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WO2016041470A1 - Inhibiteurs de sglt-2 - Google Patents

Inhibiteurs de sglt-2 Download PDF

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WO2016041470A1
WO2016041470A1 PCT/CN2015/089492 CN2015089492W WO2016041470A1 WO 2016041470 A1 WO2016041470 A1 WO 2016041470A1 CN 2015089492 W CN2015089492 W CN 2015089492W WO 2016041470 A1 WO2016041470 A1 WO 2016041470A1
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compound
methyl
aryl
mmol
phenyl
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Zhiyuan Zhang
Shaoqiang HUANG
Zhaolan ZHANG
Yaning SU
Yan Ren
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National Institute of Biological Sciences Beijin
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National Institute of Biological Sciences Beijin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • SGLT-2 inhibitors provide drugs for treating diabetes and obesity, inter alia, e.g. Diabetes, 1999, 48, 1794-1800, Dapagliflozin (Diabetes, 2008, 57, 1723-1729) .
  • Various O-aryl and O-heteroaryl glycosides have been reported as SGLT-2 inhibitors, e.g. WO 01/74834, WO 03/020737, US04/0018998, WO 01/68660, WO 01/16147, WO 04/099230, WO 05/011592, US 06/0293252 and WO 05/021566.
  • SGLT-2 iinhibitors e.g. WO 01/27128, WO 04/080990, US 06/0025349, WO 05/085265, WO 05/085237, WO 06/054629 and WO 06/011502.
  • Other publications include: US 7838498; US 8586550; WO 2012172566; WO2013191549; US2006074031; US8,614,195; US20060074031; US20080004336; WO2005012326.
  • the invention provides glucopyranoside compounds of formula I:
  • R1-R3 is oxo and two of R1-R3 are independently H, F, –OR6, wherein each R6 is independently H, methyl or acetyl (CH 3 CO-) ;
  • R4 is H, F or OR7, where R7 is H, methyl or acetyl (CH 3 CO-) ;
  • R5 is aryl or heteroaryl, or a salt or acetate thereof.
  • R2 or R3 is oxo; R2 is oxo; two of R1-R3 are independently F or –OR6, wherein each R6 is independently H, methyl or acetyl (CH 3 CO-) , and R4 is F or OR7, wherein R7 is H, methyl or acetyl (CH 3 CO-) ; two of R1-R3 are independently –OR6, wherein each R6 is independently H, methyl or acetyl (CH 3 CO-) , and R4 is OR7, wherein R7 is H, methyl or acetyl (CH 3 CO-) ; two of R1-R3 are independently –OR6, wherein each R6 is H or acetyl (CH 3 CO-) , and R4 is OR7, wherein R7 is H or acetyl (CH 3 CO-) ; and/or two of R1-R3 are independently –OR6, wherein each R6 is H, and R4 is OR7, wherein R
  • R5 is substituted phenyl
  • R5 is substituted phenyl of formula:
  • each R8 is a hydrocarbon or heteroatom-containing functional group (non-hydrogen substituent) , R9 is aryl and n is 0, 1, 2, 3 or 4, wherein R8 can also bind C1 of the glucopyranoside ring (e.g. MeO forming an ether) ;
  • each R8 is independently substituted or unsubstituted lower alkyl (e.g. Me) , lower alkenyl, lower alkynyl (e.g. ethynyl) , alkyloxy (e.g. OMe, OEt) , halide, hydroxyl, carbonyl, aldehyde, carboxyl, ester, acetal, carboxamide, amine, imine, azide, azo, cyanate, nitrate, nitrile, nitro, nitroso, sulfydryl, sulfide, sufone, thocyanate, phosphine, phosphate, etc. ;
  • R5 is substituted phenyl of formula:
  • R8 is H, halide, lower alkyl (e.g. Me or Et) , lower alkenyl, lower alkynyl (e.g. ethynyl) , alkyloxy (e.g. OMe or OEt) , and
  • R8’ is H, halide, lower alkyl (e.g. Me or Et) , lower alkenyl, lower alkynyl (e.g. ethynyl) , alkyloxy (e.g. OMe or OEt) , wherein the alkyloxy (e.g. OMe or OEt) also binds C1 of the glucopyranoside ring;
  • lower alkyl e.g. Me or Et
  • alkenyl e.g. ethynyl
  • alkyloxy e.g. OMe or OEt
  • R9 is substituted or unsubstituted, homo-or hetero, 5-or 6-membered cyclic or 9 or 10 membered bi-cyclic aryl;
  • R9 is substituted or unsubstituted:
  • each R10 is a hydrocarbon or heteroatom-containing functional group (non-hydrogen substituent) , including alkyl or heterolkyl, alkyloxy or heteroalkyloxy, including cyclic forms of each, and such as independently substituted or unsubstituted (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 1 -C 4 ) alkyloxy, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, halide, fluoro-substituted (C 1 -C 2 ) alkyl, (C 1 -C 4 ) alkyl-SO 2 -, (C 3 -C 6 ) cycloalkyl, or a (C 5 -C 6 ) heterocycle having 1 or 2 heteroatoms each independently selected from N, O, or S, such as Cl, F, hydroxyl, carbonyl, aldeh
  • R9 is:
  • the invention provides 2-aryl, 6-methyl-B-dihydro-pyran-one compounds, wherein the methyl may be substituted.
  • the compound is a 3-oxo-glucopyranoside or 4-oxo-glucopyranoside.
  • aryl is substituted phenyl
  • aryl is 3- (methyl-aryl) 5- (lower alkyl) phenyl, wherein the methyl-aryl is methyl- (substituted or unsubstituted, homo-or hetero, 5-or 6-membered cyclic or 9 or 10 membered bi-cyclic aryl) ;
  • aryl is 3- (methyl-aryl) 5- (lower alkyl) phenyl, wherein the methyl-aryl is methyl- (
  • aryl is: 4-ethoxyphenyl; 4-fluorophenyl thiophen-2-yl; benzo [b] thiophen-2-yl;tetrahydrofuran-3-yloxy-phenyl; or chroman-6-yl-phenyl.
  • the invention provides an acetate of a disclosed compound, or salt thereof.
