WO2010046926A2 - Novel stilbene analogs - Google Patents

Novel stilbene analogs Download PDF

Info

Publication number
WO2010046926A2
WO2010046926A2 PCT/IN2009/000580 IN2009000580W WO2010046926A2 WO 2010046926 A2 WO2010046926 A2 WO 2010046926A2 IN 2009000580 W IN2009000580 W IN 2009000580W WO 2010046926 A2 WO2010046926 A2 WO 2010046926A2
Authority
WO
WIPO (PCT)
Prior art keywords
ethenyl
dimethoxyphenyl
phenyl
mol
alkyl
Prior art date
Application number
PCT/IN2009/000580
Other languages
French (fr)
Other versions
WO2010046926A3 (en
Inventor
Venkata Subbaraju Gottumukkala
Rama Mohan Hindupur
Mahesh Masna
Original Assignee
Aptuit Laurus Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aptuit Laurus Pvt Ltd filed Critical Aptuit Laurus Pvt Ltd
Publication of WO2010046926A2 publication Critical patent/WO2010046926A2/en
Publication of WO2010046926A3 publication Critical patent/WO2010046926A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • C07C39/215—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring containing, e.g. diethylstilbestrol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C305/00—Esters of sulfuric acids
    • C07C305/22—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings
    • C07C305/24—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers

Definitions

  • the present invention relates to novel stilbene derivatives and their pharmaceutically acceptable salts thereof. Furthermore, the purpose of this invention is also to provide a process for the preparation of said novel derivatives.
  • Resveratrol trans-3, 5, 4'- Trihydroxy stilbene
  • a compound found largely in the skins of red grapes has been shown to have chemo preventive activity against cardiovascular disease and a variety of cancers, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans.
  • Pterostilbene (trans-3, 5-dimethoxy-4-hydroxystilbene), is a dimethylated analogue of resveratrol, a stilbene shown to have anti-cancer activity across many cell lines and it is a naturally occurring stilbene found in deer berry and rabbit eye blueberries, several varieties of grapes, and in the tree species Pterocarpusmarsupium and Guibourtia tessmanii. In addition, pterostilbene has also been demonstrated to have anti-diabetic and anti-oxidant properties.
  • the resveratrol as well as pterostilbene have less absorption due to low water solubility and bioavailability. Due to less bioavailability and low solubility of the drugs mentioned, the fraction of an administered dose of unchanged drug that reaches the systemic circulation is less. It is particularly due to incomplete absorption and first-pass metabolism.
  • Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.
  • the two major hurdles including low water solubility found with the known compounds need to be resolved.
  • these novel derivatives have been made.
  • the said novel compounds have proven their value as active ingredients since they act as anti- tumor substances and been shown to have advantageous properties such as high water solubility and bioavailability that must be required in order to determine that the compounds are pharmacokinetically acceptable.
  • Stilbene derivatives according to the present invention correspond to the general formula I
  • R 1 , R 2 which may be the same or different each represent -OR 7 , in which R 7 is hydrogen, an alkyl group having 1 to 3 carbon atoms; R represents hydrogen, -OR , in which R is an alkyl group having 1 to 3 carbon atoms- or tetrahydropyranyl; R 3 is a halogen atom, an alkyl group having 1 to 3 carbon atoms with proviso that when R 4 , R 5 are solely hydrogen; R 4 represents nitro, mono alkyl amino, carbamic acid alkyl ester group, alkyl or aryl amido, aryl amino, diphenyl amino, diaryl amino, alkyl sulphanamino, phenyl or aryl sulphanamino, sulphamic acid group or its sodium salt, alkyl or aryl carbamic acid group, morpholino, N-alkyl substituted or unsubstituted piperzinyl; R 4 further represents hydroxy with pro
  • an alkyl group having 1 to 3 carbon atoms means methyl, ethyl and propyl;
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom;
  • N-alkyl means N-methyl, N-ethyl;
  • alkoxy means methoxy, ethoxy and propoxy; a suitable value for the substituent when it is (2-4C) alkanoyl is, for example, acetyl, propionyl and butyryl;
  • R 1 , R 2 are preferably methoxy groups or hydroxyl groups.
  • a suitable pharmaceutically acceptable salt of general formula I of the invention is, for example, an acid-addition salt with, for example, inorganic acid or organic .acid, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric and the like.
  • inorganic acid or organic .acid for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric and the like.
  • the salts derived from inorganic bases include sodium, potassium, lithium, ammonium and the like.
  • the specific preferred compounds of the invention are the following stilbene derivatives, which correspond to general formula I, or a pharmaceutically acceptable salt thereof.
  • aromatic aldehyde (V) is condensed with phopshonate ester (IV) in a suitable solvent such as terahydrofuran (THF) in presence of suitable bases for forming the ylide.
  • a suitable solvent such as terahydrofuran (THF)
  • suitable bases for forming the ylide.
  • Butyl lithium (BuLi), sodium hydride (NaH) and sodium methoxide (NaOMe) are identified as suitable bases.
  • NaH in THF at optimized conditions affords the acceptable yield of single (E)-stilbene analog (I) as compared to the other bases.
  • the resulting phosphate byproduct is readily separated by simply washing with water leaving the desired selective trans isomer.
  • the methyl ester compounds (III) are prepared in good yield using methylating agents such as dimethyl sulphate, dimethyl carbonate and the like.
  • methylating agents such as dimethyl sulphate, dimethyl carbonate and the like.
  • DMC dimethyl carbonate
  • Preparation of methyl ester from substituted carboxylic acids is carried out efficiently with dimethyl carbonate (DMC) which can be accelerated by using sulphuric acid as catalyst.
  • the methyl ester thus obtained now is subjected to reduction in order to obtain corresponding alcohol compound.
  • the reducing agents used for this purpose are sodium borohydride or lithium aluminum hydride or the like, preferably in ether solvents.
  • the primary alcohol can optionally be isolated or it can be used without being isolated for further reaction.
  • the substituted benzyl alcohol is now halogenated in a suitable solvents for example toluene or dichloromethane, in presence of halogenating agents such as thionyl chloride or Phosphorus tribromide leads to the formation of substituted benzyl halide.
  • halogenating agents such as thionyl chloride or Phosphorus tribromide
  • the phosphonate esters (IV), which serve as key precursors for Wittig-Horner reaction, are prepared from the reaction between triethyl phosphite P(OEt) 3 and v foregoing substituted benzyl halide in presence of suitable solvents for example dioxane, THF or toluene.
  • suitable solvents for example dioxane, THF or toluene.
  • Reagents and conditions (a) dimethyl carbonate, catalytic amount of H 2 SO 4 , reflux, 6hr. (b) NaBH/THF, MeOH, reflux, 3hr.(c) PBr 3 , toluene, room temperature, 1 hr. (d) triphenyl phosphate, toluene, reflux , 3 hr.(e) NaH 1 THF
  • Example-1 Preparation of 1, 3-dimethoxy-5-[(£)-2-(3-methyIphenyl)-l-ethe ⁇ yl] benzene
  • Example-4 Preparation of 2-4-[(2s)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2,6-diinethoxy phenoxy tetrahydro-2H-pyran a) T ⁇ P protection of 4-hydroxy-3, 5-dimethoxybenzaldehyde (Syringaldehyde): To a solution of 4-hydroxy-3, 5-dimethoxybenzaldehyde (10 g, 0.055 mol, 1 eq) in DCM (100 mL) was added D ⁇ P (6.9 g, 0.082 mol, 1.5 eq) and PPTS (1.3 g, 0.005 mol, 0.1 eq) at room temperature and stirring continued for overnight at room temperature.
  • Finely powdered potassium carbonate (18.1 g, 0.131 mol, 2 eq) was added to a well stirred solution of 3-chloro-4-hydroxybenzaldehyde (10 g, 0.064 mol, 1 eq) in acetone (80 mL) under nitrogen. After 10 min., dimethylsulphate (8 g, 0.064 mol, 1 eq) was added slowly at room temperature and stirred for 30 min. The reaction mixture was allowed to reflux for 2h. Reaction progress was monitored by TLC, Reaction mixture cooled to room temperature and K 2 CO 3 was filtered, acetone was distilled out in vacuo to obtain residue and was triturated with hexane (20 mL) at O 0 C for 30 min. to result pale green colored solid. Yield 9.2 g (85%).
  • Example-9 Preparation of iV-(2-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyI] phenoxyethyl)- ⁇ yV-dimethylamine
  • Example-13 Preparation of 4- ⁇ (.E)-2-(3,5-diinethoxyphenyl)-l-ethenyI]phenyI hydrogen sulfate
  • Ser-BOC-OH-THP-pterostilbene (compound obtained from step-c) (10 g, 0.017 mol, 1 eq) was dissolved in ethyl acetate and cooled to 0° C. The HCl in isopropyl alcohol was added dropwise to the reaction mass and maintained at rt for 3 h. Precipitated compound was filtered and washed with ethyl acetate to get pure title compound. Yield: 4.2 g, 60 %.
  • Zinc dust (10.2 g, 0.140 mol, 4 eq) was added slowly at 0° C and allowed to warm to rt for 30 min in stirring. The reaction mass was refluxed for 1 h. Acetic acid was distilled in vacuo and residue was diluted with water. Compound extracted with ethyl acetate, washed with water and brine. Removal of solvent gave residue which was purified by silica-gel column chromatography (ethyacetate/hexane-1 :3 as eluent) to obtain pure title product. Yield 2.7 g (30%).
  • Example-28 Preparation of N-4-[(E)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyWV- methylamine hydrochloride a) Methylation of tert-butyl iV-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl] phenyl carbamate
  • Example-35 Preparation of 4-4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl morpholine hydro chloride
  • Example-36 Preparation of l-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-4-methyl piperazine dihydrochloride
  • the said compounds are 5-[(£)-2-(4-morpholinophenyl)-l-ethenyl]-l, 3-benzenediol; 5- [(E)-2-(4-morpholinophenyl)-l-ethenyl]-l, 3-benzenediol hydrochloride; 5- ⁇ ( ⁇ )-2-[4-(4- Methyl-piperzin-l-yl)-phenyl]-vinyl ⁇ -benzene-l,3-diol;5- ⁇ (E)-2-[4-(4-Methyl-piperzin-l -yl) -phenyl] -vinyl ⁇ -benzene-1, 3-diol dihydrochloride;

Abstract

The present invention relates to Stilbene derivatives of the general formula I or a pharmaceutically acceptable salt thereof have properties such as high water solubility, bioavailability and effective as carcinostatics.

