WO1998042351A1 - Acides difluoronucleosides-phosphoniques et leurs derives - Google Patents

Acides difluoronucleosides-phosphoniques et leurs derives

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Publication number
WO1998042351A1
WO1998042351A1 PCT/US1998/005477 US9805477W WO9842351A1 WO 1998042351 A1 WO1998042351 A1 WO 1998042351A1 US 9805477 W US9805477 W US 9805477W WO 9842351 A1 WO9842351 A1 WO 9842351A1
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WO
WIPO (PCT)
Prior art keywords
desoxy
difluoro
pyrimidin
oxo
desoxyribose
Prior art date
Application number
PCT/US1998/005477
Other languages
English (en)
Inventor
Larry W. Hertel
Julian S. Kroin
Original Assignee
Eli Lilly And Company
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 Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to JP54582098A priority Critical patent/JP2001518931A/ja
Priority to EP98910503A priority patent/EP0994715A4/fr
Priority to AU64730/98A priority patent/AU6473098A/en
Priority to CA002284263A priority patent/CA2284263A1/fr
Publication of WO1998042351A1 publication Critical patent/WO1998042351A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the invention relates to the art of organic chemistry. Specifically it relates to difluoronucleosides that have utility in certain pharmaceutical applications.
  • difluoronucleosides have been found to have utility as anti-viral compounds (U.S. Patent No. 4,808,614) and as anti-neoplastic compounds (U.S. Patent No 5,464,826).
  • a difluoronucleoside compound which is currently being used in the treatment of solid tumors in humans is gemcitabine hydrochloride (formula (I) ) :
  • This invention relates to difluoronucleoside phosphonic acids and derivatives thereof of formula (Ii;
  • R is a base selected from the group consisting of
  • R! is hydrogen, methyl, bromo, fluoro, chloro or iodo
  • R ⁇ is hydroxy or -NR ⁇ R ⁇ , where R ⁇ and R ⁇ are independently selected from the group consisting of hydrogen, methyl, ethyl and propyl ;
  • R ⁇ is hydrogen, bromo, chloro or iodo; both R ⁇ are the same, and are either, -OR 7 or -(0 ⁇ R ⁇ ), where
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, and isopropyl
  • R8 is a pharmaceutically acceptable cation; and pharmaceutically acceptable salts and solvates thereof.
  • This invention also relates to halogenated difluoronucleoside compounds of formula (B) :
  • This invention also relates to a method of treating susceptible neoplasms in mammals comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (II) .
  • This invention also relates to a method of treating Herpes viral infections in mammals comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (II) .
  • This invention also relates to pharmaceutical compositions comprising one or more compounds of formula (II) in combination with pharmaceutically acceptable excipients and/or diluents.
  • pharmaceutically acceptable cations includes, but is not limited to, pharmaceutically acceptable alkali metal, alkaline earth metal and organic amine cations. These cations can be mono-, di- or trivalent cations.
  • Preferred cations include, but are not limited to, sodium (Na + ) , potassium (K + ) , lithium (Li + ) , calcium (Ca ++ ) , magnesium (Mg ++ ) , aluminum (Al +++ ) , zinc (Zn ++ ), ammonium (NH 4 +) , trimethylammonium ((CH 3 )3NH + ), and triethanolammonium ( (HOCH2CH 2 ) 3 NHA .
  • a “pharmaceutically acceptable salt” may be any non-toxic salt derived from an inorganic or organic acid that is suitable for administration as a drug.
  • the salts are derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid, p-toluene-sulfonic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, lactic acid, o- (4-hydroxy-benzoyl) benzoic acid, 1,2- ethane
  • terapéuticaally effective amount refers to a dosage sufficient to cause a positive change in the disease state being treated.
  • positive change will vary in meaning depending on the patient, the disease and the treatment being undergone.
  • an effective amount of an oncolytic can be an amount that causes a reduction in the size of a cancerous tumor, or where no reduction in tumor size occurs, an effective amount of an oncolytic could be that amount that causes a decrease in analgesic consumption for the patient suffering from cancer .