  • the invention provides a compound of any of the Tables herein, or an acetate thereof, or a salt thereof, particularly a pharmaceutically acceptable salt, or a hydride or stereoisomer thereof.
  • the invention provides a disclosed compound that is a sodium-glucose linked transporter-1 (SGLT2) inhibitor.
  • SGLT2 sodium-glucose linked transporter-1
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a disclosed compound in unit dosage form, and/or coformulated or copackaged or coadministered with a different anti-diabetes drug
  • the invention also provides methods of using a disclosed compound or composition comprising administering it to a person determined to be in need thereof, and optionally, detecting a resultant therapeutic effect.
  • the invention provides pharmaceutical compositions comprising the subject compounds, and methods of making and using the subject compounds, including methods of inhibiting SGLT-2.
  • the compositions may comprise a pharmaceutically-acceptable excipient, be in effective, unit dosage form, and/or comprise another, different therapeutic agents for the targeted disease or condition.
  • the invention provides methods of treating a person in need thereof with an effective amount of the subject compound or pharmaceutical composition, and optionally, detecting a resultant improvement in the person’s health or condition.
  • the methods may also optionally include the antecedent step of determining that the person, particularly diagnosing and applicable disease or condition (herein) .
  • Fig. 1 Single oral doses of Example 5 reduce blood glucose in ZDF rats over 24-h.
  • Fig. 2 Single oral doses of Example 5 increase urine volume and urinary glucose excretion in ZDF rats over 24-h.
  • the invention provides 2-aryl, 6-methyl-B-dihydro-pyran-one compounds and related articles, compositions, formulations, methods of making and methods of using.
  • the invention provides myriad embodiments, as detailed herein.
  • Applicable diseases or conditions are mediated at least in part through SGLT-2 activity and ameliorated or treatable at least in part by inhibiting SGLT-2, and include diabetes and obesity.
  • the terms “a” and “an” mean one or more, the term “or” means and/or and polynucleotide sequences are understood to encompass opposite strands as well as alternative backbones described herein.
  • genuses are recited as shorthand for a recitation of all members of the genus; for example, the recitation of (C1-C3) alkyl is shorthand for a recitation of all C1-C3 alkyls: methyl, ethyl and propyl, including isomers thereof.
  • heteroatom as used herein generally means any atom other than carbon or hydrogen.
  • Preferred heteroatoms include oxygen (O) , phosphorus (P) , sulfur (S) , nitrogen (N) , and halogens
  • preferred heteroatom functional groups are haloformyl, hydroxyl, aldehyde, amine, azo, carboxyl, cyanyl, thocyanyl, carbonyl, halo, hydroperoxyl, imine, aldimine, isocyanide, iscyante, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, and sulfhydryl.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (i.e. C1-C8 means one to eight carbons) .
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
  • alkenyl by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono-or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more double bonds.
  • alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) and higher homologs and isomers thereof.
  • alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono-or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more triple bonds.
  • alkynyl groups include ethynyl, 1-and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.
  • alkylene by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH 2 -CH 2 -CH 2 -CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkoxy " alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, P, Si and S, wherein the nitrogen, sulfur, and phosphorous atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom (s) O, N, P and S may be placed at any interior position of the heteroalkyl group.
  • the heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 -CH 2 -and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
  • cycloalkyl and heterocycloalkyl represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl” , respectively. Accordingly, a cycloalkyl group has the number of carbon atoms designated (i.e., C3-C8 means three to eight carbons) and may also have one or two double bonds.
  • a heterocycloalkyl group consists of the number of carbon atoms designated and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include 1- (1, 2, 5, 6-tetrahydropyrid-yl) , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • halo and “halogen, " by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl, " are meant to include alkyl substituted with halogen atoms, which can be the same or different, in a number ranging from one to (2m'+1) , where m'is the total number of carbon atoms in the alkyl group.
  • halo (C1-C4) alkyl is mean to include trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group) .
  • perhaloalkyl means, unless otherwise stated, alkyl substituted with (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group.
  • perhalo (C1-C4) alkyl is meant to include trifluoromethyl, pentachloroethyl, 1, 1, 1-trifluoro-2-bromo-2-chloroethyl and the like.
  • acyl refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl and 1, 2, 3, 4-tetrahydronaphthalene.
  • heteroaryl refers to aryl groups (or rings) that contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like) .
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naph
  • R' , R" and R′ each independently refer to hydrogen, unsubstituted (C1-C8) alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl- (C1-C4) alkyl groups.
  • R' a nd R" When R' a nd R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-or 7-membered ring.
  • -NR' R" is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) .
  • the aryl group When the aryl group is 1, 2, 3, 4-tetrahydronaphthalene, it may be substituted with a substituted or unsubstituted (C3-C7) spirocycloalkyl group.
  • the (C3-C7) spirocycloalkyl group may be substituted in the same manner as defined herein for "cycloalkyl" .
  • an aryl or heteroaryl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention.
  • an aryl or heteroaryl group will be unsubstituted or monosubstituted.
  • an aryl or heteroaryl group will be unsubstituted.
  • Preferred substituents for aryl and heteroaryl groups are selected from: halogen, -OR' , -OC (O) R' , -NR' R" , -SR' , -R' , -CN, -NO 2 , -CO 2 R' , -CONR' R" , -C (O) R' , -OC (O) NR' R" , -NR" C (O) R' , -S (O) R' , -SO 2 R' , -SO 2 NR' R" , -NR" SO 2 R, -N 3 , -CH (Ph) 2 , perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, where R' a nd R" are as defined above.
  • substituents are selected from: halogen, -OR' , -OC (O) R' , -NR' R" , -R' , -CN, -NO 2 , -CO 2 R' , -CONR' R" , -NR" C (O) R' , -SO 2 R' , -SO 2 NR' R” , -NR" SO 2 R, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl.
  • the substituent -CO 2 H includes bioisosteric replacements therefor; see, e.g., The Practice of Medicinal Chemistry; Wermuth, C. G., Ed. ; Academic Press: New York, 1996; p. 203.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C (O) - (CH 2 ) q-U-, wherein T and U are independently -NH-, -O-, -CH 2 -or a single bond, and q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A- (CH2) r-B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S (O) -, -S (O) 2 -, -S (O) 2 NR' -or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CH 2 ) s-X-(CH 2 ) t--, where s and t are independently integers of from 0 to 3, and X is -O-, -NR' -, -S-, -S(O) -, -S (O) 2 -, or -S (O) 2 NR' -.
