WO2007104254A1 - Nouveau type de dérivés de pyrimidine ayant une petite molécule, procédés de préparation et utilisations desdits dérivés - Google Patents

Nouveau type de dérivés de pyrimidine ayant une petite molécule, procédés de préparation et utilisations desdits dérivés Download PDF

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WO2007104254A1
WO2007104254A1 PCT/CN2007/000793 CN2007000793W WO2007104254A1 WO 2007104254 A1 WO2007104254 A1 WO 2007104254A1 CN 2007000793 W CN2007000793 W CN 2007000793W WO 2007104254 A1 WO2007104254 A1 WO 2007104254A1
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preparation
hydrogen
mhz
nmr
replaced
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PCT/CN2007/000793
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Chinese (zh)
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Youhong Hu
Liguang Lou
Gang Cheng
Yongping Xu
Fuchun Xie
Weidong Tang
Jia Li
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel 2,4,5-substituted pyrimidine small molecule compounds, processes for their preparation, and their antitumor and antiviral activities. Specifically, the present invention relates to a novel substituted pyrimidine small molecule compound synthesized by a multicomponent reaction, which has high antitumor and antiviral activity and is useful as an antitumor and antiviral drug. The invention also relates to methods of preparation and use of such compounds. BACKGROUND OF THE INVENTION Tumors and viruses are diseases that seriously endanger human health and are difficult to overcome, and the degree of harm is increasing. At present, malignant tumors have become the first killer of Chinese urban residents.
  • the outbreak of SARS virus and highly pathogenic avian influenza virus in recent years has seriously affected people's normal production and living order.
  • countries around the world have stepped up research on anti-tumor and anti-viral drugs.
  • China's research on innovative drugs in this area is relatively backward.
  • the invention develops novel pyrimidine small molecule compounds, and develops a new class of antitumor and antiviral compounds through in-depth structure-activity relationship research.
  • One object of the present invention is to provide a novel class of pyrimidine small molecule compounds and methods for their synthesis.
  • a commercially available chromone compound is used as a raw material, and a halogenated product obtained by halogenation is used as a component of a multicomponent reaction, and is coupled with various aryl or heterocyclic boronic acid compounds or thio nitrogen heterocyclic compounds. Further, it is condensed with an anthracene compound to obtain a pyrimidine small molecule compound.
  • a further object of the present invention is to select a highly active antitumor and antiviral effect from such novel pyrimidine compounds by pharmacological screening, and to develop a drug which is simple and more active for antitumor and antiviral drugs. . '
  • R 2 is a various substituted aromatic ring, a heterocyclic ring or the like; R 2 may also be SR 2 or S0 2 R 2 , wherein
  • R 2 various 5-membered nitrogen heterocycles of 2-(1-alkylimidazolyl) or 3-(4 ⁇ -1,2,4-triazolyl);
  • R 3 is hydrogen, an alkyl group, a substituted or unsubstituted phenyl group, a heterocyclic substituent group, a thiol group, a substituted or unsubstituted amino group, a decyloxy group or the like; a pyrimidine compound having a structure of the above general formula of the present invention is further preferred.
  • the compound is:
  • R1 is hydrogen, 4-chloro, 4-fluoro, 4-bromo, 4-indolyl, 4-isobutyl, 4-decyloxy, 4-nitro group;
  • R 2 is p-methoxyphenyl, m-decyloxyphenyl, 2-methoxyphenyl, p-trifluorodecyl Phenyl, m-trifluorodecylphenyl, p-fluorophenyl, 2-fluorophenyl, p-chlorophenyl, p-isobutylphenyl, p-nonylthiophenyl, p-aminophenyl, p-substituted aminobenzene , 3-alkyl-4-methoxyphenyl, 3, 4, 5-trimethoxyoxyphenyl, 3-P-p-peptidyl, 3-pyridyl, 4-pyridyl;
  • R3 is hydrogen, methyl, isobutyl, phenyl, p-aminophenyl, p-chlorophenyl, 4-pyridyl, decylthio, substituted or unsubstituted amino, methoxy.
