WO2004037808A1 - Composes heterocycliques substitues en position 2 et composition antitumorale renfermant lesdits composes - Google Patents

Composes heterocycliques substitues en position 2 et composition antitumorale renfermant lesdits composes Download PDF

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WO2004037808A1
WO2004037808A1 PCT/KR2003/002258 KR0302258W WO2004037808A1 WO 2004037808 A1 WO2004037808 A1 WO 2004037808A1 KR 0302258 W KR0302258 W KR 0302258W WO 2004037808 A1 WO2004037808 A1 WO 2004037808A1
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mmol
compound
nmr
cdc1
300mhz
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Sang Sup Jew
Hyeung Geun Park
Boon Saeng Park
Doo Yeon Lim
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Chong Kun Dang Pharmaceutical Corp.
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D213/83—Thioacids; Thioesters; Thioamides; Thioimides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid

Definitions

  • the present invention relates to 2-substituted heterocyclic compounds and antitumor composition comprising the same.
  • telomere is located at the terminal end of chromosome in eukaryotic cell, and has a structure of uniquely repeated bases (guanine-rich sequence), and in case of vertebrate, hundreds to thousands of base sequence of telomere, 'TTAGGG', are serially connected, and this guarantees stability of chromosome and allows completion of DNA replication.
  • telomere nucleotides are lost to lead to shorter length, and when the length of the telomere becomes shorter than certain level, this functions as sign for no more cell division, causing instability of DNA and aging, resulting in cell death.
  • Enzyme involved in the replication of telomere is telomerase and it is directly responsible for endless multiplication of tumor cell.
  • telomere Since telomerase was discovered by Dr. Blackburn (Berkeley University) in 1984, studies have been intensively conducted.
  • the enzyme is reverse transcription enzyme, ribonucleoprotein complex consisting of RNA template and protein component and allows synthesis and maintenance of repeated structure of telomere, thereby enabling the length of telomere which is to be gradually reduced according to cell division to be maintained at a constant level, leading to infinite cell division, that is, multiplication of cancer cell.
  • Geron company discovered the existence of telomerase activity in 90 of 101 kinds of human carcinoma cell, and conformed by experiments that when telomerase in mouse was artificially destroyed, no more differentiation of cell was possible and aging was stimulated. Considering all the available results obtained until 1997, it was conformed that regardless of the kind of carcinoma, telomearse activity exists in at least 85 to 90%> of the carcinoma and no normal cell except germ cell showed the activity (Table 1).
  • telomere-telomerase is tumor-specific and selective
  • the antitumor agent using such mechanism can improve and resolve the side effects (nausea, vomiting, depilation and bleeding) due to absence of selectivity between normal cell and tumor cell.
  • cross resistance to the conventional drugs can be overcome.
  • Object of the present invention lies in providing novel compounds exhibiting telomerase- inhibitory activity based on novel tumor-selective telomere-telomerase action mechanism and antitumor agent comprising the same, to resolve the problems of conventional antitumor agent, i.e. side effects and cross resistance between related mechanisms on using chemotherapeutics.
  • the present invention provides novel compounds of the following formula I:
  • M means H, CN, NO 2 , OH, OR a , OC(O)R b , F, CI, Br, I, NH 2 , NHR C , NHC(O)R d or R e substituted at 3,4 or 5 position in case X is pyridine, at 3 or 4 position in case X is thiophene or furan, and R a ⁇ R e define C 1-4 alkyl;
  • Y means CO or CH 2 substituted at 2 or 6 position in case X is pyridine, or at 2 or 5 position in case X is thiophene or furan;
  • Z defines O, NH or S;
  • L is wherein, R t means that 2, 3, 4, 5 and 6 position of phenyl are independently substituted with hydrogen, methyl, methoxy, halogen, trihalogenmethyl, nitro, t-butyl or acetamido group;
  • N is substituted at 2 or 6 position, in case X is pyridine, or at 2 or 5 position, in case X is thiophene or furan, and selected among the following groups:
  • R f defines phenyl or C 1-4 alkyl.
  • L can be specifically exemplified as follows:
  • Said compounds according to the present invention are novel derivatives of small molecule, 6-substituted pyridine, 5 -substituted furan and 5-substituted thiophene exhibiting telomerase inhibition activity based on novel tumor selective telomere- telomerase mechanism.
  • in-vitro telomerase activity assay Telomeric Repeat Amplification protocol was conducted, and several kinds among the compounds showing superior activity were selected and subjected to in-vitro cytotoxicity test and in-vivo telomerase activity assay using nude mouse, thereby deriving antitumor candidate substance based on novel mechanism.
