WO2022121317A1 - Composé 1,1'-biphényl-2,6-diphénolique et son utilisation - Google Patents

Composé 1,1'-biphényl-2,6-diphénolique et son utilisation Download PDF

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WO2022121317A1
WO2022121317A1 PCT/CN2021/107218 CN2021107218W WO2022121317A1 WO 2022121317 A1 WO2022121317 A1 WO 2022121317A1 CN 2021107218 W CN2021107218 W CN 2021107218W WO 2022121317 A1 WO2022121317 A1 WO 2022121317A1
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compound
biphenyl
esi
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张婷
林祖铭
张靖
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福建省中科生物股份有限公司
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
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    • C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
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    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
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    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/34—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having amino groups and esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
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    • 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
    • C07C233/29—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 an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
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    • 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
    • C07C271/16—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 singly-bound oxygen atoms
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    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/15—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with all hydroxy groups on non-condensed rings, e.g. phenylphenol
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    • 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
    • C07C65/01—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 hydroxy or O-metal groups
    • C07C65/105—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 hydroxy or O-metal groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicinal chemistry, in particular to a class of 1,1'-biphenyl-2,6-diphenol compounds with broad-spectrum antitumor activity and applications thereof.
  • Cancer also known as malignant tumor, is a malignant and common disease that seriously threatens human health, and has become the "second killer” after cardiovascular disease.
  • malignant tumor deaths accounted for 23.91% of all deaths among residents, and its morbidity and mortality rates have continued to rise in the past decade.
  • the present invention aims to develop a compound with broad-spectrum antitumor activity with high efficiency and low toxicity.
  • the present invention obtains a series of 1,1'-biphenyl-2,6-diphenol compounds through screening, design and synthesis, the compounds have the activity of inhibiting the proliferation of tumor cells.
  • One object of the present invention is to provide a 1,1'-biphenyl-2,6-diphenol compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the chemical structural formula of the compound is as shown in formula (I) Show:
  • R1, R2, R3, R4 are each independently selected from:
  • the heteroaryl group is a 3-10-membered heteroaryl group containing 1-3 kinds of heteroatoms in N, S, and O.
  • R1, R2, R3, R4 are respectively preferably selected from:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the 1,1'-biphenyl-2,6-diphenol compound represented by formula (I).
  • the present invention provides 1,1'-biphenyl-2,6-diphenol compounds represented by formula (I), pharmaceutically acceptable salts or stereoisomers thereof, and compounds comprising 1,1'-biphenyl-
  • formula (I) 1,1'-biphenyl-2,6-diphenol compounds represented by formula (I)
  • pharmaceutically acceptable salts or stereoisomers thereof and compounds comprising 1,1'-biphenyl-
  • compounds comprising 1,1'-biphenyl- The use of the pharmaceutical composition of 2,6-diphenol compounds in the preparation of antitumor drugs.
  • the specific use is for inhibiting tumor cell proliferation.
  • the present invention provides a new compound with good biological activity. Through the method of in vitro tumor cell activity test, it is found that it has inhibitory activity on tumor cell proliferation, and has the potential to develop anti-tumor drugs.
  • Electrospray (ESI) mass spectra were acquired on a Finnigan LCQ ion trap.
  • DCM dichloromethane
  • HPLC high performance liquid chromatography
  • TFA trifluoroacetic acid
  • DIPEA N,N-diisopropylethylamine
  • EDCI 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole
  • rt room temperature
  • EA ethyl acetate
  • DMAP 4-dimethylaminopyridine
  • DMP 2,2-dimethoxypropane
  • HATU 2-(7-azabenzotriazole)-N,NN,N'-tetramethylurea hexafluorophosphate
  • THF tetrahydrofluorofuran
  • Boc 2 O di-tert-butyl dicarbonate
  • DMF N,N-dimethylformamide
  • DME ethylene glycol dimethyl ether
  • PPTS pyridinium p-toluenesulf
  • the preparation method of compound 3 take 25ml reaction tube, add compound 2 (0.22mmol), compound 1 (0.18mmol), Cs 2 CO 3 (0.36 mmol), Pd(PPh 3 ) 4 (0.02 mmol), 1,4- Dioxane (2ml) replaced Ar gas and then placed in an oil bath at 80°C to react for 12h, and the reaction was completed by TLC detection. Filter through celite, remove the solvent under reduced pressure, and separate and purify compound 3 by column chromatography.
  • Preparation method of compound I-1 ⁇ I-6 take a 25ml reaction tube, add compound 3 (0.18mmol), 2mL of DCM, put it in an ice-ethanol bath (-15°C), slowly add 0.9ml of BBr3 (1.0M) dropwise in DCM), the reaction was naturally heated up for 12h, and the reaction was completed by TLC detection. The system was placed in an ice-water bath and quenched by adding 0.2 ml of MeOH. Then water and dichloromethane were added, followed by liquid separation extraction, drying over anhydrous sodium sulfate, concentration under reduced pressure, and separation and purification by column chromatography to obtain compounds I-1 to I-6.
  • Preparation of compound 7 take a 25ml reaction tube, add compound 6 (25mg, 0.07mmol), DMAP (1.3mg, 0.01mmol), EDCI (20mg, 0.10mmol), DIPEA (36ul, 0.21mmol) at room temperature and stir for 30min at room temperature, then add N-acetyl-L-isoleucine (0.08mmol), the reaction was carried out for 12h, and the completion of the reaction was detected by TLC. Saturated NaHCO 3 was added, extracted with dichloromethane, the organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain amide intermediate 7.
  • HepG2 and human lung cancer cells A549 were cultured in a petri dish with DMEM complete medium (containing 10% fetal bovine serum and 1X penicillin-streptomycin double antibody solution), and cells in logarithmic growth phase were taken. At 70%-80% confluence, after trypsinization, resuspend the cells in culture medium and count them, prepare a cell suspension with a density of about 7 ⁇ 104 cells/mL, and inoculate the cells in a 96-well plate with 100 ⁇ L of cell suspension per well. Incubate in a 37°C incubator until cells adhere.
  • DMEM complete medium containing 10% fetal bovine serum and 1X penicillin-streptomycin double antibody solution
  • DMSO methyl methoxysulfoxide
  • the culture medium was used to dilute to the required working concentration during the experiment. After discarding the culture medium in the 96-well plate, 100 ⁇ L of compound solutions with different working concentrations were added to the experimental group, 100 ⁇ L of culture medium was added to the blank control group, and 100 ⁇ L of antitumor drug cisplatin and gemcitabine solutions of different concentrations were added to the positive control group. Place in an incubator for culture.
  • the inhibitory effect of other compounds on HepG2 cells was better than that of the positive drug cisplatin, and the inhibitory effect of compound I-4 on HepG2 cells was Equivalent to the positive drug gemcitabine; the above compounds also have inhibitory effect on lung cancer A549 cells, but the inhibitory activity is slightly inferior to the positive drugs cisplatin and gemcitabine.
  • the biologically active 1,1'-biphenyl-2,6-diphenol compounds provided by the present invention have the activity of inhibiting the proliferation of tumor cells, have great potential for drug research and development, and can be used as lead compounds. in the development of anticancer drugs.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé 1,1'-biphényl-2,6-diphénolique et son utilisation. Le composé 1,1'-biphényl-2,6-diphénolique est un nouveau composé, et a une bonne activité biologique. Au moyen d'expériences in vitro liées à l'activité de cellules tumorales, il a été découvert que le composé a une activité inhibitrice sur la prolifération des cellules tumorales, et a le potentiel pour le développement d'un médicament antitumoral.
PCT/CN2021/107218 2020-12-10 2021-07-20 Composé 1,1'-biphényl-2,6-diphénolique et son utilisation WO2022121317A1 (fr)

