imgf000041_0001
gave the crude title compound. This crude product was used in excess for amide coupling reactions. LC- MS: 0.47 min. (m/Z 146.1).
Preparative Example 55
Figure imgf000042_0001
3-(Butylamino)-2,2-dimethylproρan-l-ol
Step A. N-Butyl-3-hydroxy-2,2-dimethylpropanamide A mixture of 4.54 g 3-hydroxy-2,2- dimethylpropanoic acid, 4.21 g n-butylamine, 7.78 g HOBt5 and 14.89 g DEEA in 100 mL DMF was treated with 18.4 g EDC overnight at room temperature. Solvent was removed under reduced pressure and residue was diluted with saturated NH4Cl solution and extracted with EtOAc. The combined extract was washed with water and saturated brine and concentrated to give the title compound. 1H NMR (CDCl3, 500 MHz) δ: 3.57 (s, 2H), 3.24-3.28 (m, 2H), 1.47-1.52 (m, 2H), 1.33-1.38 (m, 2H)5 1.19 (s, 6H), 0.94 (t, 7.3 Hz, 3H).
Step B. 3-(ButyIamino)-2,2-dimethylpropan-l-ol
N-Butyl-3-hydroxy-2,2-dimethylpropanamide was reduced with excess LAH in refluxing ether overnight. The reaction mixture was quenched with adding small portions of saturated sodium sulfate solution while cooled with an ice bath. The resulting mixture was filtered and the filtrate concentrated to give the title compound as white solid. LC-MS: 0.7 min. (m/Z 160.1). 1H ΝMR (CDCl3. 500 MHz) δ: 3.50 (s, 2H), 2.62 (s, 2H), 2.59 (t, 7.1 Hz, 2H)3 1.45-1.48 (m, 2H), 1.31-1.38 (m, 2H), 0.93 (s, 6H), 0.92 (t, 7.3 Hz, 3H).
Preparative Example 56
Figure imgf000042_0002
3-[(3,3-Dimethylbutyl)amino]-2,2-dimethyIproρan-l-ol
The title compound was prepared using the same method described in Preparative Example 54 except the reduction was carried out in refluxing dioxane. LC-MS: 1.69 min. (m/Z 188.3). 1H ΝMR (CDCl3, 500 MHz) δ: 3.52 (s, 2H), 2.64 (s, 2H)5 1.45-1.48 (m5 2H), 1.61 (s, IH)5 2.58-2.61 (m7 2H)5 1.38-1.42 (m5 2H), 0.95 (s, 6H), 0.92 (s, 9H).
Preparative Example 57
Figure imgf000042_0003
4-[(3,3-Dimethylbutyl)arnino]-2,2-dirnethylbutan-l-oI The title compound was prepared as described in Preparative Example 55 from 3,3-dimethylbutanoyI chloride and methyl 4-amino-2,2- dimethylbutanoate hydrochloride. LC-MS: 2.09 min. (m/Z 202.3). 1H NMR (CDCl3, 500 MHz) δ: 3.25 (s, 2H)5 1.58-1.68 (m, 2H), 2.60-2.63 (m, 2H), 1.40-1.45 (m, 4H), 0.92 (s, 6H)5 0.91 (s, 9H).
Preparative Example 58
Figure imgf000043_0001
[3-[4-(3-Hydroxypropyl)pheny]]-7-methoxy-2-oxoquinoxalin-l(2H)-yl]acetic acid
Step A. 5-Methoxy-N-(4-methoxybenzyl)-2-nitroaniline The title compound was prepared from 3-fluoro- 4-nitrophenol5 methyl iodide, and 4-methoxybenzylamine using the procedure described in Preparative Example 51 Method B Step A. LC-MS: 3.44 min. (m/Z 311.0). 1HNMR (CDCl3, 500 MHz) δ: 8.63 (s, IH)5 8.18 (d, 9.6 Hz, IH), 7.29-7.32 (m, 2H), 6.91-6.94 (m, 2H), 6.27 (dd, 2.6 & 9.7 Hz, IH), 6.17 (d, 2.9 Hz5 IH), 4.47 (d, 5.3 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H)
Step B. Methyl {4-[3-(acetyIoxy)propyl]phenyl}(oxo)acetate A solution of 5 g 3-phenyl propylacetate and 4.1 g methyl oxalyl chloride in 20 mL DCM was added slowly to a mixture of 8.2 g anhydrous aluminum chloride in 30 mL DCM at 00C. The reaction mixture is then allowed to warm up to room temperature overnight. Aqueous work-up with saturated NHjCl and EtOAc followed by SGC using 3:1 hexanes and EtOAc afforded the title compound as clear oil. 1HNMR (CDCl3, 500 MHz) δ: 7.97 (d, 8.2 Hz, 2H)5 7.35 (d, 8.2 Hz, 2H), 4.11 (t, 6.3 Hz, 2H), 3.99 (s, 3H),2.80 (t, 7.7 Hz, 2H), 2.07 (s, 3H), 1.98-2.03 (m, 2H).
Step C. 4-Methoxy-N2-(4-methoxybenzyl)benzene-l,2-diamine
A mixture of 2.5 g 5-methoxy-N-(4-methoxybenzyl)-2-nitroaniIine, 7.3 g iron powders, 7.8 g HOAc, 25 mL EtOH, and 70 mL water was refluxed under nitrogen for 1 hour." After cooling, most solvents were removed under reduced pressure. Add 200 mL 2.5 Ν NaOH to the residue and filter the mixture through a pad of Celite with EtOAc- Separate the layers, wash the organic layer with brine, and evaporate to give the crude title compound, which was used without further purification. LC-MS: 2.39 min. (m/Z 259). 1H ΝMR (CDCl3, 500 MHz) δ: 7.32-7.35 (m, 2H), 6.90-6.92 (m, 2H)5 6.69 (d, 8.2 Hz, IH)5 6.32 (d, 2.8 Hz, IH), 6.22 (dd, 2.9 & 8.2 Hz, IH), 4.25 (s, 2H), 3.83 (s, 3H)5 3.75 (s, 3H).
Step D. 3 - {4-[6-Methoxy-4-(4-methoxybenzyl)-3 -oxo-3,4-dihydroquinoxalin-2-yI]phenyl} propyl acetate
The title compound was prepared from 4-methoxy-iV2-(4-methoxybenzyl)-benzene-l,2-diamine and methyl {4-[3-(acetyloxy)propyl]ρhenyl}(oxo)acetate in HOAc at 45°C in 6 hours. Similar reaction in THF was very slow. SGC purification using hexanes-EtOAc afforded pure title compound. LC-MS: 3.97 min. (m/Z 473.1). 1H ΝMR (CDCl35 500 MHz) δ: 8.29 (d, 8.3 Hz, 2H), 7.87 (d, 8.7 Hz, IH), 7.29-7.33 (m, 4H), 6.93 (dd, 2.5 & 8.7 Hz, IH), 6.87-6.89 (m, 2H), 6.79 (d, 2.6 Hz, IH), 5.49 (s, 2H)5 4.14 (t, 6.6 Hz, 2H)6 3.85 (s, 3H), 3.79 (s, 3H)5 2.78 (t, 7.8 Hz, 2H), 2.10 (s, 3H), 1.99-2.05 (m, 2H).
Step E. 3-[4-(6-Methoxy-3-oxo-3,4-dihydroquinoxalin-2-yl)phenyl]propyl acetate
Refluxing 0.57 g 3-{4-[6-methoxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydroquinoxalin-2- yl]phenyl} propyl acetate and 1.4 mL anisole in 10 mL neat TFA for 12 hours or stir it at room temperature in 2% triflic acid in TFA for 3 days gave the title compound. SGC purification gave pure material. LC-MS: 3.32 min. (m/Z 353.1). 1H NMR (CDCl3, 500 MHz) δ: 8.32 (d, 8.3 Hz52H), 7.85 (d, 8.9 Hz, IH), 7.33 (d, 8.2 Hz, 2H), 6,98 (dd, 2.3 & 8.9 Hz5 IH), 6.69 (d, 2.6 Hz, IH), 4.14 (t, 6.6 Hz, 2H), 3.93 (s, 3H)5 2.79 (t, 7.7 Hz, 2H), 2.10 (s, 3H), 2.00-2.05 (m, 2H) .
Step F. 3-[4-(3-Hydroxypropyl)phenyl]-7-methoxyquinoxalin-2(lH)-one
A solution of 297 mg 3-[4-(6-methoxy-3-oxo-3,4-dihydroquinoxalin-2-yl)phenyl]propyl acetate in 10 mL MeOH and 1 mL water was treated with 0.84 mL 5 N NaOH at room temperature overnight. Solvents were removed under reduced pressure, the residue re-dissolved in water, and extracted with ether. The combine organic extract was washed with brine and evaporated to give the title compound. LC-MS: 2.83 min. (m/Z 311.0). 1H NMR (CD3OD, 500 MHz) δ: 8.16 (d, 8.3 Hz, 2H)5 7.76 (d, 8.9 Hz, IH)5 7.32 (d5 8.2 Hz, 2H), 6.97 (dd, 2.8 & 8.9 Hz IH), 6.92 (s, IH), 6.80 (d, 2.5 Hz, IH), 3.91 (s, 3H), 3.60 (t, 6.6 Hz, 2H), 2.76 (t, 7.7 Hz, 2H), 1.89 (s, IH), 1.86-1.91 (m, 2H).
Step G. Methyl [3-[4-(3-hydroxypropyl)phenyl]-7-methoxy-2-oxoquinoxalin-l(2H)-yl]acetate
The title compound was prepared from 3-[4-(3-hydroxypropyl)phenyl]-7-methoxyquinoxalin- 2(lH)-one and methyl bromoacetate using the method described in Preparative Example 51 Method A Step B. It was separated from faster-eluting isomeric methyl ({3-[4-(3-hydroxypropyl)phenyl]-7- methoxyquinoxalin-2-yl}oxy)acetate using SGC with 1:1 to 1:2 hexanes/EtOAc. LC-MS: 3.18 min. (m/Z 383.2). 1H NMR (CD3OD, 500 MHz) δ: 8.15 (d, 8.3 Hz, 2H), 7.85 (d, 9.0 Hz, IH), 7.32 (d, 8.2 Hz, 2H), 7.05 (dd, 2.6 & 9.0 Hz IH), 6.85 (d, 2.5 Hz5 IH), 5.19 (s, 2H), 4.86 (br s, IH)5 3.93 (s, 3H)5 3.81 (s5 3H), 3.60 (t, 6.6 Hz5 2H)5 2.76 (t, 7.8 Hz, 2H), 1.89 (s, IH)5 1.86-1.92 (m, 2H).
