WO2013177253A2 - Inhibiteurs de l'acide gras synthase - Google Patents

Inhibiteurs de l'acide gras synthase Download PDF

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Publication number
WO2013177253A2
WO2013177253A2 PCT/US2013/042173 US2013042173W WO2013177253A2 WO 2013177253 A2 WO2013177253 A2 WO 2013177253A2 US 2013042173 W US2013042173 W US 2013042173W WO 2013177253 A2 WO2013177253 A2 WO 2013177253A2
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Prior art keywords
alkyl
cycloalkyl
phenyl
oxa
cyclopropyl
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PCT/US2013/042173
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English (en)
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WO2013177253A3 (fr
Inventor
Nicholas David ADAMS
Terence John Kiesow
Kenneth Wiggall
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Glaxosmithkline Llc
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Publication of WO2013177253A2 publication Critical patent/WO2013177253A2/fr
Publication of WO2013177253A3 publication Critical patent/WO2013177253A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • FIELD OF INVENTION This invention relates to novel spirocyclic piperidines which are inhibitors of fatty acid synthase (FAS), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of cancers.
  • FAS fatty acid synthase
  • Fatty acids have an essential role in a variety of cellular processes including building blocks for membranes, anchors for targeting membrane proteins, precursors in the synthesis of lipid second messengers and as a medium to store energy, Menendez JS and Lupu R, Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis, Nature Reviews Cancer, 7: 763-777 (2007).
  • Fatty acids can either be obtained from the diet or can be synthesized de novo from carbohydrate precursors. The biosynthesis of the latter is catalyzed by the muliti-functional homodimeric FAS.
  • FAS synthesizes long chain fatty acids by using acetyl-CoA as a primer and Malonyl Co-A as a 2 carbon donor, and NADPH as reducing equivalents
  • acetyl-CoA Lipids, Structure and function of animal fatty acid synthase, 39: 1045-1053 (2004), Asturias FJ et al., Structure and molecular organization of mammalian fatty acid synthase, Nature Struct. Mol. Biol. 12:225-232 (2005), Maier T, et al, Architecture of Mammalian Fatty Acid Synthase at 4.5 ⁇ Resolution, Science 311 : 1258-1262 (2006)).
  • De novo fatty acid synthesis is active during embryogenesis and in fetal lungs where fatty acids are used for the production of lung surfactant. In adults, most normal human tissues preferentially acquire fatty acids from the diet. Therefore, the level of de novo lipogensis and expression of liopogenic enzymes is low (Weiss L, et al, Fatty-acid biosynthesis in man, a pathway of minor importance. Purification, optimal assay conditions, and organ distribution of fatty-acid synthase. Biological Chemistry Hoppe-Seyler
  • RNA mediated inhibition of FAS has demonstrated a preferential inhibition of cancer cell proliferation. Additionally, these inhibitors induce apoptosis in cancers cells in vitro and retard growth in human tumors in murine xenograft models in vivo (Menendez JS and Lupu R, Nature Reviews Cancer, 7: 763-777 (2007)). Based upon these findings, FAS is considered a major potential target of antineoplastic intervention.
  • This invention relates to compounds of the Formula (I), as shown below:
  • R 1 is phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or 10-membered heterocyclyl wherein said phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or
  • Ci-C 4 alkyl -S0 2 NR 5 R 6 , cyano, oxo, hydroxyl, halogen, Ci-C 4 alkoxy,
  • each R 2 is independently selected from the group of Ci-C 6 alkyl, cyano, Ci-C 6 alkoxy, hydroxyl, and halogen;
  • R 3 is selected from the group consisting of: Ci-C 6 alkyl, C3-C 7 cycloalkyl,
  • each R 4 is independently selected from the group consisting of halogen, hydroxyl, hydrogen, Ci-C 6 alkoxy, and Ci-C 6 alkyl;
  • R 5 is selected from the group consisting of hydrogen, Ci-C 4 alkyl, phenyl,
  • R 6 is hydrogen, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or -Ci-C 3 alkylC 3 -C 7 cycloalkyl;
  • R 5 and R 6 taken together with the nitrogen to which they are attached represent a 4- to 7-membered saturated or unsaturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, wherein said ring is optionally substituted by 1 to 3 substituents independently selected from hydoxyl, Ci-C 3 alkyl, and hydroxyCi-C 4 alkyl-;
  • R 7 is hydrogen or methyl
  • Rg is hydrogen, hydroxyl, or -OCi-C 3 alkyl
  • R 9 is a 5- or 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents independently selected from halogen, Ci-C 4 alkyl, -CF 3 , Ci-C 4 alkoxy, and -NR 5 R 6 ;
  • Y is C or N; when Y is N, R 8 is absent;
  • n 0, 1, 2, 3, or 4;
  • n 0, 1, 2, 3, or 4;
  • This invention also relates to pharmaceutical compositions, which comprise compounds of Formula (I) and pharmaceutically acceptable carriers.
  • This invention also relates to methods of treating cancer which comprise
  • This invention also relates to methods of treating cancer which comprise co-administering a compound of Formula (I) and a second compound to a human in need thereof.
  • the present invention also provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer.
  • the present invention provides a c ompound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of cancer.
  • This invention relates to the compounds of Formula (I), and pharmaceutically acceptable salts thereof.
  • This invention also relates to compounds of Formula (I)(A):
  • R 1 , R 2 , R 3 , R 4 , n and m are defined according to Formula (I).