  • Preferred compounds of formula (II) are those compounds where the stereochemical orientation between the carbohydrate derivative ring and the base is in the ⁇ configuration
  • a more preferred compound of Formula (II) is where the stereochemical orientation between the carbohydrate derivative ring and the base is in the ⁇ configuration, R is :
  • R ⁇ is -(0 R ⁇ ) where R ⁇ is a pharmaceutically acceptable cation.
  • An especially preferred compound of formula (II) is 1 ' -desoxy-1 ' - ⁇ - (lH-2-oxo-4-amino-pyrimidin-l-yl) -2 ' , 2 ' - difluoro-5 ' -desoxyribose 5 ' -diammoniumphosphonate, which has the formula :
  • IP 1 ' -desoxy-1 ' - ( lH-2-oxo-4-hydroxy-5- (2-chloroethylenyl ) - pyrimidin-1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -phosphono ribose;
  • 3D 1 ' -desoxy-1 ' - (1, 3-dihydro-2 , 4-dioxo-5-fluoro-pyrimidin- 1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' -diethylphosphonate;
  • 3E 1 ' -desoxy-1 '-(1,3 -dihydro-2 , 4-dioxo-5-chloro-pyrimidin- 1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' -diethylphosphonate;
  • 3F 1 ' -desoxy-1 ' - (lH-2-oxo-4-amino-pyrimidin-l-yl) -2 ' , 2 ' - difluoro-5 ' -desoxyribose 5 ' -diethylphosphonate;
  • 3G 1
  • 3M 1 ' -desoxy-1 ' - ( l-dehydro-2-desamino-6-desoxo-6- aminoguanin-9-yl) -2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' - diethylphosphonate; 3N) 1 ' -desoxy-1 ' - (lH-2-oxo-4-hydroxy-5-ethylenyl-pyrimidin-
  • 4A 1 ' -desoxy-1 ' - (1, 3-dihydro-2 , 4-dioxo-pyrimidin-l-yl ) - 2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' -diisopropylphosphonate; 4B) 1 ' -desoxy-1 ' - (1, 3-dihydro-2, 4-dioxo-5-methyl-pyrimidin- 1-yl) -2 ', 2 ' -difluoro-5 ' -desoxyribose 5 ' -diisopropylphosphonate;
  • 4C 1 ' -desoxy-1 ' - (1, 3-dihydro-2, 4-dioxo-5-bromo-pyrimidin-l- yl) -2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' -diisopropylphosphonate; 4D) 1 ' -desoxy-1 ' - (1, 3-dihydro-2 , 4-dioxo-5-fluoro-pyrimidin- 1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' -diisopropylphosphonate;
  • 4P 1 ' -desoxy-1 ' - (lH-2-oxo-4-hydroxy-5- (2-chloroethylenyl) - pyrimidin-1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' - diisopropylphosphonate; 4Q) 1 ' -desoxy-1 ' - ( lH-2-oxo-4-hydroxy-5- (2-bromoethylenyl) - pyrimidin-1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' - diisopropylphosphonate; pharmaceutically acceptable salts; pharmaceutically acceptable solvates; and mixtures thereof.
  • 6A 1 ' -desoxy-1 ' - (1, 3-dihydro-2, 4-dioxo-pyrimidin-l-yl) - 2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' -disodiumphosphonate
  • 6B 1 ' -desoxy-1 ' - (1, 3-dihydro-2, 4-dioxo-5-methyl-pyrimidin- 1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' -disodiumphosphonate
  • 6C 1 ' -desoxy-1 ' - (1, 3-dihydro-2 , 4-dioxo-5-bromo-pyrimidin-l- yl) -2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' -disodiumphosphonate
  • 6D 1
  • 6J 1 ' -desoxy-1 ' - (lH-2-oxo-4-amino-5-chloro-pyrimidin-l-yl) - 2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' -disodiumphosphonate; 6K) 1 ' -desoxy-1 ' - (lH-2-oxo-4-amino-5-iodo-pyrimidin-l-yl) - 2 ' , 2 ' -difluoro-5 ' -desoxyribose 5 ' -disodiumphosphonate; 6L) 1 ' -desoxy-1 '- (guanin-9-yl) -2 ' ,2 ' -difluoro-5 ' - desoxyribose 5 ' -disodiumphosphonate; 6M) 1 ' -desoxy-1 ' - (l-dehydro-2-
  • 6P 1 ' -desoxy-1 ' - (lH-2-oxo-4-hydroxy-5- (2-chloroethylenyl) - pyrimidin-1-yl) -2 ', 2 ' -difluoro-5 ' -desoxyribose 5'- disodiumphosphonate; 6Q) 1 ' -desoxy-1 ' - (lH-2-oxo-4-hydroxy-5- (2-bromoethylenyl) -pyrimidin-1-yl) -2 ' , 2 ' -difluoro-5 ' - desoxyribose 5 ' -disodiumphosphonate; pharmaceutically acceptable solvates; and mixtures thereof.