Step H. [3-[4-(3-Hydroxypropyl)phenyl]-7-methoxy-2-oxoquinoxalin-l(2H)-yl]acetic acid
The title compound was prepared from methyl [3-[4-(3-hydroxypropyl)phenyl]-7-methoxy-2- oxoquinoxalin-l(2H)-yl]acetate using procedure described in Step F above. LC-MS: 2.87 min. (m/Z 369.1). 1H NMR (CD3OD5 500 MHz) δ: 8.15 (d5 8.2 Hz5 2H), 7.84 (d, 8.9 Hz, IH), 7.32 (d, 8.2 Hz, 2H), 7.05 (dd, 2.3 & 8.8 Hz, IH), 6.84 (d, 2.3 Hz, IH), 5.15 (s, 2H), 3.94 (s, 3H), 3.61 (t, 6.5 Hz, 2H), 2.77 (t, 7.8 Hz, 2H), 1.86-1.92 (m, 2H). NOE difference spectrum further confirmed its structure.
Preparative Example 59
Figure imgf000045_0001
[3-[4-(hydroxymethyl)phenyl]-7-methoxy-2-oxoquinoxalin-l(2H)-yl]acetic acid Step A. Methyl (4-methylphenyl)(oxo)acetate
The title compound was prepared from toluene and methyl oxalyl chloride as described in Preparative Example 57 Step B. 1H MMR (CDCl3, 500 MHz) δ: 7.94 (d, 8.2 Hz, 2H), 7.33 (d, 8.0 Hz, 2H), 3.99 (s, 3H)5 2.46 (s, 3H).
Step B. Methyl {4-[(acetyloxy)methyl]phenyl}(oxo)acetate
The title compound was prepared from methyl (4-methylphenyl)(oxo)acetate using the method of Barnish et al. (J. Med. Chem. 1981, 24, 399) in two steps. 1H NMR (CDCl3, 500 MHz) δ: 8.05 (d, 8.5 Hz, 2H), 7.51 (d, 8.1 Hz, 2H), 5.2 (s, 2H), 4.01 (s, 3H), 2.16 (s, 3H).
Step C. 4-[6-Methoxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydroquinoxalin-2-yl]benzyl acetate
The title compound was prepared from methyl {4-[(acetyloxy)methyl]phenyl}(oxo)acetate and 4- methoxy-N2-(4-methoxybenzyl)benzene-l,2-diamine using method described in Preparative Example 57 Step D. 1H NMR (CD3OD, 500 MHz) δ: 8.27 (d, 8.2 Hz, 2H), 7.82 (d, 9.0 Hz, IH)5 7.48 (d, 8.2 Hz, 2H), 7.27 (d, 8.9 Hz, 2H), 6.99 (dd, 2.2 & 8.9 Hz, IH), 6.89-6.90 (m, 3H), 5.55 (s, 2H), 5.19 (s, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.12 (s, 3H).
Step D. 3-[4-(Hydroxymethyl)phenyl]-7-methoxyquinoxalin-2(lH)-one
The title compound was prepared from stirring 0.23 g 4-[6-methoxy-4-(4-methoxybenzyl)-3-oxo- 3,4-dihydroquinoxalin-2-yl]benzyl acetate overnight in 10 mL TFA containing 0.14 mL triflic acid and 0.56 mL anisole. Evaporation under vacuum, aqueous work-up with EtOAc afforded the title compound and its hydrolyzed alcohol as a mixture. Hydrolysis of this mixture as described in Preparative Example 57 Step F afforded the title compound. LC-MS: 2.40 min. (m/Z 283.2). 1H NMR (CD3OD, 500 MHz) δ: 8.03 (d, 8.0 Hz, 2H), 7.61 (d, 9.1 Hz, IH), 7.43 (d, 8.0 Hz, 2H)5 6.88 (d, 2.5 Hz, IH), 6.81 (dd, 2.5 & 9.0Hz, IH), 4.67 (s, 2H), 3.88 (s, 3H).
Step E. Methyl [3-[4-(hydroxymethyl)phenyl]-7-methoxy-2-oxoquinoxalin-l(2H)-yl]acetate
The title compound was prepared from 3-[4-(hydroxymethyl)phenyI]-7-methoxyquinoxalin- 2(lH)-one and methyl bromoacetate using the method described in Preparative Example 57 Step G. LC- MS: 2.75 min. (m/Z 355.2). 1H NMR (CD3OD, 500 MHz) δ: 8.23 (d, 8.5 Hz, 2H), 7.86 (d, 8.9 Hz, IH), 7.46 (d, 8.2 Hz, 2H), 7.06 (dd, 2.6 & 9.0 Hz, IH), 6.86 (d, 2.5 Hz, IH), 5.20 (s, 2H), 4.69 (s, 2H), 3.94 (s, 3H), 3.81 (s, 3H). Step F. [3-[4-(Hydroxymethyl)phenyl]-7-methoxy-2-oxoquinoxalin-l(2H)-yl]acetic acid
The title compound was prepared from methyl [3-[4-(hydroxymethyl)phenyl]-7-methoxy-2- oxoquinoxalin-l(2/7)-yI]acetate using the method described in Preparative Example 57 Step H. LC-MS: 2.47 min. (m/Z 341.3). 1H NMR (CD3OD, 500 MHz) δ: 8.22 (d, 8.2 Hz, 2H), 7.85 (d, 8.9 Hz5 IH)5 7.46 (d, 8.3 Hz, 2H), 7.05 (dd, 2.3 & 8.9 Hz, IH)5 6.84 (d, 2.3 Hz5 IH)5 5.16 (s5 2H)5 4.69 (s5 3H)5 3.94 (s5 3H).
Figure imgf000046_0001
[3-(4-Hydroxy-l,l-dimethylbutyl)-7-methoxy-2-oxoquinoxalϊn-l(2H)-yl]acetic acid Step A. 3,3-Dimethyl-2-oxohexanedioic acid
The title compound was prepared from 4,4-dimethylcyclohexane-l53-dione using the method of Langley et al. (J. Chem. Soc. 1962, 2972). It was obtained as a 6:5 mixture of 3,3-dimethyl-2- oxohexanedioic acid and 2,2-dimethylpentanedioic acid based on 1H NMR and was used in the next step without purification.
Step B . 4- {4- [6-Methoxy-4-(4-methoxy benzy l)-3-oxo-3 ,4-dihydroquinoxal in-2-y l]phenyl } -4- methylpentanoic acid
The title compound was prepared from 3,3-dimethyl-2-oxohexanedioic acid and 4-methoxy-N2- (4-methoxybenzyl)benzene-l52-diamine using method described in Preparative Example 57 Step D. LC- MS: 3.5 min. (m/Z 411.3). 1H NMR (CDCl3, 500 MHz) δ: 7.74 (d5 8.9 Hz, 2H)5 7.20 (d, 8.4 Hz, 2H), 6.85-6.87 (m, 3H), 6.70 (d, 2.5 Hz, IH), 5.39 (s, 2H), 3.81 (s, 3H), 3.78 (s, 3H)5 2.33-2.39 (m5 4H)5 1.52 (S5 6H).
Step C. 4-[4-(6~Methoxy-3-oxo-3,4-dihydroquinoxalin-2-yl)phenyl]-4-methylpentanoic acid
The title compound was prepared from 4-{4-[6-methoxy-4-(4-methoxybenzyl)-3-oxo-354- dihydroquinoxalin-2-yl]phenyl}-4-methylpentanoic acid using the method described in the first half of Preparative Example 58 Step D and purified by SGC. LC-MS: 2.75 min. (m/Z 291.2). 1H NMR (CD3OD5 500 MHz) δ: 7.68 (d, 8.9 Hz5 IH), 6.90 (dd, 2.8 & 9.0 Hz, IH)5 6.73 (d, 2.5 Hz, IH)5 3.87 (s, 3H)5 2.28-2.31 (m, 2H), 2.14-2.17 (m, 2H), 1.44 (s, 6H).
Step D. 3-[4-(4-Hydroxy- 1 , 1 -dimethylbutyl)phenyl]-7-methoxyquinoxalin-2( 1 H)-one
The title compound was prepared from 4-[4-(6-methoxy-3-oxo-3,4-dihydroquinoxalin-2- yl)phenyl]-4-methy]pentanoic acid using the method of Soai et al (Synthesis (7), 647, 1987). LC-MS: 2.77 min. (m/Z 277.2). 1HNMR (CD3OD5 500 MHz) δ: 7.67 (d, 9.0 Hz, IH)5 6.90 (dd, 2.8 & 8.9 Hz5 IH), 6.73 (d, 2.7 Hz, IH), 3.87 (s, 3H), 3.48 (t, 6.9 Hz, 2H), 1.98-2.02 (m, 3H), 1.43 (s, 6H), 1.32-1.38 (m, 2H).
Step E. Methyl [3-(4-hydroxy-l,l-dimethylbutyI)-7-methoxy-2-oxoquinoxalϊn-l(2H)-yl]acetate
The title compound was prepared from 3-[4~(4-hydroxy-l,l-dimethylbutyl)phenyl]-7- methoxyquinoxalin-2(lH)-one and methyl bromoacetate using the method described in Preparative Example 57 Step G. LC-MS: 3.03 min. (m/Z 349.3). 1HNMR (CD3OD, 500 MHz)
δ: 7.74 (d, 8.9 Hz, IH), 6.97 (dd, 2.1 & 8.8 Hz, IH), 6.76 (d, 2.1 Hz, IH), 5.07 (s, 2H), 3.89 (s, 3H), 3.78 (s, 3H), 3.46 (t, 6.9 Hz, 2H), 1.94-2.00 (m, 2H), 1.43 (s, 6H), 1.31-1.37 (m, 2H).