  • This invention also relates to compounds of Formula (I)(B):
  • R 1 , R 2 , R 3 , R 4 , n and m are defined according to Formula (I).
  • This invention also relates to compounds of Formula (I)(C):
  • R 1 , R 2 , R 3 , R 4 , n and m are defined according to Formula (I).
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 1 is phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or 10-membered heterocyclyl wherein said phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or
  • 10-membered heterocyclyl is optionally substituted with from 1 to 3 substituents
  • Ci-C 4 alkyl -S0 2 NR 5 R 6 , cyano, oxo, hydroxyl, halogen, Ci-C 4 alkoxy,
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 1 is benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, indoyl, benzofuranyl, benzoxazoyl, indazoyl, benzimidazoyl, benzothienyl, phenyl, naphthyl, isoquinolinyl, or quinolinyl, wherein said benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, indoyl, benzofuranyl, benzoxazoyl, indazoyl, benzimidazoyl, benzothienyl, phenyl, naphthyl, isoquinolinyl, or quinolinyl is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of:
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 1 is selected from the group consisting of phenyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl,
  • this invention relates to compounds of Formula (I), (I)(A),
  • R 2 is independently selected from the group of Ci-C 6 alkyl, cyano, Ci-C 6 alkoxy, hydroxyl, and halogen.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 3 is selected from the group consisting of: Ci-C 6 alkyl,
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 3 is Ci-C 6 alkyl or C 3 -C 6 cycloalkyl wherein said Ci-C 6 alkyl and C 3 -C 6 cycloalkyl is optionally substituted by Ci-C 3 alkyl.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 3 is Ci-C 6 alkyl.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 3 is C 3 -C 6 cycloalkyl.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 3 is C 3 -C 6 cycloalkyl, wherein said C 3 -C 6 cycloalkyl is optionally substituted by Ci-C3alkyl.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 3 is cyclopropyl.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 4 is independently selected from the group consisting of halogen, hydroxyl, hydrogen, Ci-C 6 alkoxy, and Ci-C 6 alkyl.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 4 is halogen.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 5 is selected from the group consisting of hydrogen, Ci-C 4 alkyl, phenyl, C 3 -Cycycloalkyl, -C 3 -C 7 alkylC 3 -Cvcycloalkyl, and Ci-C 3 alkyl-phenyl.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 6 is hydrogen, Ci-C 4 alkyl, C 3 -Cycycloalkyl, or
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 5 and R 6 taken together with the nitrogen to which they are attached represent a 4- to 7-membered saturated or unsaturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, wherein said ring is optionally substituted by 1 to 3 substituents independently selected from hydoxyl, Ci-C 3 alkyl, and hydroxyC i -C 4 alkyl- .
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 5 and R 6 taken together with the nitrogen to which they are attached represent a 5- to 6-membered saturated or unsaturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, wherein said ring is optionally substituted by 1 to 3 substituents independently selected from hydoxyl, Ci-C3alkyl, and hydroxyC i -C 4 alkyl- .
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 7 is hydrogen or methyl.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 8 is hydrogen, hydroxyl, or -OCi-C 3 alkyl.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 9 is a 5- or 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents independently selected from halogen, Ci-C 4 alkyl, -CF 3 , Ci-C 4 alkoxy, and -NR 5 R 6 .
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 9 is a 5-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents independently selected from halogen, Ci-C 4 alkyl, -CF 3 , Ci-C 4 alkoxy, and -NR 5 R 6 .
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 9 is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, or isothiazolyl.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 9 is a 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents independently selected from halogen, Ci-C 4 alkyl, -CF 3 , Ci-C 4 alkoxy, and -NR 5 R 6 .
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein R 9 is pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl.
  • Y is C, or N, and when Y is N, R 8 is absent. In an embodiment of this invention, Y is C. In another embodiment of this invention, Y is N.
  • n is 0, 1 , 2, 3, or 4. In an embodiment of this invention, m is 0 or 1. In another specific embodiment of this invention, m is 0. In another embodiment of this invention, m is 1.
  • n is 0, 1 , 2, 3, or 4. In another embodiment of this invention, n is 0 or 1. In another embodiment of this invention, n is 0. In another embodiment of this invention, n is 1.
  • this invention relates to compounds of Formula (I), (I)(A), (I)(B), or (I)(C), wherein at least one of m or n is other than zero and there is an excess of one enantiomer over the other.
  • This invention also relates to the following compounds:
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise acid addition salts. In general, the salts are formed from
  • suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.
  • salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate
  • the compound of Formula (I) or a salt thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms).
  • the individual stereoisomers may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms).
  • alkyl refers to a straight or branched chain hydrocarbon radical, preferably having from one to twelve carbon atoms, which may be unsubstituted or substituted, with multiple degrees of substitution included within the present invention.
  • Ci-Cealkyl refers to an alkyl moiety containing from 1 to 6 carbon atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, t-butyl, isopentyl, n-pentyl, and the like, as well as substituted versions thereof.
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring.
  • Cs-Cycycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from three to eight ring carbon atoms.
  • Exemplary "Cs-Cycycloalkyl” groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • alkoxy refers to alkyl radical containing the specified number of carbon atoms attached through an oxygen linking atom.
  • the term "Ci-C 4 alkoxy” refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • Exemplary "(Ci-C 4 )alkoxy” groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and t-butoxy.