Description

"Novel Stilbene Analogs"
Field of the invention:
The present invention relates to novel stilbene derivatives and their pharmaceutically acceptable salts thereof. Furthermore, the purpose of this invention is also to provide a process for the preparation of said novel derivatives.
Back ground of the invention
Various analogs of stilbene as core moiety are mentioned in WO 01/21165 Al, US 5,525,632 as anti-tumor substances. The substance, the synthesis, the use and the advantages of 3, 5, 3', 4', 5 '-substituted and related analogs of the present invention, are not disclosed in the art. The present inventors have already accomplished the 4'-O- tetrahydropyranyl stilbene derivatives and mentioned in their co pending Indian application numbered 1766/CHE/2008.
Resveratrol (trans-3, 5, 4'- Trihydroxy stilbene), a compound found largely in the skins of red grapes, has been shown to have chemo preventive activity against cardiovascular disease and a variety of cancers, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans.
Pterostilbene (trans-3, 5-dimethoxy-4-hydroxystilbene), is a dimethylated analogue of resveratrol, a stilbene shown to have anti-cancer activity across many cell lines and it is a naturally occurring stilbene found in deer berry and rabbit eye blueberries, several varieties of grapes, and in the tree species Pterocarpusmarsupium and Guibourtia tessmanii. In addition, pterostilbene has also been demonstrated to have anti-diabetic and anti-oxidant properties. Hypoglycemic activity of a naturally occurring pterostilbene, trans-l-(3,5-dimethoxyphenyl)-2-(4-hydroxy phenyl ) -ethylene, isolated from the heartwood of pterocarpus marsupium has been reported by Manickam et al., J. Nat. Prod.,
1997, 60:609-610.
H. Yang et al performed in vitro screens for stilbenes that could modulate human SIRTl and Howitz et al examined structure-activity relationship of SIRTl activation by stilbenes. Resveratrol derivatives such as 4' hydroxyl is replaced with thiomethyl group
(3,5-dihydroxy-4'-thiomethyl-trα»5-stilbene), methyl (3,5-dihydroxy-4'-methyl-/rα«5- stilbene) and ethyl (3, 5-dihydroxy-4'-ethyl-frww-stilbene) have been disclosed by H.
Yang et al. Methoxy group at 4' position (3, 5-dihydroxy-4'-methoxy-trαw-stilbene) , showing similar resveratrol activity, but the derivative 3, 5-dihydroxy-4'-acetoxy-trø/7.ϊ- stilbene is the least potent due to the presence of an ester group, which is relatively large volume at the 4'- position.
It is evident by the art that the resveratrol as well as pterostilbene have less absorption due to low water solubility and bioavailability. Due to less bioavailability and low solubility of the drugs mentioned, the fraction of an administered dose of unchanged drug that reaches the systemic circulation is less. It is particularly due to incomplete absorption and first-pass metabolism.
Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. The two major hurdles including low water solubility found with the known compounds need to be resolved. As an alternative, these novel derivatives have been made. The said novel compounds have proven their value as active ingredients since they act as anti- tumor substances and been shown to have advantageous properties such as high water solubility and bioavailability that must be required in order to determine that the compounds are pharmacokinetically acceptable.
Summary of the invention
The Stilbene derivatives according to the present invention correspond to the general formula I
Figure imgf000003_0001
Wherein
R1, R2 which may be the same or different each represent -OR7, in which R7 is hydrogen, an alkyl group having 1 to 3 carbon atoms; R represents hydrogen, -OR , in which R is an alkyl group having 1 to 3 carbon atoms- or tetrahydropyranyl; R3 is a halogen atom, an alkyl group having 1 to 3 carbon atoms with proviso that when R4, R5 are solely hydrogen; R4 represents nitro, mono alkyl amino, carbamic acid alkyl ester group, alkyl or aryl amido, aryl amino, diphenyl amino, diaryl amino, alkyl sulphanamino, phenyl or aryl sulphanamino, sulphamic acid group or its sodium salt, alkyl or aryl carbamic acid group, morpholino, N-alkyl substituted or unsubstituted piperzinyl; R4 further represents hydroxy with proviso that R5 is exclusively halogen; R4 further represents amino, dialkyl amino , only when R1 , R2 are hydroxy; R4 further represents hydrogen with proviso that R5 is not hydrogen, alkoxy and R4 further represents halogen with proviso that when R6 is solely a halogen atom; R4 further represents -OR9 in which R9 represents tetrahydropyranyl with proviso that R3 is not hydrogen; Furthermore R9 represents an alkyl group having 1 to 3 carbon atoms, (2-4C) alkanoyl when R5 is exclusively a halogen atom; R9 further represents alkyl morphonyl, alkyldiamino, vinyl, allyl, suphonyl and its corresponding sulphonate salts, phenyl sulphonyl, aryl sulphonyl, suphonic acid group, amino acid group, alkoxy carbonyl amino acid group, alkanoic acid group, alkanoic acid alkyl ester group and its corresponding alkali metal salts; R represents hydrogen, a halogen atom , alkoxy; R6 represents hydrogen;
Detailed description of the invention
In formula (I), the term "an alkyl group having 1 to 3 carbon atoms" means methyl, ethyl and propyl; the term "a halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; the term " N-alkyl" means N-methyl, N-ethyl; the term " alkoxy" means methoxy, ethoxy and propoxy; a suitable value for the substituent when it is (2-4C) alkanoyl is, for example, acetyl, propionyl and butyryl;
The preferred compounds of the present invention wherein, R1, R2 are preferably methoxy groups or hydroxyl groups.
A suitable pharmaceutically acceptable salt of general formula I of the invention is, for example, an acid-addition salt with, for example, inorganic acid or organic .acid, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric and the like. When the compound of the present invention is acidic, then the salts derived from inorganic bases include sodium, potassium, lithium, ammonium and the like.
The specific preferred compounds of the invention are the following stilbene derivatives, which correspond to general formula I, or a pharmaceutically acceptable salt thereof.
2-[5-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2-(tetrahydro-2H-2-pyranyloxy)phenoxy] tetrahydro-2H-pyran;
2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2-methoxyphenoxytetrahydro-2H-pyran;
2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2,5-dimethoxyphenoxytetrahydro-2H- pyran;
4-(2-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyethyl)morpholine;
N-(2-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyethyl)-iV,iV-dimethylamine; N-(2-4-[(E)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]phenoxyethyl)-N,N-dimethylaniine;
l-(£)-2-[4-(allyloxy) phenyl]-l-ethenyl-3,5-dimethoxybenzene;
4-[(£)-2-(3,5-dimethoxyphenyl)- 1 -ethenyl]phenyl methanesulfonate;
4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl]phenyl 1-benzenesulfonate;
4-[(£)-2-(3 ,5 -dimethoxyphenyl)- 1 -ethenyl]phenyl 4-methyl- 1 -benzenesulfonate;
4-[(ϋT)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]phenyl hydrogen sulfate;
4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-aminoacetatehydrochloride;
4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-aminopropanoatehydrochloride;
4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-[(tert-butoxycarbonyl)amino] propanoate;
4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-amino-3-hydroxypropanoate hydrochloride;
2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyacetic acid;
Ethyl 2-4-[(£)-2-(3 ,5 -dimethoxyphenyl)- 1 -ethenyljphenoxyacetate;
5-(E)-2-[4-(2-morpholinoethoxy)phenyl]- 1 -ethenyl- 1 ,3-benzenediol;
5-((£)-2-4- [2-(dimethylamino)ethoxy]phenyl- 1 -ethenyl)- 1 ,3-benzenediol;
l,3-dimethoxy-5-[(E)-2-(4-nitrophenyl)-l-ethenyl]benzene;
N-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-iV-methylaminehydrochloride;
tert-Butyl iV-4-[(E)-2-(3,5-dimethoxyphenyl)- 1 -ethenyl] phenylcarbamate;
M -4-[(£)-2-(3 ,5 -dimethoxyphenyl)- 1 -ethenyljphenylacetamide;
Nl -4-[(E)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]phenylbenzamide; Λr-benzyl-N-4- [(E)-2-(3 ,5 -dimethoxyphenyl)- 1 -ethenyl] phenylamine N, N-dibenzyl-N-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylamine; N-4-[(£)-2-(3,5-dimethoxyphenyl)- 1 -ethenyl]phenylmethanesulfonamide; N-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylsulfamic acid;
M-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-l-benzenesulfonamide;
Benzyl N-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylcarbamate;
4-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylmorpholine; 1 -4-[(E)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]phenyl-4-methylpiperazine; l-[(£)-2-(3-bromophenyl)-l-ethenyl]-3,5-dimethoxybenzene;
5-(E)-2-[4-(dimethylamino)phenyl]- 1 -ethenyl- 1 ,3 -benzenediol;
5-[(£)-2-(4-morpholinophenyl)- 1 -ethenyl]- 1 ,3 -benzenediol;
5-{(E)-2-[4-(4-Methyl-piperzin-l -yl) -phenyl]-vinyl}-benzene-l,3-diol; 5 - [(£)-2-(4-aminophenyl)- 1 -ethenyl] - 1 ,3 -benzenediol ;
2-chloro-4-[(£)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]- 1 -methoxybenzene;
2-chloro-l-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-4-fluorobenzene;
2-chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenol;