Step F. [3-(4-Hydroxy-l,l-dimethylbutyI)-7-methoxy-2-oxoquinoxalin-l(2H)-yl]acetic acid
The title compound was prepared from methyl [3-(4-hydroxy-l,l-dimethylbutyl)-7-methoxy-2~ oxoquinoxalin-l(2H)-yl]acetate using the method described in Preparative Example 57 Step Η. LC-MS: 2.77 min. (m/Z 335.3). 1HNMR(CD3OD, 500 MHz) δ: 7.74 (d, 9.0 Hz, IH), 6.97 (dd, 2.3 & 8.9 Hz, IH), 6.75 (d, 2.3 Hz, IH), 5.03 (s, 2H), 3.90 (s, 3H), 3.46 (t, 6.9 Hz, 2H), 1.98-2.01 (m, 2H), 1.43 (s, 6H), 1.33-1.38 (m, 2H).
Preparative Example 61
Figure imgf000047_0001
(3-terϊ-ButyI-7-methoxy-2-oxo-l,8-naphthyridin-l(2H)-yl)acetic acid Step A. Methyl 2-[{2-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}(hydroxy)methyl]-3,3- dimethylbutanoate The title compound was prepared from N-(3-formylpyridin-2-yl)-2,2- dimethylpropanamide and methyl 3-methylbutanoate using the method of Turner (J. Org. Chem. 55, 4744, 1990). LC-MS: 2.67 min and 2.76 min. (m/Z 337.3). 1HNMR of the two diastereomers (CDCl3, 500 MHz) δ: 8.39-8.40 & 9.36-8.39 (m, IH), 8.26 & 8.06 (br s, IH), 7.91-7.93 & 7.82-7.84 (m, IH), 7.19-7.24 (m, IH), 4.09 (d, 5.9 Hz) & 3.75 (br s, IH), 3.72 &3.26 (s, 3H), 5.01-5.08 (m, IH), 2.84-2.87 (m, IH), 1.41 & 1.39 (s, 9H), 1.17 & 0.89 (s, 9H).
Step B.3-ter/-Butyl-l,8-naphthyridin-2(lH)-oneThe title compound was prepared from 5.9 g methyl 2- [{2-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}(hydroxy)methyI]-3,3-dimethylbutanoate in 20 mL dioxane and 35 mL 4 N HCl in dioxane by heating at 170 0C in a microwave reactor for 2 hours in three portions. The solvent was removed from the combined reaction mixture under reduced pressure and the residue was suspended in water and EtOAc after being neutralized to pΗ 7. The title compound was obtained by filtration. Additional crop of the desired product was obtained from the EtOAc layer following SGC using 2:1 to 1:1 hexanes and EtOAc. LC-MS: 2.69 min. (m/Z 203.2). 1H NMR (CDCl3, 500 MHz) δ: 8.46 (dd, 1.6 & 5.6 Hz, IH), 8.06 (dd, 1.6 & 7.7 Hz, IH), 7.67 (s, IH)3 7.31 (dd, 5.2 & 7.7 Hz, IH), 1.46 (s, 9H).
Step C. 3-/ert-Butyl-l,8-naphthyridin-2(lH)-one 8-oxideThe title compound was prepared by heating a solution of 2.05 g 3-ter/-butyl~l,8-naphthyridin-2(lH)-one in 20 mL 35% peracetic acid in acetic acid at 500C overnight. Aqueous work-up with EtOAc afforded the title compound. LC-MS: 2.20 min. (m/Z 219.1). 1HNMR(CDCl3, 500 MHz) δ: 8.53 (d, 6.4 Hz, IH), 7.79 (d, 7.8 Hz, IH), 7.65 (s, IH), 7.25 (dd, 6.7 & 7.8 Hz, IH), 1.46 (s, 9H).
Step D. 3-ter/-Butyl-7-methoxy-l,8-naphthyridin-2(lH)-one The title compound was prepared from 3-/er/-butyl-l,8-naphthyridin-2(lH)-one 8-oxide using a modified method of Ηayashida etal. (Ηeterocycles, 31 (7), 1325, 1990) with 10 equiv. of pTsCI and 20 equiv. OfEt3N. LC-MS: 3.12 min. (m/Z 233.1). 1H NMR (CDCl3, 500 MHz) δ: 7.74 (d, 8.2 Hz, IH), 7.59 (s, IH), 6.63 (d, 8.5 Hz, IH), 4.00 (s, 3H), 1.44 (s, 9H). Its identity was further confirmed by NOE difference spectrum.
Step E. Methyl (3-fer/-butyl-7-methoxy-2-oxo-l,8-πaphthyridin-l(2i7)-yl)acetate The title compound was prepared from 3-tert-butyl-7-methoxy-l,8-naphthyridin-2(lH)-one and methyl bromoacetate using the method described in Preparative Example 57 Step G. It was separated from the faster-el uting isomeric methyl [(3-tør/-butyl-7-methoxy-l,8-naphthyridin-2-yl)oxy]acetate on RP-ΗPLC. LC-MS: 3.54 min. (m/Z 305.1). 1H NMR (CDCl3, 500 MHz) δ: 7.74 (d, 8.5Hz, IH), 7.56 (s, IH), 6.61 (d, 8.2 Hz, IH), 5.26 (s, 2H), 3.95 (s, 3H), 3.76 (s, 3H), 1.43 (s, 9H).
Step F- (3-/eA'f-ButyI-7-methoxy-2-oxo-l,8-naphthyridin-l(2H)-yl)acetic acid The title compound was prepared from methyl (3-."erf-butyl-7-methoxy-2-oxo-l,8-naphthyridin-l(2H)-yl)acetate using the method described in Preparative Example 57 Step Η. LC-MS: 3.12 min. (m/Z 291.1). 1H NMR (CDCl3, 500 MHz) δ: 7.91 (d, 8.4 Hz, IH), 7.72 (s, IH), 6.65 (d, 8.5 Hz, IH), 5.16 (s, 2H), 3.95 (s, 3H), 1.39 (s, 9H).
Example 1
Figure imgf000048_0001
N,N-Dibutyl-2-(3-ter/-butyI-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamideThe title compound was prepared from 6 mg (3-<ert-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetic acid, 6 μL di-n-butylamine, 8 mg EDC, 6 mg HOBt, and 15 μL DlEA in 1 mL DMF at room temperature and purified using preparative HPLC followed by lyophilization. LC-MS: 4.27 min. (m/Z 423.3).
Examples 2~47
Figure imgf000049_0001
Utilizing the method described in Example 1 using (3-?er/-butyl-7-methoxy-2-oxoquinolin- l(2H)-yl)acetic acid and the amine listed in Table 4 below Examples 2 through 47 in Table 4 were prepared. In Examples 32-36, PyBOP and HOAt were used instead of EDC and HOBt.
Table 4
Ex )
Figure imgf000049_0002
Figure imgf000050_0001
Figure imgf000051_0001
3-7e/-/-butyl-l-(3,3-dimethyIbutyl)-7-methoxyquinolin-2(lH)-one
The title compound was prepared from 50 mg 3-ter/-butylquinolin-2(lH)-one (Preparative Example 1, Step E), 55 mg l-bromo-3,3-dimethylbutane, and 143 mg cesium carbonate in 1 mL DMF at 55°C for 12 hours. It was separated from less polar side-product 3-ter*-butyl-2-(3,3-dimethylbutoxy)-7- methoxyquinoline using RP-ΗPLC. The isomers were identified by comparison of NMR with isomers in Preparative Example 1, Step F. 1H NMR in CDCl3 at 500 MHz: 7.53 (s, IH), 7.46 (d, 9.0 Hz5 IH), 6.81 (dd, 9.0 & 2.0 Hz, IH), 6.77 (d, 2.0 Hz, IH), 4.29 (m, 2H), 3.92 (s, 3H), 1,68 (m, 2H)5 1.44 (s, 9H), 1.26 (s, 9H).
Example 50
Figure imgf000052_0001
3-rer/-bu1yl-7-methoxy-l-(3-methylbutyl)quinolin-2(li:/)-one
The title compound was prepared from 50 mg 3-/er/-butylquinolin-2(lH)-one (Preparative Example 1, Step E), 50 mg l-bromo-3,3-dimethylbutane, and 143 mg cesium carbonate in 1 mL DMF at 55°C for 12 hours. It was separated purified from less polar side-product 3-ter/-butyl-2-(3- methylbutoxy)-7-methoxyquinoline using ΗPLC. 1HNMR in CDCl3 at 500 MHz: 7.56 (s, IH), 7.48 (d, 8.5 Hz, IH), 6.83 (dd, 8.5 & 2.0 Hz, IH), 6.78 (d, 2.0 Hz3 IH), 4.28 (m, 2H), 3.93 (s, 3H), 1.82 (m, IH), 1.66 (m, 2H), 1.44 (s, 9H), 1.07 (d, 6.5 Hz, 6H).
Example 50
Figure imgf000052_0002
2-(3-Isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-NjV-bis(3-methylbutyl)acetamide
The title compound was prepared from (3-isoprόρyl-2-oxoquinolin-l(2H)-yl)acetic acid from Preparative Example 2, EDC, ΗOBt, and DIEA using the method in Example 1, purified on ΗPLC, and re-crystallized from EtOAc-hexanes to give colorless crystals. LC-MS: 4.17 min. (m/Z 437.1). 1H NMR in CDCl3 at 500 MHz: 7.49 (s, IH), 7.46 (d, 8.5 Hz, IH), 6.81 (dd, 8.5 & 2.0 Hz, IH), 6.60 (d, 2.0 Hz, IH), 5.15 (s, 2H), 3.88 (s, 3H), 3.43 (m, 2H), 3.38 (m, 2H), 3.28 (m, IH), 1.66-1.47 (m, 5H), 1.26 (d, 7.0 Hz, 6H), 1.00 (d, 6.5 Hz, 6H), 0.92 (d, 6.5 Hz, 6H).
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Example 98
Figure imgf000055_0002
l-(333-Dimethylbutyl)-3-isoρropyI-7-methoxyquinolin-2(lH)-one
The title compound was prepared using the method described in Example 49. LC-MS: 4.16 min. (m/Z 302.2). 1H NMR in CDCl3 at 500 MHz: 7.47 (d, 8.5 Hz, IH)3 7.45 (s, IH), 6.82 (dd, 8.5 & 2.0 Hz, IH), 6.80 (d. 2.0 Hz, IH), 4.33 (m, 2H)5 3.92 (s, 3H), 3.30 (m, IH)5 1.66 (m, 2H)5 1.26 (d5 7.0 Hz3 6H), 1.12 (s, 9H).