  • 11A 1 ' -desoxy-1 ' - ( l-dehydro-2-desamino-6-desoxo- ⁇ -amino- guanin-9-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -bromoribose;
  • 11B 1 ' -desoxy-1 ' - (l-dehydro-2-desamino-6-desoxo-6-amino- guanin-9-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -chlororibose;
  • 11C 1 ' -desoxy-1 ' - (l-dehydro-2-desamino-6-desoxo-6-amino- guanin-9-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -iodoribose
  • 12A 1 ' -desoxy-1 ' - (lH-2-oxo-4-hydroxy-5-ethylenyl-pyrimidin- 1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -bromoribose
  • 12B 1 ' -desoxy-1 ' - (lH-2-oxo-4-hydroxy-5-ethylenyl-pyrimidin- 1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -chlororibose
  • 12C 1 ' -desoxy-1 ' - (lH-2-oxo-4-hydroxy-5-ethylenyl-pyrimidin- 1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -iodoribose;
  • 13A 1 ' -desoxy-1 ' - (1, 3-dihydro-2 , 4-dioxo-5-bromo-pyrimidin- 1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -bromoribose; 13B) 1 ' -desoxy-1 ' - ( 1 , 3-dihydro-2 , 4-dioxo-5-bromo-pyrimidin- 1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -chlororibose;
  • 16A 1 ' -desoxy-1 ' - (lH-2-oxo-4-amino-5-bromo-pyrimidin-l-yl ) - 2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -bromoribose; 16B) 1 ' -desoxy-1 ' - (lH-2-oxo-4-amino-5-bromo-pyrimidin-l-yl ) - 2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -chlororibose;
  • 18A 1 ' -desoxy-1 ' - ( lH-2-oxo-4-amino-5-chloro-pyrimidin-l- yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -bromoribose; 18B) 1 ' -desoxy-1 ' - (lH-2-oxo-4-amino-5-chloro-pyrimidin-l- yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -chlororibose;
  • 21A 1' -desoxy-1 '- ( lH-2-oxo-4-hydroxy-5- (2-chloroethylenyl) - pyrimidin-1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -bromoribose; 21B) 1 ' -desoxy-1 ' - (lH-2-oxo-4-amino-5- (2-chloroethylenyl ) - pyrimidin-1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -chlororibose; 21C) 1 ' -desoxy-1 ' - (lH-2-oxo-4-amino-5- (2-chloroethylenyl ) - pyrimidin-1-yl) -2 ' , 2 ' -difluoro-5 ' '
  • An especially preferred compound of formula (B) is:
  • the first step in the process to make the difluoronucleoside phosphonic diacid compounds and derivatives thereof of formula (II) is to substitute a -Cl, -Br or -I in place of the -OH group on the 5 ' carbon of the carbohydrate derivative ring of a difluoronucleoside compound of formula (A) .
  • a difluoronucleoside of formula (A) is contacted with a halogenating agent in a solvent.
  • the halogenating agent is selected from any suitable halogenating agent such as, but not limited to, carbon tetrahalides such as carbon tetrachloride, carbon tetrabromide, and carbon tetraiodide. Additional halogenating agents include phosphorous tribromide and thionyl chloride.
  • triphenylphosphine is added to the liquid carbon tetrahalide.
  • the preferred halogen is bromine.
  • the preferred halogenating agent is carbon tetrabromide with triphenylphosphine added.
