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WO2007014491A1 - Phosphonates de nucléotides acycliques et leur utilisation dans des agents antiviraux - Google Patents

Phosphonates de nucléotides acycliques et leur utilisation dans des agents antiviraux Download PDF

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Publication number
WO2007014491A1
WO2007014491A1 PCT/CN2005/001183 CN2005001183W WO2007014491A1 WO 2007014491 A1 WO2007014491 A1 WO 2007014491A1 CN 2005001183 W CN2005001183 W CN 2005001183W WO 2007014491 A1 WO2007014491 A1 WO 2007014491A1
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WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
group
solvate
Prior art date
Application number
PCT/CN2005/001183
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English (en)
Chinese (zh)
Inventor
Jinjing Wang
Original Assignee
Beijing Fu Kang Ren Bio-Pharm Tech.Co.Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Fu Kang Ren Bio-Pharm Tech.Co.Ltd. filed Critical Beijing Fu Kang Ren Bio-Pharm Tech.Co.Ltd.
Priority to PCT/CN2005/001183 priority Critical patent/WO2007014491A1/fr
Publication of WO2007014491A1 publication Critical patent/WO2007014491A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the present invention relates to novel acyclic nucleoside phosphonate derivatives having high potency against hepatitis B virus activity and low cytotoxicity and their use as medicaments. Background technique
  • Nucleotide analogs such as adefovir dipivoxil need to be acidified in cells, which are not susceptible to drug resistance and can overcome the resistance of lamivudine.
  • adefovir dipivoxil can produce kidney toxicity. Therefore, new anti-hepatitis B drugs are urgently needed in the clinic.
  • the present invention has undergone structural modification and obtained some derivatives.
  • the advantage of the compound MCC-478 is that it can produce antiviral effects without phosphorylation in vivo, is not prone to drug resistance, and does not produce cross-resistance with lamivudine.
  • the present invention provides a novel acyclic nucleoside phosphonate derivative, a composition containing the same, and a process for the preparation thereof, and the present invention also provides the use of these compounds in the preparation of a medicament.
  • the compound of the present invention has the following structure (Formula I):
  • R1 represents an alkyl group of H or dC 3 ;
  • R2 represents H, CH 2 CF 3 , OCH 2 COOR 3 , or OCOOR 3 ;
  • R3 represents CH(CH 3 ) 2 or C(C3 ⁇ 4) 3 ;
  • X represents 0 or CH 2 ;
  • n l-3.
  • CH(CH 3 ) 2 and C(C3 ⁇ 4) 3 may be abbreviated as iPr (isopropyl) and tBu (tert.-butyl), respectively, of the present invention, and also include pharmaceutically acceptable salts, solvates, and corresponding crystalline forms thereof.
  • the compound of the present invention, or a pharmaceutically acceptable salt, solvate thereof, and the corresponding crystalline form of the substance may be a salt of their alkali metal, alkaline earth metal or ammonium species, if necessary.
  • the solvate may be a hydrate, including monohydrate, dihydrate, trihydrate, and the like.
  • R1 represents an alkyl group of H or C r C 3 ;
  • R 2 represents H or CH 2 CF 3 ;
  • X represents O or CH 2 ;
  • n l-3.
  • R1 represents H
  • R2 represents CH 2 CF 3
  • X represents CH 2
  • n l
  • R1 represents H
  • R2 represents CH 2 CF 3
  • R1 represents CH 3
  • R 2 represents C 3 ⁇ 4CF 3
  • X represents CH 2
  • n l
  • R1 represents CH 3
  • R 2 represents CH 2 CF 3
  • R1 represents CH 3
  • R 2 represents CH 2 CF 3
  • Preferred compounds of the invention are:
  • the method for synthesizing the compound of the present invention may be: firstly synthesizing the corresponding side chain reagent and the corresponding mercapto derivative, then condensing 2-amino-6-chloropurine with the corresponding side chain, and finally condensing with the mercapto derivative to obtain the target compound. .