Example 99
Figure imgf000055_0003
3-IsopropyI-7-methoxy-l-(3-methyIbutyI)quinolin-2(lH)-one
The title compound was prepared using the method described in Example 50. LC-MS: 4.05 min. (m/Z 288.2). 1H NMR in CDCl3 at 500 MHz: 7.48 (d, 8.5 Hz, IH), 7.47 (s, IH), 6.84 (dd, 8.5 & 2.0 Hz, IH), 6.81 (d, 2.0 Hz, IH), 4.32 (m, 2H), 3.93 (s, 3H), 3.30 (m, IH), 1.83 (m, IH), 1.66 (m, 2H)3 1.26 (d, 7.0 Hz, 6H), 1.07 (d, 6H).
Example 100
Figure imgf000056_0001
N^V-Dibutyl-2-(3-cyclohexyI-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide
The title compound was prepared from (3-cyclohexyl-2-oxoquinolin-l(2H)-yl)acetic acid from Preparative Example 3, EDC, ΗOBt, and DIEA using the method in Example 1, purified on ΗPLC, and re-crystallized from EtOAc-hexanes to give colorless crystals. 1H ΝMR in CDCI3 at 500 MHz: 7.47 (s, IH), 7.45 (d, 8.5 Hz, IH), 6.80 (dd, 8.5 & 2.0 Hz, IH), 6.63 (d, 2.0 Hz, IH), 5.15 (s, 2H), 3.87 (s, 3H), 3.42 (t, 7.0 Hz5 2H), 3.68 (t, 7.0 Hz, 2H), 2.94 (m, IH), 1.98 (d, 12 Hz, 2H), 1.84 (m, 2H), 1.64 (m, 2H), 1.56 (m, 2H), 1.48 (m, 2H), 1.40 (m, 2H), 1.35-1.25 (m, 6H), 0.99 (t, 7.5 Hz, 3H), 0.91 (t, 7.5 Hz, 3H).
Examples 101-124
Figure imgf000056_0002
The following compounds in Table 6 were prepared using the method described in Example 1 using (3-cyclohexyl-2-oxoquinolin-l(2H)-yl)acetic acid and the amine listed in Table 6. For Example 124, PyBOP and HO At were used instead of EDC and HOBt.
Table 6.
Example Starting amine (HNRiR2) LC-MS, min. (m/Z)
101 ^"Vsχ*K/\ 4.04 (421.2)
Figure imgf000056_0003
Figure imgf000057_0001
111 H 4.14(435.3)
Figure imgf000057_0002
Figure imgf000058_0001
3-Cyclohexyl-l-(3,3-dimethylbutyl)-7-methoxyquinoIin-2(]H)-one
The title compound was prepared using the method described in Example 49. LC-MS: 4.61 min. (m/Z 342.2). 1H NMR in CDCl3 at 500 MHz: 7.48 (d, 8.5 Hz3 IH), 7.46 (s, IH), 6.85 (dd, 8.5 Hz, 2.0 Hz, IH), 6.82 (d, 2.0 Hz3 IH), 4.34 (rn, 2H)3 3.93 (s, 3H)3 2.95 (m, IH), 1.96 (d, 12 Hz, 2H)3 1.85 (m, 2H), 1.66 (m, 2H), 1.49 (m, 2H), 1.29 (m, 4H)3 1.17 (s3 9H).
Figure imgf000058_0002
3-Cyclohexyl-7-methoxy-l-(3-methylbutyl)quinolin-2(lH)-one
The title compound was prepared using the method described in Example 50. LC-MS: 4.47 min. (m/Z 328.3). 1HNMR in CDCl3 at 500 MHz: 7.48 (d3 8.5 Hz, IH)3 7.46 (s, IH), 6.85 (dd, 8.5 & 2.0 Hz, IH), 6.82 (d3 2.0 Hz, IH), 4.32 (m, 2H), 3.93 (s, 3H), 2.95 (m, IH), 1.96 (d, 12 Hz, 2H)3 1.85 (m, 2H), 1.66 (m, 2H), 1.49 (m, 2H), 1.29 (m, 4H), 1.06 (d, 7.5 Hz, 6H).
Example 127
Figure imgf000058_0003
N-(3,3-Dimethylbutyl)-2-(7-methoxy-2-oxo-3-phenyIquinoIin-l(2H)-yl)-N-propylacetamide
The title compound was prepared from (2-oxo-3-phenylquinolin-l(2H)-yl)acetic acid from Preparative Example 4, EDC, HOBt, and DDBA using the method in Example 1 , purified on HPLC, and re-crystallized from EtOAc-hexanes to give colorless crystals. 1H NMR in CDCI3 at 500 MHz: 7.80 (d, 1.5 Hz, IH), 7.72 (m, 2H)3 7.54 (dd, 8.5 Hz, 1.5 Hz, IH), 7.43 (m, 2H), 7.35 (m, IH), 6.85 (dd, 8.5 & 1.5 Hz, IH), 6.63 (m IH), 5.19 (s, 2H), 3.90 (s, 3H), 3.40 (m, 4H), 1.77-1.48 (m, 4H), 1.03 (t, 7.5 Hz, 3H), 0.92 (s, 9H).
Examples 128-140 DMF
Figure imgf000059_0001
Figure imgf000059_0002
The following compounds in Table 7 were prepared using the method described in Example 1 using (2-oxo~3-phenylquinoIin-l(2H)-yl)acetic acid and the amine listed in Table 1.•
Table 7.
Example Starting amine (HNRiR2) LC-MS, min. (m/Z) )
Figure imgf000059_0003
Example 141
Figure imgf000059_0004
1 -(3,3-Dimethylbutyl)-7-methoxy-3-phenylquinolin-2( 1 H)-one The title compound was prepared using the method described in Example 49. LC-MS: 4.26 min. (tn/Z 336.2). 1H NMR in CDCl3 at 500 MHz: 7.76 (s, IH), 7.72 (d, 7.5 Hz3 2H), 7.55 (d, 8.5 Hz, IH), 7.44 (m, 2H), 7.37 (m, IH)5 6.85 (m, 2H)5 4.38 (m, 2H), 3.95 (s, 3H), 1.71 (m, 2H), 1.13 (s, 9H).
Example 142
Figure imgf000060_0001
7-Methoxy- 1 -(3 -methylbuty l)-3 -pheny lquinolin-2( lH)-one
The title compound was prepared using the method described in Example 50. LC-MS: 4.10 min. (m/Z 322.2). 1H NMR in CDCl3 at 500 MHz: 7.80 (s, IH), 7.68 (m, 2H), 7.58 (d, 8.5 Hz, IH), 7.44 (m, 2H), 7.38 (m, IH), 6.91 (dd, 8.5 & 2.0 Hz, IH), 6.88 (d, 2.0 Hz, IH), 4.39 (m, 2H), 3.97 (s, 3H), 1.85 (m, IH), 1.71 (m, 2H), 1.08 (d, 7.5 Hz, 6H).
Examples 143-173
Figure imgf000060_0002
The following compounds in Table 8 were prepared using the method described in Example 1 using (3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetic acid from Preparative Example 8 and the amine listed in Table 8. For Examples 172-173, PyBOP and ΗOAt were used instead of EDC and ΗOBt.
Table 8.
Example Starting amine (HNR1R2) LC-MS, min. (m/Z) 143 ^"\^- 3.73 (395.1)
144 Η 3.36 (367.0)
145 3.41 (379.1)
146 Η A. 3.67 (367.1)
-_ — -
Figure imgf000060_0003
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Examples 185-192
Figure imgf000063_0002
The following compounds in Table 10 were prepared using the method described in Example 1 using (7-methoxy-2-oxoquinolin-l(2H)-yl)acetic acid from Preparative Example 10 and the amine listed in Table 10.
Table 10.
Figure imgf000063_0003
Examples 193-199
Figure imgf000063_0004
The following compounds in Table 11 were prepared using the method described in Example 1 using (7-methoxy-3-methyl-2-oxoquinolin-l(2H)-yI)acetic acid from Preparative Example 36 and the amine listed in Table 1 1.
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
2-(2-te^Butyl-6-methoxy-3-oxopyrido[2,3-Z>]pyrazin^(3H)-yl)-N-(3,3-dimethylbuiyI)-N- propylacetamideThe title compound was prepared from (2-fer/-butyl-6-methoxy-3-oxopyrido[2,3- έ]pyrazin-4(3H)-yl)acetic acid from Preparative Example 50 using method described in Example 1. Following an aqueous work-up using EtOAc, the crude product was purified on SGC and re-crystallized from 5:1 hexanes and EtOAc. LC-MS: 4.39 min. (m/Z 417.1).
Examples 243-256
EDC, HOBt, DIEA, DMF
Figure imgf000067_0002
Figure imgf000067_0003
The following compounds in Table 13 were prepared using the method described in Example 1 using (2-/er.-butyl-6-methoxy-3-oxopyrido[2,3-έ]pyrazin-4(3H)-y0acetic acid and the amine listed in Table 13.
Table 13
Example Starting amine (HNRiR2) LC-MS, min. (m/Z)
Figure imgf000067_0004
Figure imgf000068_0001
Example 257
Figure imgf000068_0002
2-(3-te^Butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-propy!acetarnideThe title compound was prepared from (3-fer/-Butyl-7-methoxy-2-oxoquinoxalin-l(2//)-yl)acetic acid from Preparative Example 51 using method described in Example 1. Following an aqueous work-up using EtOAc, the crude product was purified on SGC and re-crystallized from 4:1 hexanes and EtOAc. LC-MS: 4.36 min. (m/Z 416.1). 1HNMR(CDC3OD, 500 MHz) δ: 7.71 (d, 8.9 Hz, IH), 6.94 (dd, 2.3 & 8.7 Hz3 IH), 6.62 & 6.58 (d, 2.2 Hz, IH)5 5.15 & 5.18 (s, 2H), 3.866 & 3.870 (s, 3H), 3.33-3.56 (m, 4H), 1.48-1.85 (m, 4H), 1.45 (s, 9H), 1.08 & 0.91 (t, 7.2 Hz, 3H), 1.05 & 0.93 (s, 9H).
Examples 258-290
Figure imgf000068_0003
The following compounds in Table 14 were prepared using the method described in Example 1 using ((3-/ert-Butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetic acid and the amine listed in Table 14. Example 287 was obtained as the side-product during the preparation of Example 286.