  • aryl refers to a carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, particularly from 6-10 carbon atoms.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
  • aryl also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1-naphthyl, 2-naphthyl,
  • heterocyclic As used herein "heterocyclic,” “heterocycle,” “heterocycl” groups or grammatical variations thereof include “heteroaryl” and “heterocycloalkyl” groups.
  • heteroaryl an aromatic ring system containing carbon(s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 8 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junctions, for example, bicyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms).
  • Exemplary 5- to 6- memebered heteroaryls include, but are not limited to, furanyl, thiophenyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-traizolyl, oxazolyl, isoxazolyl, 1, 2,
  • 3-oxadiazolyl 1, 2, 5-oxadiazolyl, thiadiazolyl, isothiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
  • Other exemplary heteroaryl groups include, but are not limited to benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl,
  • pyrazolopyridinyl pyrazolopyrimidinyl, benzoxadiazolyl, benzthiadiazolyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,
  • Heterocycloalkyl represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocycloalkyls useful in the present invention include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1 ,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, hexahydro-lH-l,4-diazepinyl, azabicylo[3.2.1]octyl,
  • heterocyclyl refers to an unsubstituted or substituted mono- or polycyclic ring system containing one or more heteroatoms.
  • Preferred heteroatoms include nitrogen, oxygen, and sulfur, including N-oxides, sulfur oxides, and dioxides.
  • the term "9- or 10-membered heterocyclyl” represents a fully unsaturated or partially unsaturated, bicyclic group, containing 9 or 10 ring atoms, including 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, which group may be unsubstituted or substituted by one or more of the substituents defined herein.
  • Selected 9- or 10-membered heterocycyl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1, 2, 3, or 4 additional nitrogen ring atoms and/or 1 additional oxygen or sulfur atom.
  • 9- or 10-membered heterocyclyl groups include, but are not limited to benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl,
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.
  • Enantiomerically enriched refers to products whose enantiomeric excess is greater than zero.
  • enantiomerically enriched refers to products whose enantiomeric excess is greater than about 50% ee, greater than about 75% ee, and greater than about 90% ee.
  • Enantiomeric excess or "ee” is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
  • Enantiomerically pure refers to products whose enantiomeric excess is 100% ee.
  • Diastereomer refers to a compound having at least two chiral centers.
  • Diastereomer excess or "de” is the excess of one Diastereomerover the others expressed as a percentage.
  • Diastereomerically pure refers to products whose diastereomeric excess is 100% de.
  • Half-life refers to the time required for half of a quantity of a substance to be converted to another chemically distinct specie in vitro or in vivo.
  • Halo or halogen refers to fluoro, chloro, bromo, or iodo substituents
  • Heteroatom refers to a nitrogen, sulphur, or oxygen atom.
  • cyano refers to the group -CN.
  • Member atoms refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
  • physiologically functional derivative refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing
  • the invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of Formula (I) or pharmaceutically acceptable salt, thereof and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts).
  • a pharmaceutical composition also referred to as pharmaceutical formulation
  • excipients also referred to as carriers and/or diluents in the pharmaceutical arts.
  • the excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
  • a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of Formula (I) or salt thereof with at least one excipient.
  • compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain a therapeutically effective dose of the compound of Formula (I) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).
  • pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate,
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
  • the compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages.
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient.
  • Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
  • tablets and capsules are preferred for delivery of the pharmaceutical composition.
  • treatment includes prophylaxis and refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
  • Prophylaxis or prevention or delay of disease onset is typically accomplished by administering a drug in the same or similar manner as one would to a patient with the developed disease or condition.
  • the present invention provides a method of treating a mammal, especially a human, suffering from disease conditions targeted by the present compounds.
  • Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula (I) or salt thereof to said mammal, particularly a human.
  • the present invention provides methods of treating cancer comprising administering to a human in need thereof a pharmaceutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula (I) or salt thereof to said mammal, particularly a human.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • terapéuticaally effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy,
  • therapeutically effective amounts of a compound of Formula (I), as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
  • a therapeutically effective amount of a compound of Formula (I) or salt thereof may be administered as the raw chemical, it is typically presented as the active ingredient of a pharmaceutical composition or formulation.
  • the precise therapeutically effective amount of a compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian.
  • a compound of Formula (I) or salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day.
  • Acceptable daily dosages may be from about 1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of Formula (I) per se.
  • the present invention provides a method of treating cancer wherein the cancer is selected from the group consisting of: gastric, brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, renal, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, bladder, stomach, and giant cell tumor of bone and thyroid.
  • the cancer is selected from the group consisting of: gastric, brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's
  • the present invention provides a method of treating cancer in a human in need thereof, which comprises: administering to such human an effective amount of the compound or salt of Formula (I) and at least one anti-neoplastic agent.
  • a compound of Formula (I) When a compound of Formula (I) is administered for the treatment of cancer, the term “co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a FAS inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment.
  • the term further active ingredient or ingredients, as used herein includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • anti-neoplastic agent that has activity versus a susceptible tumor being treated
  • examples of such agents can be found in Cancer Principles and Practice f Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins
  • anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors;
  • Examples of a further active ingredient or ingredients for use in combination or co-administered with the present FAS inhibiting compounds are chemotherapeutic agents.