  • Particularly preferred compounds of the invention include:
  • R1 is hydrogen, R3 is isobutyl, R 2 is SR 2 ' or S0 2 R 2 ', R2' is 2-(1-mercaptoimidazolyl); R1 is hydrogen, and R2 is p-isobutylphenyl.
  • R3 is p-aminophenyl;
  • R1 is hydrogen, R2 is p-nonyloxyphenyl, R3 is methyl, hydrogen, methoxy, amino, formylamino, decylamino, dinonylamino, 3-chloro-4- Trifluoromethylurea, thiourea;
  • R1 is hydrogen, R2 is p-thiophenyl, R3 is amino;
  • R1 is hydrogen, R2 is p-methylaminophenyl, R3 is amino;
  • R1 is hydrogen, R2 is 3-mercapto-4-methoxyphenyl, R3 is a fluorenyl group, an amino group; or
  • R1 is hydrogen, R2 is a p-diaminoaminophenyl group, and R3 is an amino group.
  • the present invention still further provides the use of the above pyrimidine small molecule compound for the preparation of antitumor and antiviral drugs.
  • Method 1 Add iodochromone a, Pd(PPh 3 ) 4 , aryl or heterocyclic boronic acid compound and potassium carbonate to the bottle, then add tetrahydrofuran, acetonitrile, dioxane or DMF, and stir at 50 ° C overnight. Add hydrazine and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and stir at room temperature.
  • Example 2 Preparation of c-2 0.286 mmol of al, 1.14 mmol of potassium carbonate and 0.314 mmol of 2-decyl-1-mercaptoimidazole were placed in a small test tube, added to DMF, and stirred at room temperature for 4 h. An additional 0.43 mmol of phenylhydrazine was added and stirred overnight. The solvent was evaporated to dryness.
  • Example 11 Preparation of c-11 0.2 mmol of 6-chloro-3-iodochromone, 0.8 mmol of potassium carbonate and 0.21 mmol of 2-mercapto-1-methylimidazole were added to a small test tube, DMF was added, and stirred at room temperature for 4 h. . Add 0.3 mmol of acetamidine and stir overnight. The solvent was evaporated to dryness.
  • Example 15 Preparation of c-15 A solid (c-15) was obtained in the same manner as in Example c-14 except that ethylbenzene was changed to t-butylhydrazine.
  • Example 16 Preparation of c-16 except for the conversion of 6-chloro-3-iodochromone to 6-fluoro-3 - Color ketone, prepared in the same manner as in Example c-14 to give a solid (c-16).
  • Example 17 Preparation of c-17 except that 6-chloro-3-chromozone was replaced with 6-fluoro-3-iodochromone, and ethyl hydrazine was replaced with benzamidine. Prepared in the same manner as in Example c-14 to give a solid (c-17).
  • Example 18 Preparation of c-18 except that 6-chloro-3-iodochromone was replaced by 6-bromo-3-iodochromone, as in Example c-14 The method was prepared to give a solid (c-18).
  • Example 19 Preparation of c-19 except that 6-chloro-3-iodochromone was replaced with 6-bromo-3-iodochromone, and ethyl hydrazine was replaced with 4-mercaptopyridine. Further, it was prepared in the same manner as in Example c-14 to give a solid (c-19).
  • Example 20 Preparation of c-20 except that 6-chloro-3-iodochromone was replaced by 6-tert-butyl-3-iodochromone, and according to Example C-14 Prepared in the same manner to give a solid (c-20).
  • Example 21 Preparation of c-21 except that 6-chloro-3-indole was replaced with 6-tert-butyl-3-iodochromone, and acetic acid was replaced with 4-mercaptopyridine. Further, it was prepared in the same manner as in Example c-14 to give a solid (c-21).