  • the substituent R' in -NR' -and -S (O) 2 NR' - is selected from hydrogen or unsubstituted (C1-C6) alkyl.
  • substituents are disclosed herein and exemplified in the tables, structures, examples, and claims, and may be applied across different compounds of the invention, i.e. substituents of any given compound may be combinatorially used with other compounds.
  • applicable substituents are independently substituted or unsubstituted heteroatom, substituted or unsubstituted, optionally heteroatom C1-C6 alkyl, substituted or unsubstituted, optionally heteroatom C2-C6 alkenyl, substituted or unsubstituted, optionally heteroatom C2-C6 alkynyl, or substituted or unsubstituted, optionally heteroatom C6-C14 aryl, wherein each heteroatom is independently oxygen, phosphorus, sulfur or nitrogen.
  • applicable substituents are independently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, amine, azo, halogens, carbamoyl, carbonyl, carboxamido, carboxyl, cyanyl, ester, halo, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl or trifluromethyl ether (OCF3) .
  • OCF3 trifluoromethyl or trifluromethyl ether
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phospho
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
  • Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.
  • the invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that undergo chemical changes under physiological conditions to provide the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be more bioavailable by oral administration than the parent drug.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (the "prodrug” ) , but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound of the invention.
  • Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention.
  • the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) . All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
  • therapeutically effective amount refers to the amount of the subject compound that will elicit, to some significant extent, the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, such as when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.
  • the therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • the invention also provides pharmaceutical compositions comprising the subject compounds and a pharmaceutically acceptable excipient, particularly such compositions comprising a unit dosage of the subject compounds, particularly such compositions copackaged with instructions describing use of the composition to treat an applicable disease or condition (herein) .
  • compositions for administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refer to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, losenges or the like in the case of solid compositions.
  • the compound is usually a minor component (from about 0.1 to about 50%by weight or preferably from about 1 to about 40%by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • compositions may be administered separately, jointly, or combined in a single dosage unit.
  • the amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg, according to the particular application.
  • unit dosage forms are packaged in a multipack adapted for sequential use, such as blisterpack, comprising sheets of at least 6, 9 or 12 unit dosage forms.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art.
  • treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • the compounds can be administered by a variety of methods including, but not limited to, parenteral, topical, oral, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment.
  • the therapeutic protocols e.g., dosage amounts and times of administration
  • the therapeutics of the invention can be administered in a therapeutically effective dosage and amount, in the process of a therapeutically effective protocol for treatment of the patient.
  • microgram (ug) amounts per kilogram of patient may be sufficient, for example, in the range of about 1, 10 or 100 ug/kg to about 0.01, 0.1, 1, 10, or 100 mg/kg of patient weight though optimal dosages are compound specific, and generally empirically determined for each compound.
  • a dosage regimen of the compoundss can be oral administration of from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.
  • Table B Exemplary Compounds: 3-oxo-glucopyranoside and 4-oxo-glucopyranosides:
  • Step 1 (3R, 4S, 5S) -3, 4-bis (benzyloxy) -5- (benzyloxymethyl) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydrofuran-2-ol
  • Step 1b To a stirred -78°Csolution of 5-bromo-2-chloro-4’ -ethoxydiphenylmethane (0.64 g, 1.54 mmol) in THF (5 mL) under N 2 was added n-BuLi (0.77 mL, 2.4 M, 1.84 mmol) dropwise while keeping the temperature below -70°C.
  • Step 2 (2S, 3S, 4S, 5S) -3, 4-bis (benzyloxy) -2- (benzyloxymethyl) -5- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydrofuran (1c)
  • Et 3 SiH (0.27 mL, 1.68 mmol
  • Et 2 O (0.31 mL, 1.18 mmol) and stirred for 4.5 h.
  • Step 3 (2S, 3R, 4R, 5S) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-(hydroxymethyl) tetrahydrofuran-3, 4-diol (1) and (2S, 3R, 4R, 5S) -2- (3- (4-ethoxybenzyl) phenyl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol (2) 10%Pd/C (38 mg) was added to a solution of compound 1c (0.38 g, 0.58 mmol) in EtOAc (10 mL) . After the resulting suspension was stirred under an atmosphere of H 2 at room temperature for 2 h.
  • Step 1 (3R, 4S, 5S) -3, 4-bis (benzyloxy) -5- (benzyloxymethyl) -2- (3- (4-ethoxybenzyl) -4-methylphenyl) tetrahydrofuran-2-ol (3a)
  • lactone 1a 0.5 g, 1.64 mmol
  • 1b 0.79 g of 3a as colorless oil, yield: 75%.
  • Step 2 (2S, 3S, 4S, 5S) -3, 4-bis (benzyloxy) -2- (benzyloxymethyl) -5- (3- (4-ethoxybenzyl) -4-methylphenyl) tetrahydrofuran (3b)
  • lactol 3a (0.79 g, 1.19 mmol) as described above for the reduction of 1b to 1c, afforded 0.62 g of 3b as colorless oil, yield: 91%.
  • Step 3 (2S, 3R, 4R, 5S) -2- (3- (4-ethoxybenzyl) -4-methylphenyl) -5-(hydroxymethyl) tetrahydrofuran-3, 4-diol (3)
  • 3b (0.62 g, 0.99 mmol) as described above for the deprotection of 1c to 1, gave 0.16 g of 3 as white syrup, yield: 46%.
  • Step 1 (4aR, 6S, 7R, 8R, 8aS) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -2-phenylhexahydropyrano [3, 2-d] [1, 3] dioxine-7, 8-diol (4a)
  • a mixture of dapagliflozin, 24 (1.05 g, 2.57 mmol)
  • benzaldehyde dimethyl acetal (0.58 mL, 3.86 mmol
  • catalytic p-toluenesulfonic acid 49 mg, 0.26 mmol
  • Step 2 (4aR, 6S, 7S, 8R, 8aR) -7, 8-bis (benzyloxy) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -2-phenylhexahydropyrano [3, 2-d] [1, 3] dioxine (4b)
  • 4a (0.27 g, 0.54 mmol)
  • BnBr (0.20 g, 0.14 mL) was added to the above mixture, the reaction was continued for another 2 h, then quenched by adding saturated aq.