  • the method of preparing the compound of the present invention may comprise the following steps:
  • a compound of the formula (I) is subjected to a condensation reaction with a compound of the formula (iv) to prepare a compound of the formula (I).
  • the synthetic route is:
  • R 2 represents H, CH 2 CF 3 , OCH 2 COOR 3 , or OCOOR 3
  • R 3 represents CH(CH 3 ) 2 or C(CH 3 ) 3
  • n 1-3.
  • Rl represents H or C r C 3 alkyl with the;
  • R2 represents H or CH 2 CF 3;
  • X represents O or CH 2;
  • n l-3 .
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, and corresponding crystalline form, which composition may, if desired, contain a pharmaceutically acceptable carrier and/or form Agent.
  • composition of the present invention can be formulated into any pharmaceutically acceptable dosage form when formulated into a pharmaceutical preparation, and these dosage forms include: tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, capsules, hard capsules, Soft capsule, oral liquid, buccal, granule, granule, pill, powder, ointment, dan, suspension, solution, injection, suppository, ointment, plaster, cream, spray, drop , patch.
  • the preparation of the present invention is preferably an oral preparation such as a capsule, a tablet, an oral solution, a granule, a pill, a powder, a dandruff, a paste or the like, and more preferably a capsule or a tablet.
  • a pharmaceutically acceptable carrier and/or excipient may be added in the preparation of the medicament, which may be: starch, sucrose, lactose, mannitol, silicon derivatives , cellulose and its derivatives, alginate, gelatin, polyvinylpyrrolidone, glycerin, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactant, polyethylene glycol, cyclodextrin, ⁇ - Cyclodextrin, phospholipids Materials, kaolin, talc, calcium stearate, magnesium stearate, etc.
  • the pharmaceutical preparation of the present invention is used according to the condition of the patient at the time of use, and can be taken three times a day, each time 1 to 20 doses, such as: 1 to 20 tablets or tablets.
  • the pharmaceutical composition of the present invention when formulated into a medicament, the unit dose of the medicament may contain the compound of the present invention or a pharmaceutically acceptable salt, solvate thereof, and the corresponding crystalline form of the substance 0.1 to 1000 mg, the remainder being pharmaceutically Acceptable carrier.
  • the pharmaceutically acceptable carrier may be from 0.1 to 99.9% by weight based on the total weight of the preparation.
  • the desiccant was filtered off, and the filtrate was evaporated under reduced pressure to remove solvent, and the residue was fractionated to give 1.5 g of 3,4-dimethoxythiobenzene, and the boiling point was 86-88 ° C / 0.4 mmHg.
  • Nuclear magnetic resonance spectroscopy ⁇ (ppm, CDC13): 7.76 (s, IH); 7.18-7.20 (dd, IH); 7.12 (d, IH); 6.78-6.90 (d, IH); 4.85( b, 2H ) 4.42—4.48 (m, 4H); 4.00-4.03(m, 2H); 3.90 ( s, 3H); 3.86( s, 3H ) ; 3.76-3.80( m, IH ); 3.51-3.55 ( d, 2H ) , 1.27—1.29 (d, 3H).
  • 1,3 - dimethylbenzene is reacted with chlorosulfonic acid to prepare 2,4-dimethyl-benzenesulfonyl chloride, which is reduced with concentrated sulfuric acid + Zn powder to obtain 2,4-dimethylphenylbenzene.
  • chlorosulfonic acid to prepare 2,4-dimethyl-benzenesulfonyl chloride, which is reduced with concentrated sulfuric acid + Zn powder to obtain 2,4-dimethylphenylbenzene.
  • Compound 1-6 was developed by Beijing Ji Kang Ren Bio-Pharmaceutical Technology Co., Ltd., and was prepared according to the methods of Examples 1 to 6 above. Formulated as a white powder, physiological saline.
  • Positive drug MCC-478 Developed by Beijing Kangkangren Biopharmaceutical Technology Co., Ltd. It is prepared as a white powder and physiological saline.
  • Adefovir dipivoxil Developed by Beijing Yukangren Biopharmaceutical Technology Co., Ltd. Formulated as a white powder, physiological saline.