  • Example 22 Preparation of c-22 0.15 mmol of 6-methyl-3-iodochromone, 0.6 mmol of potassium carbonate, 0.158 mmol of 2-mercapto-1-nonyl imidazole was added to a small test tube and added DMF, stirring at room temperature for 4 ho plus 0.23 mmol of 4-mercaptopyridine, stirring overnight. The solvent was evaporated to dryness, and then purified (jjjjjd
  • Example 23 The preparation of c-23 was carried out in the same manner as the preparation of c-22 except that 4-mercaptopyridine was changed to t-butylindole, and finally solid (c-23).
  • Example 24 Preparation of c-24 Add 0.2 mmol of 6-fluorenyl-3-chromanone, 0.8 mmol of potassium carbonate, 0.21 mmol of 3-mercapto-1,2,4-triazole into a small test tube, and add DMF. Stir at room temperature for 10 h. Further, 0.3 mmol of 4-mercaptopyridine was added and stirred overnight. The solvent was evaporated to dryness, and then purified to silica gel column chromatography (chlorobenzene and EtOAc).
  • Example 25 Preparation of c-25 except that 4-mercaptopyridine was replaced with t-butyl oxime, a solid was obtained in the same manner as in Example 24 ( C-25).
  • Example 26 Preparation of c-26 except that 6-mercapto-3-iodochromone was replaced with 6-nitro-3-iodochromone, 4-mercaptopyridine was changed to tert-butylfluorene, and stirred at 70 ° C. Prepared in the same manner as in Example 24, except overnight, to give a solid (c-26).
  • Example 27 Preparation of c-27 0.3 mmol of 6-methoxy-3-iodochromone, 1.2 mmol of potassium carbonate, 0.31 mmol of 2-mercapto-1-indolizole was added to a small test tube, DMF was added, and stirred at room temperature. 10h. Plus 0.
  • Example 29 Preparation of c-29 0.15 mmol 6-decyloxy-3- Iodine ketone, 0.6 mmol of potassium carbonate, 0.151 mmol of 2-decyl-1-mercaptoimidazole were added to a small test tube, DMF was added, and the mixture was stirred at room temperature for 10 h. An additional 0.23 mmol of benzamidine was added and stirred at room temperature overnight. The solvent was evaporated to dryness, and then purified to silica gel column chromatography (chlorobenzene and EtOAc).
  • Example 34 Preparation of c-34 0.2 mmol of 6-decyloxy-3-iodochromone, 0.8 mmol of potassium carbonate and 0.21 mmol of 2-mercapto-1-indolizole were added to a small test tube, DMF was added, and stirred at room temperature. 10h. Add 0.3 mmol of hydrazine and stir at room temperature overnight. The solvent was evaporated to dryness, purified by silica gel column chromatography (chloroform ram and Yue alcohol), the solvent was evaporated to dryness to give a solid (c -34).
  • Example 40 Preparation of e-4 The specific procedure was the same as the preparation of e -1, except that ethyl hydrazine was changed to 4-mercaptopyridine, and finally compound e-4 was obtained.
  • Example 45 Preparation of e-9 e _l prepared with the specific operation, but will be replaced by Yue phenylboronic acid for phenylboronic acid trifluoroacetic Yue, Yue amidine acetamidine into benzene, to give the final compound e- 9.
  • Example 46 Preparation of e-10 was prepared in the same e _i specific operation, but will methoxyphenylboronic acid into p-trifluoromethylphenyl boronic acid, p-aminophenyl replaced by acetamidine amidine Yue, to give the final compound E- 10.
  • Example 47 Preparation of e-11 The specific procedure is the same as the preparation of e- i except that the p-methoxyphenyl boronic acid is replaced with p-trifluoromethylphenylboronic acid, and the ethyl bromide is replaced with 4-mercaptopyridine.
  • Compound el l The specific procedure is the same as the preparation of e- i except that the p-methoxyphenyl boronic acid is replaced with p-trifluoromethylphenylboronic acid, and the ethyl bromide is replaced with 4-mercaptopyridine.
  • Compound el l Compound el l.