2-chloro-4-[(£)-2-(3,5-dihydroxyphenyl)- 1 -ethenyl]phenyl acetate; 5-[(£)-2-(3-chloro-4-hydroxyphenyl)-l-ethenyl]-l,3-benzenediol; l,3-Dimethoxy-5-[(E)-2-(3-methylphenyl)-l-ethenyl]benzene; In the synthesis of stilbene analogs of the present invention, the general method typically involves the condensation of aromatic aldeheyde with phosphonate esters leads to olefins with excellent ^-selectivity.
Using Wittig-Horner reaction, aromatic aldehyde (V) is condensed with phopshonate ester (IV) in a suitable solvent such as terahydrofuran (THF) in presence of suitable bases for forming the ylide. Butyl lithium (BuLi), sodium hydride (NaH) and sodium methoxide (NaOMe) are identified as suitable bases. Out of which, NaH in THF at optimized conditions affords the acceptable yield of single (E)-stilbene analog (I) as compared to the other bases.
The resulting phosphate byproduct is readily separated by simply washing with water leaving the desired selective trans isomer.
Starting from substituted benzoic acid (II), the methyl ester compounds (III) are prepared in good yield using methylating agents such as dimethyl sulphate, dimethyl carbonate and the like. In order to be eco-friendly, or green, DMC is a safe substitute for dimethyl sulfate as it yields by-products that are hard to dispose of. Preparation of methyl ester from substituted carboxylic acids is carried out efficiently with dimethyl carbonate (DMC) which can be accelerated by using sulphuric acid as catalyst.
The methyl ester thus obtained now is subjected to reduction in order to obtain corresponding alcohol compound. The reducing agents used for this purpose are sodium borohydride or lithium aluminum hydride or the like, preferably in ether solvents. The primary alcohol can optionally be isolated or it can be used without being isolated for further reaction.
The substituted benzyl alcohol is now halogenated in a suitable solvents for example toluene or dichloromethane, in presence of halogenating agents such as thionyl chloride or Phosphorus tribromide leads to the formation of substituted benzyl halide. In view of economic aspects and corrosive nature of halide compounds, it is recommended not to isolate these halo compounds.
The phosphonate esters (IV), which serve as key precursors for Wittig-Horner reaction, are prepared from the reaction between triethyl phosphite P(OEt)3 and v foregoing substituted benzyl halide in presence of suitable solvents for example dioxane, THF or toluene. The total process is depicted in the following scheme:
Figure imgf000008_0001
Phosphonate ester
Figure imgf000008_0002
Reagents and conditions: (a) dimethyl carbonate, catalytic amount of H2SO4, reflux, 6hr. (b) NaBH/THF, MeOH, reflux, 3hr.(c) PBr3, toluene, room temperature, 1 hr. (d) triphenyl phosphate, toluene, reflux , 3 hr.(e) NaH1 THF
The present invention will now be defined in more detail by way of following examples, which are intended to be illustrative and not limiting.
EXAMPLES
Example-1: Preparation of 1, 3-dimethoxy-5-[(£)-2-(3-methyIphenyl)-l-etheαyl] benzene
To an ice cold suspension of sodium hydride (6 g, 0.249 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (24 g, 0.083 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to room temperature and stirred for 30 min. After cooling the solution to 0° C, 3-methyl benzaldehyde (10 g, 0.083 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and at room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure l,3-dimethoxy-5-[(£)-2-(3-methylphenyl)-l-ethenyl]benzene Yield 13.3g (60 %).
Η NMR (CDCl3, 300 Mz): δ 7.33 -7.24 (m, 3H), 7.04 (m, 3H,), 6.67-6.66 (d, 2H,'J= 2.2 Hz), 6.4-6.39 (m, IH, J = 2.2 Hz;, 3.8 (s, 6H), 2.37 (s, 3H). LCMS: 255 (M+); HPLC: 99.77% ExampIe-2: Preparation of 2-[5-[(E)-2-(β, 5-dimethoxyphenyl)-l-ethenyl]-2-(tetrahydro-2H- 2-pyranyloxy) phenoxy] tetrahydro-2H-pyran a) TΗP protection of 3, 4-dihydroxybenzaldehyde To a solution of 3, 4-dihydroxybenzaldehyde (10 g, 0.072 mol, 1 eq) in DCM (100 mL) was added DΗP (18.2 g,, 0.217 mol, 3 eq) and PPTS (1.8 g, 0.001 mol, 0.2 eq) at room temperature and stirred for overnight at room temperature. Reaction mass poured in water, separated DCM layer and washed with 10% NaOH solution (20 mL), water (twice) and finally with brine, dried over sodium sulfate. Removal of the solvent in vacuo provided colorless oil. Yield: 16.5 g (75%).
b) Preparation of 2-[5-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2-(tetrahydro-2H-2- pyranyloxy)phenoxy]tetrahydro-2H-pyran
To an ice cold suspension of sodium hydride (2.3 g, 0.097 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (9.4 g, 0.032 mol, 1 eq) diluted in TΗF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to room temperature and stirred for 30 min. After cooling the solution to O0 C, 3, 4-bis(tetrahydro-2Η-pyran-2-yloxy) benzaldehyde (10 g, 0.032 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and at room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 X 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-[5-[(£)-2-(3,5-dimethoxyphenyl)-l- ethenyl]-2-(tetrahydro-2H"-2-pyranyloxy) phenoxy]tetrahydro-2H-pyran. Yield 8.2 g (60%).
Η NMR (DMSO, 300 Mz): δ 7.34-7.33 (d, 1Η, J= 1.6 Hz), 7.19-6.97 (m, 5H), 6.73-6.72 (d, 2H, J= 2.1 Hz), 6.36-6.35 (t, IH, J= 2.1 Hz), 5.54-5.53(t, IH, J=2.6 Hz),5.47-5.46 (t, IH, J=3 Hz),3.9-3.8 (m, 2H), 3.8 (s, 6H), 3.6-3.5 (m, 2H), 2.0-1.79 (m, 6H), 1.78-1.53 (m, 6H). LCMS: 441 (M+); HPLC: 98.65%
ExampIe-3: Preparation of 2-4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl]-2-methoxyphenoxy tetra hydro-2//-pyran a) THP protection of 4-hydroxy-3-methoxybenzaldehyde (vanillin)
To a solution of 4-hydroxy-3-methoxybenzaldehyde (10 g, 0.065 mol, 1 eq) in DCM (100 mL) was added DHP (8.2 g, 0.098 mol, 1.5 eq) and PPTS (1.6 g, 0.006 mol, 0.1 eq) at room temperature and continued stirring for overnight at room temperature. Reaction progress was monitored by TLC. Reaction mass poured in water, separated DCM layer and washed with 10% NaOH solution (20 mL), water (twice) and finally with brine, dried over sodium sulfate. Removal of the solvent in vacuo provided colourless oil. Yield 16.5 g (75%).
b) Preparation of 2-4-[(E)-2-(3, 5-dimethoxyphenyl)-l-ethenyl]-2-methoxy phenoxy tetra hydro-2//-pyran
To an ice cold suspension of sodium hydride (3 g, 0.126 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (12.2 g, 0.042 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm room temperature and stirred for 30 min. After cooling the solution to O0 C, 3-methoxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (10 g, 0.0423 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and at room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-4-[(£)-2-(3, 5-dimethoxyphenyl)-l- ethenyl]-2-methoxy phenoxy tetra hydro-2H-pyran Yield 8.2 g (55 %).
Η NMR (CDCl3, 300 Mz): δ 7.12-6.87 (m, 5Η), 6.65-6.64 (d, 2H J= 2.2 Hz)3 6.38-6.37 (t, IH, J= 2.2 Hz), 5.43-5.40 (t, IH, J=3.1 Hz), 4.0 (m, IH), 3.9 (s, 3H), 3.8 (s, 6H), 3.7- 3.5 (m, IH), 2.1-1.8 (m, 3H), 1.81-1.58 (m, 3H). LCMS: 370 (M+); HPLC: 99.66%
Example-4: Preparation of 2-4-[(2s)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2,6-diinethoxy phenoxy tetrahydro-2H-pyran a) TΗP protection of 4-hydroxy-3, 5-dimethoxybenzaldehyde (Syringaldehyde): To a solution of 4-hydroxy-3, 5-dimethoxybenzaldehyde (10 g, 0.055 mol, 1 eq) in DCM (100 mL) was added DΗP (6.9 g, 0.082 mol, 1.5 eq) and PPTS (1.3 g, 0.005 mol, 0.1 eq) at room temperature and stirring continued for overnight at room temperature. Reaction progress was monitored by TLC. Reaction mass poured in water, separated DCM layer and washed with 10% NaOH solution (20 mL), water (twice) and finally with brine, dried over sodium sulfate. Removal of the solvent in vacuo provided colorless oil. Yield 10.9 g, (75%)
b) Preparation of 2-4-[(2J)-2-(3,5-dimethoxyphenyi)-l-ethenyl]-2,6-dimethoxy phenoxy tetrahydro-2H-pyran To an ice cold suspension of sodium hydride (2.7 g, 0.112 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (10.8 g, 0.037 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to room temperature and stirred for 30 min. After cooling the solution to 0° C, 3, 5-dimethoxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (10 g,0.037 mol, 1 eq) in TΗF (20 mL) was added and stirred at ice cold temperature for 30 min. and room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated TΗF layer, aqueous layer extracted with ethyl acetate (2 X 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-4-[(£)-2-(3,5-dirnethoxyphenyl)-l- ethenyl]-2,6-dimethoxy phenoxy tetrahydro-2H-pyran. Yield 8.2 g (55 %). Η NMR (CDCl3, 300 Mz): δ 6.97-6.93 (dd, 2Η, J= 11.6 Hz), 6.72 (s, 2H), 6.65-6.64 (d, 2H, J = 2.2 Hz), 6.39-6.37 (t, IH, J = 2.2 Hz), 5.44 (m, 1H),4.3 (m, IH), 3.88 (s, 6H), 3.82 (s, 6H), 3.47 (m, 4H), 2.02 -1.98 (m, 2H), 1.96 (m, IH). LCMS: 401 (M+); HPLC: 98.89%
ExampIe-5: Preparation of 2-chloro-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-l-methoxy benzene a) Methyl protection of 3-chloro-4-hydroxybenzaldehyde
Finely powdered potassium carbonate (18.1 g, 0.131 mol, 2 eq) was added to a well stirred solution of 3-chloro-4-hydroxybenzaldehyde (10 g, 0.064 mol, 1 eq) in acetone (80 mL) under nitrogen. After 10 min., dimethylsulphate (8 g, 0.064 mol, 1 eq) was added slowly at room temperature and stirred for 30 min. The reaction mixture was allowed to reflux for 2h. Reaction progress was monitored by TLC, Reaction mixture cooled to room temperature and K2CO3 was filtered, acetone was distilled out in vacuo to obtain residue and was triturated with hexane (20 mL) at O0C for 30 min. to result pale green colored solid. Yield 9.2 g (85%).