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CN112500293B (zh) * 2020-12-10 2022-10-18 福建省中科生物股份有限公司 1,1′-联苯-2,6-二酚类化合物及其应用
CN114605236B (zh) * 2022-03-16 2023-12-29 福建省中科生物股份有限公司 联芳基酚类化合物及其药物组合物、制备方法和应用

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WO2008013963A2 (fr) * 2006-07-28 2008-01-31 University Of Connecticut Inhibiteurs d'hydrolase des amides d'acides gras
WO2009052319A1 (fr) * 2007-10-16 2009-04-23 Northeastern University Inhibiteurs de la monoacylglycérol lipase de modulation de l'activité cannabinoïde
CN101668425A (zh) * 2007-03-02 2010-03-10 田纳西州立大学研究基金会 三芳基/杂芳族大麻素类和其应用
WO2014134127A1 (fr) * 2013-02-26 2014-09-04 Northeastern University Nitro-esters cannabinergiques et analogues associés
CN112500293A (zh) * 2020-12-10 2021-03-16 福建省中科生物股份有限公司 1,1′-联苯-2,6-二酚类化合物及其应用

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CN1671639A (zh) * 2002-08-23 2005-09-21 康涅狄格大学 新型联苯大麻素和类似联苯的大麻素
WO2008013963A2 (fr) * 2006-07-28 2008-01-31 University Of Connecticut Inhibiteurs d'hydrolase des amides d'acides gras
CN101668425A (zh) * 2007-03-02 2010-03-10 田纳西州立大学研究基金会 三芳基/杂芳族大麻素类和其应用
WO2009052319A1 (fr) * 2007-10-16 2009-04-23 Northeastern University Inhibiteurs de la monoacylglycérol lipase de modulation de l'activité cannabinoïde
WO2009052320A1 (fr) * 2007-10-16 2009-04-23 Northeastern University Procédés et composés permettant la modulation de l'activité cannabinoïde
WO2014134127A1 (fr) * 2013-02-26 2014-09-04 Northeastern University Nitro-esters cannabinergiques et analogues associés
CN112500293A (zh) * 2020-12-10 2021-03-16 福建省中科生物股份有限公司 1,1′-联苯-2,6-二酚类化合物及其应用