Table 14
Figure imgf000069_0001
Figure imgf000070_0001
285 H 3.08 (473.3)
Figure imgf000070_0002
Example 291
Figure imgf000070_0003
3-[[(3-/er?-Butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetyl](3,3-dimethylbutyl)amino]-2,2- dimethylpropyl dihydrogen phosphate
Step A. Di-tert-butyl 3-[(3,3-dimethylbutyl)amino]-2,2-dimethylpropyl phosphate Treat a solution of 100 mg 3-[(3,3-dimethylbutyl)amino)-2,2-dimethylpropan-l-ol and 156 mg di-Zert-butyl diethylamidophosphite in 0.6 mL anhydrous DCM with 3.5 mL of 0.45 M tetrazole in MeCN at room temperature overnight. Cool half of this mixture to -400C and add a solution of 140 mg 72% mCPBA in 2.5 mL DCM. Remove the cooling bath and let the reaction mixture warm up to room temperature. LC- MS showed desired oxidation product. Treat the other half of the original reaction in the same manner. Combine the two halves of the reaction and quench with 10 mL 10% NaHCO3 solution and adjust the pH to ~10 with 5 N NaOH solution. Separate the layers, extract the aqueous layer with DCM (2x20 mL), wash the organic extract with saturated brine, dry over anhydrous Na2SO-), and evaporate to give crude title compound, which was used in the next step without further purification. LC-MS: 3.02 min. (m/Z 380.3, 324.4, 268.2). 1H NMR (CDCl3, 500 MHz) δ: 3.74 (d, 4.6 Hz, IH), 2.62 (m, 2H), 2.50 (s, 2H), 1.51 (s, 9H), 1.50 (s, 18 H), 1.42 (m, 2H)5 0.97 (s, 6H), 0.91 (s, 9H).
Figure imgf000071_0001
dimethylethyl hydrogen phosphate using procedure described in Example 1. LC-MS: 4.01 min. (m/Z 616.2, 428.3).
Step C. 2-[[(3-terr-Butyl-7-methoxy-2-oxoquinoxalin-l(2H)-y0acetyl](3,3-dimethylbutyl)amino]-l,l- dimethylethyl dihydrogen phosphate
Treat a mixture of 23.1 mg benzyl 2-[[(3-ter/-butyl-7-methoxy~2-oxoquinoxalin-l(2H)- yl)aceryl](3,3-dimethylbutyl)amino]-l,l-dimethylethyl hydrogen phosphate and 2.0 mg 10% Pd/C in 1 mL MeOH with hydrogen balloon for 3.25 hours. The catalyst was removed by filtration and solvent removed under reduced pressure. The residue was purified on RP-ΗPLC using 40~80% MeCN with 0.05% TFA Combine pure product fractions and lyophilize to give the title compound. LC-MS: 3.54 min. (m/Z 526).
Example 293
Figure imgf000072_0001
3-/er^-Butyl-l-(3,3-dimethylbutyl)-7-methoxyquinoxalin-2(lH)-one A solution of 21.3 mg 3-tert- Butyl-7-methoxyquinoxalin-2(lH)-one and 21.5 mg l-bromo-3,3-dimethylbutane in 0.5 mL DMF was treated with 35.8 mg cesium carbonate at 46°C for 3 days. The title compound was separated from slower-eluting isomeric 2-tør/-butyl-3-(333-dirnethylbutoxy)-6-methoxyquinoxaline on RP-ΗPLC. LC- MS: 4.55 min. (m/Z 317.2).
Example 294
Figure imgf000072_0002
3-ter/-ButyI-l-(3,3-dimethyl-2-oxobutyl)-7-methoxyquinoxalin-2(lH)-one A solution of 47 mg 3- ierf-Butyl-7-methoxyquinoxaIin-2(lH)-one and 43 mg l-bromo-3,3-dimethylbutan-2-one in 2 mL DMF was treated with 79 mg cesium carbonate at room temperature. The title compound was separated from minor slower-eluting isomeric 1 -[(3-/er/-butyl-7-methoxyquinoxaIin-2-yl)oxy]-3,3-dimethylbutan-2-one on RP-ΗPLC. LC-MS: 4.02 min. (m/Z 331.3). 1H NMR (CD3OD5 500 MHz) δ: 7.73 (d, 8.9 Hz, IH), 6.95 (dd, 2.5 & 8.9 Hz3 IH), 6.49 (d, 2.2 Hz, IH)3 5.40 (s, 2H)3 3.86 (s, 3H), 1.44 (s3 9H), 1.36 (s, 9H). The structure of the title compound was further confirmed by NOE spectroscopy.
Examples 295-301
Figure imgf000073_0001
Examples 295-301 in Table 15 were prepared using the same method described in Example 294. Some of the bromoketones used were prepared using the method of Gaudry and Marguet (Org. Syn. Coll. Vol. 6, 193).
Table 15
Example Starting amine LC-MS, min. (m/Z)
295 t-amyl 4.04 (345.2)
296 3-methyl-pent-3-yl 4.18 (359.1)
297 i-propyl 3.89 (317.1)
298 cyclohexyl 4.16 (357.2)
299 phenyl 3.95 (351.2)
300 cyclopentyl 4.06 (343.3)
301 1-adamantyl 4.42 (409.4)
Example 302
Figure imgf000073_0002
1 -(3,3-Dimethyl-2-oxobutyl)-3-isopropyl-7-methoxyquinoxalin-2( lH)-one The title compound was prepared from 3-isopropyl-7-methσxyquinoxalin-2(lH)-oneand l-bromo-3,3-dimethylbutan-2-one using the method in Example 294. LC-MS: 3.56 min. (m/Z 317.1 ).
Examples 303-315
EDC5 HOBt, DffiA, DMF
Figure imgf000073_0003
Figure imgf000073_0004
The following compounds in Table 16 were prepared using the method described in Example 1 using (3-isoρropyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetic acid and the amine listed in Table 16. Table 16
)
Figure imgf000074_0001
308 fi^4 3.65 (372.2)
Figure imgf000074_0002
Example 316
Figure imgf000074_0003
2-[3-(4-Cyanopheπyl)-7-methoxy-2-oxoquinoxalin-l(2H)-yl]-NyΛ''-bis(3-methylbutyl)acetamide
Step A. tert-Butyl [3-(4-cyanophenyl)-7-methoxy-2-oxoquinoxalin-l(2H)-yI]acetate The title compound was prepared from tert-buty] iV-(5-methoxy-2-nitrophenyI)gIycinate and ethyl (4- cyanophenyl)(oxo)acetate using method described in Preparative Example 51 Method B Step B. LC-MS: 3.75 min. (m/Z 392.0).1H NMR (CD3OD, 500 MHz) δ: 8.49 (dd, 1.8 Sc 6.6 Hz, 2H), 7.89 (d, 9.0 Hz3 1 H), 7.82 (dd, 1.8 & 6.8 Hz5 2H), 7.08 (dd, 2.3 & 8.3 Hz, IH), 6.82 (d, 2.6 Hz, IH), 5.11 (s, 2H), 3.95 (s, 3H).
Figure imgf000075_0001
Figure imgf000076_0001
Example 334
Figure imgf000076_0002
l-(3,3-Dimethyl-2-oxobutyI)-3-[4-(3-hydroxypropyl)phenyl]-7-methoxyquinoxalin-2(lH)-one
The title compound was prepared from 3-[4-(3-hydroxypropyl)phenyl]-7-methoxyquinoxalin- 2(lH)-one and l-bromo-3,3-dimethylbutan-2-one using method described in Example 294. LC-MS: 3.50 min. (m/Z 409.1).1H NMR (CDCl3, 500 MHz) δ: 8.16-8.17 (m, 2H), 7.90 (d, 8.9 Hz, IH)3 7.31 (d, 8.2 Hz, 2H), 6.97 (dd, 2.3 & 8.9 Hz, IH), 6.34 (d, 2.5 Hz, IH), 5.32 (s, 2H), 3.90 (s, 3H), 3.70 (t, 6.4 Hz, 2H), 2.78 (t, 7.4 Hz, 2H)5 1.94-1.97 (m, 2H), 1.40 (s, 9H).
Examples 335-333
Figure imgf000076_0003
The following compounds in Table 18 were prepared using the method described in Example 1 using [[3- [4-(hy droxymethyl)phenyl]-7-methoxy-2-oxoquinoxaI in- l(2//)-yl] acetic acid and the amine listed in Table 18.
Table 18
Figure imgf000077_0001
Example 340
Figure imgf000077_0002
l-(3,3-dimethyl-2-oxobutyl)-3-[4-(hydroxymethyl)phenyl]-7-methoxyquinoxalin-2(lH)-one
The title compound was prepared from 3-[4-(hydroxymethyl)phenyl]-7-methoxyquinoxalin- 2(lH)-one and l-bromo-3,3-dϊmethylbutaπ-2-one using method described in Example 294. LC-MS: 3.15 min. (m/Z 381.2).
Example 341
Figure imgf000077_0003
3,3-Dimethyl-2-oxobutyl 4-[4-(3,3-dimethyl-2-oxobutyl)-6-methoxy-3-oxo-3,4-dihydroquinoxaIin-2-yl]- 4-methylpentanoate
The title compound was prepared from 4-[4-(6-methoxy~3-oxo-3,4-dihydroquinoxaIin-2- yI)phenyI]-4-methylpentanoic acid and 1.5 equiv. of l-brσmo-3.,3-dimethylbutan-2-one using method described in Example 294. LC-MS: 4.02 min. (m/Z 487.2).
Example 342
Figure imgf000078_0001
The following compounds in Table 20 were prepared using the method described in Example 1 using (3-ter/-Butyl-7-methoxy-2-oxo-l,8-naphthyridin-l(2H)-yl)acetic acid and the amine listed in Table 20.