b) Preparation of 2-chloro-4-[(£)-2-(3,5-dimethoxyphenyI)-l-ethenyl]-l-methoxybenzene
To an ice cold suspension of sodium hydride (4.2 g, 0.175 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (16.9 g, 0.058 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to room temperature and stirred for 30 min. After cooling the solution to 0° C, 3-chloro-4-methoxy benzaldehyde (10 g, 0.058 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethylacetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-chloro-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-l- methoxybenzene. Yield 10.7 g (60 %). 'H NMR (CDCl3, 300 Mz): δ 7.55-7.54 (d, IH, J= 2.1 Hz), 7.34-7.32 (m, IH), 6.94-6.89 (m, 3H), 6.64-6.63 (d, 2H, J =2.1 Hz), 6.39-6.37 (t, IH, J=2.1 Hz), 3.91 (s, 3H), 3.82 (s, 6H). LCMS: 305 (M+); HPLC: 98.24%
Example-6: Preparation of 5-[(£)-2-(3-chloro-4-hydroxyphenyl)-l-ethenyI]-l, 3-benzenediol
The solution of 4-(3, 5-dimethoxystyryl)-2-chlorophenol (2 g, 0.006 mol, 1 eq) in DCM (15 mL) was cooled to 0° C in an ice bath. BBr3 (6.8 g, 0.027 mol, 4 eq) diluted in DCM (5 mL) was added slowly to the reaction mass at 0° C. The solution was slowly allowed to room temperature and stirred for overnight at room temperature. Reaction mass poured in ice-cold water and compound extracted with ethyl acetate, organic layer was washed with water and brine. Removal of solvent afforded crude product and purified by silica-gel column chromatography (ethyl acetate/hexane-2:8 as eluent) to obtain pure product. Yield 0.63 g (35%).
1H NMR (DMSO, 300 Mz): δ 10.24 (s, -OH), 9.2 (s, 2-OH), 7.55-7.54 (d, IH, J = 2.1 Hz), 7.35-7.31 (m, IH), 6. 92-6. 87 (m, 3H), 6.36-6.35 (d, 2H, J =2.1 Hz), 6.1-6.09 (t, IH, J= 2.1 Hz). LCMS: 263 (M+); HPLC: 93.22% Example-7: Preparation of 2-chloro-4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenol a) THP protection of 3-chloro-4-hydroxybenzaldehyde
To a solution of 3-chloro-4-hydroxybenzaldehyde (1O g, 0.064 mol, 1 eq) in DCM (100 mL) was added DHP (8 g, 0.096 mol, 1.5 eq) and PPTS (1.6 g, 0.006 mol, 0.1 eq) at room temperature. The solution was stirred for overnight at room temperature. The reaction mixture was poured in water, organic layer was separated and treated with 10% NaOH (20 mL), water (twice) and finally with brine, dried over sodium sulfate. Removal of the solvent in vacuo provided brown colored oil. Yield: 16.5 g (75%).
b) Preparation of 2-{2-Chloro-4-[(E)-2-(3,5-diinethoxyphenyI)-vinyl]-phenoxy}- tetrahydropyran To an ice cold suspension of sodium hydride (3 g, 0.124 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (11.9 g, 0.041 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to room temperature and stirred for 30 min. After cooling the solution to O0 C, 3-chloro-4-(tetrahydro-2H-pyran-2-yloxy) benzaldehyde (10 g, 0.041 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-{2-Chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-vinyl]- phenoxy}-tetrahydropyran. Yield 6.2 g (40%). c) Preparation of 2-chloro-4-[(£)-2-(3,5-dimethoxyphenyl)-l-etheny-]phenol
To a solution of 2-{2-Chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-vinyl]-phenoxy}- tetrahydropyran (10 g, 0.026 mol, 1 eq ) in methanol (100 mL) was added pyridinium p- toluenesulphonate (0.67 g, 0.002 mol, 0.1 eq) at room temperature and refluxed for 1 h. Removal of methanol in vacuo, to result crude product and was diluted in ethyl acetate and washed with 10% NaHCO3, 5% HCl, water and finally with brine. Organic layer was distilled in vacuo to get residue and purified by column chromatography (ethyl acetate- hexane, 1:3, v/v) to give pure 2-chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenol. Yield 5.4g (70 %).
1H NMR (CDCl3, 300 Mz): δ 7 '.48-7.47 (d, IH, J= 2.1 Hz), 7.33-7.29 (m, IH), 7.01-6.9 (m, 3H), 6.63-6.62 (d, 2H, /=2.1 Hz), 6.39-6.38 (t, IH, J=2.1 Hz), 5.63(s, -OH), 3.82 (s, 6H). LCMS: 291 (M+); HPLC: 99.35%
Εxample-8: Preparation of 2-chloro-4-[(jE)-2-(3,5-dihydroxyphenyl)-l-ethenyl] phenyl acetate
To a solution of 2-chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenol (10 g, 0.034 mol, 1 eq) in DCM (100 mL) at O0C added triethylamine (5.4 g, 0.068 mol, 2 eq) and stirred for 30 min. Acetyl chloride (2.96 g, 0.037, 1.1 eq) was added slowly at 0 0C and slowly reaction mass was allowed to warm to room temperature, and stirred for 2 h.
Reaction progress was monitored by TLC. Reaction mass poured in ice-cold water, separated DCM layer, washed with 10% NaHCO3. Crude product was obtained on removal of solvent in vacuo and triturated with diisopropylether to get pure title product
4-(3, 5-dimethoxystyryl)-2-chlorophenyl acetate. Yield 6.8 g (60%).
1H NMR (CDCl3, 300 Mz): δ 7.58-7.57 (d, IH, J = 2 Hz), 7.40-7.36 (dd, IH, J =2 Hz), 7.12-7.10 (dd, IH, J= 8.4 Hz), 6.98 (s, 2H), 6.65-6.64 (d, 2H, J= 2.0 Hz), 6.41-6.40 (t, IH, J= 2.0 Hz), 3.82 (s, 6H), 2.35 (s, 3H). LCMS: 333 (M+); HPLC: 96.07%
Example-9: Preparation of iV-(2-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyI] phenoxyethyl)- ΛyV-dimethylamine
To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in DMF (50 ml), potassium carbonate (8 g, 0.058 mol, 3 eq), N, N-Dimethyl-2-chloroethane (3 g, 0.021 mol, 1.1 eq) was added at room temperature, and then the reaction mass was heated to 70° C for Ih. Reaction mass was filtered, washed with saturated ammonium chloride and product extracted with ethyl acetate. Removal of solvent in vacuo to obtain residue, and it was purified by silica-gel column chromatography (ethyl acetate/hexane-l:3) to obtain pure title product as solid. Yield: 3.6 g (50%).
1H ΝMR (CDCl3, 300 Mz): δ 7.44-7.41 (d, IH, J= 8.7 Hz), 7.00-6.92 (d, IH, J= 24 Hz), 6.92-6.89 (m, 3H), 6.64-6.63 (d, 2H, J = 2.2 Hz), 6.36 (m, IH) , 4.08 (t, 2H), 3.82 (s, 6H), 2.73 (t, 2H), 2.34 (s, 6H). LCMS: 328 (M+); HPLC: 97.66%
Example-10: Preparation of 4-(2-4-[(jE)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenoxyethyl) morpholine
To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in DMF (50 ml), potassium carbonate (8 g, 0.058 mol, 3 eq) was added. 4-(2-Chloro ethane) morpholine (3.9 g, 0.020 mol, 1.1 eq) at room temperature. The reaction mass was heated to 7O0C. The reaction mass was filtered and treated with saturated ammonium chloride solution and extracted product with ethyl acetate (100 mL). Removal of solvent gave crude product, which was triturated by methanol at 00C to obtain pure title product as solid. Yield 3.6 g (50%).
1H ΝMR (CDCl3, 300 Mz): δ 1.44-7.41 (d, 2H, J= 8.7 Hz)5 7.00-6.92 (d, IH, J= 24 Hz), 6.87-6.86 (m, 3H), 6.64-6.63 (d, 2H, J= 2.2 Hz), 6.37-6.37 (t, IH, 2.2 Hz) , 4.10-4.12 (t, 2H, 5.7 Hz),3.82 (s, 6H), 3.72-3.73 (t, 4H, 4.7 Hz),2.80-2.82 (t, 2H, J= 5.7 Hz),2.58-2.59 (t, 4H, J= 4.7 Hzj. LCMS: 370 (M+); HPLC: 99.66%
Example-11: Preparation of l-(2j)-2-[4-(allyIoxy) phenyI]-l-ethenyI-3, 5-dimethoxybenzene
To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in acetone (40 mL), potassium carbonate (8 g, 0.058 mol, 3 eq), allyl bromide (2.5 g, 0.021 mol, 1.1 eq) was added at rt and stirred for 5 h at room temperature. The reaction mass was filtered and solvent was evaporated to give residue. The residue was diluted with ethyl acetate (100 mL) and washed with water and brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and purified by silica-gel column chromatography (ethyl acetate/hexane 5:95 as eluent) to afford l-(E)-2-[4-(allyloxy)phenyl]-l-ethenyl-3,5- dimethoxybenzene as solid. Yield 4.0 g (70%).
1H ΝMR (DMSO, 300 Mz): δ 7.51-7.48 (d, 2H, J= 8.4 Hz), 7.21-7.16 (d, IH, J= 16 Hz), 6.96-6.91 (m, 3H), 6.71 (s, 2H), 6.36 (s, IH) ,6.0 (m, IH), 5.4-5.34 (d, 1H,17 Hz) , 5.25- 5.22 (d, IH, 10.5 Hz), 4.55-4.54 (d, 2H, 5 HzJ, 3.74 (s, 6H). LCMS: 297 (M+); HPLC: 99.87% Example-12: Preparation of 4-[(JET)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl ' 1-benzene sulfonate
To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in dichloromethane (50 ml), pyridine (4.7 g, 0.058 mol, 3 eq) was added at rt and stirred for 30 min. Benzenesulfonyl chloride (3.8 g, 0.021 mol, 1.1 eq) was slowly added to reaction mass at 0° C and was allowed to rt for 2 h. Reaction mass was poured in water, separated dichloromethane layer and treated with IN hydrochloric acid (25 mL). Separated organic layer was washed with water and neutralized with 10% sodium bicarbonate solution and washed with water. Removal'of solvent gave crude product, which was triturated with hexane to obtain 4-[(E)-2-(3, 5- dimethoxyphenyl)-l-ethenyl] phenyl 1-benzenesulfonate as solid. Yield 2.3 g (30%).
1H NMR (CDCl3, 300 Mz): δ 7.85-7.77 (m, 3H), 1.61-1.62 (m, 5H), 7.19-7.14 (dd, 2H, J = 13 Hz), 7.0 -6.97 (d, 2H, J= 8.7 Hzj, 6.73-6.72 (d, 2H, J= 2.2 Hz), 6.40-6.39 (t, IH, J = 2.1 Hz), 3.74(s, 6H). LCMS: 397 (M+); HPLC: 96.98%
Example-13: Preparation of 4-{(.E)-2-(3,5-diinethoxyphenyl)-l-ethenyI]phenyI hydrogen sulfate
To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL) triethyl amine (5.9 g, 0.058 mol, 3 eq) was added at rt. Chloro sulphonic acid (2.5 g, 0.021 mol, 1.1 eq) was added to the solution at 0° C and stirred at rt for 2 h. Removal of solvent gave residue, which was purified by silica-gel column chromatography (ethyl acetate/hexane 1:1 as eluent) to obtain pure product 4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl hydrogen sulfate. Yield 1.0 g (15%).