  • Example 48 Preparation of e-12 The specific operation was the same as the preparation of e- i except that p-methoxyphenylboronic acid was replaced with p-trifluorodecylphenylboronic acid, and ethyl hydrazine was replaced with p-chlorobenzoquinone. Compound e-12.
  • Example 49 Preparation of e-13 The specific procedure was the same as the preparation of e-1 except that the p-methoxyphenyl boronic acid was replaced with p-trifluorodecylphenylboronic acid, and the ethyl bromide was changed to t-butylfluorene.
  • E- 13 The specific procedure was the same as the preparation of e-1 except that the p-methoxyphenyl boronic acid was replaced with p-trifluorodecylphenylboronic acid, and the ethyl bromide was changed to t-butylfluorene.
  • Example 50 Preparation of e-14 The specific procedure was the same as the preparation of e- i except that p-methoxyphenylboronic acid was replaced with p-fluorophenylboronic acid, and finally compound e-14 was obtained.
  • Example 51 Preparation of e-15 was prepared in the same e _i specific operation, but will be replaced by Yue phenylboronic acid p-fluorophenyl boronic acid, replaced by acetamidine benzamidine, to give the final compound e-15.
  • Example 53 Preparation of e-17 was prepared in the same e _i specific operation, but will be replaced by Yue-phenyl boronic acid p-fluorophenyl, 4-amidino-acetamidine replaced by pyridine, to give the final compound e-17 .
  • Example 54 Preparation of e-18 The specific operation is the same as the preparation of e- i except that p-nonylphenylboronic acid is replaced with p-fluorophenylboronic acid, and ethyl hydrazine is replaced with p-chlorobenzoquinone, and finally compound e-18 is obtained.
  • Example 55 Preparation of e-19 The specific procedure was the same as the preparation of e i except that p-methoxyphenyl boronic acid was replaced by p-fluorophenylboronic acid, and ethyl hydrazine was changed to t-butyl hydrazine, and finally compound e-19 was obtained.
  • Example 56 Preparation of e-20 The specific procedure was the same as the preparation of e-1 except that p-methoxyphenylboronic acid was replaced with p-tert-butylphenylboronic acid, and ethyl hydrazine was replaced with phenylhydrazine, and finally compound e- 20.
  • Example 57 Preparation of specific operations with the e-21 e _i, but will be replaced by methoxyphenylboronic acid tert-butylphenyl boronic acid, p-aminobenzoic replaced acetamidine benzamidine, to give the final compound e -twenty one.
  • Example 58 Preparation of e-22 The specific procedure was the same as the preparation of e-1 , except that p-nonylphenyl boronic acid was replaced with p-tert-butylphenylboronic acid, and ethyl hydrazine was replaced with p-chlorobenzoquinone. -twenty two.
  • Example 59 Preparation of e-23 The specific procedure was the same as the preparation of e i except that p-methoxyphenylboronic acid was replaced with p-tert-butylphenylboronic acid, and ethyl hydrazine was changed to t-butyl hydrazine, and finally compound e- twenty three.
  • Example 62 Preparation of e-26 was prepared in the same e _i specific operation, but will be replaced methoxyphenylboronic acid 3-thiophene boronic acid, acetamidine replaced Yue amidine p-aminophenyl, and finally the compound e-26.
  • Example 63 The preparation of e-27 was carried out in the same manner as the preparation of e- i except that p-methoxyphenylboronic acid was replaced with 3-thiopheneboronic acid, and ethyl hydrazine was replaced with 4-mercaptopyridine, and finally compound e-27 was obtained.
  • Example 64 Preparation of e-28 The specific operation is the same as the preparation of e -1, except that the p-methoxyphenylboronic acid is replaced with 3-thiopheneboronic acid, the ethyl hydrazine is replaced with p-chlorophenylhydrazine, and the compound e-28 is obtained.
  • Example 70 Preparation of e-34 The specific procedure was the same as the preparation of e- i except that 3-iodochromone was replaced by 6-methoxy-3-iodochromone, and the compound was finally obtained. E-34.
