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WO2006012577A2 - Derives de la quinazolinone utiles pour la regulation de l'homeostasie du glucose et de prise d'aliments - Google Patents

Derives de la quinazolinone utiles pour la regulation de l'homeostasie du glucose et de prise d'aliments Download PDF

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Publication number
WO2006012577A2
WO2006012577A2 PCT/US2005/026192 US2005026192W WO2006012577A2 WO 2006012577 A2 WO2006012577 A2 WO 2006012577A2 US 2005026192 W US2005026192 W US 2005026192W WO 2006012577 A2 WO2006012577 A2 WO 2006012577A2
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Prior art keywords
methyl
quinazolin
optionally substituted
isopropylpiperidin
mmol
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WO2006012577A3 (fr
Inventor
Joachim Rudolph
Stephen O'connor
Philip Coish
Philip Wickens
Georgiy Bondar
Chih-Yuan Chuang
Philip Ramsden
Derek Lowe
Donald Bierer
Libing Chen
Wenlang Fu
Uday Khire
Xiao-Gao Liu
Andrea Mcclure
Lei Wang
Lin Yi
William Esler
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Bayer Pharmaceuticals Corp
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Bayer Pharmaceuticals Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine

Definitions

  • This invention relates to compounds that may be useful for the treatment of diabetes, obesity and related disorders and regulation of food intake (e.g., stimulation and suppression).
  • it relates to certain quinazolinone derivatives which are useful in the treatment of said conditions.
  • It also relates to certain quinazolinone derivatives which are useful for the treatment of wasting (e.g., cachexia) associated with various diseases or conditions, for example, wasting associated with cancer, AIDS, chronic liver disease, chronic obstructive pulmonary disease (COPD) or respiratory insufficiency, as well as wasting associated with bone fractures or with aging.
  • wasting e.g., cachexia
  • various diseases or conditions for example, wasting associated with cancer, AIDS, chronic liver disease, chronic obstructive pulmonary disease (COPD) or respiratory insufficiency, as well as wasting associated with bone fractures or with aging.
  • COPD chronic obstructive pulmonary disease
  • Type 1 diabetes or insulin dependent diabetes mellitus (IDDM) arises when patients lack insulin-producing beta-cells in their pancreatic glands.
  • IDDM insulin dependent diabetes mellitus
  • Type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM)
  • IIDDM insulin dependent diabetes mellitus
  • the current treatment for type 1 diabetic patients is injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin.
  • the drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, and metformin.
  • This disorder is a significant risk factor for type 2 diabetes and is also associated with decreased life span and numerous other medical problems, including adverse psychological development, coronary artery disease, hypertension, stroke, hyperlipidaemia, and some cancers, (see, e.g., Nishina, et al., Metab. 43:554-558, 1994; Grundy and Barnett, Dis. Mon. 36:641-731 , 1990; Rissanen, et al., British Medical Journal, 301:835-837, 1990).
  • Wasting is a condition associated with various diseases or other conditions, for example, wasting associated with cancer, AIDS, chronic liver disease, chronic obstructive pulmonary disease (COPD) or respiratory insufficiency, as well as wasting associated with bone fractures or with aging.
  • COPD chronic obstructive pulmonary disease
  • COPD respiratory insufficiency
  • the invention relates to substituted quinazolinone derivatives that have utility for the regulation of glucose homeostasis and food intake, said derivatives of Formula (I)
  • R 1 is selected from
  • R 2 is selected from
  • R 3 is selected from
  • R 4 is selected from
  • R 5 is selected from
  • R 6 is selected from
  • R 7 is selected from
  • R 8 is selected from
  • R 9 is (CrCeJalkyl or phenyl
  • n O, 1 , or 2;
  • n 1 or 2;
  • p is O, 1 , or 2;
  • (C 1 -C 2 )alkyl mean a linear or branched saturated hydrocarbon groups having from about 1 to about 2 carbon atoms, from about 1 to about 3 carbon atoms, and from about 1 to about 6 carbon atoms, respectively.
  • Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.
  • (C 1 -C 2 )alkoxy mean a linear or branched saturated hydrocarbon group having from about 1 to about 2 carbon atoms, from about 1 to about 3 carbon atoms, from about 1 to about 4 carbon atoms, and from about 1 to about 6 carbon atoms, respectively, said group being attached to an oxygen atom.
  • the oxygen atom is the atom through which the alkoxy substituent is attached to the rest of the molecule.
  • groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n- hexyloxy, 3,3-dimethylpropoxy, and the like.
  • (C 1 -C 2 )haloalkoxy means a (C 1 -C 2 JaIkOXy group substituted on C with one or more halogen atom.
  • groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloroethoxy, 1-fluoro-2,2,-dichloroethoxy, and the like.
  • (C 2 -C 4 )alkenyl means a linear or branched unsaturated hydrocarbon radical containing a double bond and from about 2 to about 4 carbon atoms. The double bond may be between any two available carbon atoms in the chain. Such groups include, but are not limited to, vinyl, allyl, isopropenyl, 2-butenyl, 2-ethyl-2-butenyl, 1-hexenyl, and the like.
  • (CrC ⁇ alkylthio means a linear or branched saturated hydrocarbon radical having from about 1 to about 3 C atoms, said radical being attached to an S atom.
  • the S atom is the atom through which the alkylthio substituent is attached to the rest of the molecule.
  • alkylthio substituents include, but are not limited to, methylthio, ethylthio, n-propylthio, and isopropylthio.
  • halo means F, Br, Cl, and I.
  • (CrCaJhaloalkyl” and “(CrC 4 )haloalkyl” mean a (C r C 2 )alkyl group or (C 1 - C 4 )alkyl group, respectively, substituted on C with a halogen atom.
  • Such groups include, but are not limited to, trifluoromethyl, difluoroethyl, 1-fluoro-2,2-dichloroethyl, 3-chloropropyl, 4- bromohexyl, and the like.
  • (C 3 -C 6 )cycloalkyl means a saturated monocyclic alkyl group of from 3 to about 6 carbon atoms and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the term "five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from the group of N and O, and said ring being optionally substituted with (CrC 3 )alkyl or (C 1 -C 3 JaIkOXy” is intended to mean a stable 5-membered monocyclic heterocyclic unsaturated ring which consists of carbon atoms and from one to two heteroatoms independently selected from the group consisting of N and O.
  • the heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a chemically stable structure.
  • the heterocyclic ring may optionally be substituted with a (d-C 3 )alkyl group or an (C 1 -C 3 JaIkOXy group either on a carbon or on a nitrogen atom if the resulting compound is stable.
  • the total number of O atoms does not exceed one.
  • said ring systems include, but are not limited to, furanyl, pyrrolyl, oxazolyl, imidazolyl, isoxazolyl, and pyrazolyl.
  • the term "five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from N, O, and S, and said ring being optionally substituted with up to two R 7 groups” is intended to mean a stable 5-membered monocyclic heterocyclic unsaturated ring which consists of carbon atoms and from one to two heteroatoms independently selected from the group consisting of N, O, and S.
  • the heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a chemically stable structure.
  • the heterocyclic ring may optionally be substituted with from one to two independently selected R 7 groups either on a carbon or on a nitrogen atom if the resulting compound is stable.
  • the total number of S and O atoms does not exceed one.
  • ring systems include, but are not limited to, thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, and pyrazolyl.
  • the term "five-membered heterocyclic aromatic ring containing one heteroatom selected from N, O, and S, and said ring being fused to a phenyl ring optionally substituted at any position with halo and (CrC ⁇ alkyl” is intended to mean a stable 9-membered bicyclic heterocyclic ring which consists of a five-membered and a phenyl ring that are fused and form an unsaturated ring system.
  • the five-membered ring consists of carbon atoms and one heteroatom independently selected from the group consisting of N, O, and S.
  • This ring system may be attached to its pendant group at any heteroatom or carbon atom of the five-membered ring which results in a chemically stable structure.
  • This 9-membered bicyclic heterocyclic ring may optionally be substituted with a halo atom or a (C r C 3 )alkyl group either on a carbon or on a nitrogen atom if the resulting compound is stable.
  • Examples of said ring systems include, but are not limited to, benzothiophenyl, benzofuranyl, and indolyl.
  • phenyl that is fused to a five-membered or six-membered aromatic ring optionally containing one heteroatom selected from N, O, or S, and said ring system being optionally substituted at any position with halo and (CVCaJalkyl" is intended to mean a stable nine- to ten-membered bicyclic heterocyclic ring which consists of a five- to six-membered and a phenyl ring that are fused and form an unsaturated ring system.
  • the five- to six-membered ring consists of carbon atoms and one heteroatom independently selected from the group consisting of N, O, and S.