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Title
DATABASE REGISTRY ANONYMOUS : "[1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-2'-(2-hydroxyethyl)- (CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-2'-(2-hydroxyethyl)[1,1'-biphenyl]-2,6-diol MF -C23 H32 O3 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942149, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "[1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-2'-(3-hydroxypropyl)- (CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-2'-(3-hydroxypropyl)[1,1'-biphenyl]-2,6-diol MF -C24 H34 O3 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942146, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "[1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-2'-(hydroxymethyl)-5'- (trifluoromethyl)-(CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-2'-(hydroxymethyl)-5'-(trifluoromethyl)[1,1'- biphenyl]-2,6-diol MF -C23 H29 F3 O3 SR -Other Sources Database: GVK BIO 1/1 -(C) FILE REGISTRY RN ", XP055942131, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "[1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-3'-(hydroxymethyl)- (CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-3'-(hydroxymethyl)[1,1'-biphenyl]-2,6-diol MF -C22 H30 O3 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942134, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "[1,1'-Biphenyl]-2-carboxamide, 4'-(1,1-dimethylheptyl)-2',6'-dihydroxy-N,N- bis(1-methylethyl)-5-(trifluoromethyl)-(CA INDEX NAME) OTHER CA INDEX NAMES: CN -4'-(1,1-Dimethylheptyl)-2',6'-dihydroxy-N,N-bis(1-methylethyl)-5- (trifluoromethyl)[1,1'-biphenyl]-2-carboxamide MF -C29 H40 F3 N O3 SR -Other ", XP055942108, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "[1,1'-Biphenyl]-3-carboxaldehyde, 4'-(1,1-dimethylheptyl)-2',6'-dihydroxy- (CA INDEX NAME) OTHER CA INDEX NAMES: CN -4'-(1,1-Dimethylheptyl)-2',6'-dihydroxy[1,1'-biphenyl]-3-carboxaldehyde MF -C22 H28 O3 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942155, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "[1,1'-Biphenyl]-3-carboxylic acid, 4'-(1,1-dimethylheptyl)-2',6'-dihydroxy-6-(1-methylethenyl)- (CA INDEX NAME) MF -C25 H32 O4 SR -Other Sources Database: ChemSpider (ChemZoo, Inc.) **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942157, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "1,1'-Biphenyl]-2,3',6-triol, 4-(1,1-dimethylheptyl)-6'-(3-hydroxypropyl)- (CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-6'-(3-hydroxypropyl)[1,1'-biphenyl]-2,3',6-triol MF -C24 H34 O4 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942119, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "1,1'-Biphenyl]-2,6-diol, 2'-(bromomethyl)-4-(1,1-dimethylheptyl)- (CA INDEX NAME) OTHER CA INDEX NAMES: CN -2'-(Bromomethyl)-4-(1,1-dimethylheptyl)[1,1'-biphenyl]-2,6-diol MF -C22 H29 Br O2 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942111, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-2'-(hydroxymethyl)-5'- (trifluoromethyl)-(CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-2'-(hydroxymethyl)-5'-(trifluoromethyl)[1,1'- biphenyl]-2,6-diol MF -C23 H29 F3 O3 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE I", XP055942122, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-3'-methyl- (CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-3'-methyl[1,1'-biphenyl]-2,6-diol MF -C22 H30 O2 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942116, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "1,1'-Biphenyl]-3,5-dicarboxylic acid, 4'-(1,1-dimethylheptyl)-2',6'-dihydroxy-, 3,5-dimethyl ester (CA INDEX NAME) OTHER CA INDEX NAMES: CN -3,5-Dimethyl 4'-(1,1-dimethylheptyl)-2',6'-dihydroxy[1,1'-biphenyl]-3,5- dicarboxylate MF -C25 H32 O6 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAIL", XP055942105, retrieved from STN *
GAREAU YVES, DUFRESNE CLAUDE, GALLANT MICHEL, ROCHETTE CHANTAL, SAWYER NICOLE, SLIPETZ DEBORAH M, TREMBLAY NATHALIE, WEECH PHILIP : "Structure activity relationships of tetrahydrocannabinol analogues on human cannabinoid receptors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 6, no. 2, 1 January 1996 (1996-01-01), AMSTERDAM, NL , pages 189 - 194, XP055942160, ISSN: 0960-894X, DOI: 10.1016/0960-894X(95)00573-C *
MINUTOLO F. ET AL.: "Metabolically Labile Cannabinoid Esters: A 'Soft Drug' Approach for the Development of Cannabinoid-Based Therapeutic Drugs", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, no. 17, 20 June 2007 (2007-06-20), XP022184927, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2007.06.055 *

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