1H NMR (CDCl3, 300 Mz): δ 7.49-7.46 (d, IH, J= 8.7 Hz), 7.18-7.06 (m, 4H), 6.74-6.73 (d, 2H, J= 2.2 HzJ, 6.36 (m, IH), 3.74 (s, 6H). LCMS: 337 (M+); HPLC: 98.42%
Example-14: Preparation of 4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl 4-methyl-l- benzenesulfonate
To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL), pyridine (4.7g, 0.058 mol, 3 eq) was added at room temperature. /7-toluene sulfonyl chloride (3.7 g, 0.019 mol, 1 eq) was added to the solution at 0° C. The mixture was stirred at room temperature for 6 h. The reaction mass was poured in water, separated dichloromethane layer treated with IN hydrochloric acid (50 mL) and washed with water.
Evaporation of solvent gave crude product, which was triturated with hexane to obtain pure product 4-[(£)-2-(3,5-dimethoxyρhenyl)-l-ethenyl] phenyl 4-methyl-l- benzenesulfonate as solid. Yield 5.4 g (70%). Example-15: Preparation of 4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyI]phenyI methane sulfonate
To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL) pyridine (4.7 g, 3 eq, 0.058 mol) was added at rt. Methane sulfonyl chloride (4.5 g, 0.039 mol, 2 eq) was added to the solution at 0° C. The solution was stirred at room temperature for 6 h. the reaction mass was poured in water and washed with IN hydrochloric acid (25 mL) and water. Evaporation of solvent gave crude product, which was triturated with hexane to obtain 4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl methanesulfonate as solid. Yield 3.2 g (50%).
1H NMR (CDCl3, 300 Mz): δ 7.54-7.52 (d, 2H, J= 8.7 Hz), 7.28-7.25 (d, 2H, J = 9 Hz), 7.03-7.02 (d, 2H, J =4.3Hz), 6.66-6.65 (d, 2H, J =2.2 Hz), 6.41 (m, IH), 3.82 (s, 6H), 3.15 (S, 3H). LCMS: 335 (M+); HPLC: 96.46%
Exaniple-16: Preparation of ethyl 2-4-[(£)-2-(3^-dimethoxyphenyI)-l-ethenyl] phenoxy acetate
To a solution of pterostilbene (10 g, 0.039 mol, 1 eq) in acetone (80 mL), potassium carbonate (16 g, 0.117 mol, 3 eq), ethylbromoacetate (7.1 g, 0.042 mol, 1.1 eq) diluted in acetone (20 mL) were added at rt. The reaction mass was refluxed for 3 h. The reaction mass was filtered and evaporated solvent to yield residue. The residue was diluted with ethyl acetate (100 mL) and washed with water and brine. Removal of organic solvent resulted crude product, which was triturated with isopropyl ether to obtain pure ethyl 2-4- [(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyacetate as solid. Yield 7.5 g (58%).
1H NMR (CDCl3, 300 Mz): δ 7.45-7.42 (d, 2H, J = 8.7 Hz), 7.00 (s, IH), 6.93-6.87 (m, 3H), 6.64-6.63 (d, 2H, J = 2.2 Hz), 6.38-6.36 (t, IH, J= 2.2 Hz), 4.63 (s, 2H), 4.28-4.24 (q, 2H), 3.82 (s, 6H), 1.32-1.27 (t, 3H, J= 7.2Hz; LCMS: 343 (M+); HPLC: 86.43%
Εxample-17: Preparation of 2-4-[(£)-2-(3,5-diinethoxyphenyl)-l-etheny-] phenoxyacetic acid
ethyl 2-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyacetate (4 g, 0.011 mol, 1 eq) was dissolved in 5% NaOH solution (20 mL) and refluxed for 1 h. Product was extracted with ethyl acetate, organic layer was washed with water and brine, removal of solvent afforded crude product, which was triturated with diisopropylether to obtain pure 2-4- [(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyacetic acid. Yield 2 g (55%). 1H NMR (DMSO, 300 Mz): δ 1.5-1 Al (d, 2H, J = 8.7Hz), 7.15 (s, IH), 7.0-2 (s, IH), 6.89-6.86 (m, 2H, J = 8.7 Hz), 6.71-6.70 (d, 2H, J =2.2 Hz), 6.36-6.34 (t, IH, J = 2.1 Hz),4.62 (s, 2H), 3.74 (s, 6H). LCMS: 315(M+); HPLC: 97.10%
Example-18: Preparation of 4-[(£)-2-(3,5-dimethoxyphenyI)-l-ethenyl]phenyl 2- aminoacetate hydrochloride
a) BOC protection of Glycine
To a solution of glycine (10 g, 0.133 mol, 1 eq) in water (70 mL), NaOH (5.3 g, 0.133 mol, 1 eq), in 40 ml water solution was added and cooled to 0° C. BOC anhydride (29 g, 0.133 mol, 0.112 eq) was diluted in acetone (50 mL) and added dropwise to the reaction mass at 0°C. Reaction mass stirred at it for 3 h. Acetone was removed in vacuo to get residue and triturated with hexane to obtain solid product. Yield 22 g (95%).
b) Coupling reaction of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyI] phenol & BOC-Glycine
To a solution of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyl] phenol (10 g, 0.039 mol, 1 eq) in DCM (100 mL), HOBT (5.2 g, 0.039 mol, 1 eq), DCC (8 g, 0.039 mol, 1 eq), DMAP (0.47 g, 0.003 mol, 0.1 eq) were added at 0°C and stirred for 30 min. BOC-Glycine (6.8 g, 0.039 mol, 1 eq) diluted in CH2Cl2 (50 mL) was added slowly to the reaction mass at 0° C. Reaction mass was slowly allowed to warm to rt and stirred for 4 h. Acetic acid (2 mL) was added and stirred for 5 min and filtered. The organic layer washed with 5% sodium carbonate (20 mL), IN HCl (20 mL). Organic solvent evaporated to give crude product, which was triturated with hexane to obtain pure desired product as solid. Yield 10 g (42%).
c) Preparation of 4-[(£)-2-(3,5-dimethoxyphenyI)-l-ethenyI]phenyl 2-amino acetate hydrochloride
Compound (4 g, 0.011 mol, 1 eq), obtained from step-b of this example, was added to the pre cooled HCl in ethyl acetate at 0° C. The reaction mass allowed to rt and stirred for 3 h at it. The precipitate filtered and washed with hexane and dried to obtain title product. Yield 2 g (66 %).
1H NMR (DMSO, 300 Mz): δ 8.41 (s, 2H), 7.67-7.64 (d, 2H, J = 8.7 Hz), 7.30-7.12 (m, 4H), 6.76-6.75 (d, 2H, J = 2.2 Hz), 6.71-6.70 (d, 2H, J =2.2 Hz), 6.41-6.4 (t, IH, J = 2.1 Hz),4.05 (s, 2H), 3.82 (s, 6H). LCMS: 314 (M+); HPLC: 84.06%
Example-19: Preparation of 2-tert-ButoxycarbonyIamino-propionic acid 4-[(E)-2-(3,5- dimethoxy-phenyl)-vinyl]-phenyl ester a) BOC protection of alanine
To a solution of alanine (10 g, 0.112 mol, 1 eq) in water (70 mL), NaOH (4.8 g, 0.112 mol, 1 eq), in 40 mL water, solution was added and cooled to O0C. BOC anhydride (24.5 g, 0.112 mol, 1 eq) was diluted in acetone (50 mL) and added drop wise to the reaction mass at 0° C. Reaction mass stirred at it for 3 h. Acetone was removed in vacuo to get residue and triturated with hexane to obtain solid desired product. Yield 20 g (94 %)
b) Coupling reaction of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyl] phenol & BOC-Alanine
To a solution of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyl] phenol (10 g, 0.039 mol, 1 eq) in dichloromethane ( 100 mL), HOBT (5.2 g, 0.039 mol, 1 eq), DCC (8 g, 0.039 mol, 1 eq), DMAP (0.47 g, 0.0039 mol, 0.1 eq) were added at O0C and stirred for 30 min. BOC- alanine (7.3 g, 0.039 mol, 1 eq) diluted in dichloromethane (50 mL) was added slowly to the reaction mass at 0° C. Reaction mass was slowly allowed to warm to rt and stirred for 4 h. Acetic acid (2 mL) was added and stirred for 5 min and filtered. The organic layer washed with 5% sodium carbonate (20 mL), IN HCl (20 mL). Organic solvent evaporated to give crude product, which was triturated with hexane to obtain pure 2-tert- Butoxycarbonylamino-propionic acid 4-[(E)-2-(3,5-dimethoxy-phenyl)-viny'l]-phenyl ester (Ala-(BOC)-OH-Pterostilbene) as solid. Yield 10 g (60%).
Example-20: Preparation of 4-[(jE)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-2-ainino propanoate hydrochloride
Ala-(BOC)-OH-pterostilbene (1O g, 0.023 mol, 1 eq) was dissolved in ethyl acetate and cooled to temperature 0° C. HCl was added to the reaction mixture. The reaction maintained at rt for 3 h. Precipitated compound was filtered and washed with ethyl acetate to get pure product. Yield 6 O g (70%).
1H NMR (DMSO, 300 Mz): δ 8.76 (s, 2H), 7.67-7.64 (d, 2H, J =8.7 Hz), 7.25-7.18 (m, 4H), 6.76-6.75 (d, 2H, J =2.2 Hz), 6.71-6.70 (d, 2H, J =2.2 Hz), 6.41-6.39.(t, IH, J =2.1 Hz), 4.35-4.32 (d, IH, J = 7Hz), 3.75 (s, 6H), 1.58-1.55 (d, 3H, J = 7.0 Hz). LCMS-: 328(M>, HPLC: 88.03%
Example-21: Preparation of 4-[(2T)-2-(3,5-dimethoxypheny-)-l-ethenyl] phenyl 2-amino-3- hydroxy propanoate hydrochloride
a) BOC protection of serine
To a solution of serine (10 g, 0.095 mol, 1 eq) in water (70 mL), NaOH (3.8 g, 0.095 mol, leq) in 40 mL water, solution was added and cooled to O0C. BOC anhydride (20.7 g, 0.095 mol, 1 eq) was diluted in acetone (50 mL) and added dropwise to the reaction mass at 0° C. Reaction mass stirred at rt for 3 h. Acetone was removed in vacuo to get residue and triturated with hexane to obtain desired product as solid. Yield 17.5 g (90%)
b) THP protection of BOC-Serine To a solution of BOC-serine (1O g, 0.048 mol, 1 eq) in dichloromethane (100 mL) was added DHP (4 g, 0.048 mol, 1 eq) and PPTS (1.2 g, 0.004 mol, 0.1 eq) at room temperature. The solution was stirred for 6 h at rt. The reaction mixture was poured in water, organic layer was separated and treated with 10% NaOH (20 mL), water (twice) and finally with brine, dried over sodium sulfate. Removal of the solvent in vacuo provided colorless oil. Yield H g (75%).
c) Coupling reaction of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyl] phenol & BOC-Ser-(THP)- OH