  • Step 3 (2R, 3R, 4S, 5S, 6S) -4, 5-bis (benzyloxy) -2- (benzyloxymethyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3-ol (4c) TFA (0.15 mL, 1.92 mmol) was added dropwise to a solution of 4b (0.26 g, 0.38 mmol) and Et 3 N (0.3 mL, 1.92 mmol) in CH 2 Cl 2 (5 mL) at 0°C. When the addition was complete, the reaction was warmed to room temperature for 2 h.
  • Step 4 (2R, 4R, 5S, 6S) -4, 5-bis (benzyloxy) -2- (benzyloxymethyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) dihydro-2H-pyran-3 (4H) -one (4d)
  • Step 5 (2R, 4R, 5R, 6S) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -4, 5-dihydroxy-2-(hydroxymethyl) dihydro-2H-pyran-3 (4H) -one (4)
  • 4d 0.2 g, ⁇ 60%HPLC purity
  • Pd/C 10 wt%; 20 mg
  • Step 1 ( (2R, 3S, 4R, 5R, 6S) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -3, 4, 5-trihydroxytetrahydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (6a)
  • a well stirred solution of dapagliflozin, 24 (0.54 g, 1.32 mmol) in anhydrous pyridine (10 mL) was added p-toluenesulfonyl chloride (0.63 g, 3.3 mmol) .
  • the obtained system was stirred for another 2h.
  • Step 2 (2S, 3R, 4S, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6-methyltetrahydro-2H-pyran-3, 4, 5-triol (6b)
  • 6a 0°C
  • LiAlH 4 89 mg, 2.36 mmol
  • Step 3 (4aR, 5R, 7S, 8S, 8aR) -7- (4-chloro-3- (4-ethoxybenzyl) phenyl) -2, 3-dimethoxy-2,3, 5-trimethylhexahydro-2H-pyrano [4, 3-b] [1, 4] dioxin-8-ol (6c) and (4aS, 5S, 7R, 8R, 8aS) -5-(4-chloro-3- (4-ethoxybenzyl) phenyl) -2, 3-dimethoxy-2, 3, 7-trimethylhexahydro-2H-pyrano [4, 3-b] [1, 4] dioxin-8-ol (7a) A solution containing 6b (0.38 g, 0.97 mmol) , 2, 3-butanedione (0.42 g, 4.85 mmol, 0.42 mL) , trimethylorthoformate (0.41 g, 3.88 mmol) , and 10-camphorsulfonic acid (0
  • Step 4 (4aR, 5R, 7S, 8aS) -7- (4-chloro-3- (4-ethoxybenzyl) phenyl) -2, 3-dimethoxy-2,3, 5-trimethyltetrahydro-2H-pyrano [4, 3-b] [1, 4] dioxin-8 (3H) -one
  • 6c (0.19 g, 0.38 mmol)
  • PCC (0.33 g, 1.52 mmol
  • sodium acetate (0.21 g, 1.52 mmol
  • 4A activated molecular sieves (0.55 g) was placed in a light protected flask under Ar, and then anhydrous CH 2 Cl 2 (20 mL) was added, after 2 h, the reaction mixture was diluted with CH 2 Cl 2 , silica gel was added, and the mixture was evaporated to dryness.
  • Step 5 (2S, 4S, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -4, 5-dihydroxy-6-methyldihydro-2H-pyran-3 (4H) -one (6)
  • 10: 1 of TFA-H 2 O (4.4 mL) the reaction mixture was stirred at r.t. for 1 h, then separated the organic phase by adding H 2 O into the above reaction, the exceed TFA was neutralized with saturated aq.
  • Step 1 (4aS, 5S, 7R, 8aR) -5- (4-chloro-3- (4-ethoxybenzyl) phenyl) -2, 3-dimethoxy-2,3, 7-trimethyltetrahydro-2H-pyrano [4, 3-b] [1, 4] dioxin-8 (3H) -one (7b)
  • 7a (0.33 g, 0.65 mmol) as described above for the oxidation of 6c to 6d, with purification of the product by flash column chromatography gave 0.28 g of 7b as white syrup, yield: 85%.
  • Step 2 (2R, 4R, 5R, 6S) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -4, 5-dihydroxy-2-methyldihydro-2H-pyran-3 (4H) -one (7)
  • Treatment of 7b (0.28 g, 0.55 mmol) as described above for the deprotection of 6d to 6, with purification of the product from flash column chromatography gave 0.21 g of 7 as white solid, yield 100%;
  • Step 1 (2R, 3R, 4S, 5S, 6S) -4, 5-bis (benzyloxy) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -2- (hydroxymethyl) tetrahydro-2H-pyran-3-ol
  • 4b (0.27 g, 0.40 mmol) was dissolved in a mixture of 80%HOAc and CH 2 Cl 2 (5:1, 6 mL) , which was stirred at r.t. overnight. Concentrated the solvent and dissolved in EtOAc (10 mL) , washed with saturated aq. NaHCO 3 (3 mL) .
  • Step 2 ( (2R, 3R, 4S, 5S, 6S) -4, 5-bis (benzyloxy) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -3-hydroxytetrahydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate
  • 8b At 0°C, to a well stirred solution of 8a (0.31 g, 0.53 mmol) in anhydrous pyridine (5 mL) was added p-toluenesulfonyl chloride (0.63 g, 3.3 mmol) . The obtained system was stirred for another 2h.
  • Step 3 (2R, 3R, 4S, 5S, 6S) -4, 5-bis (benzyloxy) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -2- (methoxymethyl) tetrahydro-2H-pyran-3-ol
  • 8c A solution of 8b (0.13 g, 0.17 mmol) in a mixture of DMF ( (2 mL) and MeOH (0.26 mL) was added NaOMe (28 mg, 0.51 mmol) , which was heated for 3 h at 85°C. Cooled to r.t.