  • This ring system may be attached to its pendant group at any carbon atom of the phenyl ring which results in a chemically stable structure.
  • This nine- to ten-membered bicyclic heterocyclic ring may optionally be substituted with a halo atom or a (CrCsJalkyl group either on a carbon or on a nitrogen atom if the resulting compound is stable.
  • Examples of said ring systems include, but are not limited to, benzothiophenyl, benzofuranyl, indolyl, quinolinyl, and isoquinolinyl.
  • phenyl that is fused to a five-membered or six-membered non-aromatic ring optionally containing up to two oxygen atoms is intended to mean a stable nine- to ten-membered bicyclic heterocyclic ring which consists of a five- to six-membered saturated ring and a phenyl ring that are fused.
  • the five- to six-membered saturated ring consists of carbon atoms and from zero to two oxygen atoms which are located at positions of the ring that result in a chemically stable structure.
  • This ring system may be attached to its pendant group at any carbon atom of the phenyl ring which results in a chemically stable structure.
  • ring systems include, but are not limited to, tetrahydronaphthyl, dihydroindenyl, chromanyl, isochromanyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, 1 ,2-ethylenedioxybenzenyl, and 1 ,2-methylenedioxybenzenyl.
  • C(O) means a radical in which the C atom bears a doubly bonded oxygen atoms, (an oxo substituent) and in which there remain two additional binding sites, that is, represents a radical of the formula:
  • the formula SO 2 means a radical in which the S atom bears two doubly bonded oxygen atoms, (oxo substituents) and in which there remain two additional binding sites, that is, represents a radical of the formula:
  • each substituent may replace any H atom on the moiety so modified as long as the replacement is chemically possible and chemically stable.
  • each substituent is chosen independently of any other substituent and can, accordingly, be the same or different.
  • Representative salts of the compound of Formula (I) include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methane
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and ⁇ /-methyl-D-glucamine.
  • basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, lauryl
  • the esters in the present invention are non-toxic, pharmaceutically acceptable ester derivatives of the compound of Formula (I).
  • This includes, for example, ester derivatives of hydroxy-containing a compound of Formula (I) prepared with acetic, benzoic, mandelic, stearic, lactic, salicylic, hydroxynaphthoic, glucoheptonic, and gluconic acid.
  • the compound of Formula (I) may be esterified by a variety of conventional procedures well known by those skilled in the art. One skilled in the art would readily know how to successfully carry out these as well as other methods of esterification.
  • Sensitive or reactive groups on the compound of Formula (I), may need to be protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art.
  • the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (R 1 S) configuration.
  • protecting groups may be required for the synthesis of compounds containing certain substituents.
  • a description of suitable protecting groups and appropriate methods of adding and removing such groups may be found, for example, in Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991.
  • Another object of this invention is to provide methods of making the compounds of the invention.
  • the compounds may be prepared from readily available materials by the methods outlined in the reaction scheme and Examples below, and by obvious modifications thereto.
  • compounds of the Formula (I) can be synthesized as shown in Reaction Scheme 1 starting from an anthranilic acid (2-aminobenzoic acid) derivative of Formula (III).
  • Formula (III) compounds are either commercially available, or readily synthesized by standard methods (e.g., reduction of the readily available nitrobenzoic acids of Formula (II) using hydrogen and a Pd catalyst or Zn/HOAc).
  • Reaction Scheme 2 illustrates the addition of a protected amine of Formula (Via) with the lactone of Formula (V) to form the intermediate of Formula (Vila) and subsequent treatment with an inorganic base, such as aqueous NaOH, to produce the protected intermediate of Formula (VIII). Deprotection of this compound with an acid, such as TFA, gives the salt of Formula (Ib).
  • the intermediate of Formula (Vila) may be cyclized and deprotected through treatment with acid to form the product of Formula (Ib) in one step.
  • the salt of Formula (Ib) may be converted, either by a reductive amination procedure using an aldehyde of Formula (IX) and a reducing agent, or an alkylating agent such as an alkyl halide, mesylate or tosylate of Formula (X) and a base to give the product of Formula (Ic).
  • the salt of Formula (Ic) may be further converted to the free base (Id) through a neutralization reaction. Depending on the workup or purification method, free base (Id) may also be directly produced from the reductive amination or alkylation reaction introducing R 4 .