To a solution of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyl] phenol (10 g, 0.039 mol, 1 eq) in dichloromethane ( 100 mL), HOBT (5.2 g, 0.039 mol, 1 eq), DCC (8 g, 0.039 mol, 1 eq), DMAP (0.47 g, 0.003 mol, 0.1 eq) were added at 0° C and stirred for 30 min. BOC- ser-(THP)-OH (11.8 g, 0.039 mol, 1 eq) diluted in 50 ml of dichloromethane was added slowly to the reaction mass at 0° C. Reaction mass was slowly allowed to warm to rt and stirred for 4 h. Acetic acid (2 mL) was added and stirred for 5 min and filtered. The organic layer washed with 5% sodium carbonate (20 mL), IN HCl (20 mL). Organic solvent was evaporated to give crude product, which was triturated with hexane to obtain pure desired product as solid. Yield 13.0 g (60%).
d) Preparation of 4-[(2j)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-amino-3-hydroxy propanoate hydrochloride
Ser-BOC-OH-THP-pterostilbene (compound obtained from step-c) (10 g, 0.017 mol, 1 eq) was dissolved in ethyl acetate and cooled to 0° C. The HCl in isopropyl alcohol was added dropwise to the reaction mass and maintained at rt for 3 h. Precipitated compound was filtered and washed with ethyl acetate to get pure title compound. Yield: 4.2 g, 60 %.
1H NMR (DMSO, 300 Mz): δ 8.77 (s, 2H), 7.67-7.64 (d, 2H, J = 8.7 Hz), 7.31-7.13 (m, 4H), 6.76-6.75 (d, 2H, J = 2.2 Hz), 6.41-6.39 (t, IH/ = 2.1 Hz), 5.83 (s, OH), 4.39 (t, IH), 4.07-4.02 (m, 2H), 3.75 (s, 6H). LCMS: 344 (M+); HPLC: 90.61%
ExampIe-22: Preparation of l,3-dimethoxy-5-[(/ϊ)-2-(4-nitrophenyl)-l-ethenyl]benzene
To an ice cold suspension of sodium hydride (4.7 g, 0.198 mol, 3 eq) in tetrahydrofuran
(30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (19 g, 0.066 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to room temperature and stirred for 30 min. After cooling the solution to 0° C, 4-nitro benzaldehyde (10 g, 0.066 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and at room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted - with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure l,3-dimethoxy-5-[(£)-2-(4-nitropheny])-l-ethenyl]benzene. Yield 13.7 g (70%).
1H NMR (CDCl3, 300 Mz): δ 8.23-8.20 (d, 2H, J= 8.8 Hz), 7.84-7.81 (d, 2H, J = 8.8 Hz), 7.43 (s, IH), 6.84-6.83 (d, 2H, J= 2.2 Hz), 6.46-6.45 (t, IH, J= 2.1 Hz) 3.76 (s, 6H). LCMS: 286 (M+); HPLC: 97.99% ExampIe-23: Preparation of 5-[(£)-2-(4-aminophenyl)-l-ethenyl]-l, 3-benzenedioI a) Preparation of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyI]-phenyl amine l,3-Dimethoxy-5-[(E)-2-(4-nitrophenyl)-vinyl] benzene (10 g, 0.035 mol, 1 eq) was dissolved in acetic acid (50 mL) and cooled to O0C. Zinc dust (10.2 g, 0.140 mol, 4 eq) was added slowly at 0° C and allowed to warm to rt for 30 min in stirring. The reaction mass was refluxed for 1 h. Acetic acid was distilled in vacuo and residue was diluted with water. Compound extracted with ethyl acetate, washed with water and brine. Removal of solvent gave residue which was purified by silica-gel column chromatography (ethyacetate/hexane-1 :3 as eluent) to obtain pure title product. Yield 2.7 g (30%).
Η NMR (CDCl3, 300 Mz): δ 7.33-7.30 (d, 2H, J = 8.4 Hz), 7.25 (s, IH), 6.86 (s, lH),6.68-6.62(m, 4H), 6.35-6.34 (t, IH, J = 2.2Hz ), 7.84-7.81 (d, 2H, J = 8.8 Hz), 7.43 (s, IH), 6.84-6.83 (d, 2H, J= 2.2 Hz), 6.46-6.45 (t, IH, J= 2.1 Hz) 3.81(s, 6H). LCMS: 256 (M+); HPLC: 98.63%
b) Preparation of 5-[(£)-2-(4-aminophenyl)-l-ethenyl]-l,3-benzenediol The solution of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyl]-phenyl amine (5 g, 0.019 mol, 1 eq) in dichloromethane (40 mL) was cooled to 0° C. BBr3 (14.7 g, 0.058 mol, 3 eq) was diluted in dichloromethane (10 mL) and added slowly to reaction mass at 0° C. The solution was slowly allowed to warm to rt and continued stirring for overnight at rt. The reaction mass was poured in ice-cold water, compound extracted with ethyl acetate and organic layer washed with water and brine. Removal of solvent in vacuo afforded crude product, and purified by silica-gel column chromatography (ethyl acetate/hexane-2:8 as eluent) to obtain pure title compound. Yield 1.76 g (40%). Η NMR (DMSO, 300 Mz): «$ 9.10 (s, 2-OH), 7.22-7.19 (d, 2H, J= 8.4 Hz), 6.74-6.78 (d, IH, J= 16 Hz), 6.68-6.62 (d, 4H, J= 16 Hz), 6.52-6.49 (d, 2H, J = 8.4 Hz), 6.31-6.3 (d, 2H, J= 2.2 Hz), 6.06-6.04 (t, IH, J = 1.9 Hz), 5.24 (s, 2H). LCMS: 228 (M+); HPLC: 96.58%
Example-24: Preparation of _V-benzyl-iV-4-[(2i)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl amine
To a solution of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyl]-phenyl amine (5g, 0.0196mol, leq) in dichloromethane (50 mL), Triethyl amine (3.1 g, 0.0392 mol, 2 eq) was added at rt and cooled to O0C5. Benzoyl chloride (3 g, 0.0215 mol, 1.1 eq) was added to the solution at O0C. The reaction mass was stirred at rt for 2hours. Reaction mass was poured in water. The organic layer washed with IN hydrochloric acid (25 mL), water and solvent evaporated to give crude product, which was triturated with isopropyl ether to obtain pure title compound. Yield 3.5 g (50%).
Example-25: Preparation of M-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl acetamide
To a solution of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyl]-phenyl amine (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL), triethylamine ((3.1 g, 0.039 mol, 2 eq) was added at rt and reaction mass cooled to 0° C with stirring. After 30 min, acetyl chloride (1.7 g, 0.021 mol, 1.1 eq,) was slowly added to reaction mass at 0° C and stirred at rt for 2 h. Reaction mass was poured into water and organic layer washed with IN hydrochloric acid and water. The organic layer evaporated in vacuo to give crude product, which was triturated with isopropyl ether to obtain Nl-4-[(E)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl acetamide as solid. Yield 5.3 g (95%).
Example-26: Preparation of benzyl iV-4-[(2j)-2-(3,5-dimethoxyphenyI)-l-ethenyI] phenylcarbamate
To a solution of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyl]-phenyl amine (5 g, 0.019 mol, 1 eq) in acetone (50 mL). 10% sodium bicarbonate solution (3.3 g, 0.039 mol, 2 eq) was added at rt and cooled to 0° C with stirring. Benzyl chloroformate (1.7 g, 0.021 mol, 1.1 eq,) was added to the solution at 0° C. Reaction mass was allowed to warm to rt and stirred at rt for 2 h. Acetone was distilled in vacuo to get residue. Residue diluted with water and washed with IN hydrochloric acid (25 mL), and water, the organic layer was separated, and removed to afford crude product, which on trituration with isopropyl alcohol gave pure title compound. Yield 2.9 g (50%).
1H NMR (DMSO, 300 Mz): δ 9.84 (s, H), 7.5-7.3 (m, 9H), 7.20-6.99 (m, 2H), 6.72-6.71 (d, 2H, J = 2 Hz), 6.36 (m, IH), 5.13 (s, 2H), 3.74 (s, 6H). LCMS: 390 (M+); HPLC: 92.35%
Example-27: Preparation of tert-butyl Λ^-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyI carbamate
To a solution of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyl]-phenyl amine (5 g, 0.019 mol, 1 eq) in acetone (50 mL), 10% sodium bicarbonate solution (1.62 g, 0.019 mol, 1 eq) was added at rt, stirred for 10 min, BOC anhydride (4.7 g, 0.021 mol, 1.1 eq) diluted in acetone was slowly added to reaction mass at rt and stirred for overnight. Acetone was removed in vacuo to get residue, which on trituration with isopropyl ether gave pure title product. Yield 6.5 g (93%).
1H NMR (CDCl3, 300 Mz): δ 7.44-7.41 (d, 2H J= 8.7 Hz), 7.35-7.33 (d, 2H J = 8.7Hz), 7.1 -6.9 (m, 2Η), 6.65-6.64 (d, 2H, J = 2 Hz), 6.51 (s, lH),6.38-6.36(t, IH, J = 2.0 Hz), 3.82 (s, 6H), 1.60 (s, 9H). LCMS: 356 (M+); HPLC: 98.37%
Example-28: Preparation of N-4-[(E)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyWV- methylamine hydrochloride a) Methylation of tert-butyl iV-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl] phenyl carbamate
To a cooled suspension of sodium hydride (1.4 g, 0.058 mol, 3 eq) in THF (20 mL) at 0° C, BOC protected 4-(3, 5-dimethoxystyryl)benzenamine diluted in THF (30 mL) was added to reaction mass at 0° C and stirred for 30 min. Methyl iodide was added slowly and reaction was allowed to warm to it and stirred for 1 h. Reaction mass was poured in ice-cold water, compound extracted with ethyl acetate. Organic layer washed with water and brine, on removal of organic solvent obtained pure desired product. Yield 4.6 g (90%).
b) Preparation of Λr-4-[(JE)-2-(3,5-dimethoxyphenyl)-l-ethenyI]phenyl-Λ''-methylamine hydrochloride
Compound (4 g, 0.01126 mol, 1 eq), obtained from step-a of this example, was added to the pre cooled hydrochloride in ethyl acetate at 0° C. The reaction mass allowed to warm to rt and stirred for 3 h at rt. The precipitate filtered and washed with hexane to obtain title product. Yield 2 g (66%).
1H NMR (CDCl3, 300 Mz): δ 7.57-7.54 (d, 2H, J= 8.5 Hz), 7.24-7.03(m, 4H), 6.73-6.72 (t, IH, J = 2.1 Hz), 6.37-6.36 (t, IH, J= 2.1 Hz), 3.74 (s, 6H), 2.8 (s, 3H). LCMS: 270 (M+); HPLC: 96.85% ExampIe-29: Preparation of 5-(£)-2-[4-(dimethylamiπo) phenyl]-l-ethenyl-l, 3-benzenediol
The solution of 4-(3, 5-bis (benzyloxy)styryl)-N,iV-dimethylbenzenamine (5 g, 0.009 mol, 1 eq) in HBr/acetic acid (30 mL) was refluxed for 4 h and aollowed to warm to it for overnight under stirring. The crude product was filtered and washed with water to obtain pure product as solid. Yield 1.1 g (50%).
Η ΝMR (DMSO, 300 Mz): δ 9.13 (s, 2-OH), 7.37-7.35 (d, 2H, J= 8.8 Hz), 6.85-6.75 (m, 4H), 6.34-6.33 (d, 2H, J= 2 Hz), 6.05 (m, 1 H), 2.89 (s, 6H). LCMS: 256 (M+); HPLC: 98.41%
Example-30: Preparation of N, iV-dibenzyl-iV-4-[(2s)-2-(3,5-diinethoxypheny-)-l-ethenyl] phenyl amine