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids which are derived from natural sources, are phase specific anti -cancer agents that operate at the G 2 /M phases of the cell cycle. It is believed that the diterpenoids stabilize the ⁇ -tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • Paclitaxel 5P,20-epoxy-l,2a,4,7P,10p,13a-hexa-hydroxytax-l l-en-9-one
  • Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. Intern, Med., I l l :273,1989) and for the treatment of breast cancer (Holmes et al. , J. Nat. Cancer Inst. , 83: 1797, 1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al, Sem. Oncol, 20:56, 1990).
  • the compound also shows potential for the treatment of polycystic kidney disease (Woo et. al, Nature, 368:750. 1994), lung cancer and malaria.
  • Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guide, ! 1998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree.
  • the dose limiting toxicity of docetaxel is neutropenia.
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into
  • Mitosis is believed to be arrested in metaphase with cell death following.
  • vinca alkaloids examples include, but are not limited to, vinblastine, vincristine, and vinorelbine.
  • Vinblastine vincaleukoblastine sulfate
  • VELBAN® an injectable solution.
  • testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.
  • Myelosuppression is the dose limiting side effect of vinblastine.
  • Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as
  • ONCOVIN® as an injectable solution.
  • Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.
  • Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
  • Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
  • Cisplatin cis-diamminedichloroplatinum
  • PLATINOL® an injectable solution.
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
  • the primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
  • Carboplatin platinum, diammine [l,l-cyclobutane-dicarboxylate(2-)-0,0'], is commercially available as PARAPLATIN® as an injectable solution.
  • Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
  • Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles.
  • alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan;
  • nitrosoureas such as carmustine
  • triazenes such as dacarbazine
  • Cyclophosphamide is indicated as a single agent or in combination with other
  • chemotherapeutic agents in the treatment of malignant lymphomas, multiple myeloma, and leukemias.
  • Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan. Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets.
  • Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
  • Busulfan 1 ,4-butanediol dimethanesulfonate, is commercially available as
  • Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
  • Carmustine, l,3-[bis(2-chloroethyl)-l -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®.
  • Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
  • dacarbazine 5-(3,3-dimethyl-l-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®.
  • dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
  • Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death.
  • antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
  • Dactinomycin also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
  • Daunorubicin (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo
  • naphthacenedione hydrochloride is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.
  • Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
  • ADRIAMYCIN RDF® ADRIAMYCIN RDF®.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
  • Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of
  • Streptomyces verticillus is commercially available as BLENOXANE®.
  • Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
  • Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of
  • epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • VePESID® and is commonly known as VP- 16.
  • Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
  • -lucopyranoside is commercially available as an injectable solution as VUMON® and is commonly known as VM-26.
  • Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
  • 5 -fluorouracil 5-fluoro-2,4- (1H,3H) pyrimidinedione
  • fluorouracil is commercially available as fluorouracil.
  • Administration of 5 -fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
  • 5 -fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas.
  • fluoropyrimidine analogs include 5-f uoro deoxyuridine (floxuridine) and
  • Cytarabine 4-amino-l-P-D-arabinofuranosyl-2 (lH)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2',2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
  • Mercaptopurine l,7-dihydro-6H-purine-6-thione monohydrate
  • PURINETHOL® is commercially available as PURINETHOL®.
  • Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses.
  • a useful mercaptopurine analog is azathioprine.
  • Thioguanine 2-amino-l,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®.
  • Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting.
  • Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
  • Gemcitabine 2'-deoxy-2', 2'-difluorocytidine monohydrochloride ( ⁇ -isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S-phase and by blocking progression of cells through the Gl/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
  • methotrexate sodium is commercially available as methotrexate sodium.
  • Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate.
  • Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
  • Myelosuppression leucopenia, thrombocytopenia, and anemia
  • mucositis are expected side effect of methotrexate administration.
  • Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of
  • Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the
  • topoisomerase I DNA : irintecan or SN-38 ternary complex with replication enzymes.
  • Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum.
  • the dose limiting side effects of irinotecan HC1 are myelosuppression, including neutropenia, and GI effects, including diarrhea.
  • Topotecan HC1, (S)- 10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy- 1 H-pyrano [3 ',4',6,7]indolizino[l ,2-b]quinoline-3, 14-(4H, 12H)-dione monohydrochloride, is
  • Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The dose limiting side effect of topotecan HC1 is myelosuppression, primarily neutropenia.
  • camptothecin derivative of formula A following, currently under development, including the racemic mixture (R,S) form as well as the R and S enantiomers:
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
  • hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children;
  • aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors
  • progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma
  • estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy
  • anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S.
  • SERMS selective estrogen receptor modulators
  • GnRH gonadotropin-releasing hormone
  • LH leutinizing hormone
  • FSH follicle stimulating hormone
  • Letrozole (trade name Femara) is an oral non-steroidal aromatase inhibitor for the treatment of hormonally-responsive breast cancer after surgery. Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Estrogens then bind to an estrogen receptor, which causes cells to divide. Letrozole prevents the aromatase from producing estrogens by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids.
  • Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation.
  • Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases,
  • SH2/SH3domain blockers serine/threonine kinases, phosphotidyl inositol-3 kinases, myo-inositol signaling, and Ras oncogenes.
  • protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth.
  • protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
  • Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods.
  • Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene.
  • EGFr epidermal growth factor receptor
  • PDGFr platelet derived growth factor receptor
  • erbB2 erbB4
  • VEGFr vascular endothelial growth factor receptor
  • TIE-2 vascular endothelial growth factor receptor
  • TIE-2 t
  • inhibitors of growth receptors include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.
  • Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
  • Tyrosine kinases which are not growth factor receptor kinases are termed
  • Non-receptor tyrosine kinases useful in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl.
  • cSrc Lck
  • Fyn Yes
  • Jak Jak
  • cAbl cAbl
  • FAK Fluor adhesion kinase
  • Brutons tyrosine kinase Brutons tyrosine kinase
  • non-receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.
  • SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.
  • Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).
  • IkB kinase family IKKa, IKKb
  • PKB family kinases AKT kinase family members
  • TGF beta receptor kinases TGF beta receptor kinases.
  • Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391; and
  • Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku are also useful in the present invention.
  • Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545.
  • Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues.
  • signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
  • Another group of signal transduction pathway inhibitors are inhibitors of Ras
  • Oncogene Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and Bennett, C.F. and Cowsert, L.M. BioChim. Biophys. Acta, (1999)
  • antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors.
  • This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases.
  • Imclone C225 EGFR specific antibody see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat.
  • Herceptin ® erbB2 antibody see Tyrosine Kinase Signalling in Breast cancenerbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183
  • 2CB VEGFR2 specific antibody see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124).
  • Non-receptor kinase angiogenesis inhibitors may also find use in the present invention.
  • Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases).
  • Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression.
  • the combination of an erbB2/EGFR inhibitor with an inhibitor of angiogenesis makes sense.
  • non-receptor tyrosine kinase inhibitors may be used in combination with the EGFR/erbB2 inhibitors of the present invention.
  • anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha v beta 3 ) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed erb family inhibitors.
  • VEGFR the receptor tyrosine kinase
  • small molecule inhibitors of integrin alpha v beta 3
  • endostatin and angiostatin non-RTK
  • Pazopanib which commercially available as VOTRIENT® is a tyrosine kinase inhibitor (TKI).
  • TKI tyrosine kinase inhibitor
  • Pazopanib is presented as the hydrochloride salt, with the chemical name 5 - [[4- [(2,3 -dimethyl-2H-indazol-6-yl)methy lamino] -2-pyrimidinyl] amino]-2-methylbenzenes ulfonamide monohydrochloride.
  • Pazoponib is approved for treatment of patients with advanced renal cell carcinoma.
  • Bevacisumab which is commercially available as AVASTIN® is a humanized monoclonal antibody that blocks VEGF -A.
  • AVASTIN® is approved form the treatment of various cancers including colorectal, lung, breast, kidney, and glioblastomas.
  • mTOR inhibitors include but are not limited to rapamycin (FK506) and rapalogs,
  • RAD001 or everolimus (Afmitor), CCI-779 or temsirolimus, AP23573, AZD8055,
  • Everolimus is sold as Afinitor® by Novartis and is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers. It has the following chemical structure (formula II) and chemical name:
  • Bexarotene is sold as Targretin® and is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs).
  • RXRs retinoid X receptors
  • RARs retinoic acid receptors
  • Bexarotene is used to treat cutaneous T-cell lymphoma (CTCL, a type of skin cancer) in people whose disease could not be treated successfully with at least one other medication.
  • CTCL cutaneous T-cell lymphoma
  • Sorafenib marketed as Nexavar® is in a class of medications called multikinase inhibitors. Its chemical name is 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide. Sorafenib is used to treat advanced renal cell carcinoma (a type of cancer that begins in the kidneys). Sorafenib is also used to treat unresectable hepatocellular carcinoma (a type of liver cancer that cannot be treated with surgery).
  • Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of formula (I).
  • immunologic strategies to generate an immune response against erbB2 or EGFR. These strategies are generally in the realm of tumor vaccinations.
  • the efficacy of immunologic approaches may be greatly enhanced through combined inhibition of erbB2/EGFR signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in ReiUy RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.
  • Examples of erbB inhibitors include lapatinib, erlotinib, and gefitinib.
  • Lapatinib, N-(3 -chloro-4- ⁇ [(3 -fluorophenyl)methyl]oxy ⁇ phenyl)-6- [5 -( ⁇ [2-(methylsulfonyl)ethyl] amino ⁇ methyl)-2-furanyl]-4-quinazolinamine (represented by Formula I, as illustrated), is a potent, oral, small-molecule, dual inhibitor of erbB-1 and erbB-2 (EGFR and HER2) tyrosine kinases that is approved in combination with capecitabine for the treatment of HER2 -positive metastatic breast cancer.
  • the free base, HCl salts, and ditosylate salts of the compound of formula (I) may be prepared according to the procedures disclosed in WO 99/35146, published July 15, 1999; and WO 02/02552 published January 10, 2002.
  • the free base and HCl salt of erlotinib may be prepared, for example, according to
  • Gefitinib which is commercially available under the trade name IRESSA® (Astra-Zenenca) is an erbB-1 inhibitor that is indicated as monotherapy for the treatment of patients with locally advanced or metastatic non- small-cell lung cancer after failure of both platinum-based and docetaxel chemotherapies.
  • the free base, HC1 salts, and diHCl salts of gefitinib may be prepared according to the procedures of International Patent Application No.
  • Trastuzumab (HEREPTIN®) is a humanized monoclonal antibody that binds to the HER2 receptor. It original indication is HER2 positive breast cancer.
  • Cetuximab (ERBITUX®) is a chimeric mouse human antibody that inhibits epidermal growth factor receptor (EGFR).