  • Reaction Scheme 3 illustrates the addition of the benzyl-protected aminomethyl- substituted morpholine derivative of Formula (VIb) with the lactone of Formula (V) to form the intermediate of Formula (VIIb) and subsequent treatment with an inorganic base, such as aqueous NaOH, to produce the ring-closed benzyl-protected intermediate of Formula (Xl).
  • an inorganic base such as aqueous NaOH
  • Removal of the benzyl group for example with hydrogen/catalytic palladium on carbon or chloromethylchloroformate, gives the unprotected morpholine derivative (XII).
  • Compound (XII) may be converted, either by a reductive amination or alkylation reduction, as described in Reaction Scheme 2, to the alkylated product (Ie).
  • Reaction Scheme 4 illustrates the addition of the aminoalkyl-substituted pyridine of Formula (VIc) with the lactone of Formula (V) to form the intermediate of Formula (VIIc) and subsequent treatment with an inorganic base, such as aqueous NaOH, to produce the ring-closed pyridine intermediate of Formula (XIII).
  • Alkylation of this compound with an alkylating reagent R 4 - Y of Formula (X) gives the pyridinium salt intermediate (XIV) which is further converted to the 1 ,2,3,6-tetrahydropyridine product of Formula (If) using a reducing agent (e.g., NaBH 4 ).
  • a reducing agent e.g., NaBH 4
  • This transformation can be done using Suzuki coupling conditions, that is, a boronic acid of Formula (XV) or (XVa), a palladium catalyst, and a base such as potassium carbonate.
  • Alkenes of Formula (Ii) can be reduced, for example, by using hydrogen and palladium on carbon, to compounds of Formula (Ij).
  • Reaction Scheme 5 The methodology described in Reaction Scheme 5 may also be used at an earlier stage of the synthetic sequence outlined in Reaction Scheme 1 , as illustrated below in Reaction Scheme 7.
  • intermediate (Ig) may also be used for heteroatom bond formation reactions as outlined in Reaction Scheme 8 below.
  • an intermediate of Formula (Ig) can be transformed to an ether derivative of Formula (Im) by using Ullmann type coupling conditions, that is, reaction of an alcohol of Formula (XVIII) in the presence of a base, such as potassium carbonate, and a copper catalyst.
  • a base such as potassium carbonate
  • the intermediate of Formula (Ig) can be transformed to an amino derivative of Formula (In) or a sulfonamido derivative of Formula (Ip) by applying Buchwald- Hartwig type coupling conditions, that is, reaction of an amine R 3 -NH 2 [Formula (XIX)] or a sulfonamide R 3 -SO 2 NH 2 [Formula (XX)] in the presence of a base, such as cesium carbonate, and a palladium catalyst.
  • the intermediate of Formula (Ig) can be transformed to a thioether derivative of Formula (Iq) by using Ullmann type coupling conditions as described above, using a thiol R 3 -SH [Formula (XXI)] as starting material.
  • the thioether product of Formula (Iq) may be further converted to a sulfone derivative of Formula (Ir) through oxidation reactions known in the art, for example, using oxone ® .
  • Carbon-linked and oxygen-linked compounds as described in Reaction Schemes 5 and 8, respectively, may also be synthesized in a reverted manner, as outlined in Reaction Scheme 9.
  • a halogen intermediate of Formula (Ig) can, through reaction with bis-pinacolatodiboron, a palladium catalyst, and a base, be transformed into the boronate of Formula (Is).
  • This compound can be further converted to a product of Formula (Ih) by using Suzuki coupling conditions, that is, reaction with a compound R 3 -hal, a palladium catalyst, and a base.
  • the compound of Formula (Is) can be converted to the corresponding hydroxy derivative of Formula (It) through reaction with hydrogen peroxide and base.
  • the hydroxy compound of Formula (It) may be further alkylated using an alkylating reagent R 3 -hal and a base to form a product of Formula (Im).
  • halogen intermediate (Ig) may also be converted to a thioamide derivative of Formula (Iv) that can be further transformed into a thiazole derivative of Formula (Iw) shown below.
  • the two R 7 groups attached to the ⁇ -haloketone and the thiazole ring, respectively, are selected independently from the other so that they may be the same or they may be different.
  • R 1 may be introduced prior to R 2 .
  • the halogenated aminoamide intermediate of Formula (XXIIIa), obtained after incorporating R 1 can be transformed to a product of Formula (Ih) through a variety of different reaction sequences as outlined in Reaction Scheme 12 below.