  • the compounds represented by the formula I can be synthesized according to the following reaction schemes 1 to 15.
  • 2,6-pyridinedicarboxylic acid commercial material
  • the compound 2 is subjected to partial reduction with NaBH 4 to convert the position 2 to hydroxymethyl group (compound 3), and subjected to partial oxidation and hydrolysis to lead to compound 5, which is basic parent nucleus necessary for the synthesis of telomerase inhibitor.
  • the compound 5 is subjected to esterfication with various benzenethiols to form compound 6 group included in the scope of the formula I.
  • R1 2,5-CH 3
  • R1 2,4,6-CI 1
  • R1 2,4 1 6-CI 41
  • R1 s p ⁇ nta-F m .R1 3,4-F 4m;R1 ⁇ 3,4-F n
  • R1 2-CI 4n
  • R1 4-CF 3 o
  • R1 3"CI 4o
  • 4-CI p R1 2,5-CI 4p
  • R1 2-Cl,4-F q
  • R1 2,6-CI *q
  • R1 3,5-CI 4r;
  • R1 2,4- F 4s; R1 -2,4-F t ;
  • R1 ⁇ e ⁇ ta-F 4t;
  • R1 2,4.0CH 3 4u;
  • 5-formylfuran-2-carboxylic acid (compound 12) is reacted with trimethyl orthoformate to convert position 5 to acetal group, subjected to condensation with various anilines to form compound 16, and the acetal protecting group is converted to formyl group by using p-toluenesulfonic acid thereby to form compound 17 group included in the scope of the formula I.
  • Compound 19 was obtained from 5-hydroxymethylfurfural (compound 18), commercial product, by introducing alkyl halide into the position 5 thereof. Alkylation of the compound 19 with various benzenetliiols forms compound 20 group included in the scope of the formula I, and alkylation of the compound 19 with various phenols according to the same method forms compound 21 group included in the scope of the formula I.
  • Compound 23 is obtained from 2,5-thiophene dicarboxylic acid (compound 22), commercial product, by introducing ester group to 2 and 5 positions thereof using thionyl chloride.
  • the compound 23 is subjected to partial reduction with NaBH 4 to convert the position 5 to hydroxymethyl group thereby to form compound 24, the compound 24 is subjected to partial oxidation to form compound 25, and the compound 25 is subjected to hydrolysis to yield compound 26 which is basic parent nucleus necessary for the synthesis of telomerase inhibitor.
  • Esterfication of the compound 26 with various phenols forms compound 27 group included in the scope of the formula I
  • esterfication of the compound 26 with various benzenetliiols forms compound 29 group included in the scope of the formula I. [Reaction scheme 7]
  • Alkyl halide is introduced to position 2 of the compound 24 synthesized according to the reaction scheme 6, and alkylation is conducted with various phenols to form compound 31.
  • the compound 31 is subjected to partial reduction using DIBAL- H(diisobutylaluminum hydride) and partial oxidation to form compound 33 group included in the scope of the formula I.
  • Alkylation of the compound 30 with various benzenethiols according to the same method leads to the formation of compound 34 group, and the compound 34 is subjected to partial reduction and partial oxidation to form compound 36 group included in the scope of the formula I.
  • Benzylic alcohol moiety of the compound 3 obtained in the reaction scheme 1 is protected with THP to form compound 37, and via hydrolysis, compound 38 is obtained.
  • the compound 38 is subjected to condensation with 3,4-dichlorobenzenethiol, commercial product, deprotection and acylation to form compounds 40 and 41 included in the scope of the formula I.
  • the compound 2 obtained in the reaction scheme 1 is used as the starting material and condensation is carried out with 3,4-dichlorobenzenethiol, commercial product, to form compound 44 included in the scope of the formula I.
  • the compound 50 of the reaction scheme 12 is reacted with TMS- diazomethane, methyl chloroformate, p-toluenesulfonyl chloride, acetic anhydride and methanesulfonyl chloride to form, respectively, compound 51, compound 52, compound 53, compound 54 and compound 55 which are included in the scope of the formula I.
  • the compound 6j of the reaction scheme 1 is oxidized with sodium chlorite to form compound 56 included in the scope of the formula I.
  • the compound 13r of the reaction scheme 3 is subjected to oxidation with sodium chlorite to form compounds 57, 58, 59 and 60 included in the scope of the formula I.