  • the solvent for this halogenation is selected from a group of suitable organic solvents including, but not limited to, dimethylformamide (DMF) , dimethyl acetamide (DMAc) , N-methylpyrrolidinone (NMP) , 1, 3 -dimethyl-3 , 4, 5 , 6- tetrahydro-2 (1H) -pyrimidinone (dMPU) , hexamethyl- phosphoramide (HMPA) and mixtures thereof.
  • DMF dimethylformamide
  • DMAc dimethyl acetamide
  • NMP N-methylpyrrolidinone
  • dMPU 1, 3 -dimethyl-3 , 4, 5 , 6- tetrahydro-2 (1H) -pyrimidinone
  • HMPA hexamethyl- phosphoramide
  • 3-dimethyl- 3 , 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone is the preferred solvent when carbontetra bromide with triphenylphosphine is used
  • the halogenation reaction is conducted at elevated temperatures, between at least about 40°C and at most about 75°C, preferably between about 50°C and about 70°C and most preferably about 60°C, for from at least about 30 minutes to at most about 5 hours, preferably from at least about 45 minutes to at most about 2 hours and most preferably for about 1 hour .
  • Halogenation at the 5 ' position of unprotected nucleosides is further described in "Facile 5 ' -Halogenation of Unprotected Nucleosides", Nucl eosides & Nucleotides , 6(3) , 575-580 (1987) .
  • formula (B) where X is -Cl, -Br, or -I, and R is as defined previously; is then isolated and purified using standard techniques known in the art, such as, but not limited to crystallization, filtration and chromatography .
  • the purified compound of formula (B) can be used in the next step of the process.
  • a compound of formula (B) can also be converted to a pharmaceutically acceptable salt or solvate, using standard techniques known in the art, and the compound, salt or solvate can be used as an antineoplastic or antiviral pharmaceutical compound.
  • the halogenated difluoronucleoside of formula (B) is next contacted by one or more suitable protecting group reagents such that any unprotected primary and secondary amino groups and -OH groups can all be protected. It should be noted that if all the amino substituents present were already protected on the difluoronucleoside starting material of formula (A) it is only necessary to provide a protecting group for the -OH moieties at this point. It is preferred that the protecting group reagent is selected such that the primary and second amino groups and -OH groups can be protected by the same protecting group.
  • protecting group reagent there be only one protecting group reagent selected in order not to have to conduct multiple protecting group reagent addition reactions.
  • One such suitable protecting group reagent capable of supplying a protecting group that is capable of protecting primary and second amino groups and -OH groups is an acetylating reagent.
  • An acetylating reagent acts to protect primary and secondary amino groups and -OH groups with a -COCH3 group.
  • Acetylating reagents can be any of those known in the art, including, but not limited to, acetyl chloride and acetic anhydride.
  • the preferred acetylating reagent is acetic anhydride .
  • introduction of a protecting group takes place in a suitable solvent .
  • suitable solvents for this reaction is organic solvents such as pyridine, DMF, DMAc, NMP, dMPU, HMPA and mixtures thereof.
  • a preferred solvent for this reaction is pyridine.
  • the reaction to affix the protecting group is usually conducted at lowered temperatures, between about -25°C and about 10°C, preferably between about -10°C and about 8°C and most preferably between about 0°C and about 5°C; for from at least about 1 hour to at most about 30 hours, preferably from at least about 5 hours to at most about 20 hours and most preferably for about 18 hours.
  • each Pg is individually a suitable hydroxy and amino protecting group which is (are) bonded to the -O affixed to the 3 ' carbon on the ribose ring and also bonded to any primary and secondary amino group affixed to the (R) ring, and X, R, R- 1 - ⁇ and R ⁇ are as defined previously; is then isolated and purified using standard techniques known in the art, such as, but not limited to those, previously listed.
  • the next step is for the protected halogenated nucleoside of formula (C) to be contacted by a reagent capable of displacing the halogen on the number 5 carbon of the carbohydrate derivative ring with a -PO(O-R 2 0)2 moiety, where R ⁇ O is methyl, ethyl or isopropyl.