  • the anthranilic acid derivative of Formula (lllb) or isatoic acid anhydride derivative of Formula (MIc) can be first converted to the aminoamide of Formula (XXIIIa).
  • an anthranilic acid derivative the use of a coupling reagent and base is required.
  • an isatoic acid derivative as the starting material, the presence of a base is sufficient.
  • the aminoamide derivative of Formula (XXIIIa) can be transformed to the product of Formula (Ih) through a variety of different sequences.
  • Reaction Scheme 13 shown below, illustrates a variation of Reaction Scheme 12 that allows access of the intermediate of Formula (Ig) from the aminoamide of Formula (XXIIIa) in one step.
  • Reaction Scheme 15 Another, closely related, variation of the reaction sequence shown in Reaction Scheme 14 is depicted in Reaction Scheme 15. Instead of substituting a fluorine atom during the cyclization reaction, ethylene glycol substitutes a thfluoroethoxy group to yield a product of Formula (laa).
  • Boronates of the Formula (XV) can be prepared if needed, from compounds of the Formula (XXV) using a borylating agent, such as tetraalkoxydiboron, a palladium catalyst, such as PdCI 2 (dppf), and a base, such as potassium acetate (Reaction Scheme 17).
  • a borylating agent such as tetraalkoxydiboron
  • a palladium catalyst such as PdCI 2 (dppf)
  • a base such as potassium acetate
  • Amines of Formula (Vl) used as starting materials can be prepared if needed, by the method shown in Reaction Scheme 18.
  • This route employs the N-alkylation conditions described above for the preparation of the compound of Formula (Ic), namely, reductive amination of the protected cyclic amine of Formula (XXVI) using an aldehyde and reducing agent, or an alkyl halide, etc., and a base to give the protected intermediate of Formula (XXVII). Removal of the protecting group provides the intermediates of Formula (VId) [Formula (Vl) in which R 1 is a cyclic amino group substituted with R 4 ].
  • Y halo, MsO, or TsO
  • At acid anion, e.g., Cl " , CF 3 CO 2 ' , etc.
  • TLC was performed on EM Science pre-coated glass-backed silica gel 60 A F-254 250 ⁇ m plates.
  • Method A Spectra were obtained using a Hewlett Packard 1100 HPLC system equipped with a quaternary pump, a variable wavelength detector, a YMC Pro 18 2.0 mm x 23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 5 minutes was used on the HPLC. Buffer A was 98% water, 2% acetonitrile, and 0.02% TFA, and Buffer B was 98% acetonitrile, 2% water, and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source. If not otherwise stated in the experimental section, method A was used as the standard HPLC-MS method for characterizing compounds described herein.
  • Method B Spectra were obtained using a Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 Autosampler, a Gilson diode array detector, a Waters Symmetry column (4.6 x 50mm, 5um), and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. Spectra were scanned from 120-1000 amu over 2 seconds. Gradient elution was used with Buffer A as 2% acetonitrile in water with 0.02% TFA and Buffer B as 2% water in acetonitrile with 0.02% TFA at 4.0 mL/min. Samples were eluted as follows: 90% A for 1.0 minutes ramped to 95% B over 3.0 minutes and held at 95% B for 0.8 minutes and then the column is brought back to initial conditions over 0.1 minutes.
  • Proton ( 1 H) nuclear magnetic resonance (NMR) spectra were measured using the following spectrometers: (a) General Electric G ⁇ /-Omega 300 (300 MHz) spectrometer using either Me 4 Si ( ⁇ 0.00) or residual protonated solvent (CHCI 3 ⁇ 7.26; MeOH ⁇ 3.30; DMSO ⁇ 2.49) as standard, (b) Varian Mercury Plus 400 (400 MHz) spectrometer using the compounds mentioned above as standard.
  • Celite ® diatomaceous earth filter agent Celite Corp.
  • PS-DIEA polystyrene-bound diisopropylethylamine p-tol-BINAP 2,2'-bis(di-p-tolyl-phosphino)-1 ,1 '-binaphthyl
  • step 2 To a solution of 1-[1-(cyclopropylmethyl)piperidin-3-yl]methanamine dihydrochloride (106.9 mg, 0.44 mmol) (step 2) in toluene (2.0 mL) was added triethylamine (120 mg, 1.18 mmol, 0.17 mL). The mixture was stirred at rt under a nitrogen atmosphere, and then 6-[butyl(methyl)- amino]-2-(2-methoxyphenyl)-4H-3,1-benzoxazin-4-one (100 mg, 0.296 mmol) (Example 1 , step 3) was added. The reaction mixture was stirred at 85 0 C for 18 h.