  • Step 4 (2R, 4R, 5S, 6S) -4, 5-bis (benzyloxy) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -2-(methoxymethyl) dihydro-2H-pyran-3 (4H) -one (8d)
  • 8c 47 mg, 0.78 mmol
  • 6c oxidation 6c to 6d
  • 13 mg of 8d as colorless oil, yield: 28%.
  • Step 5 (2R, 4R, 5R, 6S) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -4, 5-dihydroxy-2-(methoxymethyl) dihydro-2H-pyran-3 (4H) -one (8) 10%Pd/C (3 mg) was added to a solution of 8d (13 mg, 0.022 mmol) in EtOAc (5 mL) . After the resulting suspension was stirred under an atmosphere of H 2 at room temperature for 2 h. the system was bubbled with N 2 , and the Pd/C was filtered off. The solution was concentrated under vacuo and purified by flash column chromatography to 3 mg of 8 as colorless oil, yield: 33%.
  • Step 1 (4aR, 6S, 7R, 8R, 8aS) -6- (3- ( (5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -2-phenylhexahydropyrano [3, 2-d] [1, 3] dioxine-7, 8-diol (11a)
  • Step 2 (4aR, 6S, 7S, 8R, 8aR) -7, 8-bis (benzyloxy) -6- (3- ( (5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -2-phenylhexahydropyrano [3, 2-d] [1, 3] dioxine (11b)
  • 11a Treatment of 11a (1.8 g, 3.38 mmol) as described above for the conversion of 4a to 4b, gave 2.29 g of 11b as white solid, yield: 95%.
  • Step 3 (2R, 3R, 4S, 5S, 6S) -4, 5-bis (benzyloxy) -6- (3- ( (5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -2- (hydroxymethyl) tetrahydro-2H-pyran-3-ol (11c)
  • 11b (1.36 g, 1.91 mmol) as described above for the deprotection of 6d to 6, gave 1.13 g of 11c as yellow oil, yield: 95%.
  • Step 4 ( (2R, 3R, 4S, 5S, 6S) -4, 5-bis (benzyloxy) -6- (3- ( (5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -3-hydroxytetrahydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (11d)
  • 11c (1.13 g, 1.81 mmol) as described above for the tosylation of 8a to 8b, gave 1.15 g of 11d as white syrup, yield: 82%.
  • Step 5 (2R, 3R, 4S, 5S, 6S) -4, 5-bis (benzyloxy) -6- (3- ( (5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -2-methyltetrahydro-2H-pyran-3-ol (11e)
  • 11d (1.15 g, 1.48 mmol) as described above for the conversion of 6a to 6b, gave 0.77 g of 11e as white solid, yield: 79%.
  • Step 6 (2R, 4R, 5S, 6S) -4, 5-bis (benzyloxy) -6- (3- ( (5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -2-methyldihydro-2H-pyran-3 (4H) -one (11f)
  • 11e (0.77 g, 1.26 mmol) as described above for the oxidation of 6c to 6d, gave 0.38 g of 11f as yellow oil, yield: 49%.
  • Step 7 (2R, 4R, 5R, 6S) -6- (3- ( (5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -4, 5-dihydroxy-2-methyldihydro-2H-pyran-3 (4H) -one (11)
  • pentamethylbenzene (0.15 g, 0.98 mmol
  • BCl 3 1.0 M in hexane; 0.52 mL, 0.52 mmol
  • Step 1 ( (2R, 3S, 4R, 5R, 6S) -6- (3- (benzo [b] thiophen-2-ylmethyl) -4-fluorophenyl) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-yl) methyl acetate (15) Treatment of as described above for the conversion of dapagliflozin to 9, ipragliflozin, 26 (510 mg, 1.26 mmol) gave 230 mg of 15 as a white solid, yield: 41%.
  • Step 2 ( (2R, 3R, 5S, 6S) -6- (3- (benzo [b] thiophen-2-ylmethyl) -4-fluorophenyl) -3, 5-dihydroxy-4-oxotetrahydro-2H-pyran-2-yl) methyl acetate (12) Treatment of 15 (80 mg, 0.18 mmol) as described above for the oxidation of dapagliflozin to 5, gave 10 mg of 12, yield: 13%.
  • Step 1 ( (2R, 3S, 4R, 5R, 6S) -6- (3- (benzo [b] thiophen-2-ylmethyl) -4-fluorophenyl) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (14a)
  • ipragliflozin, 26 1.5 g, 3.71 mmol
  • dapagliflozin to 6a gave 1.8 g of 14a, yield: 72%.
  • Step 2 (2S, 3R, 4S, 5S, 6R) -2- (3- (benzo [b] thiophen-2-ylmethyl) -4-fluorophenyl) -6-methyltetrahydro-2H-pyran-3, 4, 5-triol (14b)
  • 14a Treatment of 14a (1.3 g, 2.33 mmol) as described above for the conversion of 6a to 6b, gave 0.6 g of 14b, yield: 66%.
  • Step 3 (2S, 3S, 5R, 6R) -2- (3- (benzo [b] thiophen-2-ylmethyl) -4-fluorophenyl) -3, 5-dihydroxy-6-methyldihydro-2H-pyran-4 (3H) -one (14)
  • 14b (0.15 g, 0.39 mmol) as described above for the oxidation of dapagliflozin to 5, gave 40 mg of 14, yield: 27%.
  • 16a was prepared using a method publicated in US 2011/0171159, treatment of 16a (0.45 g, 1.07 mmol) as described above for the oxidation of dapagliflozin to 5, gave 0.22 g of 16 as a light yellow solid, yield: 49%.
  • Step 1 (2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -6- (4-methoxyphenoxy) tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (19a)
  • a cold (0°C) solution of 1, 2, 3, 4, 6-penta-O-acetyl- ⁇ -D-glucopyranose (50.0 g, 128 mmol) and 4-methoxyphenol (19.1 g, 154 mmol) in dry CH 2 Cl 2 (400 mL) was added BF 3 ⁇ Et 2 O (17.7 mL, 141 mmol) under Ar.
  • Step 2 (2R, 3S, 4S, 5R, 6S) -2- (hydroxymethyl) -6- (4-methoxyphenoxy) tetrahydro-2H-pyran-3, 4, 5-triol (19b)
  • a solution of 19a (20.0 g, 44 mmol) in MeOH (200 mL) was added a solution of NaOMe in MeOH (1M, 17.6 mL, 17.6 mmol) .