Table 20
Example Starting amine (HNR1R2) LC-MS, min. (m/Z) 348 4.17 (402.1) 349 JL 4.24 (416.1)
Examples 350
Figure imgf000079_0001
3-fe^-Butyl-7-chloro-l-(3,3-dimethyl-2-oxobutyl)-l,8-naphthyridin-2(lH)-one
Step A.3-/er/-Buryl-7-chloro-l,8-naphthyridin-2(lH)-one The title compound was prepared by treating 14.5 mg 3-.eri-butyl-l,8-naphthyridin-2(lH)-one 8-oxide with 1 mL thionyl chloride at room temperature overnight. It was separated from its 7-hydroxy and 4-chloro derivatives on RP-ΗPLC. LC- MS: 3.21 min. (m/Z 237.1). 1H NMR (CDCl3, 500 MHz) δ: 7.85 (d, 8.0 Hz3 IH), 7.64 (s, IH), 7.22 (d, 8.0 Hz5 IH)3 1.45 (s, 9H)
Step A.3-/erf-Butyl-7-chloro-l-(333-dimethyl-2-oxobutyl)-l,8-naphthyrϊdiπ-2(lH)-one
The title compound was prepared from 3-/-?r^butyl-7-chloro-l38-naphthyridin-2(lH)-one and 1- brorno-3,3-dimethylbutan-2-one using method described in Example 294. LC-MS: 3.97 min. (m/Z 335.1).
Examples 351
Figure imgf000079_0002
N,N-Dibutyl-2-(3-tert-butyl-2-oxo-l,6-naphthyridin-l(2H)-yl)acetamide
Step A. Methyl 2-[{4-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}(hydroxy)methyI]-3,3- dimethylbutanoate The title compound was prepared from N-(3-formylpyridin-4-yl)-2,2- dimethylpropanamide and methyl 3-methylbutanoate using the method of Turner (J. Org. Chem. 55, 4744, 1990). LC-MS: 2.64 and 2.78 min. (m/Z 337.2). 1HNMR of two diastereomers (CDCl3, 500 MHz) 5: 9.68 & 9.60 (br s, IH)5 8.43 & 8.28 (d, 5.8, IH), 8.32 (d, 5.7 Hz, IH), 8.23 & 8.05 (br s, IH), 5.10-5.16 (m, IH), 3.78 & 3.30 (s, 3H), 3.00 & 2.86 (d, 5.1 or 10.8 Hz, IH), 1.35 & 1.34 (s, 9H), 1.21 & 0.96 (s, 9H).
Step B. 3-tør/-Butyl-l,6-naphthyridin-2(l//)-oneThe title compound was prepared from methyl 2-[{4- [(2,2-dimethylpropanoyl)amino]pyridin-3-yl} (hydroxy )methyl]-3,3-dimethylbutanoate using the method described in Preparative Example 60 Step B by heating in a microwave reactor at 160 0C for 2 hours. LC- MS: 1.75 min. (m/Z 203.1). 1HNMR (CDCl3, 500 MHz) δ: 8.83 (s, IH), 8.54 (d, 5.7 Hz, IH), 7.75 (s, IH), 7.18 (d, 5.7 Hz, IH), 1.51 (s, 9H).
Step C. Methyl (3-te/"/-butyl-2-oxo-t,6-naphthyridin-l(2H)-yl)acetate The title compound was prepared from 3-tørr-butyl-l,6-naphthyridin-2(lH)-one and methyl bromoacetate using the method described in Preparative Example 57 Step G. It was separated from the slower-eluting isomeric methyl [(3-ter/-buryl-l,6-naphthyridin-2-yl)oxy]acetate on RP-ΗPLC. LC-MS: 2.18 min. (m/Z 275.1 ). 1H NMR (CDC3OD, 500 MHz) δ: 9.20 (s, IH), 8.67 (d, 7.1 Hz, IH), 8.10 (s, IH), 7.89 (d, 7.1 Hz, IH), 5.21 (d, 2H), 3.82 (s, 3H), 1.43 (s, 9H).
Step D. (3-ter/'-Butyl-2-oxo-l,6-naphthyridin-l(2H)-yl)acetic acidThe title compound was prepared from methyl (3-tert-butyl-2-oxo-l,6-naphthyridin-l(2H)-yl)acetate using the method described in Preparative Example 57 Step Η. LC-MS: 1.92 min. (m/Z 261.2).
Step E. N,iV-Dibutyl-2-(3-ferir-butyl-2-oxo- 1 ,6-naphthyridin- 1 (2H)-yI)acetamide
The title compound was prepared using the method described in Example 1 using (3-/er/-butyl-2- oxo-l,6-naphthyridin-l(2H)-yl)acetic acid and dibutylamine. LC-MS: 3.23 min. (m/Z 372.2).
Examples 352
Figure imgf000080_0001
2-(3-iTert-Butyl-2-oxo-l,6-naphthyridin-l(2H)-yI)-iV-(3,3-dimethylbutyl)-N-propylacetamide
The title compound was prepared using the method described in Example 1 using (3-/er/-buryl-2- oxo-l,6-naphthyridin-l(2H)-yl)acetic acid and 3,3-dimethyl-N-propylbutan-l-amine. LC-MS: 3.33 min. (m/Z 386.2). FUNCTIONAL ASSAYS A. Maxi-K Channel
The identification of inhibitors of the Maxi-K channel can be accomplished using Aurora Biosciences technology, and is based on the ability of expressed Maxi-K channels to set cellular resting potential after transient transfection of both α and β subunits of the channel in TsA-201 cells. In the absence of inhibitors, cells display a hyperpolarized membrane potential, negative inside, close to Eκ (-80 mV) which is a consequence of the activity of the Maxi-K channel. Blockade of the Maxi-K channel will cause cell depolarization. Changes in membrane potential can be determined with voltage-sensitive fluorescence resonance energy transfer (FRET) dye pairs that use two components, a donor coumarin (CC2DMPE) and an acceptor oxanol (DiSBAC2(3)). Oxanol is a lipophilic anion and distributes across the membrane according to membrane potential. Under normal conditions, when the inside of the cell is negative with respect to the outside, oxanol is accumulated at the outer leaflet of the membrane and excitation of coumarin will cause FRET to occur. Conditions that lead to membrane depolarization will cause the oxanol to redistribute to the inside of the cell, and, as a consequence, to a decrease in FRET. Thus, the ratio change (donor/acceptor) increases after membrane depolarization.
Transient transfection of the Maxi-K channel in TsA-201 cells can be carried out as previously described (Hanner et al. (1998) J. Biol. Chem. 273, 16289-16296) using FUGENE6™ as the transfection reagent. Twenty four hours after transfection, cells are collected in Ca2+-Mg2+-free Dulbecco's phosphate-buffered saline (D-PBS), subjected to centrifugation, plated onto 96-well poly-'d- lysine coated plates at a density of 60,000 cells/well, and incubated overnight. The cells are then washed Ix with D-PBS, and loaded with 100 μl of 4 μM CC2DMPE-0.02% pluronic-127 in D-PBS. Cells are incubated at room temperature for 30 min in the dark. Afterwards, cells are washed 2x with D-PBS and loaded with 100 μl of 6 μM DiSBAC2(3) in (mM): 140 NaCl5 0.1 KCl, 2 CaCl2, 1 MgCl2, 20 Hepes- NaOH, pH 7.4, 10 glucose. Test compounds are diluted into this solution, and added at the same time. Cells are incubated at room temperature for 30 min in the dark.
Plates are loaded into a voltage/ion probe reader (VlPR) instrument, and the fluorescence emission of both CC2DMPE and DiSBAC2(3) are recorded for 10 sec. At this point, 100 μl of high- potassium solution (mM): 140 KCl, 2 CaCl2, 1 MgCl2, 20 Hepes-KOH, pH 7.4, 10 glucose are added and the fluorescence emission of both dyes recorded for an additional 10 sec. The ratio CC2DMPE/DiSBAC2(3), before addition of high-potassium solution equals 1. In the absence of any inhibitor, the ratio after addition of high-potassium solution varies between 1.65-2.0. When the Maxi-K channel has been completely inhibited by either a known standard or test compound, this ratio remains at 1. It is possible, therefore, to titrate the activity of a Maxi-K channel inhibitor by monitoring the concentration-dependent change in the fluorescence ratio.
The compounds of this invention were found to cause concentration-dependent inhibition of the fluorescence ratio with IC5o's in the range of about 5 nM to about 500 μM, more preferably from about 5 nM to about 20 nM. B. Electrophysiological assays of compound effects on high-conductance calcium-activated potassium channels
Human non-pigmented ciliary epithelial cells
The activity of high-conductance calcium-activated potassium (maxi-K) channels in human non-pigmented ciliary epithelial cells was determined using electrophysiological methods. Currents through maxi-K channels were recorded in the inside-out configuration of the patch clamp technique, where the pipette solution faces the extracellular side of the channel and the bath solution faces the intracellular side. Excised patches contained one to about fifty maxi-K channels. Maxi-K channels were identified by their large single channel conductance (250-300 pS), and by sensitivity of channel gating to membrane potential and intracellular calcium concentration. Membrane currents were recorded using standard electrophysiological techniques. Glass pipettes (Garner 7052) were pulled in two stages with a Kopf puller (model 750), and electrode resistance was 1-3 megohms when filled with saline. Membrane currents were recorded with EPC9 (HEKA Instruments) or Axopatch ID (Axon Instruments) amplifiers, and digital conversion was done with ITC- 16 interfaces (Instrutech Corp). Pipettes were filled with (mM); 150 KCl, 10 Hepes, 1 MgCl2, 0.01 CaCl2, 3.65 KOH5 pH 7.20. The bath (intracellular) solution was identical, except, in some cases, calcium was removed, 1 mM EGTA was added and 20 mM KCl was replaced with 20 mM KF to eliminate calcium to test for calcium sensitivity of channel gating. Drugs were applied to the intracellular side of the channel by bath perfusion.
Human non-pigmented ciliary epithelial cells were grown in tissue culture as described (Martin-Vasallo, P., Ghosh, S., and Coca-Prados, M., 1989, J. Cell. Physiol. HL, 243-252), and plated onto glass cover slips prior to use. High resistance seals (>1 Gohm) were formed between the pipette and cell surface, and inside out patches were excised. Maxi-K channels in the patch were identified by their gating properties; channel open probability increased in response to membrane depolarization and elevated intracellular calcium. In patches used for pharmacological analysis, removing intracellular calcium eliminated voltage-gated currents. Maxi-K currents were measured after depolarizing voltage steps or ramps that caused channel opening.
The compounds of this invention were applied to the intracellular side of the channel in appropriate concentrations (0.001 to 100 μM). The compounds reduced channel open probability, and this effect was reversed upon washout of compounds from the experimental chamber. The IC50 for block of maxi-K channels under these conditions for the compounds of this invention ranged from about 0.2 nM to about 100 μM.