  • step 1 tert-Butyl ⁇ [1-(4,4,4-trifluorobutyl)piperidin-3-yl]methyl ⁇ carbamate (0.31 g, 0.95 mmol) (step 1) was dissolved in MeOH (0.5 mL), and then 2 M aq HCI (5.0 ml_, 10 mmol) was added. The mixture was stirred at rt for 15 h. The mixture was concentrated in vacuo and dried for 5 h in the vacuum oven at 50 0 C. The product was obtained as a light yellow oil (308 mg).
  • step 2 The product was obtained by reaction of 1 -[1 -(4,4,4-trifluorobutyl)piperidin-3-yl] methanamine hydrochloride (step 2) and 6-[butyl(methyl)amino]-2-(2-methoxyphenyl)-4H-3,1- benzoxazin-4-one (Example 1 , step 3) in a similar manner as described in Example 4, step 3.
  • tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate (3.00 g, 14.0 mmol) in toluene (20 mL) was added to 6-bromo-2-(2-methylphenyl)-4H-3,1-benzoxazin-4-one (3.69 g, 11.7 mmol) (step 1), and the solution was stirred at reflux for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and passed through a silica gel plug using EtOAc as eluent. Removal of the solvent under reduced pressure gave the intermediate as a yellow oil which was used in the next step without further purification.
  • o-Toluoyl chloride (23.30 g, 150.8 mmol) was added slowly into a mixture of 2-amino-5- hydroxybenzoic acid (23.09 g, 150.8 mmol) and triethylamine (63.05 mL, 452.3 mmol) in DCM (250 mL) at O 0 C. After addition, the flask was stirred at rt for 14 h. Half of the DCM was removed under reduced pressure, and acetic anhydride (125 mL) was added to the mixture, followed by heating to 5O 0 C for 2 h. The reaction mixture was cooled to rt, slowly quenched with ice water, and diluted with DCM.
  • the resulting intermediate (8.50 g , 18.2 mmol) (yellow oil) was added to a dry round-bottom flask followed by ethylene glycol (50 mL) and LiOH (1.53 g, 36.4 mmol). This mixture was stirred at 135 0 C for 16 h and subsequently diluted with DCM and water. The mixture was extracted with DCM (100 mL x 2), and the combined organic layers were concentrated under reduced pressure. The crude product was then purified via silica gel column chromatography using ethyl acetate/hexanes (70:30; v/v). ES-MS m/z 450.1 (MH + ); HPLC RT (min) 3.15.
  • step 2 To a mixture of 2-(2-methylphenyl)-3-(piperidin-3-ylmethyl)-6-(trifluoromethoxy)quinazolin- 4(3H)-one (200 mg, 0.48 mmol) (step 2) and Cs 2 CO 3 (624 mg, 1.92 mmol) in DMF (8 mL) was added oxetan-3-yl-4-methylbenzenesulfonate (164 mg, 0.72 mmol). The reaction mixture was stirred at 125 0 C for 14 h, then cooled to rt, and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (2 x 20 mL).
  • the mixture was degassed and heated to 12O 0 C for 16 h, then diluted with EtOAc, and filtered through celite.
  • the filtrate was separated using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 90% acetonitrile in water containing 1% TFA to afford 78 mg (74%) of the product.
  • Step 2 Preparation of 6-(4-fluorophenoxy)-2-(2-methoxyphenyl)-3-(piperidin-3- ylmethyl)quinazolin-4(3H)-one
  • step 2 tert-Butyl (3R)-3-[(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)methyl]pipehdine-1- carboxylate (step 2) was treated with 20% TFA in DCM (30 mL) at rt for 15 h. The solvent and excess TFA were removed under reduced pressure. The residue was then treated with potassium carbonate (16.8g, 121 mmol) and 2-isopropanyl iodide (6.2 g, 36 mmol) in acetonitrile (50 mL) at 70 0 C for 15 h.
  • the reaction mixture was then filtered and the filtrate was purified using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA.
  • the desired fractions were combined, treated with 10% Na 2 CO 3 , and extracted with EtOAc (3x). The extract was then washed with water and brine, dried over MgSO 4 , and evaporated to afford 255 mg (38%) of the title product.
  • the reaction mixture was then heated to 100°C for 20 h.