  • the reaction mixture was stirred for 2 h, then neutralised by addition of Dowex 50wx8 (100-200, H + ) .
  • Step 3 ( (2R, 3R, 4R, 5R, 6S) -4-acetoxy-3, 5-dihydroxy-6- (4-
  • Step 4 (2R, 3S, 4R, 5R, 6S) -2- (hydroxymethyl) -6- (4-methoxyphenoxy) tetrahydro-2H-pyran-3, 4, 5-triol (19d)
  • MeOH a solution of dark red oil obtained in the last step in MeOH (200 mL)
  • NaOMe NaOMe in MeOH (1M, 30 mL, 30 mmol mmol)
  • the reaction mixture was stirred for 2 h, then neutralised by addition of Dowex 50wx8 (100-200, H + ) .
  • Step 5 (2R, 3R, 4R, 5R, 6S) -3, 4, 5-tris (benzyloxy) -2- (benzyloxymethyl) -6- (4-methoxyphenoxy) tetrahydro-2H-pyran (19e) NaH (6.3 g, 157.2 mmol) was added to a solution of compound 19d (10.0 g, 34.9 mmol) in dry DMF (150 mL) at 0°C. After stirring for 30 min, a solution of benzyl bromide (20.7 mL, 174.6 mmol) in dry DMF (50 mL) was added dropwise at 0°C.
  • Step 6 (3R, 4R, 5R) -3, 4, 5-tris (benzyloxy) -6- (benzyloxymethyl) tetrahydro-2H-pyran-2-ol (19f)
  • a solution of CAN 28.8 g, 52.4 mmol
  • H 2 O 105 mL
  • the reaction mixture was stirred at -15°Cfor 2 h and then partitioned between DCM (400 mL) and H 2 O (50 mL) .
  • the aqueous layer was extracted with DCM (200 mL) .
  • Step 7 (3R, 4R, 5R, 6R) -3, 4, 5-tris (benzyloxy) -6- (benzyloxymethyl) tetrahydro-2H-pyran-2-one (19g)
  • Acetic anhydride (26.6 mL, 280 mmol) was added to a solution of compound 19f (9.0 g, 16.7 mmol) in anhydrous DMSO (40 mL) at 30°C.
  • the reaction mixture was stirred overnight at 30°C.
  • the reaction mixture was poured into ice-water (50 mL) , extracted with DCM (3 ⁇ 100 mL) .
  • Step 8 (3R, 4R, 5R) -3, 4, 5-tris (benzyloxy) -6- (benzyloxymethyl) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-2-ol (19h)
  • a solution of (4-chloro-3- (4-ethoxybenzyl) phenyl) magnesium bromide in anhydrous THF (10 mL) was prepared freshly from 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene (486 mg, 1.5 mmol) and magnesium (54 mg, 2.25 mmol) .
  • Step 9 (2R, 3R, 4S, 5S, 6S) -3, 4, 5-tris (benzyloxy) -2- (benzyloxymethyl) -6- (4-chloro-3-(4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran (19i)
  • Et 3 SiH (0.06 mL, 0.38 mmol
  • BF 3 ⁇ Et 2 O (0.03 mL, 0.21 mol
  • Step 10 (2S, 3R, 4S, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (19)
  • compound 19i 103 mg, 0.13 mmol
  • EtOAc 5 mL
  • Pd/C 10 wt%
  • Step 11 (2S, 3S, 5R, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -3, 5-dihydroxy-6-(hydroxymethyl) dihydro-2H-pyran-4 (3H) -one (5)
  • Compound 19 14 mg, 0.034 mmol
  • catalyst A B, or C
  • LC-MS showed the reaction to be completed.
  • Step 1 (2R, 3S, 4S, 5R, 6S) -2- ( ( (tert-Butyldimethylsilyl) oxy) methyl) -6- (4-methoxyphenoxy) tetrahydro-2H-pyran-3, 4, 5-triol (5a)
  • imidazole (1.96 g, 28.8 mmol) in DMF (30 mL)
  • TBSCl (2.37 g, 15.7 mmol) in DMF (5 mL) dropwise at 0°Cunder a nitrogen atmosphere.
  • Step 2 tert-Butyldimethyl ( ( (2R, 3R, 4S, 5R, 6S) -3, 4, 5-tris (benzyloxy) -6- (4-methoxyphenoxy) tetrahydro-2H-pyran-2-yl) methoxy) silane (5b)
  • compound 5a 4.4 g, 11 mmol
  • DMF 40 mL
  • NaH 60%, 1.76 g, 44 mmol
  • BnBr (5.19 mL, 44 mmol) was added dropwise and the reaction was stirred at room temperature overnight.
  • Step 3 (2R, 3R, 4S, 5R, 6R) -3, 4, 5-tris (Benzyloxy) -6- (hydroxymethyl) tetrahydro-2H-pyran-2-ol (5c)
  • a solution of CAN (14.6 g, 26.6 mmol) in H 2 O (15 mL) was added dropwise at 0°C.
  • the reaction mixture was stirred at room temperature for 4 hrs and then partitioned between DCM (100 mL) and H 2 O (30 mL) .
  • the aqueous layer was extracted with DCM (500 mL) .
  • Step 4 (2R, 3R, 4S, 5R, 6R) -3, 4, 5-tris (Benzyloxy) -6- ( (tert-butyldimethylsilyloxy) methyl) tetrahydro-2H-pyran-2-ol (5d)
  • imidazole 618 mg, 9.08 mmol
  • TBSCl 746 mg, 4.95 mmol
  • DMF 5 mL
  • Step 5 (3R, 4S, 5R, 6R) -3, 4, 5-tris (Benzyloxy) -6- ( (tert-butyldimethylsilyloxy) methyl) tetrahydro-2H-pyran-2-one (5e)
  • Oxalic chloride (0.27 mL, 3.19 mmol) in anhydrous DCM (5 mL) was added to a solution of DMSO (0.46 mL, 6.39 mmol) in anhydrous DCM (10 mL) at -65°Cunder nitrogen atmosphere. After stirring for 30 min at that temperature, a solution of compound 5d (1.5 g, 2.66 mmol) in anhydrous DCM (15 mL) was added at -65°C.