Claims

Figure imgf000083_0001
(CH2)n(CHR7)s(CH2)mOR, -(CH2)nC(R7)2(CH2)mOR, CF3, _(CH2)n(CHR7)s(CH2)mSO2R, - (CH2)n(CHR7)s(CH2)mSO2N(R)2, -(CH2)n(CHR7)s(CH2)mCON(R)2, -
(CH2)n(CHR7)s(CH2)mCONHC(R)3, -(CH2)IICONHC(R)2CO2R, -(CH2)n(CHR7)s(CH2)mCOR8, nitro, cyano or halogen, said alkyl, cycloalkyl, alkoxy, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups of Ra,
or, when Q is N, R2 and R3 taken together with the intervening N atom form a 4-10 membered heterocyclic ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR3 and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from Ra;
or, when Q equals CRy, R2 and R3 taken together with the intervening CRY form a 4-10 membered carbocyclic or heterocyclic aromatic ring or fused ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-5 double bonds, and optionally substituted by 1-3 groups selected from Ra;
R4 represents hydrogen, C1-6 alkoxy, halogen, cyano, OH5 C\.β alkyl, COOR, SO3H, C1-6 alkylcarbonyl, S(O)qRy, -O(CH2)nN(R)2, -O(CH2)nCO2R, -OPO(OH)2, CF3, -N(R)2, nitro, or Ci_6 alkylamino;
R7 represents hydrogen, Ci-6 alkyl, -(CH2)nCOOR or -(CH2)nN(R)2,
R8 represents -(CH2)nC3-8 cycloalkyl, -(CH2)n 3-10 heterocyclyl, Cl_6 alkoxy or -(CH2)nC5_i0 heteroaryl, -(CH2)nC6_l0 aryl said heterocyclyl, cycloalkyl, aryl or heteroaryl optionally substituted with 1-3 groups selected from Ra;
Ra represents F, Cl, Br, I, CF3, N(R)2, NO2, CN, -(CH2)nCOR8, -(CH2)nCONHR8, -
(CH2)nCON(R8)2, -O(CH2)nCOOR, -NH(CH2)nOR, -COOR, -OCF3, -O-, -NHCOR, -SO2R, - SO2NR2, -SR, (C1-C6 alkyOO-, -(CH2)nO(CH2)mOR, -(CH2)nCi_6 alkoxy, (aryl)O-, -OH, (C1-C6 alkyI)S(O)m-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)NH-, -(C1-C6 alkyl)NRw(CH2)nC3-10 heterocyclyl-Rw, -(C1-C6 alkyl)O(CH2)nC3-10 heterocyclyl-Rw, -(C1-C6 alky[)S(CH2)nC3_io heterocyclyl-Rw, -(C1-C6 alkyl)-C3-io heterocyclyl-Rw, -(CH2)n-K-C(=K)N(R)2, - (C2-6 alkenyl)NRw(CH2)nC3-l0 heterocyclyI-Rw, -(C2-6 alkenyl)O(CH2)nC3_i0 heterocyclyl-Rw, -(C2. 6 aIkenyl)S(CH2)nC3-io heterocyclyl-RW3 -(C2_6 alkenyl)-C3-io heterocyclyl-Rw, -(C2-6 alkenyl)-K- C(=K)N(R)2, -(CH2)nSO2R, -(CH2)nSO3H, -(CH2)nPO(OR)2, -(CH2)nOPO(OR)2, cyclohexyl, cyclopentyl, morpholinyl, piperidyl, pyrrolidinyl, thiophenyl, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl, C2-6 alkenyl, and Cj-C1Q alkyl, said alkyl, alkenyl, alkoxy, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, and isothiazolyl optionally substituted with 1-3 groups selected from CpCg alkyl, and COOR;
K independently represents CH, CH.2 or NH;
Rw represents H, C\-6 alkyl, -C(O)Ci_6 alkyl, -C(O)OCi_6 alkyl, -SO2N(R)2, -SO2C1-6 alkyl, -SO2C6- 10 aryl, NO2, CN or -C(O)N(R)2;
Rb represents Cχ-6 alkyl, -COOR, -SO3R, CN, (CH2)nOR, C(O)O(CH2)nC(O)R, -OPO(OH)2, - (CH2)nC6-10 aryl, or -(CH2)nC5-io heteroaryl;
Re represents hydrogen, C \.$ alkyl, or -(CH2)nC6-10 aryl;
m is 0-3; n is 0-3; q is 0-2; s is 0-l;and p is 0-2.
2. A compound according to claim 1 wherein Q is N5 X is -(CHR7)pC(O)-, Ri is Cj.6 alkyl, Z is N, Zj, Z2, and Z3 are each CH, QR2R3 is a dialkylamine, hydroxydialkylamine or hydroxylamine and R7 is hydrogen or Ci-6 alkyl, and all other variables are as originally described.
3. A compound according to claim 1 wherein R2 and R3 are taken together with the intervening N atom form a 4-10 membered heterocyclic carbon ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from Ra
4. A compound according to claim 1 of structural formula E:
Figure imgf000085_0001
π or a pharmaceutically acceptable salt, ester including phosphate, enantiomer, diastercomer or mixture thereof:
Figure imgf000086_0001
2-(3-rerr-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3-hydroxy-2,2-dimethylpropyl)"N'-(3- methylbutyl)acetamide,
2-(3-rer/-butyl-7-methoxy-2-oxoquinolin-l(2H)-y])-iV-(5-hydroxy-4,4-diinethylpentyl)-N-(3- methylbutyl)acetamide,
2<3-7e^butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-(3,3-dirnethylbutyl)-N-(3-hydroxy-2,2- dimethylpropyl)acetamide,
2-(3-rβ/-/-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-(3,3-dirπethylbutyl)-N-(2-hydroxy-2- methylpropyl)acetamide,
2-(3-7er^utyl-7-methoxy-2-oxoquinolin-l(2i^-yl)-.V-(5-hydroxypentyl)-N-(3-methylbutyl)acetamide,
2-(3-7erf-butyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3:,3-dimethylbutyI)-N-(5- hydroxypentyl)acetamide,
2<3-rer^butyl-7-me1hoxy-2-oxoquinolin-l(2//)-yl)-iV-(3,3-dimethylbutyl)-N-(2-hydroxy-l , 1 - dimethylethyl)acetamide,
3-rerf-butyl-l-(3,3-dimethyl-2-oxobutyl)-7-methoxyquinolin-2(lH)-one,
7vζN-Dibutyl-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide,
ΛyV"-Diisobufyl-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2//)-yI)acetamide,
N-(3,3-Dimethylbutyl)-N-ethyl-2-(3-isopropyI-7-πiethoxy-2-oxoquinoIin-l(2H)-yl)acetainide,
N-(3,3-Dirnethylbutyl)-2-(3-isopropyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-N-propyIacetamide3
2-(3-Isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-octyl-iV:-pentylacetaniide,
N-Ethyl-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-l,3-thiazol-2-ylacetamide, (±)-3-Isopropyl-7-methoxy-l-{2-[trans-octahydroisoquinolin-2(lH)-yl]-2-oxoethyl}quinolin-2(lH)-one,
ΛζN-Bis(2,2-dimethylpropyl)-2-(3-isopropyl-7-raethoxy-2-oxoquinolin- 1 (2H)-yl)acetamide,
2-(3 -Isopropyl-7-nlethoxy-2-oxoquinolin- 1 (2H)-yl)-N-(3-methylbutyl)-N-propylacetamide,
N-Butyl-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3-methylbutyl)acetamide, iV-Isobutyl-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-7V-propy]acetamide5
N-Butyl-N-isobutyl-2-(3-isopropyI-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide,
N-(5-Ηydroxy-4,4-dimethyIpentyl)-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-(3- methylbutyl)acetamide,
N-(3,3-Dimethylbutyl)-N-(5-hydroxypentyI)-2-(3-isopropyl-7-methoxy-2-oxoquinolin-l(2i/)- yl)acetamide,
N^-Dibutyl-2-(3-cyclohexyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)acetamide>
2-(3-Cyclohexyl-7-methoxy-2-oxoqυinolin-l(2H)-yl)-NrΛ''-dipropylacetamideJ
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(cyclopropylmethyl)-N-propylacetamide,
N-Cyclohexyl-2-(3-cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yI)-N-ethylacetamide,
2-(3-Cyclohexy]-7-methoxy-2-oxoquinolin-l(2H)-yl)-N:^-diisobutylacetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N^V-bis(3-methylbutyl)acetamideJ
2-(3-Cyclohexyl-7-methoxy-2-oxoquino]in-l(2H)-yl)-N-ethyl-N-(3-methyIbutyl)acetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-ethylacetamide, 2-(3-Cyclohe)iyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethylbutyI)-N-propylacetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(2,2-dimethylpropyl)-N-ethylacetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinoIin-l(2H)-yI)-N-(3-methyIbutyl)-iV-proρylacetarnϊde,
N-Butyl-2-(3 -cyclohexyl-7<nethoxy~2-oxoquinolin- 1 (2H)-yl)-N-(3-methylbutyl)acetamide,
2-(3 -Cyclohexyl-7-methoxy-2-oxoquinolin- 1 (2H)-yl)-N-methyl-N-(3 -methylbutyl)acetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(2-hydroxyethyl)-N"-(3-methylbutyl)acetamide,
2-(3 -Cyclohexyl-7-methoxy-2-oxoquinolin- 1 (2H)-yI)-N-ethyl-N-isobuty lacetamide,
2-(3 -Cyclohexy]-7-methoxy-2-oxoquinoIin- 1 (2H)-yI)-N-isobutyl-N-propylacetamide,
N-Butyl-2-(3-cycIohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-isobutylacetamide,
2-(3-Cyclohexyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3-hydroxy-2,2-dimethylpropyl)-N-(3- methyl buty l)acetamide, iV-(3,3-Dimethylbutyl)-2-(7-methoxy-2-oxo-3-phenylquinolin-l(2H)-yl)-N-propylacetamide i\ζN-Dibutyl-2-(7-methoxy-2-oxo-3-phenylquinolin-l(2H)-yl)acetamide:> i\r-(Cyclopropylmethyl)-2-(7-methoxy-2-oxo-3-phenylquinolin-l(2H)-yI)-N-propylacetamide,
N;,N-Diisobutyl-2-(7-methoxy-2-oxo-3-phenylquinolin-l(2H)-yl)acetamide,
2-(7-Methoxy-2-oxo-3-phenylquinolin-l(2//)-yl)-ΛζN-bis(3-methyIbutyl)acetamide,
N-Ethyl-2-(7-methoxy-2-oxo-3-phenylquinolin-l(2H)-yl)-N-(3-metliylbutyl)acetamide,
N-(3,3-DimethyIbutyl)-N-ethyl-2-(7-methoxy-2-oxo-3-phenylquinolin-l(2H)-yl)acetamide, iV-(2,2-Dimethylpropyl)-N-ethyl-2-(7-methoxy-2-oxo-3-phenylquinolin-l(2H)-yl)acetamide,