  • Example 72 Preparation of e-36 The specific operation is the same as the preparation of e-1, except that 3-iodochromone is replaced by 6-chloro-3-iodochromone, and p-nonylphenylboronic acid is replaced by p-tert-butylphenylboronic acid. Aminophenylhydrazine, the final compound e-36.
  • Example 73 Preparation of specific operations with e _i e-37, except that 3- iodochromone replaced methoxy-3-iodochromone of Yue phenylboronic acid into p-tert Phenylboronic acid, acetamidine to p-aminobenzidine, and finally compound e-37.
  • Example 74 Preparation of specific operations with e _i e-38, except that 3-iodo-6-nitro chromone replaced --3- iodochromone, acetamidine benzamidine replaced amino, to give the final compound E-38.
  • Example 75 Preparation of e-39 E _i prepared with the specific operation, but one color will be replaced by 3-iodo-6- yl Yue --3- iodochromone of Yue phenylboronic acid tert-butyl phenyl boronic acid replaced, to replace acetamidine Aminobenzidine, the final compound e-39.
  • Example 77 Preparation of e-41 The specific procedure was the same as the preparation of e- i except that p-nonylphenylphenylboronic acid was replaced with p-tert-butylphenylboronic acid, and ethyl hydrazine was replaced with 4-mercaptopyridine. E-41.
  • Example 79 Preparation of e-43 Iodochromone a, 10% Pd/C, m-methoxyphenylboronic acid compound and potassium carbonate were added to a bottle, and then acetonitrile and water were added thereto, and stirred at 50 ° C overnight, and filtered. To the Pd/C, added water, extracted with ethyl acetate, dried over sodium sulfate, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The solvent was evaporated, and purified by column chromatography eluting elut elut elut
  • Example 80 Preparation of e-44 The procedure was the same as that of e-43 except that m-decyloxyphenylboronic acid was replaced with m-trifluorodecylphenylboronic acid to give compound e- 44.
  • Example 81 Preparation of e-45 was prepared in the same e _43 specific operation, but the inter-methoxyphenylboronic acid into Yue trifluoromethyl phenyl boronic acid acetamidine replaced guanidine, to give the final compound e-45.
  • Example 83 Preparation of e-47 with the same operation as e - The preparation of 43 was carried out by replacing m-decyloxyphenylboronic acid with o-nonyloxyphenylboronic acid, and converting ethyl hydrazine into hydrazine, and finally obtaining compound e-47.
  • Example 85 Preparation of e-49 The specific procedure was the same as the preparation of e -43 except that m-decyloxyphenylboronic acid was replaced with o-fluorophenylboronic acid, and ethyl hydrazine was replaced with hydrazine, and finally compound e-49 was obtained.
  • Example 87 Preparation of e-51 was prepared in the same E _ ⁇ specific operation, but will be replaced methoxyphenylboronic acid 4-pyridyl boronic acid, acetamidine replaced guanidine, to give the final compound e-51.
  • Example 88 Preparation of specific operations e-52 e -43 preparing same, except that between the acid into Yue-phenyl 3-pyridyl boronic acid to give the final compound e-52.
  • Example 88 Preparation of e-53 The specific procedure was the same as that of e -43 except that m-decyloxyphenylboronic acid was replaced with 3-pyridylboronic acid, and ethyl hydrazine was changed to hydrazine to give compound e-53.
  • Example 89 Preparation of e-54 was prepared in the same e _43 the specific operation, except that m-methoxyphenyl boronic acid into p-chlorophenyl group, to give the final compound e- 54.
  • Example 90 Preparation of e-55 The specific procedure was the same as the preparation of e -43 except that m-decyloxyphenylboronic acid was replaced with p-nonylthiophenylboronic acid, and ethyl hydrazine was changed to hydrazine to give compound e-55.