  • the mixture was cooled to rt, filtered through a silica gel plug using ethyl acetate as eluent, concentrated to dryness, and purified using a Gilson reversed-phase HPLC system with a gradient elution from 10% to 90% acetonitrile in water to afford 19 mg (6%) of the product.
  • the crude material was passed through Celite® to remove the solids, and methanol was used to elute the product.
  • the methanolic solution was purified by HPLC using a gradient from 5- 55% acetonitrile in water to afford the title product (33 mg, 35%) after evaporation.
  • step 1 6-Bromo-2-(2-methoxyphenyl)-4H-3,1-benzoxazin-4-one (2.5 g, 7.53 mmol) (step 1 ), 4- chlorophenylboronic acid (1.77, 11.3 mmol), and PdCI 2 (dppf) CH 2 CI 2 (275 mg, 3.6 mmol) were dissolved in a toluene/dioxane mixture (25 ml_, 4/1) followed by addition of 2 N aq Na 2 CO 3 (10 ml.) and K 2 CO 3 (3.1 g, 22.6 mmol). The mixture was degassed and heated to 9O 0 C for 1 h.
  • the mixture was then diluted with CH 2 CI 2 (100 mL) and sat aq NaHCO 3 (100 mL). The layers were separated and the organic layer was dried over MgSO 4 , filtered, and concentrated under reduced pressure. The product was taken up in EtOAc (100 mL) and was washed with sat aq NaHCO 3 (4 x 100 mL). The organic layer was then dried with MgSO 4 , filtered, and concentrated under reduced pressure to give the product as a white solid (7.60 g, 98 %).
  • step 2 To a dry 100 mL round-bottom flask was added tert-butyl 3- ⁇ [6-bromo-2-(2-methoxy- phenyl)-4-oxoquinazolin-3(4H)-yl]methyl ⁇ piperidine-1-carboxylate (1.23 g, 2.33 mmol) (step 2), followed by anhydrous toluene (20.0 mL) and dioxane (5.00 mL).
  • step 1 The compound was prepared using 6-bromo-3- ⁇ [1-(cyclopropylmethyl)piperidin-3- yl]methyl ⁇ -2-(2-methoxyphenyl)quinazolin-4(3H)-one trifluoroacetate (step 1) and reacting it with 3- chlorophenylboronic, applying the method described in Example 49, step 2.
  • the crude reaction mixture was diluted with MeOH (1.0 mL) and purified on a Gilson reversed-phase HPLC system eluting with 20-80% of a MeCN/water solvent system (containing 0.1% TFA) to afford 40 mg (31%) of the product.
  • step 1 6-Bromo-3-[(1-isopropylpiperidin-3-yl)methyl]-2-(2-methylphenyl)quinazolin-4(3H)-one (44.4 mg, 0.10 mmol) (step 1), 3-methylphenyl boronic acid (27.2 mg, 0.20 mmol), and anhydrous DMA (2 mL) were combined in a microwave vial along with 2 N aq potassium carbonate (0.31 mmol), followed by PdCI 2 (dppf) (2.2 mg, 0.003 mmol). DMA (0.5 mL) was added to wash the solids off the sides of the vial, and the mixture was degassed for 10 min.
  • the vial cap was crimped, and the mixture was irradiated in a microwave reactor at 140 0 C for 10 min.
  • the mixture was passed through a filter and purified by preparative HPLC (Waters Symmetry column; gradient elution with 90% A [CH 3 CN/water (2:98; v/v)] for 1.0 min ramped to 95% B [CH 3 CN/water (98:2; v/v)] over 3.0 min and held at 95% B for 0.8 min) to afford 29.2 mg (62.7 %) of product.
  • Step 1 Preparation of 6-bromo-2-isopropyl-3-(r(3S)-1-isopropylpiperidin-3-v ⁇ methyl)- quinazolin-4(3H)-one
  • the reaction mixture was sealed with a cap and then heated in a microwave reactor at 13O 0 C for 15 min. After cooling to rt, the mixture was filtered through a silica gel plug, and the precipitate was washed with DMSO (1.5 mL). The filtrate was then purified on a Gilson HPLC system equipped with an Xterra reversed-phase column using a gradient elution from 30% acetonitrile to 90% acetonitrile in water under basic conditions with 0.1% NH 3 as modifier. The title product was obtained in a yield of 28.3 mg (56%).