To the solution of 4-[(E)-2-(3, 5-Dimethoxy-phenyl) vinyl] phenylamine (5 g, 0.019 mol, 1 eq) in acetone (50 mL). K2CO3 (8.11 g, 0.058 mol, 3 eq) was added and stirred for 30 min. Benzyl bromide (3.7 g, 0.021 mol, 1.1 eq) was added at it and refluxed for 4 h. Reaction mass was filtered and solvent evaporated to get residue. The residue was purified by silica-gel column chromatography (ethyl acetate/hexane 1:9 as eluent) to obtain pure product. Yield 2 g (20%).
1H ΝMR (CDCl3, 300 Mz): δ 9.98 (s, H), 7.37-7.24 (m, 12H), 7.02 -6.96 (d, IH, J = 16 Hz), 6.83-6.78 (d, IH, J = 16 Hz), 6.74-6.71 (d, 2H, J = 8.8 Hz), 6.63-6.62 (d, 2H, J = 2.1 Hz), 4.68 (s, 4H), 3.81 (s, 6H). LCMS: 437 (M+); HPLC: 96.17%
Example-31: Preparation of N-4-[(E)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl methane sulfonamide
To a solution of 4-[(E)-2-(3, 5-Dimethoxy-phenyl) vinyl] phenyl amine (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL), pyridine (1.85 g, 0.023 mol, 1.2 eq) was added at it and stirred for 30 min. Methane sulfonyl chloride (2.2 g, 0.019 mol, 1 eq) was added to the solution at 0° C and stirred at it for 6 h. Reaction mass was poured in water, organic layer washed with IN hydrochloric acid (25 mL) and water. Removal of solvent gave crude product, which was triturated with isopropyl alcohol to obtain pure product as solid. Yield 6.2 g (95%).
1H ΝMR (CDCl3, 300 Mz): δ 1.5-1 Al (d, 2H, J=6.7 Hz), 7.25-7.2 (d, IH, J= 17 Hz), 7.01- 6.99 (d, IH, J = 5.4 Hz), 6.67-6.65 (m, 3H), 6.4-6.390 (t, IH, J= 2.2 Hz), 3.82 (s, 6H), 3.02 (s, 3H). HPLC: 95.98% Example-32: Preparation of M-4-[(2?)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl-1- benzene sulfonamide
To a solution of 4-[(E)-2-(3, 5-Dimethoxy-phenyl) vinyl] phenyl amine (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL), pyridine (1.85 g, 0.023 mol, 1.2 eq) was added at rt and stirred for 30 min. Benzene sulfonyl chloride (3.4 g, 0.019 mol, 1 eq) was slowly added to reaction mass at 0° C and was allowed to warm to rt for 6 h under stirring. Reaction mass was poured in water, separated dichloromethane layer was treated with IN hydrochloric acid (25 mL). Organic layer was washed with water and neutralized with 10% sodium bicarbonate solution and washed with water. Removal of solvent gave crude product, which was triturated with hexane to obtain pure product as solid. Yield: 6.2 g
(80%).
1H NMR (CDCl3, 300 Mz): δ 7 '.79-7.76 (d, 2H, J = 7 Hz), 7.53-7.51 (m, IH), 7.46-7.38 (m, 4H), 7.06-7.03 (d, 2H, J = 8.3 Hz), 6.95-6.94 (d, 2H, J = 3.4 Hz), 6.62-6.61 (d, 2H, J = 10.3 Hz), 6.39-6.37 (t, IH5 J = 3.2 Hz), 3.81 (s, 6H). LCMS: 396 (M+); HPLC: 98.97%
Example-33: Preparation of l-[(£)-2-(3-bromophenyI)-l-ethenyl]-3,5-dimethoxybenzene
To an ice cold suspension of sodium hydride (3.9 g, 0.162 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath. 3, 5-dimethoxybenzylphosphonate ester (15.5 g, 0.054 mol, 1 eq) diluted in tetrahydrofuran (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to rt and stirred for 30 min. After cooling the solution to 0° C, 3-bromobenzaldehyde (10 g, 0.054 mol, 1 eq) in tetrahydrofuran (20 mL) was added and stirred at ice cold temperature for 30 min. and at rt for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethylacetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure l-[(E)-2-(3-bromophenyl)-l-ethenyl]-3,5-dimethoxybenzene. Yield 12.0 g (70%).
Η NMR (CDCl3, 300 Mz): δ 7.66-7.65 (t, 2H, J = 1.6 Hz), 7.39-7.36 (t, 2H, J = 8.7 Hz), 7.25-7.21 (m, 2H), 7.01-7.00 (d, 2H, J = 3 Hz), 6.66-6.65 (d, 2H, J = 2.2 Hz), 6.42-6.41 (t, IH5 J = 2.2 Hz)5 3.82 (s, 6H). LCMS: 319 (M+); HPLC: 98.98%
Example-34: Preparation of 2-chloro-l-[(£)-2-(3, 5-dimethoxyphenyI)-l-ethenyl]-4-fluoro benzene
To an ice cold suspension of sodium hydride (3.9 g, 0.162 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath. 3, 5-dimethoxybenzylphosphonate ester (18.3 g, 0.063mol,
1 eq) diluted in tetrahydrofuran (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to rt and stirred for 30 min. After cooling the solution to 0° C, 2-chloro 4-Fluoro benzaldehyde (10 g, 0.063 mol, 1 eq) in tetrahydrofuran (20 mL) was added and stirred at ice cold temperature for 30 min. and at rt for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-chloro- l-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-4- fluoro benzene. Yield 9.3 g (50%).
1H NMR (CDCl3, 300 Mz): δ 7.65-7.60 (m, IH), 7.41-7.35 (d, 2H, J = 16 Hz), 7.15-7.11 (m, IH), 6.99-6.95 (m, 2H), 6.68-6.67 (d, 2H, J = 2.2 Hz), 6.42-6.41 (t, IH, J = 2.1 Hz), 3.83 (s, 6H). LCMS: 293 (M+); HPLC: 99.14%
Example-35: Preparation of 4-4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl morpholine hydro chloride
a) Preparation of 4-4-[(2ϊ)-2-(3,5-dimethoxy phenyl)-l-ethenyl]phenyl morpholine
An oven-dried RB flask was charged with Pd2(dba)3 (0.58 g, 0.00062 mol, 0.02 eq), xanthphos (0.09 g, 0.00015 mol, 0.005 eq), l-[(£)-2-(4-bromophenyl)-l-ethenyl]-3,5- dimethoxybenzene (10 g, 0.031 mol, leq), cesium carbonate (20 g, 0.062 mol, 2 eq), morpholine (2.7 g, 0.031 mol, 1 eq), toluene (100 mL) was degassed for about 30 min. The mixture refluxed for 8 h, during which time the solution turned from purple to deep brown. The reaction was monitored by removing small aliquots, which were analyzed by TLC. The reaction mass was filtered through a short pad of silica and toluene removed in vacuo, the residue was purified by column chromatography (ethyl acetate-hexane, 1:3, v/v) to give 4-(4-3, 5-dimethoxy styryl phenyl) morpholine as a pale yellow-colored solid. Yield 4. I g (40%).
1H NMR (CDCl3, 300 Mz): δ 7.44-7.41 (d, 2H, J = 8.7 Hz), 6.99-6.86 (m, 4H), 6.64-6.63 (d, 2H, J = 2.2 Hz), 6.36-6.35 (t, IH, J = 2.2 Hz), 3.8 (m, 10H), 3.17-3.2 (t, 4H, J = 4.5 Hz).LCMS: 326 (M+); HPLC: 99.46% b) Preparation of 4-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl morpholine hydrochloride
To a mixture of HCl-EtOAc (9% solution) (2 mL) cooled in an ice bath, 4-4-[(E)-2-(3, 5- dimethoxyphenyl)-l-ethenyl] phenyl morpholine (1 g, 0.003 mol, leq) was dissolved in ethyl acetate (5 mL) and added slowly at 0° C, the reaction mass was slowly allowed to warm to room temperature and stirring continued for 4 h at room temperature. The precipitated product was filtered and washed with cold ethyl acetate to obtain pure product. Yield: 0.8 g, (70%).
Example-36: Preparation of l-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-4-methyl piperazine dihydrochloride
a) Preparation of l-4-[(jE)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-4-methyl piperazine
An oven-dried RB flask was charged with Pd2(dba)3 (0.58 g, 0.00062 mol, 0.02 eq), xanthphos (0.09 g, 0.00015 mol, 0.005 eq), l-[(£)-2-(4-bromophenyl)-l-ethenyl]-3,5-" dimethoxybenzene (10 g, 0.031 mol, 1 eq), cesium carbonate (20 g, 0.062 mol, 2 eq), N- methylpiperizene (3.13 g, 0.031 mol, 1 eq), toluene (100 mL) was degassed for about 30 min. The mixture refluxed for 1O h, during which time the solution turned from purple to deep brown. The reaction was monitored by removing small aliquots, which were analyzed by TLC. The reaction mass was filtered through a short pad of silica and toluene removed in vacuo, the residue was purified by column chromatography (ethylacetate- hexane, 1:3, v/v) to give l-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-4-methyl piperazine as a greenish yellow-colored solid. Yield 4.0 g (40%).
Η NMR (CDCl3, 300 Mz): δ 7.42-7.39 (d, 2H, J = 8.6 Hz), 6.98-6.88 (m, 4H), 6.64-6.63 (d, 2H, J = 2 Hz), 6.35 (m, IH), 3.82 (m, 6H), 3.26-3.23 (t, 4H, J = 4.8 Hz), 2.59-2.55 (t, 4H, J = 4.8 Hz), 2.35 (s, 3H). LCMS: 339 (M+); HPLC: 95.49%
b) Preparation of l-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-4-methyI piperazine dihydrochloride
To a mixture of HCl-EtOAc (9% solution) (2 mL) cooled in an ice bath, l-4-[(E)-2-(3,5- dimethoxyphenyl)-l-ethenyl]phenyl-4-methyl piperazine (1 g, 0.002- mol, 1 eq) was dissolved in ethyl acetate (5 mL) and added slowly at 0° C, solution was slowly allowed to warm to room temperature and stirring continued for 4 h at room temperature. The precipitated product was filtered and washed with cold ethyl acetate to obtain pure product. Yield 1 g (80%).
Example-37: Preparation of 5-[(E)-2-(4-Bromophenyl) vinyl] benzene-1, 3-dioI
To the solution of l-[(E)-2-(4-bromophenyl)-l-ethenyl]-3, 5-dimethoxybenzene (5 g, 0.015 mol, 1 eq) in dichloromethane (80 mL) was cooled to O0C. BBr3 (11.7 g, 0.047 mol, 3 eq) was diluted in dichloromethane (20 mL) and added slowly to reaction mass at 0° C. Reaction mass slowly allowed to warm to room temperature and stirred overnight at room temperature. Reaction mass poured in ice-cold water and extracted compound with ethyl acetate. Removal of solvent in vacuo gave crude product, which was triturated with CH2Cl2 to obtain pure product as solid. Yield 6.0 g (70%). 1H NMR (DMSO, 300 Mz): δ 9.25 (s, 2-OH), 7.51(s, 4H), 7.04-7.01 (dd, 2H, J = 11.3 Hz), 6.42-6.41 (d, 2H, J= 2 Hz), 6.15-6.14 (d, 2H5 J= 1.8 Hz). LCMS: 290 (M+); HPLC: 99.17%
Example-38:
The following list of compounds can be prepared according to the process described in the examples 36 and 37 by using 5-[(E)-2-(4-Bromophenyl) vinyl] benzene-1, 3-diol (compound of example-38).
The said compounds are 5-[(£)-2-(4-morpholinophenyl)-l-ethenyl]-l, 3-benzenediol; 5- [(E)-2-(4-morpholinophenyl)-l-ethenyl]-l, 3-benzenediol hydrochloride; 5-{(Ε)-2-[4-(4- Methyl-piperzin-l-yl)-phenyl]-vinyl}-benzene-l,3-diol;5-{(E)-2-[4-(4-Methyl-piperzin-l -yl) -phenyl] -vinyl} -benzene-1, 3-diol dihydrochloride;