  • Compound 61 commercial product, is subjected to oxidation and methyl esterification of alcohol moiety on position 2 thereof to form compound 63.
  • the compound 63 is subjected to methylation of phenolic alcohol moiety at position 3, oxidation of nitrogen on pyridine ring and conversion of methyl group on position 6 to acetal via aldehyde thereby to form compound 69.
  • the compound 69 is subjected to condensation with thiophenol to form thioester (compounds 70 and 71), and subjected to deacetalization under an acid catalyst to form compounds 72 and 73 included in the scope of the formula I.
  • Another embodiment of the present invention is to provide telomerase inhibitor comprising the compound of the formula I.
  • Another embodiment of the present invention is to provide antitumor composition comprising the compound of the formula I as active component.
  • the antitumor composition comprising the compound of the formula I as active component can be used for parenteral or oral administration, e.g. liquid preparation such as syrup or emulsion, solid preparation such as tablets, capsules, granules or powder, and external preparation such as ointment, via mixing with proper vehicle.
  • liquid preparation such as syrup or emulsion
  • solid preparation such as tablets, capsules, granules or powder
  • external preparation such as ointment
  • Fig. 1 represents tumor volume change in in-vivo antitumor activity test for the compounds of Example 10 and Example 48 (control ⁇ ; Example 10, 20 mg/kg J& ; Example 48, 5 mg/kg ⁇ ; Example 48, 10 mg/kg A ; Example 48, 20 mg/kg •).
  • Fig. 2 represents body weight change in in-vivo antitumor activity test for the compounds of Example 10 and Example 48 (control ⁇ ; Example 10, 20 mg/kg . ; Example 48, 5 mg/kg ⁇ ; Example 48, 10 mg/kg A ; Example 48, 20 mg/kg •).
  • Example 12 6-formylpyridine-2-carbothionic acid-S-2,4,6-trichlorophenyl ester (61) The synthesis intermediate of the reaction scheme 1, the compound 5 (50 mg,
  • Example 32-1 6- dimethoxymethyl-pyridine-2-carboxylic acid methyl ester (8)
  • the compound 4 (5 g, 30.22 mmol) of the reaction scheme 1 and p-TsOH of a catalytic amount were dissolved in anhydrous methanol (100 ml). After an excess of trimethyl orthoformate (100 ml) was added thereto, the mixture was reacted at room temperature for 1 hour and methanol was removed under reduced pressure. Water (100 ml) was added to the residue solution and then an extraction process was conducted with ethylacetate (100 x 2).
  • Example 32-3 6-dimethoxymethyl-pyridine-2-carboxylic acid-(o-tolyl)amide
  • Dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et 3 N (91.9 ⁇ l, 0.65 mmol), followed by stirring for 5 min.
  • o-Toluidine (69.5 mg, 0.65 mmol) was added thereto, followed by stirring for 30min to conduct esterification. Water (2 ml) was added to the reaction solution and then an extraction process was conducted with dichloromethane (5 ml x 2).
  • the obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate ⁇ 8:1 to 5:1) to obtain the compound 10a (103.6 mg, yield 71%).
  • Example 32-6 6-dimethoxymethyl-pyridine-2-carboxylic acid-(4-fluoropheny) amide (lOd)
  • Example 32-8 6-dimethoxymethyl-pyridine-2-carboxylic acid-(4-bromophenyl) amide (lOf)
  • Example 32-13 6-dimethoxymethyl-pyridine-2-carboxylic acid-(2,3,4- trifluorophenyl)amide (10k)
  • dichloromethane (2 ml) was added to the compound 9 (100 mg, 0.51 mmol), HOBT (34.3 mg, 0.25 mmol), EDC (126 mg, 0.65 mmol) and Et 3 N (91.9 ⁇ l, 0.65 mmol), followed by stirring for 5 min.
  • 2,3,4-Trifluoroaniline (95.6 mg, 0.65 mmol) was added thereto to obtain the compound 10k (109.8 mg, yield 66%).
  • Example 32 6-formyl-pyridine-2-carboxylic acid-(o-tolyf)amide (11a) p-TsOH mono-hydrate (106 mg, 0.56 mmol) was put to the already obtained compound 10a (90 mg, 0.37 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 12hours. After confirming the completion of the reaction with TLC, NaHCO 3 (10 ml aqueous solution) was added thereto to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2).