  • Step 7 tert-Butyldimethyl ( ( (2R, 3R, 4R, 5S, 6S) -3, 4, 5-tris (benzyloxy) -6- (4-chloro-3-(4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-2-yl) methoxy) silane (5g)
  • Et 3 SiH 0.3 mL, 1.88 mmol
  • BF 3 ⁇ Et 2 O (0.14 mL, 1.13 mmol
  • Step 8 (2R, 3S, 4R, 5R, 6S) -2- ( (tert-butyldimethylsilyloxy) methyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triol (5h)
  • Step 9 (2S, 3S, 5R, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -3, 5-dihydroxy-6-(hydroxymethyl) dihydro-2H-pyran-4 (3H) -one (5)
  • Compound 5h (186 mg, 0.356 mmol) was dissolved in acetonitrile/water (12 mL, 10:1) .
  • catalyst A (B, or C) (19 mg, 5 mol%) was added, and the mixture was stirred at room temperature for 2 days.
  • LC-MS showed the reaction to be completed.
  • CHO Chinese Hamster Ovary (CHO) Cells expressing hSGLT1, hSGLT2 were maintained in Ham's F-12 Nutrient Mixture supplemented with 500 ⁇ g/ml hygromycin and 10%FBS using standard cell culture techniques. The cells were plated in tissue culture treated 96-well Isoplate and cultured for 24 hours at 37°C.
  • the sodium-dependent glucose transport assay was initiated by adding 10uCi/ml [ 14 C] -AMG in KRH-Na + buffer or KRH-NMG buffer and inhibitors or DMSO vehicle. The assay plates were incubated for 1 h at 37°C. [14C] -AMG-uptake was stopped by adding 100 ⁇ L of ice-cold stop buffer (KRH-Na + buffer plus 0.5 mM phlorizin) . The cells were washed five times with stop buffer and then lysed with 20ul/well ice-cold buffer (100mM NaOH) .
  • Microscint 40 80 ⁇ l/well Microscint 40 was added and the microtiter plate was counted in a MicroBeta Trilux (PerkinElmer) . Dapagliflozin was evaluated in parallel in every assay. A dose-response curve was fitted to an empirical four-parameter model using XL Fit (IDBS, Guilford, U.K. ) to determine the inhibitor concentration at half-maximal response (IC 50 ) .
  • Test Compound hSGLT2 (IC 50 ) hSGLT1 (IC 50 ) 1 1-1000 nM N 2 1-1000 nM N 3 1-1000 nM N 4 1-100 nM >1 ⁇ M 5 1-100 nM >1 ⁇ M 6 1-1000 nM > 5 uM 7 1-100 nM >1 ⁇ M 8 1-1000 nM > 5 uM 9 1-100 nM >1 ⁇ M 10 1-100 nM 0-1 ⁇ M 11 1-100 nM 0-1 ⁇ M 12 1-1000 nM N 13 1-100 nM >1 ⁇ M 14 1-1000 nM N 15 1-100 nM N 16 1-100 nM >1 ⁇ M
  • Examples 5, 13 and 16 were tested in normal rats to assess the control of blood glucose increase in Glucose Tolerance test (OGTT) and/or inhibition of glucose re-absorption via urinary glucose excretion.
  • OGTT Glucose Tolerance test
  • Dosing solutions were 0.2 mg/ml, 0.6 mg/ml, 2 mg/ml and 6 mg/ml for the 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg doses respectively.
  • Dosing volumes was 5 ml/kg of body weight of all doses.
  • One group received vehicle three groups received 3 mg/kg, 10 mg/kg or 30 mg/kg dose of Example 5, three groups received 3 mg/kg, 10 mg/kg or 30 mg/kg dose of Example 13, and others received 1 mg/kg, 3 mg/kg or 10 mg/kg dose of Example 16.
  • the vehicle was 5%1-methyl-2-pyrrolidinone, 20%polyethylene glycol, and 20 mmol/L sodium diphosphate.
  • rats were dosed orally with 40%aqueous glucose solution (2 g/kg) . Blood glucose concentration was measured before compound dosing, before the glucose challenge, 15 min, 30 min, 60 min and 120 min post-glucose challenge. Blood glucose was measured using a glucometer (One touch, LifeScan Inc.
  • the total AUC of blood glucose was calculated to assess the glucose control efficacy of compounds and the results are shown in Table 2.
  • Male Sprague Dawley rats ( ⁇ 300 g) were singly housed in metabolic cages for urine collection. Compounds (Example 5) and glucose were dosed as the same as described above. And urine was collected from 0 to 6-h and 6 to 24-h post-glucose challenge.
  • Urine glucose concentration was determined using the Glucose (GO) Assay Kit (Sigma GAGO-20) by measuring absorbance at 540 nm using the plate reader Enspire (PerkinElmer, Inc. ) . The urine volume was recorded and normalized to body weight using the formula below:
  • Normalized urine volume Urine volume (ml) ⁇ 200/rat body weight (g) .
  • the total amount of urinary glucose excretion (UGE) was calculated as the product of urine glucose concentration and urine volume using the formula below:
  • UGE (mg) /200 g body weight urinary glucose concentration (mg/dl) ⁇ urine volume (dl) ⁇ 200/rat body weight (g) .
  • Amounts of UGE were obtained from rats for Example 5 by the method described above and are shown in Table 3.
  • Examples 5 and 16 were tested in ZDF rat to assess the control of blood glucose increase in diabetic animals and/or inhibition of glucose re-absorption via UGE.
  • Urine glucose and urine volume data were normalized per 400 g body weight using the formula similar as described above for SD rat studies, and the results are shown in Figure 2.
  • Ad-lib fed blood glucose was measured at the beginning and the end of the experiments, and the results are shown in Table 4.
  • Examples 5, 7, 10, 13, 16, 18 was tested in rats to assess pharmacokinetic parameters including maximum concentration (C max ) , area under the plasma concentration time curve (AUC) , clearance (CL) , steady state volume of distribution (V ss ) , half life (t 1/2 ) , and bioavailability (F) .