  • Pertuzumab (also called 2C4, trade name Omnitarg) is a monoclonal antibody. The first of its class in a line of agents called "HER dimerization inhibitors". By binding to HER2, it inhibits the dimerization of HER2 with other HER receptors, which is hypothesized to result in slowed tumor growth. Pertuzumab is described in WOO 1/00245 published January 4, 2001.
  • Rituximab is a chimeric monoclonal antibody which is sold as RITUXAN® and MABTHERA®.
  • Rituximab binds to CD20 on B cells and causes cell apoptosis.
  • Rituximab is administered intravenously and is approved for treatment of rheumatoid arthritis and B-cell non-Hodgkin's lymphoma.
  • Ofatumumab is a fully human monoclonal antibody which is sold as ARZERRA®.
  • Ofatumumab binds to CD20 on B cells and is used to treat chronic lymphocytic leukemia (CLL; a type of cancer of the white blood cells) in adults who are refractory to treatment with fludarabine (Fludara) and alemtuzumab (Campath).
  • Agents used in proapoptotic regimens e.g., bcl-2 antisense oligonucleotides
  • Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance.
  • Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle.
  • a family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle.
  • CDKs cyclin dependent kinases
  • Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
  • the cancer treatment method of the claimed invention includes the co-administration a compound of Formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
  • anti-neoplastic agent such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor t
  • the compounds of Formula (I) may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • the skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts,
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • a protected piperidone can be readily converted to an epoxide, which can be opened with various amines to give an amino alcohol intermediate (Scheme I).
  • Cyclization to the spirocyclic lactam can be accomplished in two steps with a reagent such as chloroacetyl chloride. After removal of the protecting group with an acid such as hydrogen chloride, the resulting spirocyclic piperidine intermediate can be converted to a sulfonyl chloride using reagents such as chlorosulfonic acid and phosphorus pentachloride.
  • a spirocyclic piperidine sulfamide can then be prepared by condensation of a spirocyclic piperidine sulfonyl chloride intermediate with an aryl or heteroaryl piperazine or piperidine to give final products.
  • An aryl or heteroaryl piperazine or piperidine intermediate can be prepared from palladium-catalyzed cross-coupling of a piperazine or piperidine with various aryl or heteroaryl bromides or triflates (Scheme II).
  • the spirocyclic piperidine sulfonyl chloride intermediate can also be condensed with a protected piperazine (Scheme III), which can then be deprotected and further elaborated to the final products using chemistry described in Scheme II.
  • final products can be obtained by first preparing an aryl or heteroaryl piperazine sulfonyl chloride from an aryl or heteroaryl piperazine using chemistry described above followed by condensation with the core spirocycle (Scheme IV).
  • Analogs containing substitution on the piperidine can be made from commercially available piperidinones or by enolate chemistry via a metal enolate or by reaction of a silyl enol ether with a suitable electrophile (Scheme V).
  • the functionalized piperidinones can then be elaborated to the spirocyclic products using methodology described above.
  • 1,1-dimethylethyl 4-oxo-l-piperidinecarboxylate (50.2 mmol) in one portion.
  • the ice bath was removed and stirring continued at room temperature for 18 h.
  • Ice cold water 150 mL was added and the mixture was extracted into diethyl ether (3x).
  • the extracts were washed with brine, dried (sodium sulfate) then evaporated under reduced pressure to a yellow oil.
  • the oil was dissolved in ethyl acetate, treated with silica powder (-20 g), and evaporated to dryness. This was placed on a short pad of silica in a sintered glass funnel and washed with hexanes (500 mL; the filtrate was discarded).
  • the aqueous layer was drained and the organic layer diluted with t-butyl methyl ether (1.5 L) and washed with a mixture of brine and saturated aq ammonium chloride (250 mL).
  • the organic layer was dried (Na 2 S0 4 ) and evaporated to afford the crude title product as a gel.
  • dichloromethane (10 mL) was cooled to 0 °C and treated with chlorosulfonic acid (0.31 mL, 4.66 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was evaporated and azeotroped with toluene (2x). The residue was mixed with phosphorus pentachloride (0.844 g, 4.05 mmol) in toluene and heated at 95 °C for 2 h.
  • N,N-diisopropylethylamine (0.245 mL, 1.407 mmol) in dichloromethane (10 mL) was treated with 4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecane-9-sulfonyl chloride (159 mg, 0.516 mmol) and the mixture was stirred overnight. The mixture was washed with water and brine, then dried (sodium sulfate) and evaporated under reduced pressure.
  • a pressure bottle was charged with 1,1 -dimethylethyl l-oxa-6-azaspiro[2.5]octane -6-carboxylate (1.25 g, 5.86 mmol), ethanol (15 mL) and (l-methylcyclopropyl)amine hydrochloride (630 mg, 5.86 mmol). N,N-diisopropylethylamine (1.023 mL, 5.86 mmol) was added, the vial was purged with nitrogen, sealed and placed in a 75 °C oil bath giving a clear nearly colorless solution. The mixture was heated for 1.5 h, cooled to room temperature, and concentrated in vacuo.
  • N-methyl-N,N-dioctyl-l-octanaminium chloride 39.9 mg, 0.099 mmol
  • a 15% aqueous sodium hydroxide solution 3.04 mL, 9.13 mmol
  • the mixture was stirred for 1.5 h then diluted with ethyl acetate, water and brine.
  • the layers were separated and the aqueous layer was extracted with ethyl acetate.
  • the combined extracts were dried and evaporated under reduced pressure to give an oil.