  • Example 36 6-formyl-pyridine-2-carboxylic acid-(4-chlorophenyl)amide (lie) p-TsOH monohydrate (83.7 mg, 0.44 mmol) was added to the compound lOe
  • Example 37 6-formyl-pyridine-2-carboxylic acid-(4-bromophenyl)amide (llf) p-TsOH monohydrate (72.2 mg, 0.38 mmol) was added to the compound lOf (90 mg, 0.25 mmol) according to the same method as in Example 32, to obtain the final compound (46.5 mg, yield 61%).
  • Example 38 6-formyl-pyridine-2-carboxylic acid-(3,4-dichlorophenyf)amide (llg) p-TsOH monohydrate (75.3 mg, 0.40 mmol) was added to the compound lOg (90 mg, 0.26 mmol) according to the same method as in Example 32, to obtain the final compound (38.4 mg, yield 50%).
  • Example 39 6-formyl-pyridine-2-carboxylic acid-(2,5-dimethylphenyl)amide (llh) p-TsOH monohydrate (85.5 mg, 0.45 mmol) was added to the compound lOh (90 mg, 0.30 mmol) according to the same method as in Example 32, to obtain the final compound (55.6 mg, yield 73%).
  • Example 40 6-formyl-pyridine-2-carboxylic acid-(3,4-dimethylpheny ⁇ )amide (Hi) p-TsOH monohydrate (85.5 mg, 0.45 mmol) was added to the compound lOi (90 mg, 0.30 mmol) according to the same method as in Example 32, to obtain the final compound (57 mg, yield 75%).
  • Example 42 6-formyl-pyridine-2-carboxylic acid-(2,3,4-trifluorophenyl)amide (Ilk) p-TsOH monohydrate (78.7 mg, 0.41 mmol) was added to the compound 10k (90 mg, 0.28 mmol) according to the same method as in Example 32, to obtain the final compound (61.9 mg, yield 79%).
  • Dichloromethane (2 ml) was added to the compound 12 (50 mg, 0.35 mmol) of the reaction scheme 3, HOBT (24 mg, 0.18 mmol), EDC (75 mg,0.39 mmol) and triethylamine (50 ⁇ l , 0.33 mmol), followed by stirring for 5 min.
  • 2-Methylbenzenethiol 58.12 mg, 0.46 mmol was added thereto, followed by stirring for 30min to conduct esterification.
  • Water (2 ml) was added to the reaction solution and then an extraction process was conducted with dichloromethane (10 ml x 2).
  • the obtained organic solution was washed with saline (10 ml), dried with anliydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • the compound 12 (50 mg, 0.39 mmol) was used with 2-methoxybenzenethiol (65.6 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (64 mg, yield 63%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 3-methoxybenzenethiol (65.6 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (80.8 mg, yield 70%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 4-methoxy benzenethiol (65.6 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (66.5 mg, yield 65%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 4-fluorobenzenethiol (58.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (72.0 mg, yield 75%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 4-chlorobenzenethiol (66.5 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (72.0 mg, yield 75%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 3,4-dichlorobenzenethiol (82.3 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (79.1 mg, yield 73%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 2, 5 -dimethyl benzenethiol (49.2 mg, 0.33 mmol) according to the same method as in Example 44, to obtain the final compound (57.4 mg, yield 53%).
  • Example 55 5-formyl-furan-2-carbothionic acid-S-2,4,6-trichlorophenyl ester (131)
  • the compound 12 50 mg, 0.39 mmol
  • 2,4,6- trichlorobenzenethiol 49.2 mg, 0.33 mmol
  • Example 58 5-formyl-furan-2-carbothionic acid-S-3-chlorophenyl ester (13o) The compound 12 (50 mg, 0.39 mmol) was used with 3-chlorobenzenethiol
  • the compound 12 (50 mg, 0.39 mmol) was used with 2,6-dichlorobenzenethiol (81.8 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (68.1 mg, yield 71 %) .
  • Example 61 5-formyl-furan-2-carbothionic acid-S-3,5-dichlorophenyl ester (13r)
  • the compound 12 50 mg, 0.39 mmol
  • 3,5-dichloro benzenethiol 81.8 mg, 0.46 mmol
  • the compound 12 (50 mg, 0.39 mmol) was used with 2,4-difluoro benzenethiol (67.2 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (70.4 mg, yield 73%).
  • the compound 12 (50 mg, 0.39 mmol) was used with pentafluorobenzenethiol (92.4 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (55.7 mg, yield 53%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 2-methoxyphenol (57.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (55.8 mg, yield 63%).
  • Example 68 5-formyl-furan-2-carboxylic acid-O-4-methoxyphenyl ester (14e) The compound 12 (50 mg, 0.39 mmol) was used with 4-methoxyphenol (57.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (62.9 mg, yield 71%).