  • Biphenyl diester Peking Union Pharmaceutical Factory production Lot number: 030514
  • DHBV-DNA Duck hepatitis B virus DNA
  • DHBV-DNA Strong positive duck serum (provided by the Virus Room of the Institute of Biotechnology, Chinese Academy of Medical Sciences), collected from Shanghai Ma Duck, stored at -70 °C.
  • Wistar rats certificate number: ⁇ (01) 3084.
  • Q- 32 P-dCTP was purchased from Beijing Furui Biotechnology Engineering Co., Ltd.
  • the gap translation kit was purchased from Promega Co.: Sephadex G-50, and Ficoll PVP was purchased from Pharmacia, Sweden; SDS West Germany Merck products; fish sperm DNA, bovine serum albumin for the Institute of Biophysics, Chinese Academy of Sciences; nitrocellulose membrane 0.45um, Amersham products.
  • DHBV infected ducklings were randomly divided into drug treatment trials, 7 rats in each group, and the 3 dose groups were 5, 10, 15 mg / kg group, orally, 2 times a day, 10 days.
  • the positive medicinal MCC-478 and adefovir dipivoxil were administered orally at 50 mg/kg and 20 mg/kg, respectively, and administered for 10 days twice a day.
  • the film was simultaneously spotted in each batch to determine the dynamics of DHBV-DNA levels in duck serum.
  • the DHBV-DNA probe was labeled with 32P, and the duck blood was spotted and hybridized, and the auto-developed membrane spots were irradiated.
  • the OD value (the filter was 490 nm) was measured by an enzyme labeling instrument, and the serum DHBV-DNA density was calculated, and the hybrid spot OD value was used as the DHBV-DNA level value.
  • 120 rats weighing 120-150g, male and female were randomly divided into six groups, 20 in each group, with normal control group, carbon tetrachloride injury model group, positive drug biphenyl diester group, three doses of compound Group, starting from the experiment, except for the control group, the other five groups were injected subcutaneously with 25% carbon tetrachloride 2 ml I Kg twice a week for 3 months.
  • the drug treatment was started one month after the injection of carbon tetrachloride: the normal control group and the model group were given an equal volume of natural water, and the positive drug group was intragastrically administered with biphenyldicarboxylate 100 mg kg.
  • the three groups of the compound were intragastrically administered: 60 , 30, 15mg / kg.
  • All the above groups were administered by intragastric administration for two months. At 24 hours after the last administration, 10 rats in each group were randomly selected for blood separation to determine AST, ALT, alkaline phosphatase, albumin, total protein, transpeptidase, total bilirubin, and direct bilirubin. The A/G ratio was sacrificed, and the left lobe of the liver was fixed in 10% formalin solution, embedded in conventional paraffin, HE stained, and the degree of liver tissue damage was observed under a microscope. The nine serum biochemical test indicators were calculated for each group and compared with the damage model group. The results are shown in Table 2.1-2.6.
  • mice 20-258 male and female, were randomly divided into six groups, 10 in each group, with normal control group, injury model group, positive drug biphenyl diester group and compound three dose groups.
  • the normal control group and the model group were intragastrically administered with equal volume of tap water three times.
  • the four administration groups were intragastrically administered with biphenyldicarboxylate 200 mg/kg, compound 120, 60, 30 mg / kg-day three times.
  • the rats were intragastrically administered.
  • the other five groups were intraperitoneally injected with D-galactosamine 800 mg / kg.
  • mice On the third day, all mice were decapitated and blood was taken, and serum was separated to determine ALT, AST. ALP, GGT. Then, the liver tissue of the same part of the same leaf liver was fixed in 10% formalin solution, and the conventional paraffin was embedded in the section, and HE staining was performed for pathological biopsy. The mean values of the four enzymes in each group were compared with the model group. The results are shown in Table 3.1-3.6.
  • tl, pi DHBV-DNA OD values of duck serum at different times (T5, T10, ⁇ 3) were compared with pre-infection (TO) OD values (paired t-test). *pl ⁇ 0.05, **pl ⁇ 0.01, ***pl ⁇ 0.001. Vpl ⁇ 0.05 compared with the compound 1 15 mg/kg group.