Claims

We claim;
1. A Stilbene derivatives of the formula I
Figure imgf000028_0001
Wherein R1, R2 which may be the same or different each represent -OR7, in which R7 is hydrogen, an alkyi group having 1 to 3 carbon atoms; R represents hydrogen, — OR8, in which R8 is an alkyl group having 1 to 3 carbon atoms or tetrahydropyranyl; R3 is a halogen atom, an alkyl group having 1 to 3 carbon atoms with proviso that when R4, R5 are solely hydrogen; R4 represents nitro, mono alkyl amino, carbamic acid alkyl ester group, alkyl or aryl amido, aryl amino, diphenyl amino, diaryl amino, alkyl sulphanamino, phenyl or aryl sulphanamino, sulphamic acid group or its sodium salt, alkyl or aryl carbamic acid group, morpholino, N-alkyl substituted or unsubstituted piperzinyl; R4 further represents hydroxy with proviso that R5 is exclusively halogen; R4 further represents amino, dialkyl amino , only when R1 , R2 are hydroxy; R4 further- represents hydrogen with proviso that R5 is not hydrogen, alkoxy and R4 further represents halogen with proviso that when R6 is solely a halogen atom; R4 further represents -OR9 in which R9 represents tetrahydropyranyl with proviso that R3 is not hydrogen; Furthermore R9 represents an alkyl group having 1 to 3 carbon atoms, (2-4C) alkanoyl when R5 is exclusively a halogen atom; R further represents alkyl morphonyl, alkyldiamino, vinyl, allyl, suphonyl and its corresponding sulphonate salts, phenyl sulphonyl, aryl sulphonyl, suphonic acid group, amino acid group, alkoxy carbonyl amino acid group, alkanoic acid group, alkanoic acid alkyl ester group and its corresponding alkali metal salts; R5 represents hydrogen, a halogen atom , alkoxy; R6 represents hydrogen;
2. A compound which is
2-[5-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2-(tetrahydro-2H-2-pyranyloxy) phenoxy] tetrahydro-2H-pyran;
2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2-methoxyphenoxytetrahydro-2H-pyran;
2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2,5-dimethoxyphenoxytetrahydro-2H- pyran;
4-(2-4-[(£}-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyethyl)morpholine; iV-(2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyethyl)-iV,iV-dimethylaniine;
N-(2-4-[(J^-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyethyl)-iVJV-dimethylamine;
1 -(E)-2-[4-(allyloxy) phenyl]- 1 -ethenyl-3,5-dimethoxybenzene;
4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl methanesulfonate;
4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 1-benzenesulfonate;
4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 4-methyl- 1-benzenesulfonate;
4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl hydrogen sulfate;
4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-aminoacetatehydrochloride;
4-[(£T)-2-(3,5-dimethoxyphenyl)- 1 -ethenyl]phenyl-2-aminopropanoate hydrochloride;
4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-[(tert-butoxycarbonyl) amino] propanoate;
4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-amino-3-hydroxypropanoate hydrochloride;
2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyacetic acid;
Ethyl 2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyacetate;
5-(E)-2-[4-(2-moφholinoethoxy)phenyl]-l-ethenyl-l,3-benzenediol;
5-((E)-2-4-[2-(dimethylamino)ethoxy]phenyl- 1 -ethenyl)- 1 ,3 -benzenediol;
1 ,3-Dimethoxy-5-[(£)-2-(4-nitrophenyl)- 1 -ethenyl]benzene;
iV-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-Λr-methylamine hydrochloride;
tert-Butyl iV-4-[(£T)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylcarbamate;
N\ -4-[(£)-2-(3,5-dimethoxyphenyl)- 1 -ethenyl]phenylacetamide; JVl -4-[(£)-2-(3,5-dimethoxyphenyl)-l -ethenyljphenylbenzamide; iV-Benzyl-iV-4-[(£)-2-(3,5-diniethoxyphenyl)- 1 -ethenyl] phenylamine N, N-DibQnzyl-N-4-[(E)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyljphenylamine; A/-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylmethanesulfonamide;
N-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylsulfamic acid;
M -4-[(E)-2-(3,5-dimethoxyphenyl)- 1 -ethenyljphenyl- 1 -benzenesulfonamide;
Benzyl N-4-[(E)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]phenylcarbamate; 4-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylmorpholine; l-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-4-methylpiperazine;
1 -[(E)-2-(3-bromophenyl)- 1 -ethenyl]-3 ,5-dimethoxybenzene;
5 -(E)-2- [4-(dimethylamino)pheny I]- 1 -ethenyl- 1 ,3 -benzenediol ;
5-[(E)-2-(4-morpholinophenyl)-l-ethenyl]-l,3-benzenediol; 5-{(Ε)-2-[4-(4-Methyl-piperzin-l -yl) -phenyl]-vinyl}-benzene-l,3-diol; 5-[(E)-2-(4-aminophenyl)-l-ethenyl]-l,3-benzenediol;
2-chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-l-methoxybenzene;
2-chloro- 1 -[(E)-2-(3,5-dimethoxyphenyl)- 1 -ethenyl]-4-fluorobenzene;
2-chloro-4-[(E)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyljphenol; 2-chloro-4-[(E)-2-(3,5-dihydroxyphenyl)-l-ethenyl]phenyl acetate; 5-[(E)-2-(3-chloro-4-hydroxyphenyl)- 1 -ethenyl]- 1 ,3-benzenediol;
1 ,3-Dimethoxy-5-[(E)-2-(3-methylphenyl)- 1 -ethenyl]benzene;
3. A process for making stilbene derivatives of the formula I
Figure imgf000031_0001
Formula - 1
Wherein R1, R2 which may be the same or different each represent -OR7, in which R7 is hydrogen, an alkyl group having 1 to 3 carbon atoms; R3 represents hydrogen, - OR , in which R is an alkyl group having 1 to 3 carbon atoms or tetrahydropyranyl;
R3 is a halogen atom, an alkyl group having 1 to 3 carbon atoms with proviso that when R4, R5 are solely hydrogen; R4 represents nitro, mono alkyl amino, carbamic acid alkyl ester group, alkyl or aryl amido, aryl amino, diphenyl amino, diaryl amino, alkyl sulphanamino, phenyl or aryl sulphanamino, sulphamic acid group or its sodium salt, alkyl or aryl carbamic acid group, morpholino, N-alkyl substituted or unsubstituted piperzinyl; R4 further represents hydroxy with proviso that R5 is exclusively halogen; R4 further represents amino, dialkyl amino , only when R1 „ R2 are hydroxy; R4 further represents hydrogen with proviso that R5 is not hydrogen, alkoxy and R4 further represents halogen with proviso that when R6 is solely a halogen atom; R4 further represents -OR9 in which R9 represents tetrahydropyranyl with proviso that R3 is not hydrogen; Furthermore R9 represents an alkyl group having 1 to 3 carbon atoms, (2-4C) alkanoyl when R5 is exclusively a halogen atom; R9 further represents alkyl morphonyl, alkyldiamino, vinyl, allyl, suphonyl and its corresponding sulphonate salts, phenyl sulphonyl, aryl sulphonyl, suphonic acid group, amino acid group, alkoxy carbonyl amino acid group, alkanoic acid group, alkanoic acid alkyl ester group and its corresponding alkali metal salts; R5 represents hydrogen, a halogen atom , alkoxy; R represents hydrogen; by the condensation of aromatic aldehyde of formula (IV) with phosphonate esters of formula (V) in presence of a base.
4. The process as claimed in claim 3, wherein the base is selectedTrom sodium hydride, n-butyl lithium and sodium methoxide.
5. The process as claimed in claim 3, wherein the reaction is carried out in Tetrahydrofuran.
6. The process as claimed in claim 3, wherein the phosphonate esters of formula (IV) is prepared by; a. converting substituted benzoic acid of formula (II) to its methyl esters of formula (III) using methylating agents such as dimethyl sulphate and dimethyl carbonate b. reducing with methyl esters of formula (III) to corresponding substituted alcohol using a suitable reducing agents sodium borohydride or lithium aluminum hydride c. Converting the substituted alcohol to its halogen derivatives in a suitable solvent in presence of halogenating agent such as thionyl chloride or Phosphorus tribromide. d. Condensing the halogen derivatives with triethyl phosphite in a suitable solvent for example dioxane, THF and toluene.
PCT/IN2009/000580 2008-10-17 2009-10-15 Novel stilbene analogs WO2010046926A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2553/CHE/2008 2008-10-17
IN2553CH2008 2008-10-17

Publications (2)

Publication Number Publication Date
WO2010046926A2 true WO2010046926A2 (en) 2010-04-29
WO2010046926A3 WO2010046926A3 (en) 2011-03-31

Family

ID=42119783

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2009/000580 WO2010046926A2 (en) 2008-10-17 2009-10-15 Novel stilbene analogs

Country Status (1)

Country Link
WO (1) WO2010046926A2 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103073440A (en) * 2013-02-21 2013-05-01 四川大学 Diphenylvinyloxy alkylamine compound and preparation method as well as application thereof
JP2014530217A (en) * 2011-10-06 2014-11-17 ローディア オペレーションズ Method for preparing vanillin derivatives
WO2016067311A1 (en) * 2014-10-29 2016-05-06 Council Of Scientific & Industrial Research (z)-3,4,5-trimethoxystyrylbenzenesulfonamides as potential anticancer agents
CN106117076A (en) * 2016-07-07 2016-11-16 北京理工大学 A kind of novel toluylene derivant and preparation method thereof
WO2019122140A1 (en) 2017-12-21 2019-06-27 L'oreal Xyloside derivatives of resveratrol for use thereof in cosmetics
FR3097435A1 (en) 2019-06-19 2020-12-25 L'oreal Xyloside derivatives of resveratrol for their use in cosmetics
FR3100981A1 (en) 2019-06-19 2021-03-26 L'oreal Xyloside derivatives of resveratrol for their use in cosmetics
TWI826795B (en) * 2020-06-12 2023-12-21 樹頂分子生技股份有限公司 Novel analogs of pterostilbene amino acid bearing carbonates for treating a non-alcoholic fatty liver disease and nonalcoholic steatohepatitis

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042231A2 (en) * 1999-12-06 2001-06-14 Welichem Biotech Inc. Polyhydroxystilbenes and stilbene oxides as antisoriatic agents and protein kinase inhibitors
WO2001060774A1 (en) * 2000-02-16 2001-08-23 Brigham Young University Synthesis of resveratrol
WO2005002555A2 (en) * 2003-07-01 2005-01-13 President And Fellows Of Harvard College Sirt1 modulators for manipulating cell/organism lifespan/stress response
WO2008012108A2 (en) * 2006-07-28 2008-01-31 Portela & Ca., S.A. Process for the preparation of polyhydroxylated stilbenes via claisen condensation
WO2008070872A1 (en) * 2006-12-07 2008-06-12 Rutgers, The State University Of New Jersey Prevention and treatment of colon cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042231A2 (en) * 1999-12-06 2001-06-14 Welichem Biotech Inc. Polyhydroxystilbenes and stilbene oxides as antisoriatic agents and protein kinase inhibitors
WO2001060774A1 (en) * 2000-02-16 2001-08-23 Brigham Young University Synthesis of resveratrol
WO2005002555A2 (en) * 2003-07-01 2005-01-13 President And Fellows Of Harvard College Sirt1 modulators for manipulating cell/organism lifespan/stress response
WO2008012108A2 (en) * 2006-07-28 2008-01-31 Portela & Ca., S.A. Process for the preparation of polyhydroxylated stilbenes via claisen condensation
WO2008070872A1 (en) * 2006-12-07 2008-06-12 Rutgers, The State University Of New Jersey Prevention and treatment of colon cancer

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014530217A (en) * 2011-10-06 2014-11-17 ローディア オペレーションズ Method for preparing vanillin derivatives
CN103073440A (en) * 2013-02-21 2013-05-01 四川大学 Diphenylvinyloxy alkylamine compound and preparation method as well as application thereof
CN103073440B (en) * 2013-02-21 2015-06-03 四川大学 Diphenylvinyloxy alkylamine compound and preparation method as well as application thereof
WO2016067311A1 (en) * 2014-10-29 2016-05-06 Council Of Scientific & Industrial Research (z)-3,4,5-trimethoxystyrylbenzenesulfonamides as potential anticancer agents
US10246411B2 (en) 2014-10-29 2019-04-02 Council Of Scientific & Industrial Research (Z)-3,4,5-trimethoxystyrylbenzenesulfonamides as potential anticancer agents
CN106117076A (en) * 2016-07-07 2016-11-16 北京理工大学 A kind of novel toluylene derivant and preparation method thereof
WO2019122140A1 (en) 2017-12-21 2019-06-27 L'oreal Xyloside derivatives of resveratrol for use thereof in cosmetics
FR3097435A1 (en) 2019-06-19 2020-12-25 L'oreal Xyloside derivatives of resveratrol for their use in cosmetics
FR3100981A1 (en) 2019-06-19 2021-03-26 L'oreal Xyloside derivatives of resveratrol for their use in cosmetics
TWI826795B (en) * 2020-06-12 2023-12-21 樹頂分子生技股份有限公司 Novel analogs of pterostilbene amino acid bearing carbonates for treating a non-alcoholic fatty liver disease and nonalcoholic steatohepatitis

Also Published As

Publication number Publication date
WO2010046926A3 (en) 2011-03-31

Similar Documents

Publication Publication Date Title
WO2010046926A2 (en) Novel stilbene analogs
ES2209457T3 (en) NEW DERIVATIVES OF 3-ARIL-PROPIONIC ACID, AND ANALOGS.
US20030083341A1 (en) 2,3,5-Substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
NO162113B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PHENETANOLAMINE COMPOUNDS.
NZ529351A (en) Modulators of peroxisome proliferator activated receptors
KR20020070508A (en) Propionic acid der1vatives and their use in the treatment of diabetes and obesity
US8624056B2 (en) Halogenated analogues of anti-fibrotic agents
JP2006522118A (en) New compounds
KR100787072B1 (en) New tri-substituted phenyl derivatives and analogues
JPWO2005044780A1 (en) Aminocarboxylic acid derivatives and their addition salts and S1P receptor modulators
CA2519582A1 (en) Substituted p-diaminobenzene derivatives
MXPA02005328A (en) New phenalkyloxy phenyl derivatives.
JPS6110528A (en) Phenol derivative, manufacture and antiestrogenic medicinal composition
USRE38921E1 (en) Phenoxyalkylcarboxylic acid derivatives and process for their preparations
EP0375670B1 (en) Process for preparing 3-polyfluoroalkylisoxazolylamines
KR20100028550A (en) Novel derivatives of 3-phenyl acrylic acid activating ppar-type receptors, method for preparing same and use thereof in cosmetic or pharmaceutical compositions
US20100048550A1 (en) Selective tr-beta 1 agonist
JP4213960B2 (en) Pyrrole derivatives
US5281742A (en) Bis(fluorophenyl) carbonate derivatives
US20040260088A1 (en) Novel compounds
JP4209684B2 (en) New compounds
US20110105544A1 (en) Carboxylic derivatives for use in the treatment of cancer
US20010018525A1 (en) 2, 3, 5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
JP2007001921A (en) Aminosulfonic acid derivative and its addition salt and s1p receptor regulator
JP2009091267A (en) Amide derivative, and selective agonist for sphingosine-1-phosphoric acid-1 (s1p1) receptor comprising the same as effective component

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09821700

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09821700

Country of ref document: EP

Kind code of ref document: A2