  • Example 69 5-formyl-furan-2-carboxylic acid-O-4-fluorophenyl ester (14f)
  • the compound 12 50 mg, 0.39 mmol
  • 4-fluorophenol 51.6 mg, 0.46 mmol
  • Example 71 5-formyl-furan-2-carboxylic acid-O-4-bromophenyl ester (14h)
  • the compound 12 50 mg, 0.39 mmol
  • 4-bromophenol 79.5 mg, 0.46 mmol
  • the compound 12 (50 mg, 0.39 mmol) was used with 3,4-dichlorophenol (74.9 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (77.9 mg, yield 76%).
  • Example 78 5-formyl-furan-2-carboxylic acid-O-2,3 5 4-trichlorophenyl ester (14o) The compound 12 (50 mg, 0.39 mmol) was used with 2,3,4-trichloro phenol
  • the compound 12 (50 mg, 0.39 mmol) was used with 2-chloro-4-fluorophenol (67.4 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (78.3 mg, yield 81%).
  • the compound 12 (50 mg, 0.39 mmol) was used with 4-t-butylphenol (69.1 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (77.4 mg, yield 79%).
  • the compound 12 (50 mg, 0.39 mmol) was used with phenol (43.3 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (52.1 mg, yield 67%).
  • Example 85 5-formyl-furan-2-carboxylic acid pyridin-2-yl ester (14v)
  • the compound 12 50 mg, 0.39 mmol
  • 2-hydroxy ⁇ yridine 43.7 mg, 0.46 mmol
  • Example 44 The compound 12 (50 mg, 0.39 mmol) was used with 2-hydroxy ⁇ yridine (43.7 mg, 0.46 mmol) according to the same method as in Example 44, to obtain the final compound (46.9 mg, yield 60%).
  • Example 86-3 5-dimethoxymethyl-furan-2-carboxylic acid-(m- tolyl)amide (16b) m-Toluidine (73.9 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16b (107.1 mg, yield 72%).
  • Example 86-4 5-dimethoxymethyl-furan-2-carboxylic acid-(p-tolyl)amide (16c) p-Toluidine (73.9 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16c (115.9 mg, yield 78%).
  • Example 86-5 5-dimethoxymethyI-furan-2-carboxyIic acid-(2-methoxyphenyl) amide (16d) o-Anisidine (84.9 mg, 0.69 mmol) was added to the compound 15 (100 mg, 0.54 mmol) according to the same method as in Example 86-2, to obtain the compound 16d (102.2 mg, yield 65%).
  • Example 86-6 5-dimethoxymethyl-furan-2-carboxylic acid-(4-methoxyphenyl) amide (16e) p-Anisidine (84.9 mg, 0.69 mmol) was added to the compound 15 (100 mg,
  • Example 86 5- formyl-furan-2-carboxylic acid-(2-methylphenyl)amide (17a)
  • p-TsOH monohydrate (91.3 mg, 0.48 mmol) was added to the obtained compound 16a (90 mg, 0.32 mmol), followed by replacing with argon.
  • Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours.
  • NaHCO 3 (aq 10 ml) was added to stop the reaction.
  • the mixture was extracted with dichloromethane (10 ml x 2).
  • the obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate ⁇ 6:1) to obtain the final compound (52.1 mg, yield 71%).
  • Example 88 5-formyl-furan-2-carboxylic acid-(4-methylphenyl)amide (17c) p-TsOH monohydrate (91.3 mg, 0.48 mmol) was added to the compound 16c (90 mg, 0.32 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO 3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2). The obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • Example 92 5-formyl-furan-2-carboxylic acid-(2,5-dimethylphenyl)amide (17g) p-TsOH monohydrate (88.2 mg, 0.46 mmol) was added to the compound 16g (90 mg, 0.31 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO 3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2).
  • Example 93 5-formyl-furan-2-carboxylic acid-(3,4-dimethylphenyl)amide (17h) p-TsOH monohydrate (88.2 mg, 0.46 mmol) was added to the compound 16h (90 mg, 0.31 mmol), followed by replacing with argon. Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO 3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2).
  • the obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate ⁇ 6:1) to obtain the final compound (49.0 mg, yield 65%).
  • Example 94 5-formyl-furan-2-carboxylic acid-(4-trif ⁇ uoromethanepheny ⁇ )amide (17i)
  • p-TsOH monohydrate (77.9 mg, 0.41 mmol) was added to the compound 16i (90 mg, 0.27 mmol), followed by replacing with argon.
  • Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours. After confirming the completion of the reaction with TLC, NaHCO 3 (aq 10 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (10 ml x 2).
  • the obtained organic solution was washed with saline (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • Example 95 5-formyl-furan-2-carboxylic acid-(2,3,4-trifluorophenyl)amide (17j)
  • p-TsOH monohydrate (81.5 mg, 0.43 mmol) was added to the compound 16j (90 mg, 0.29 mmol), followed by replacing with argon.
  • Anhydrous benzene (20 ml) was added thereto, followed by heating under reflux for 24hours.
  • NaHCO 3 (aq 10 ml) was added to stop the reaction.
  • the mixture was extracted with dichloromethane (10 ml x 2).
  • Example 97 5-(m-torylsulfanylmethyl)-furan-2-carbaldehyde (20b)
  • the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg) and m-methylbenzenethiol (50.1 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (50.5 mg, 63%).
  • Example 98 5-(p-tolylsulfanylmethyf)-furan-2-carbaldehyde (20c)
  • the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5, anhydrous potassium carbonate (62 mg) and p-methylbenzenethiol (50.1 mg, 0.41 mmol) were used according to the same method as in Example 96, to obtain the final compound (60 mg, 63%).
  • Example 99 5-(2-methoxy-phenylsulfanylmethyl-furan-2-carbaldehyde (20d)
  • the compound 19 50 mg, 0.34 mmol
  • anhydrous potassium carbonate 60 mg
  • 2-methoxybenzenethiol 57.4 mg, 0.41 mmol
  • Example 109 5-(4-methoxy-phenoxymethyl)-furan-2-carbaldehyde (21b)
  • the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 4-methoxyphenol (50.8 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (56.0 mg, 71%).
  • Example 110 5-(4-chloro-phenoxymethyf)-furan-2-carbaldehyde (21c)
  • the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with 4-chlorophenol (52.7 mg, 0.41 mmol) according to the same method as in Example 96, to obtain the final compound (70.8 mg, 88%).
  • Example 117 5-(2,3 ? 4,5,6-pentafluoro-phenoxymethyl)-furan-2-carbaldehyde (21j)
  • the compound 19 (50 mg, 0.34 mmol) of the reaction scheme 5 and anhydrous potassium carbonate (62 mg, 0.45 mmol) were used with pentafluorophenol
  • Example 125-1 2,5-thiophene dicarboxylate (23) 2,5-Thiophenedicarboxylic acid (5 g, 29 mmol), which is compound 22 and commercial, was dissolved in methanol (300 ml) and thionyl chloride (SOCl 2 ) was slowly added dropwise thereto at 0 ° C. The reaction vessel was warmed up to room temperature, followed by reflux for 3hours. After confirming the disappearance of the starting material using TLC, methanol was removed under reduced pressure. The residue was dissolved in 200 ml of chloroform and the solution was slowly added to 300ml of chloroform saturated with NH 3.
  • SOCl 2 thionyl chloride
  • the water layer was titrated with IN HC1 solution in pH 1-2 and then extracted with ethyl acetate (200 ml x 5) to obtain the desirable compound 25 (1.2 g, yield 59%).
  • Example 131 5-formyl-thiophene-2-carboxylic acid-3,4-dichlorophenyl ester (27g) According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et 3 N (58.5 ⁇ l, 0.42 mmol), followed by stirring for 5 min and then 3,4-dichlorophenol (61.9 mg, 0.38 mmol) was added thereto to obtain the final compound (65.5 mg, yield 68%).
  • Example 132 5-formyl-thiophene-2-carboxylic acid-2,5-dimethylphenyl ester (27h) According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC
  • Example 138 5-formyl-thiophene-2-carboxylic acid-2,4-difluorophenyl ester (27n) According to the same method as in Example 125, dichloromethane (2 ml) was added to the compound 26 (50 mg, 0.32 mmol), HOBT (21.6 mg, 0.16 mmol), EDC (79.8 mg, 0.42 mmol) and Et 3 N (58.5 ⁇ l, 0.42 mmol), followed by stirring for 5 min and then 2,4-difluorophenol (47.2 mg, 0.38 mmol) was used thereto to obtain the final compound (52.4 mg, yield 61%).
  • the comound 24 (5 g, 29.0 mmol) was dissolved in anhydrous methylene chloride (200 ml).