  • tl, pi DHBV-DNA OD values of duck serum at different times (T5, ⁇ 10, ⁇ 3) were compared with pre-infection (TO) OD values (paired t-test).
  • pi DHBV-DNA OD value of duck serum at different time (T5, T10, ⁇ 3) in the administration group compared with OD value of FRK-02 group (pairing t test).
  • DHBV-DNA OD value of duck serum in group 3 treated with virus control group DHBV-DNA OD value (X ⁇ SD) in group dose duck serum Mg kg duck TO T5 T10 P3 bidx number
  • tl, pi DHBV-DNA OD values of duck serum at different times (T5, ⁇ 10, ⁇ 3) were compared with pre-infection (TO) OD values (paired t-test).
  • pi DHBV-DNA OD value of duck serum at different time (T5, ⁇ 10, P3) in the drug-administered group compared with OD value of compound 3 group (pairing t test).
  • Adefovir 20 6 1.123 ⁇ 0. 0.571 ⁇ 0.07* 0.541 ⁇ 0.09* 0.893 ⁇ 0,07** ⁇ vv
  • tl pi Duck serum DHBV-DNA OD values were compared with pre-infection (TO) OD values at different times (T5 ⁇ 10 ⁇ 3) in the dosing group (paired t-test). *pl ⁇ 0.05, **pl ⁇ 0.01, ***pl ⁇ 0.001 tl pi: DHBV-DNA OD value of duck serum at different time (T5 T10, ⁇ 3) in the drug-administered group compared with OD value of compound 4 group (paired t-test) .
  • tl, pi DHBV-DNA OD values of duck serum at different times (T5, T10, P3) were compared with pre-infection (TO) OD values (paired t-test). *pl ⁇ 0.05, **pl ⁇ 0.01, ***pl ⁇ 0.001. VVV pl ⁇ 0.001 compared to Compound 1 15 mg/kg group.
  • Compound 2 is low 10 117.7+98.5 287.7+149 282.6+98.4 2.1+0.81
  • Compound 3 is low 10 121.5 ⁇ 88.6 281.4+137.4 274.7 ⁇ 88.4 2.7 ⁇ 0.74 Dose
  • Compound 4 is low 10 111.5+84.6 279.4 ⁇ 138.1 289.4 ⁇ 78.4 2.4 ⁇ 0.68 Dose
  • ALT (IU/L) (IU/L) 1 (IU/L)
  • GGT (IU/L) blank control 10 27.6 ⁇ 5.56 217.4+95.46 255.8+64.51 2.2+0.78
  • Compound 5 is low 10 112.4+87.6 247.4+121.1 289.4 ⁇ 81.4 2.7+0.70 Dose
  • the LD 5Q of gavage compound 1 in Kunming mice was: 3948.4 (3588.5-4308.3) mg/kg, and the toxicity of oral administration was less than MCC-478 (2517.3-3067.3 mg/kg) and adefovir dipivoxil ( 3275.1-3782.1 mg/kg) is equivalent.