2-(3-Ethyl-7-methoxy-2-oxoquinolin-l(2//)-yl)-Λζ,N-bis(3-methylbutyl)acetainide,
-V-(3,3-Dimethylbutyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-propylacetamide, <,
N,N-Bis(3,3-dimethylbutyl)-2-(3-ethyl-7-methoxy-2-oxoquiπolin-l(2H)-yl)acetamide5 iVyV-Bis(2,2-dimethylpropyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide>
N-B uty l-N-(2,2-dimethylpropyl)-2-(3 -ethyl-7-methoxy-2-oxoquinol in- 1 (2H)-yl)acetamide,
N-(2,2-Dimethylpropyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-pentylacetamide3
N-(2,2-Dimethylpropyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3-methylbutyI)acetaπiide3
N-Cyclopentyl-N-(2,2-dimethyIpropyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide;ι
N-(3,3-Dimethylbutyl)-N-(2,2-dimethyIpropyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide:,
N-Butyl-N-(3,3-dimethylbutyl)-2-(3-ethyl-7-methoxy-2-oxoquinolin-l{2H)-yl)acetamide5
N-(3,3-Dimethylbutyl)-2-(3-ethyl-7-methoxy-2-oxoquino)in-l(2H)-yI)-^r-Penty1'acetaniicIe' N-Cyclopentyl-N-(3,3-dimethylbutyl)-2-(3-ethyl-7-methoxy-2-oxoquino]in-l(2H)-yl)acetamide,
N-Butyl-2-(3-ethyl-7-raethoxy-2-oxoquinolin-](2H)-yl)-N-(3-methylbutyl)acetamide,
N,N-DibutyI~2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N^V-dipropylacetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(eyclopropylmethyI)-N-propylacetamide,
N-Cyclohexyl-2-(3-cycIopenty!-7-methoxy-2-oxoquinoIin-l(2H)-yI)-N-ethylacetamide:>
N-Butyl-2-(3-cycIopentyl-7-methoxy-2-oxoquinolin-l(2iy)-yl)-N-ethylacetamide, 2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-NJ7Vr-diisobutylacetamideJ
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-ΛζN-bis(3-inethylbutyl)acetaπiide,
2-(3-Cyclopen(yl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-ethyl-N-(3-methylbutyl)acetamide,
N-Butyl-2-(3-cyclopβntyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-JV-propylacetamide,
2-(3-CycIopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dJmethylbutyl)-N-ethylacetamide,
2-(3-Cyclopen1yl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethyIbutyl)-N-propylacetarnide:,
2-(3-Cyclopenty]-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(2,2-dtmethylpropyl)-N-ethylacetamide,
N-CycIohexyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV:-isopropylacetamide5
2-(3-Cyclopentyl-7-methoxy-2-oxoquinoΗn-l(2H)-yl)-ΛyV"-bis(3,3-dimethylbutyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-iV-oc-yI-N-pentylacetamide,
N-09ec-Butyl)-2-(3-cyclopenlyl-7-inethoxy-2-oxoquinolin-l(2H)-yl)-N-propylacetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinoIin-l(2H)-yI)-N-ethyl-N-l,3-thiazoI-2-ylacetamide,
(±)-3-CycIopentyl-7-methoxy-l-{2-trans-octahydroisoquinolin-2(lH)-yl]-2-oxoethyI}quinolin-2(lH)-one,
N-Butyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-y])-N-(232-dimethylpropyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(2,2-dimethylpropyl)-N-pentylacetamide>
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(2,2-dimethylpropyl)-iV-(3- methylbutyl)acetamide,
N-Cyclopentyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-N-(2,2-dimethylpropyI)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-(2,2- dimethylproρyl)acetamide,
N-ButyI-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-y])-N-(3,3-dimethylbutyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-pentylacetamide,
N-Cyclopentyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yI)-N-(3,3-dimethylbutyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(3,3-dimethylbutyl)-^r-(3- methylbutyl)acetamide,
2-(3-CycIopentyl-7-methoxy-2-oxoqυinoΗn-l(2H)-yl)-N-(3-methylbutyl)-iV-propylacetamide,
N-Butyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinoIin-l(2H)-yI)-N-(3-methylbutyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-methyl-JV-(3-methylbutyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-(2-hydroxyethyl)-JV'-(3-πiethylbutyI)acetaniide:i
2-(3-Cyclopentyl-7-methoxy-2-oxoquinoIin-l(2H)-yl)-N-ethyl-N-isobutylacetamide-
2-(3-Cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-isobutyl-N-propylacetarπide,
N-Butyl-2-(3-cyclopentyl-7-methoxy-2-oxoquinolin-l(2H)-yl)-N-isobutylacetamide,
2-(3-CycIopentyl-7-methoxy-2-oxoquinolin- 1 (2H)-yl)-N-(3-hydroxy-2,2-dimethy lpropyl)-N-(3 - methylbutyl)acetamide,
2-(3-Cyclopentyl-7-methoxy-2-oxoqu inolin- 1 (2H)-yl)-N-(5-hydroxy-4,4-dimethylpen1y l)-N-(3- methy lbutyl)acetam ide,
Figure imgf000090_0001
2-(3-fert-Butyl-7-methoxy-2-oxoquLnoxalin-l(2H)-yl)-N-(3,3-dimethylbutyI)-N-(3-hydroxy-3- methylbutyl)acetamide,
2-(3-rert-Butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)-N-(353-dimethylbutyl)-N-(3-methylbut-2-en-l- y])acetamide,
2-(3-ter<-Butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-(2-hydroxy-2- methylpropyl)acetamide,
2-(3-tert-Butyl-7-methoxy-2-oxoquinoxaIin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-(5- hydroxypenty l)acetam ide,
3-[[(3-rerf-Butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetyl](3,3-dimethyIbutyI)amino]-2,2- dimethylpropyl dihydrogen phosphate,
2-[[(3-ter/-Butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetyl](3,3-dimethylbutyl)amino]-Ul- dimethylethyl dihydrogen phosphate,
3-/ert-ButyI-l-(3,3-dimethyl-2-oxobutyI)-7-methoxyquinoxalin-2(lH)-one,
3-/er/-ButyU-(3J3-dimethyl-2-oxopenty])-7-methoxyquinoxalin-2(lH)-one5
3-fer^-Butyl-l-(3-ethyl-3-methyl-2-oxopentyl)-7-methoxyquinoxalin-2(lH)-one,
3-tert-Buty 1-7-methoxy- 1 -(3-methyl-2-oxobutyl)quinoxalin-2( 1 H)-one,
3-/£?r/-Butyl-l-(2-cyclohexyl-2-oxoethyl)-7-methoxyquinoxalin-2(lH)-one,
3-ferf-Butyl-l-(2-cyclopentyl-2-oxoethyl)-7-methoxyquinoxalin-2(lH)-one, l-[2-(l-AdamantyI)-2-oxoethyl]-3-/er/-butyl-7-methoxyquinoxalin-2(lH)-one,
2-(3-Isopropyl-7-methoxy-2-oxoquinoxaIin-l(2H)-yl)-N:N-bis(3-methylbutyI)acetaniide,
2-[3-[4-(3 -Ηydroxypropy l)phenyl]-7-methoxy-2-oxoquinoxal in- 1 (2H)-yl] -N,N-bi s(3 - methylbutyl)acetamide,
N-(3,3-DimethylbutyI)-2-[3-[4-(3-hydroxypropyl)phenyl]-7-methoxy-2-oxoquinoxalin-lC2H)-yl]-N- propylacetamide,
3,3-Dimethyl-2-oxobutyl 4-[4-(3,3-dimethyl-2-oxobutyl)-6-methoxy-3-oxo-3,4-dihydroquinoxalin-2-yl]-
4-methylpentanoate,
2-[3-(4-Ηydroxy-l,l-dimethylbutyl)-7-methoxy-2-oxoquiπoxalin-l(2H)-yl]-Λ'>N-bis(3- methylbutyl)acetamide,
2-(3-/er/-Butyl-7-methoxy-2-oxo-l,8-naphthyridin-l(2H)-yl)-N-(3,3-dimethylbutyl)-N-propylacetamide, or a pharmaceutically acceptable salt, enantiomer, diatereomer or mixture thereof.
7. A method for treating ocular hypertension or glaucoma comprising administration to a patient in need of such treatment a therapeutically effective amount of a compound of structural formula I of claim 1.
8. A method for treating macular edema, macular degeneration, increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension, and/or a neuroprotective effect comprising administration to a patient in need of such treatment a pharmaceutically effective amount of a compound of claim ] ; or a pharmaceutically acceptable salt, ester including phosphate, enantiomer, diastereomer or mixture thereof.
9. A composition comprising a compound of formula I of claim 1 and a pharmaceutically acceptable carrier.
10. A composition according to claim 9 wherein one or more of an active ingredient belonging to the group consisting of: β-adrenergic blocking agent, parasympatho-mimetic agent, sympathomimetic agent, carbonic anhydrase inhibitor, EP4 agonist, a prostaglandin or derivative thereof, hypotensive lipid, neuroprotectant, and/or 5-HT2 receptor agonist is optionally added.
PCT/US2007/006109 2006-03-13 2007-03-09 Ophthalmic compositions for treating ocular hypertension WO2007108968A2 (en)

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EP07752786A EP2004193A2 (en) 2006-03-13 2007-03-09 Ophthalmic compositions for treating ocular hypertension
AU2007227664A AU2007227664A1 (en) 2006-03-13 2007-03-09 Ophthalmic compositions for treating ocular hypertension
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