  • Et N (8 ml, 58 mmol) and methanesulfonyl chloride (2.78 ml, 43.8 mmol) were sequently added dropwise at 0 ° C and then the mixture was reacted at room temperature for 3 hours, H O (100 ml) was added thereto to stop the reaction.
  • An extracting process was conducted with methylene chloride (10 ml x 2). The obtained organic solution was washed with brine (10 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure.
  • Example 144-3 5-(m-tolyloxymethy ⁇ )thiophene-2-carboxylic acid methyl ester (31b) According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then m-methylphenol (68.1 mg, 0.63 mmol) was added thereto to obtain the compound 31b (118.2 mg, yield 85%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then m- methoxyphenol (78.2 mg, 0.63 mmol) was added thereto to obtain the compound 31c (118.0 mg, yield 80%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K CO 3 (86.8 mg, 0.63 mmol) and then p-methoxyphenol (78.2 mg, 0.63 mmol) was added thereto to obtain the compound 3 Id (123.9 mg, yield 84%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then p-fluorophenol (70.5 mg, 0.63 mmol) was added thereto to obtain the compound 31e (124.1 mg, yield 88%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then p-bromophenol (142.2 mg, 0.63 mmol) was added thereto to obtain the compound 3 If (118.0 mg, yield 82%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then 3,4-dichlorophenol (102.9 mg, 0.63 mmol) was added thereto to obtain the compound 31g (142.0 mg, yield 85%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then 2,5-dimethylphenol (76.9 mg, 0.63 mmol) was added thereto to obtain the compound 3 lh (127.0 mg, yield 87%).
  • anliydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then pentafluorophenol (115.9 mg, 0.63 mmol) was added thereto to obtain the compound 31i (143.4 mg, yield 80%).
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then p-trifluoromethanephenol (102.2 mg, 0.63 mmol) was added thereto to obtain the compound 31 k ( 134 mg, yield 81%).
  • Example 144-13 5-(4-t-butylphenoxymethyl)thiophene-2-carboxylic acid methyl ester (311)
  • Example 144-2 According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then 4-t-butyl-phenol (94.6 mg, 0.63 mmol) was added thereto to obtain the compound 31k (134.7 mg, yield 88%).
  • Example 144-14 5-(2-chloro-4-methoxyphenoxymethyl)thiophene-2-carboxylic acid methyl ester (31m) According to the same method as in Example 144-2, anhydrous DMF (20 ml) was added to the compound 30 (100 mg, 0.53 mmol) and K 2 CO 3 (86.8 mg, 0.63 mmol) and then 2-chloro-4-methoxyphenol (92.2 mg, 0.63 mmol) was added thereto to obtain the compound 31m (148 mg, yield 90%>).
  • Example 144 5-(o-tolyloxymethyl)thiophene-carbaIdehyde (33a)
  • the compound 31a (100 mg, 0.38 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere, the temperature of the reaction solution was cooled to -78 ° C and DIBA1-H (1.0 M solution in toluene, 0.4 ml) was slowly added dropwise thereto. After reacting for 2 hours at -78 ° C, the reaction was quenched with Rochelle (saturated, 20 ml) solution. The resultant was extracted with dicliloromethane (5 ml x 2).
  • the obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure to obtain residue.
  • the residue was dried under vacuum, crude compound was dissolved in acetone (50 ml) without the more separation process and an oxidation was conducted with an excess of MnO 2 .
  • the resultant was filtered under reduced pressure with Celite545 and the filtrate was dried under reduced pressure to obtain residue.
  • the compound 31e (100 mg, 0.37 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C, reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO 2 to obtain the final compound (50.5 mg, yield of two steps: 57%).
  • the compound 31h (100 mg, 0.36 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO 2 to obtain the final compound (56.1 mg, yield of two steps: 63%).
  • the compound 31 j (100 mg, 0.35 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO 2 to obtain the final compound (43.8 mg, yield of two steps: 49%).
  • DIBAl-H 1.0 M solution in toluene, 0.4 ml
  • Example 154 5-(4-trifluoromethanephenoxymethyl)thiophene-2-carbaldehyde (33k) According to the same method as in Example 144, the compound 31k (100 mg,
  • Example 155 5-(t-butylphenoxymethyl)thiophene-2-carbaldehyde (331) According to the same method as in Example 144, the compound 311 (100 mg,
  • reaction scheme 7 0.35 mmol of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.4 ml) and oxidation was carried out with MnO 2 to obtain the final compound (48.3 mg, yield of two steps: 51%).