  • C max maximum concentration
  • AUC area under the plasma concentration time curve
  • CL clearance
  • V ss steady state volume of distribution
  • t 1/2 half life
  • F bioavailability
  • Male Sprague-Dawley rats ( ⁇ 250 g) were used. Rats received the compound by intravenous (IV) or oral gavage (PO) administration and the doses tested including vehicle to formulate dosing solutions are listed in Table 8.
  • 0.2 ml blood was sampled through eye puncture at various timepoints (Table 8) .
  • Fifty microl aliquots of plasma samples and standards were subjected to protein precipitation with acetonitrile containing an internal standard. Samples were vortexed and centrifuged to obtain supernatant which was analyzed by LC-MS/MS. Analyst (Version 2.6.0) was used to measure peak areas and peak area ratios of analytes to internal standard were calculated.
  • LC-MS/MS conditions are as follows: Mass Spectrometer + Source Type was Thermo TSQ Quantum Discovery Max; HPLC was Finnigan surveyor MS pump; Autosamples was Finnigan surveyor Autosamples; Injection volume was 10.0 microl; A gradient was used with mobile phase A: 5mM ammonium acetate in water; B: Acetonitrile; Flow rate 0.300 ml per minute (Column 3.0 x 30 mm 2.6 micro Kinetex C18 column (phenomenex) . Detection mode was negative.
  • a calibration curve was constructed from the peak area ratios of standards to the internal standard by applying a weighted linear (1/x2 ) regression.
  • the dynamic range of the standard curve was 20.00 ng/ml to 5000 ng/ml.
  • Phamacokinetic parameters were determined from individual animal data using non-compartmental analysis in phoenix 64 (winNonlin 6.3) . Concentrations below the limit of quantification (BLOQ) were recorded as 0 ng/ml for use in calculations.
  • AUC inf AUC last plus extrapolated area determined by dividing plasma concentration at last time by the slope of the terminal log-linear phase
  • V ss CL x MRT
  • F% AUC inf PO per dose /AUC inf IV per dose
  • MRT AUMC (AUC inf ) /AUC inf

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Abstract

La présente invention concerne des composés d'inhibiteurs de SGLT-2, des sels, des hydrures et des stéréoisomères pharmaceutiquement acceptables de ceux-ci. Les composés sont utilisés dans des compositions pharmaceutiques et des procédés de fabrication et d'utilisation, notamment le traitement d'une personne qui en a besoin avec une quantité efficace du composé ou de la composition, et la détection d'une amélioration obtenue de la santé ou de l'état de la personne.
PCT/CN2015/089492 2014-09-15 2015-09-14 Inhibiteurs de sglt-2 Ceased WO2016041470A1 (fr)

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CN104761523A (zh) * 2014-01-06 2015-07-08 天津药物研究院 含3-氧代葡萄糖结构的苯基c-葡萄糖苷衍生物、其制备方法和用途
WO2016128995A1 (fr) * 2015-02-09 2016-08-18 Indoco Remedies Limited Procédé de préparation de composés inhibiteurs de sglt
WO2018155970A1 (fr) * 2017-02-24 2018-08-30 동아에스티 주식회사 Nouveau dérivé de glucose en tant qu'inhibiteur de sglt-2
KR20180098173A (ko) * 2017-02-24 2018-09-03 동아에스티 주식회사 Sglt-2 억제제인 신규 글루코스 유도체
WO2019215633A1 (fr) * 2018-05-09 2019-11-14 Janssen Pharmaceutica Nv Dérivés de 5,5-difluoro-et 5-fluoro-5-méthyl-c-glycoside utiles en tant que modulateurs duglt1/sglt2
WO2020040433A1 (fr) * 2018-08-22 2020-02-27 동아에스티 주식회사 Procédé de préparation d'un inhibiteur de sglt-2, précurseur de dapagliflozine
US10696662B2 (en) * 2017-08-21 2020-06-30 Janssen Pharmaceutica Nv 5-fluoro-C-(aryl or heterocyclyl)-glycoside derivatives useful as dual SGLT1 / SGLT2 modulators

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EP3883918B1 (fr) * 2018-11-20 2023-07-19 Sironax Ltd Inhibiteurs de rip1
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CN104761523A (zh) * 2014-01-06 2015-07-08 天津药物研究院 含3-氧代葡萄糖结构的苯基c-葡萄糖苷衍生物、其制备方法和用途
WO2016128995A1 (fr) * 2015-02-09 2016-08-18 Indoco Remedies Limited Procédé de préparation de composés inhibiteurs de sglt
US10508128B2 (en) 2015-02-09 2019-12-17 Indoco Remedies Limited Process for the preparation of SGLT inhibitor compounds
WO2018155970A1 (fr) * 2017-02-24 2018-08-30 동아에스티 주식회사 Nouveau dérivé de glucose en tant qu'inhibiteur de sglt-2
KR20180098173A (ko) * 2017-02-24 2018-09-03 동아에스티 주식회사 Sglt-2 억제제인 신규 글루코스 유도체
KR101954188B1 (ko) * 2017-02-24 2019-05-23 동아에스티주식회사 Sglt-2 억제제인 신규 글루코스 유도체
JP2020514327A (ja) * 2017-02-24 2020-05-21 ドン−ア エスティ カンパニー リミテッド Ｓｇｌｔ−２阻害剤である新規グルコース誘導体
JP7160821B2 (ja) 2017-02-24 2022-10-25 ドン－ア エスティ カンパニー リミテッド Ｓｇｌｔ－２阻害剤である新規グルコース誘導体
US10696662B2 (en) * 2017-08-21 2020-06-30 Janssen Pharmaceutica Nv 5-fluoro-C-(aryl or heterocyclyl)-glycoside derivatives useful as dual SGLT1 / SGLT2 modulators
WO2019215633A1 (fr) * 2018-05-09 2019-11-14 Janssen Pharmaceutica Nv Dérivés de 5,5-difluoro-et 5-fluoro-5-méthyl-c-glycoside utiles en tant que modulateurs duglt1/sglt2
WO2020040433A1 (fr) * 2018-08-22 2020-02-27 동아에스티 주식회사 Procédé de préparation d'un inhibiteur de sglt-2, précurseur de dapagliflozine

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