  • 3-methyl-l-piperazinecarboxylate (558 mg, 2.79 mmol), palladium (II) acetate (31.3 mg, 0.139 mmol), tris(l,l-dimethylethyl)phosphane (1M solution in toluene, 0.558 mL, 0.558 mmol) and sodium tert-butoxide (536 mg, 5.58 mmol) in toluene (8 mL) was sealed under nitrogen in a microwave vessel and the mixture was heated in an oil bath at 110 °C for 2 h. The reaction mixture was cooled, diluted with ethanol, filtered to remove the palladium residue, and evaporated under reduced pressure.
  • 6-Bromoisoquinoline 333 mg, 1.601 mmol
  • palladium(II) acetate 17.97 mg, 0.080 mmol
  • piperazine 827 mg, 9.60 mmol
  • sodium tert-butoxide 215 mg, 2.241 mmol
  • / ⁇ -xylene 10 mL
  • the vial was capped and flushed with nitrogen and tris(l,l-dimethylethyl)phosphane (1M solution in toluene, 80 uL, 0.080 mmol) was injected into the vial via syringe.
  • the reaction was stirred and heated to 120 °C for 1 h.
  • N,N-diisopropylethylamine (0.246 mL, 1.407 mmol) in dichloromethane (10 mL) was treated with 4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecane-9-sulfonyl chloride (159 mg, 0.516 mmol).
  • the reaction mixture was stirred overnight at room temperature and concentrated in vacuo.
  • the resulting solid was dissolved in warm dimethyl sulfoxide, filtered, and purified on reverse phase HPLC (10-90% acetonitrile w/ 0.1 %> TF A/water w/ 0.1% TFA).
  • tert-butyl piperazine-l-carboxylate 160 mg, 0.857 mmol
  • ethyl 7-bromoquinoline-3-carboxylate 200 mg, 0.714 mmol
  • Sodium tert-butoxide 137 mg, 1.428 mmol
  • palladium(II) acetate 8 mg, 0.036 mmol
  • Ethyl 7-bromoquinoline-3-carboxylate (3.3 g, 11.7 mmol) was added to methanol (15 mL) in a microwave vial and 6N sodium hydroxide (13 mL) was added to the mixture.
  • the vial was capped and heated in an oil bath at 110 °C for 18 h.
  • the reaction was cooled and the methanol was evaporated under reduced pressure. Upon evaporation, a solid precipitated out and was collected by filtration.
  • tert-butyl 4-(3-methoxyquinolin-7-yl)piperazine-l-carboxylate 230 mg, 0.67 mmol
  • acetic acid 4 mL
  • the vial was capped and irradiated in a microwave at 150 °C for 3 h.
  • the acetic acid was evaporated under reduced pressure, and ether and water were added.
  • the mixture was neutralized using ammonium hydroxide and the layers were separated.
  • the aqueous layer was concentrated in vacuo and azeotroped with tetrahydrofuran to give crude
  • tert-butyl piperazine-1 -carboxylate (84 mg, 0.452 mmol), 2-bromo-6-methylnaphthalene (100 mg, 0.452 mmol), palladium(II) acetate (4 mg, 0.018 mmol), sodium tert-butoxide (63.0 mg, 0.656 mmol), and 1,4-dioxane (2 mL) were added.
  • tri-tert-butylphosphine (1M in toluene, 30 ⁇ , 0.030 mmol) was added.
  • the vial was capped, purged with nitrogen, and stirred at 100 °C for 8 h.
  • 4-(6-methylnaphthalen-2-yl)piperazine-l -carboxylate (140 mg, 0.429 mmol) provided the intermediate 1 -(6-methyl -2-naphthalenyl)piperazine hydrochloride as a white solid.
  • the white solid was taken up in dichloromethane (2 mL) and N,N-diisopropylethylamine (0.25 mL, 1.431 mmol) was added.
  • tert-butyl piperazine-l-carboxylate 185 mg, 0.996 mmol
  • 6-cyanonaphthalen-2-yl trifluoromethanesulfonate 300 mg, 0.996 mmol, PCT Int. Appl. 2007063523
  • potassium phosphate tribasic 300 mg, 1.415 mmol
  • palladium(II) acetate 3 mg, 0.013 mmol
  • [l,l'-biphenyl]-2-yldicyclohexylphosphine 9 mg, 0.026 mmol
  • the reaction mixture was cooled to 0 °C in an ice bath under nitrogen and a solution of 4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecane-9-sulfonyl chloride (174 mg, 0.563 mmol) in dichloromethane (2 mL) was added via pipette.
  • the reaction was stirred, allowing the ice bath to slowly warm to room temperature, for 4 h.
  • the reaction solution was diluted with dichloromethane (30 mL) and washed with brine (lx).
  • the aqueous layer was washed with dichloromethane (3 x 20 mL).
  • Phenylmethyl tra/?5-4-cyclopropyl-7-fluoro-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecane -9-carboxylate (1.4 g, 3.86 mmol) was taken up in ethanol (50 mL) and placed in a Pan- shaker vessel. The vessel was placed under nitrogen and 10%> Pd/C (90 mg, 0.846 mmol) was added. The vessel was placed on a Parr shaker and the mixture was shaken under 30 psi hydrogen for 4 h. The vessel was removed from the shaker and the solution was filtered through a pad of Celite, which was washed with ethanol (150 mL).
  • Inhibition of FAS activity can be measured based on the detection of residual NADPH substrate after the FAS assay is quenched.