  • the LD 5Q of the gavage compound 2 of Kunming mice was: 4815.9 (4381.5-5293.5) mg kg. Its oral toxicity is less than MTT (2517.3 - 3067.3 mg/kg) and adefovir dipivoxil (3275.1-3782.1 mg/kg ) 0
  • the LD 5 o of the gavage compound 3 of Kunming mice was: 4591.1 (4170.5-5054.1) mg/kg. Its oral toxicity is less than MTT (2517.3 - 3067.3 mg/kg) and adefovir dipivoxil (3275.1-3782.1 mg/kg)
  • the LD 5G of the gavage compound 4 of Kunming mice was: 4745.3 (43103-5224.2) mg/kg. Its oral toxicity is less than MTT (2517.3-3067.3 mg/kg) and adefovir dipivoxil (3275.1-3782.1 mg/kg)
  • the LD 5 o of gavage compound 5 in Kunming mice was: 3805.8 (3378.7-4286.9) mg/kg, and the toxicity of oral administration was less than MTT (2517.3 - 3067.3 mg/kg) and adefovir dipivoxil (3275.1-3782.1). Mg/kg
  • the LD 5Q of the gavage compound 6 in Kunming mice was: 4721.3 (4141.5-5382.1) mg kg. Oral administration is less toxic than MTT (2517.3 - 3067.3 mg kg) and comparable to adefovir dipivoxil (3275.1-3782.1 mg/kg). Industrial applicability
  • the acyclic nucleoside phosphonate compound of the present invention has strong anti-HBV activity and is not cytotoxic;
  • the acyclic nucleoside phosphonate compound of the present invention has a good liver protecting effect.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de la formule suivante (I) et leurs sels pharmaceutiquement acceptables, dans laquelle R1 représente H ou C1-C3-alkyl, R2 représente H, CH2CF3, OCH2COOR3, ou OCOOR3, R3 représente CH(CH3)2 ou C(CH3)3, X représente O ou CH2, n = 1-3, et leur utilisation en tant qu’agents antiviraux, en particulier en tant qu’agents viraux anti-hépatite B.
PCT/CN2005/001183 2005-08-03 2005-08-03 Phosphonates de nucléotides acycliques et leur utilisation dans des agents antiviraux WO2007014491A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101445515A (zh) * 2007-11-26 2009-06-03 张家港市国泰华荣化工新材料有限公司 全氟烷基乙基亚磷酸酯的制备方法
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
CN107849074A (zh) * 2016-01-19 2018-03-27 四川海思科制药有限公司 一种核苷类似物的烷氧烷基酯前药及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0632048A1 (fr) * 1993-06-29 1995-01-04 Mitsubishi Chemical Corporation Dérivés esters phosphoniques de nucléotides
WO1998039344A1 (fr) * 1997-03-07 1998-09-11 Metabasis Therapeutics, Inc. Nouveaux composes de purine inhibiteurs de fructose-1,6-biophasphatase
EP0919562A1 (fr) * 1996-08-13 1999-06-02 Mitsubishi Chemical Corporation Composes nucleotidiques a base de phosphonate
WO2001064693A1 (fr) * 2000-02-29 2001-09-07 Mitsubishi Pharma Corporation Compose de nucleotide de phosphonate
WO2003050129A1 (fr) * 2001-12-07 2003-06-19 Eli Lilly And Company Utilisation d'analogue de nucleotide phosphonate dans le traitement des infections par le virus de l'hepatites b

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0632048A1 (fr) * 1993-06-29 1995-01-04 Mitsubishi Chemical Corporation Dérivés esters phosphoniques de nucléotides
EP0919562A1 (fr) * 1996-08-13 1999-06-02 Mitsubishi Chemical Corporation Composes nucleotidiques a base de phosphonate
WO1998039344A1 (fr) * 1997-03-07 1998-09-11 Metabasis Therapeutics, Inc. Nouveaux composes de purine inhibiteurs de fructose-1,6-biophasphatase
WO2001064693A1 (fr) * 2000-02-29 2001-09-07 Mitsubishi Pharma Corporation Compose de nucleotide de phosphonate
WO2003050129A1 (fr) * 2001-12-07 2003-06-19 Eli Lilly And Company Utilisation d'analogue de nucleotide phosphonate dans le traitement des infections par le virus de l'hepatites b

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101445515A (zh) * 2007-11-26 2009-06-03 张家港市国泰华荣化工新材料有限公司 全氟烷基乙基亚磷酸酯的制备方法
CN101445515B (zh) * 2007-11-26 2013-04-24 张家港市国泰华荣化工新材料有限公司 全氟烷基乙基亚磷酸酯的制备方法
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10035814B2 (en) 2011-12-22 2018-07-31 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10562926B2 (en) 2011-12-22 2020-02-18 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US11279720B2 (en) 2011-12-22 2022-03-22 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
CN107849074A (zh) * 2016-01-19 2018-03-27 四川海思科制药有限公司 一种核苷类似物的烷氧烷基酯前药及其应用

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