  • reaction mixture was then filtered, and the filtrate was separated by preparative HPLC using a gradient elution from 5% to 60% acetonitrile in water containing 1 % TFA.
  • product fractions were combined, treated with 10% Na 2 CO 3 , and extracted with EtOAc (x3).
  • EtOAc EtOAc
  • the combined organic layers was washed with water and brine, dried over MgSO 4 , and concentrated under reduced pressure to afford 57 mg (35%) of the title product.
  • step 2 tert-butyl (3R)-3- ⁇ [(2-amino-5- bromobenzoyl)amino]methyl ⁇ piperidine-1-carboxylate (Example 18, step 1) was converted to tert- butyl 3-[(6-bromo-2-cyclopropyl-4-oxoquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate which was further transformed to the final product by using the Suzuki coupling procedure and subsequent BOC-deprotection procedure described in Example 43, steps 3 and 4.
  • the reaction mixture was then filtered and the filtrate purified using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA.
  • the product fractions were combined, treated with 10% aq Na 2 CO 3 , and extracted with EtOAc (3x). The combined organic fractions were then washed with water and brine, dried over MgSO 4 , and evaporated to afford 45 mg (14%) of the title product.
  • step 2 To a solution of 6-bromo-3-[(3S)-piperidin-3-ylmethyl]-2-(trifluoromethyl)quinazolin-4(3H)- one (3.1 g, 6.15 mmol) (step 2) and isopropyl iodide (1.57 g, 9.23 mmol) in acetonitrile (40 mL) was added potassium carbonate (4.25 g, 30.75 mmol) in small portions at rt while stirring. The mixture was then heated to 70 0 C for 15 h, followed by cooling to rt, addition of water and EtOAc to give a clear biphasic solution.
  • the reaction mixture was filtered and the filtrate was purified by preparative HPLC using a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA.
  • the product fractions were combined, treated with 10% Na 2 CO 3 , and extracted with EtOAc (x3). The extract was then washed with water and brine, dried over MgSO 4 , and evaporated to afford 1.82 g (86%) of the title product.
  • the reaction mixture was then filtered, and the filtrate was, after concentration, purified using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA.
  • the product fractions were combined, treated with 10% Na 2 CO 3 , and extracted with EtOAc (3x). The combined organic fractions were then washed with water and brine, dried over MgSO 4 , and dried under high vacuum to afford 82 mg (31%) of the title product.
  • EXAMPLE 70 e ⁇ -ChlorophenvD- ⁇ -ffluoromethvD-S-irOSVI-isopropylpiperidin-S-yllmethvDquinazolin-
  • reaction mixture was filtered through a pad of Celite®, concentrated, and purified by silica gel chromatography (40% ethyl acetate in hexane) to afford 0.89 g (83%) of the product.
  • the product was obtained as a side product of a Buchwald reaction performed similar to Example 29.
  • the product may also be obtained by using a similar sequence as described in Example 13 and 2-aminobenzoic acid as starting material in the first step.
  • ES-MS m/z 378.2 (MH + ); HPLC RT (min) 1.95.
  • step 1 3-[(1-lsopropylpiperidin-3-yl)methyl]-2-(2-methylphenyl)-4-oxo-3,4-dihydroquinazoline-6- carbonitrile (5.5 g, 14 mmol) (step 1) was dissolved in DMF (75 ml_), and H 2 S gas was then passed through the solution for several minutes. The reaction mixture was heated to 60 0 C and diethylamine (1.5 g, 21 mmol), dissolved in a small amount of DMF, was added. After 3.5 h stirring at 60 0 C, the orange solution was allowed to cool to rt over 10 h. The reaction mixture was purged with nitrogen for 1 h, and then the solvent was removed under reduced pressure.
  • Step 3 Preparation of 6-r4-(3-chloro-2-thienyl)-1 ,3-thiazol-2-yll-3-[(1 -isopropylpiperidin-3- yl)methv ⁇ -2-(2-rnethylphenvDquinazolin-4(3H)-one trifluoroacetate

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Abstract

La présente invention a trait à des dérivés de la quinazolinone, des compositions, et des procédés de traitement du diabète, de l'obésité et autres troubles associés, et de la régulation de la prise d'aliments (par exemple, stimulation et suppression).
PCT/US2005/026192 2004-07-22 2005-07-22 Derives de la quinazolinone utiles pour la regulation de l'homeostasie du glucose et de prise d'aliments Ceased WO2006012577A2 (fr)

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