  • This assay is run as a 10 ⁇ _, endpoint assay in 384-well format, where the reaction contains 20 ⁇ malonyl-CoA, 2 ⁇
  • the assay is run by sequentially dispensing 5 ⁇ of a malonyl-CoA solution, then enzyme solution Containing the acetyl-CoA, and NADPH) into a black, low volume assay plate (Greiner 784076) pre-dispensed with 100 nL compound solutions in DMSO.
  • the reaction is incubated at ambient temperature for 60 minutes, then quenched with 5 ⁇ ⁇ of a developing solution composed of 90 ⁇ resazurin, 0.3 IU/ml diaphorase in 50 mM sodium phosphate, pH 7.0.
  • the developed reaction is read on a Molecular Devices Analyst or Acquest (or equivalent) plate reader using a 530 nm excitation wavelength filter, a 580 nm emission filter, and 561 nm dichroic filter.
  • the test compounds are prepared in neat DMSO at a concentration of 10 mM.
  • compounds are diluted using a three fold serial dilution and tested at 11 concentrations (e.g. 25 ⁇ -0.42 nM). Curves are analysed using ActivityBase and XLfit, and results are expressed as pIC50 values.
  • Inhibition of FAS can also be quantified based on the detection of the CoA products with a thio-reactive coumarin dye.
  • This assay is run as a 10 ⁇ ⁇ endpoint assay in 384-well format, where the reaction contains 20 ⁇ malonyl-CoA, 20 ⁇ acetyl-CoA, 40 ⁇
  • NADPH and 2 nM FAS in 50 mM sodium phosphate, pH 7.0, and 0.04% Tween-20 The assay is run by adding 5 ⁇ , enzyme solution to a black, low volume assay plate (Greiner 784076) pre-dispensed with 100 nl compound solutions in DMSO. After 30 minutes, 5 ⁇ , substrate is added, and the reaction incubated at ambient temperature for an additional 60 minutes. The reaction is then quenched with 10 ⁇ ⁇ of 6M guanidine-HCl containing 50 ⁇ CPM (7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin CPM; thio-reactive dye), and incubated for 30 minutes. The plate is read on an Envision (PerkinElmer) or equivalent plate reader using a 380 nm excitation wavelength filter, and a 486 nm emission filter. Data fitting and compound preparations are done as described above. Lipogenesis assay
  • Cultured primary human pre-adipocytes (Zen-Bio, Cat# ASC062801) are plated at confluence (3x104 cells/well) in 96-well plates Costar, Cat# 3598) coated with 0.2%> gelatin (Sigma, Cat# G-6650) in DMEM/F12 medium (InvitroGen Cat# 11330-032) supplemented with 10% heat inactivated fetal bovine serum (InvitroGen, Cat# 16000-044.
  • the cell differentiation is induced by replacing the seeding medium with the differentiation medium composed of DMEM/F12 medium supplemented with 10% heat inactivated fetal bovine serum, 200 ⁇ 3-isobutyl-l-methylxanthine (Sigma, Cat# 1-5879), 20 nM dexamethasone (Sigma, Cat# D-8893), 20 nM GW1929 (Sigma, Cat# G5668) and 20 nM insulin (InvitroGen, Cat# 03-0110SA).
  • differentiation medium is replaced by the re-feed medium made of DMEM/F12 supplemented with 10% heat inactivated serum and 20 nM insulin. The appropriate concentration of tested compounds and controls are added into this medium at that time.
  • the relative amount of cellular triglyceride is estimated by using a Trinder kit (Sigma, Cat# TR0100). Re-feed medium is aspirated and cells are washed with PBS (InvitroGen, Cat# 14190-144 and the assay is performed according the kit manufacturer protocol. Briefly, reconstituted solutions A and B are mixed with 0,01 ) digitonin (Sigma, Cat# D-5628) prior to performing the assay and added onto the cells; plates are incubated at 37 °C for one hour. The absorbance is read at 540 nm.
  • the data is first normalized using the following equation: 100* ((UNK - Control 1) / Control 2 - Control 1)) where Control 1 is the Robust Mean of the 0% response control and Control 2 is the Robust Mean of the 100% response control.
  • Exemplified compounds of the present invention were tested according to the above assays and were found to be inhibitors of FAS.
  • the IC 50 values ranged from about 1 nM to about 10 ⁇ .
  • the IC 50 values of the more active compounds range from about 1 nM to about 200 nM.
  • the most active compounds are under 15 nM.
  • Example 1 The compound of Example 1 was tested generally according to the assays described herein and in at least one experimental run exhibited an IC 50 value equal to 50 nM.
  • Example 3 The compound of Example 3 was tested generally according to the assays described herein and in at least one experimental run exhibited an IC 50 value equal to 200 nM.
  • Example 15 The compound of Example 15 was tested generally according to the assays described herein and in at least one experimental run exhibited an IC 50 value equal to 251 nM.
  • Example 16 The compound of Example 16 was tested generally according to the assays described herein and in at least one experimental run exhibited an IC 50 value equal to 1584 nM.
  • Example 29 The compound of Example 29 was tested generally according to the assays described herein and in at least one experimental run exhibited an IC 50 value equal to 10 nM.

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Abstract

L'invention concerne des composés de Formule (I), où R1, R2, R3, R4, R5, R6, R7, R8, R9, Y, m, et n sont définis présentement, et des procédés d'utilisation de ceux-ci.
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