  • Example 91 Preparation of e-56 was prepared in the same specific operation e _ 43, except that the inter Yue phenylboronic acid into p-tert-butoxycarbonyl-phenylboronic acid amide group, to give the final compound e- 56.
  • Example 92 Preparation of specific operations with e e- 57 -43, but will be replaced between Yue phenylboronic acid tert-butoxycarbonyl group phenylboronic acid amide, acetamidine replaced guanidine, to give the final compound e -57.
  • Example 95 Preparation of e-60 Iodine chromone a, 10% Pd/C, p-tert-butoxycarbonylamidophenylboronic acid and potassium carbonate were added to a bottle, then acetonitrile and water were added, and stirred at 50 ° C overnight. Pd/C was filtered off, water was added, extracted with ethyl acetate, dried over sodium sulfate, evaporated and evaporated, and then evaporated, and then purified by column chromatography to give intermediates, dissolved with DNF, and added sodium hydrogen and iododecane at room temperature.
  • Example 96 Preparation of e-61 07 000793 The specific operation is the same as the preparation of e - 43 , except that m-methoxyphenylboronic acid is replaced by p-nonyloxyphenylboronic acid, and ethyl hydrazine is replaced by hydrazine, and finally compound e-61 is obtained.
  • Example 97 Preparation of e-62 was prepared in the same e _43 the specific operation, except that m-methoxyphenyl boronic acid into p-methoxyphenyl, acetamidine replaced Yue isourea group, to give the final compound e -62.
  • Example 99 Preparation of e-64 Compound e-61 (1 g, 3.4 mmol), benzyl bromide (0.6 mL, 5.1 mmol) and potassium carbonate (0.94 g, 6.8 mmol) were added to tetrahydrofuran (20 mL). Heat to reflux overnight. Reaction liquid cold However, after the solvent was removed under reduced pressure, the residue was crystallised eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted Intermediate 1 (0.1 g, 0.26 mmol) was dissolved in dry THF (2 mL). C. Then, 60% NaH (26 mg, 0.65 mmol) was added portionwise.
  • Example 100 Preparation of e-65 Intermediate 1 (68 mg, 0.17 mmol) was dissolved in dry tetrahydrofuran (2 ml), cooled to 0 ° C, then 60% NaH. (10 mg, 0.24 mmol), after stirring, was stirred at room temperature for 0.5 hr. Finally, the reaction solution was allowed to react at room temperature overnight. The next day, the reaction solution was cooled to 5 . C, water and ethyl acetate were added, the separated organic layer was dried, filtered and concentrated, and the residue was purified by column chromatography. Intermediate 3 (70 mg.
  • Example 102 Preparation of e-67
  • the specific procedure was the same as the preparation of e- 43 except that m-methoxyphenylboronic acid was replaced with p-methoxytrimethylphenylboronic acid, and ethyl hydrazine was changed to hydrazine, and finally compound e was obtained. -67.
  • Example 102 Preparation of e-69 The specific procedure was the same as the preparation of e -43 except that m-decyloxyphenylboronic acid was replaced with 3,4,5-trimethoxyoxytriphenylphenylboronic acid. Oh, finally the compound e-69.
  • Example 103 Preparation of e-70 Compound e-61 was dissolved in THF, p-chloro-trifluoromethylphenyl isocyanate was added, and the mixture was heated to reflux for 12 hrs, water was added, and ethyl acetate was evaporated. Purification by column chromatography (petroleum ether eluted with ethyl acetate) gave product e-70.
  • Example 105 Preparation of e-72 Iodochromone a, 10% Pd /C, p-tert-butoxycarbonylamidophenylboronic acid and potassium carbonate were added to the flask, and then acetonitrile and water were added thereto, and the mixture was stirred at 50 ° C overnight, Pd/C was filtered off, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated, the protective group was evaporated with trifluoroacetic acid, water was added, and ethyl acetate was evaporated. After the refluxing reaction was completed, water was added, the mixture was extracted with ethyl acetate, and dried over sodium sulfate.