  • DIBAl-H 1.0 M solution in toluene, 0.4 ml
  • the compound 34a (90 mg, 0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere, the temperature of the reaction solution was cooled to -78 ° C and DIBAl-H (1.0M solution in toluene, 0.35 ml) was slowly added dropwise thereto. After reacting for 2 hours at -78 ° C, the reaction was quenched with Rochelle (saturated, 20 ml) solution. The resultant was extracted with dichloromethane (5 ml x 2). The obtained organic solution was washed with saline (5 ml), dried with anhydrous magnesium sulfate and subjected to concentration under reduced pressure to obtain residue.
  • the compound 34b (90 mg, 0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO to obtain the final compound (42.1 mg, yield of two steps: 53%).
  • the compound 34d (90 mg, 0.32 mmol) of the reaction scheme 7 was dissolved in anhydrous toluene (50 ml) under argon atmosphere. After the temperature of the reaction solution was cooled to -78 ° C , reduction was conducted with DIBAl-H (1.0 M solution in toluene, 0.35 ml) and oxidation was carried out with MnO 2 to obtain the final compound (53.2 mg, yield of two steps: 66%).
  • Example 164 6-acetoxymethylpyridine-2-carbothionic acid-S-(3,4- dichlorophenyl)ester (41)
  • the compound 40 (8.4 mg, 0.027 mmol) was dissolved in pyridine (0.5 ml) and acetic anhydride (25 ⁇ 1, 0.27 mmol) was added thereto, followed by stirring at room temperature. After 8 hours, water was added to the reaction solution and then an extraction process was conducted with ethyl acetate.
  • Example 165 pyridine-2-carbothionic acid-S-(3,4-dichlorophenyl)ester (43)

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Abstract

La présente invention concerne des composés hétérocycliques substitués en position 2 et une composition antitumorale renfermant lesdits composés. Les composés de l'invention ont un effet inhibiteur marqué de la télomérase reposant sur un nouveau mécanisme (télomère-télomérase) permettant de résoudre les problèmes survenus pendant la chimiothérapie, tels qu'effets secondaires et résistance croisée entre des mécanismes liés à l'emploi de la chimiothérapie. De plus, la composition antitumorale renfermant le composé de l'invention inhibe efficacement la croissance des cellules cancéreuses.
PCT/KR2003/002258 2002-10-24 2003-10-24 Composes heterocycliques substitues en position 2 et composition antitumorale renfermant lesdits composes WO2004037808A1 (fr)

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WO2011045224A1 (fr) 2009-10-12 2011-04-21 Bayer Cropscience Ag 1-(pyrid-3-yl)-pyrazole et 1-(pyrimid-5-yl)-pyrazole en tant qu'agents antiparasites
US7956055B2 (en) 2008-03-25 2011-06-07 Allergan, Inc. Substituted gamma lactams as therapeutic agents
WO2018018035A1 (fr) * 2016-07-22 2018-01-25 Virginia Commonwealth University Promédicaments et formes protégées du 5-hydroxyméthylfurfural (5-hmf) et de ses dérivés
JP2018509442A (ja) * 2015-03-25 2018-04-05 ノバルティス アーゲー Ｆｇｆｒ４阻害剤としてのホルミル化ｎ−複素環式誘導体
FR3080375A1 (fr) * 2018-04-24 2019-10-25 Surfactgreen Procede de synthese de 5-dialkylacetal-2-furoates d'alkyle et leur utilisation dans la preparation d'agents tensioactifs biosources

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Publication number Priority date Publication date Assignee Title
US7956055B2 (en) 2008-03-25 2011-06-07 Allergan, Inc. Substituted gamma lactams as therapeutic agents
WO2011045224A1 (fr) 2009-10-12 2011-04-21 Bayer Cropscience Ag 1-(pyrid-3-yl)-pyrazole et 1-(pyrimid-5-yl)-pyrazole en tant qu'agents antiparasites
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US10875834B2 (en) 2016-07-22 2020-12-29 Virginia Commonwealth University Prodrug and protected forms of 5-hydroxymethylfurfuranal (5-HMF) and its derivatives
FR3080375A1 (fr) * 2018-04-24 2019-10-25 Surfactgreen Procede de synthese de 5-dialkylacetal-2-furoates d'alkyle et leur utilisation dans la preparation d'agents tensioactifs biosources
EP3560916A1 (fr) * 2018-04-24 2019-10-30 Surfactgreen Procédé de synthèse de 5-dialkylacétal-2-furoates d'alkyle et leur utilisation dans la préparation d'agents tensioactifs biosourcés

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