  • Tumor cells were cultured in RPMI 1640 or DMEM medium (Gibco) containing 10% fetal calf serum in a culture condition of 37. C, 5% C0 2 . Inoculate according to the type of tumor cells
  • Inhibition rate (OD value control - OD value administration hole I OD value control hole X 100% According to the concentration inhibition rate, the half inhibition concentration IC 5 () was calculated by Logit method.
  • the MDCK (dog kidney) cells are viral hosts and the samples are tested for inhibition of virus-induced cell pathology (CPE).
  • CPE virus-induced cell pathology
  • MDCK cells were seeded in 96-well culture plates, placed in 5% C0 2 , and cultured at 37 ° C for 24 hours.
  • MDCK cells were separately added with influenza sputum virus 1 ( ⁇ 3 (100 times TCID 5Q ), and the virus solution was decanted after adsorption at 37 ° C for 2 hours, and different dilution drugs with the same concentration were added respectively.
  • the toxic control and the cell control were cultured at 37 ° C for 36 hours, and the results were observed.
  • the CPE was recorded, and the half-inhibitory concentration ( IC 50 ) of each sample against influenza virus was calculated.
  • Table 1 Compound inhibits growth of human liver cancer BEL7402 cells (15 ⁇ )
  • Table 2 Some compounds inhibit growth inhibition (IC 50 ) of human liver cancer BEL7402 cells
  • Compound c-6 has an IC 5 o of 22 ug/ml against sputum influenza virus, a toxic TC 5Q of 194 ug/ml, and a therapeutic index SI of 9.
  • Such novel pyrimidine compounds are expected to develop into anti-tumor and anti-viral drugs.

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Abstract

La présente invention concerne un type de dérivés de pyrimidine ayant une petite molécule, leurs procédés de préparation et leurs utilisations. Les dérivés de pyrimidine selon la présente invention sont de formule (I). La présente invention utilise des chromones en tant que matière de départ. Les chromones sont halogénés pour être un des constituants d'une réaction à constituants multiples. Les halogénations sont couplées avec divers acides boroniques d'hétéroaryle, ou des composés hétérocycliques de thio-aza, ensuite condensées avec des amidines pour obtenir les composés de la présente invention. Ces composés présentent des activités anti-virales et anti-tumorales. Après l'optimisation ou le criblage à partir de ces composés, on peut obtenir de nouveaux médicaments qui peuvent être utilisés dans la prévention de virus ou de tumeur.
PCT/CN2007/000793 2006-03-10 2007-03-12 Nouveau type de dérivés de pyrimidine ayant une petite molécule, procédés de préparation et utilisations desdits dérivés WO2007104254A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103086980A (zh) * 2011-11-07 2013-05-08 北京清美联创干细胞科技有限公司 一种用于高效促进干细胞增殖的嘧啶化合物及其用途
EP3904352A4 (fr) * 2018-12-28 2022-09-07 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Composé aryle substitué, procédé de préparation correspondant et utilisation associée

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WO2004016605A1 (fr) * 2002-08-19 2004-02-26 Fujisawa Pharmaceutical Co., Ltd. Derives de 2-aminopyrimidine utilises en tant qu'antagonistes des recepteurs a2a et a1 de l'adenosine

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WO2004016605A1 (fr) * 2002-08-19 2004-02-26 Fujisawa Pharmaceutical Co., Ltd. Derives de 2-aminopyrimidine utilises en tant qu'antagonistes des recepteurs a2a et a1 de l'adenosine

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OLUWADIYA J.O. ET AL.: "The reaction of amines with isoflavones. I. Formation of phenolic pyrimidines", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 20, no. 4, 1983, pages 1111 - 1112 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103086980A (zh) * 2011-11-07 2013-05-08 北京清美联创干细胞科技有限公司 一种用于高效促进干细胞增殖的嘧啶化合物及其用途
EP3904352A4 (fr) * 2018-12-28 2022-09-07 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Composé aryle substitué, procédé de préparation correspondant et utilisation associée

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