  • Suitable phosphonating reagents include, but are not limited to trimethyl phosphite, triethyl phosphite and triisopropyl phosphite. Of these suitable phosphonating reagents, triethyl phosphite is preferred.
  • the phosphonating reaction can be conducted using the phosphonating reagent as both a reagent and a solvent. This phosphonating reaction requires both elevated temperatures and a large amount of time.
  • the reaction is conducted at elevated temperatures, between at least about 100°C and about 170°C, preferably between about 125°C and about 170°C and most preferably between about 160°C and about 170°C, for from at least about 10 hours to at most about 48 hours, preferably for from at least about 20 hours to at most about 40 hours and most preferably for about 30 hours.
  • the reaction is conducted at lowered temperatures (because of the lower boiling point (111-112°C) of the trimethyl phosphite) , between at least about 60°C and about 110°C, preferably between about 75°C and about 110°C and most preferably between about 100°C and about 110°C, for from at least about 20 hours to at most about 100 hours, preferably for from at least about 50 hours to at most about 100 hours and most preferably for about 60 hours.
  • the reaction is conducted ac much lower temperatures because of the much lower boiling point of the triisopropyl phosphite, between at least about 25°C and about 62°C, preferably between about 40°C and about 62 °C and most preferably between about 55°C and about 62°C, for from at least about 30 hours to at most about 100 hours, preferably for from at least about 50 hours to at most about 90 hours and most preferably for about 80 hours.
  • R 2 ⁇ is ethyl, methyl or isopropyl
  • Pg and R are as defined previously; is then isolated and purified using standard techniques known in the art .
  • the protected phosphonate ester of formula (D) can then be converted to the unprotected phosphonic acid of formula (E) :
  • R° is a pharmaceutically acceptable cation and R is as defined previously; by converting the ester functional groups to either the acid or salt functional groups and by removing the protecting group ( s ) on the primary and secondary amino and -OH moieties in the remainder of the difluoronucleoside .
  • R is as defined previously; is to contact the phosphonate ester of formula (D) with reagents suitable to remove the protecting groups and convert the ester moieties to salts.
  • a suitable reagent combination for these reactions has been found to be bromotrimethylsilane followed by anhydrous ammonia. This reaction can be performed in a suitable non-reactive organic solvent such as acetonitrile .
  • the bromotrimethylsilane reaction can take place at about room temperature of about 25°C and requires between about 2 hours and about 4 hours, preferably between about 2.5 hours and about 3 hours and most preferably about 2.5 hours.
  • the diammonium salt is formed by contacting the phosphonic acid product of the above bromotrimethylsilane reaction with anhydrous ammonia and heating the reaction mixture between at least about 50°C and about 100°C, preferably between about 60°C and about 90°C and most preferably between about 70°C and about 90°C, for from at least about 10 hours to at most about 30 hours, preferably from at least about 15 hours to at most about 25 hours and most preferably for about 18 hours.
  • ammonium salt of formula (G) is then isolated and purified using standard techniques known in the art.
  • the present invention includes solvates of the compounds of formula (II) .
  • a particular compound of the present invention may form solvates with water or common organic solvents. Such solvates are included within the scope of claimed compounds of the present invention.
  • the present invention includes pharmaceutically acceptable salts of the compounds of formula (II) .
  • These salts may be made using standard salt forming reagents, previously listed. It is noteworthy that only the diester phosphonate derivatives can form salts in the usual manner, as the phosphonic diacid compounds are amphoteric and as as such are capable of protonating themselves .
  • difluoronucleoside phosphonic acids or derivatives thereof can be tested for their antiviral and antineoplastic properties using standard techniques known in the art.
  • a suitable test method to determine activity against Herpes simpl ex virus, type I, and type II is described in U.S. Patent No. 4,808,614, Columns 18-19, which has been previously incorporated by reference.
  • Suitable test methods for determining anti- neoplastic activity are described in U.S. Patent No. 5,464,826, Columns 19-23, which has been previously incorporated by reference.
  • the compounds are tested for their ability to inhibit the growth of certain cancerous cell lines by the standard cytotoxicity screening tests involving cell lines CCRF-CEM. The results of these tests are given as "IC50" which is the concentration of compound giving 50% growth inhibition.
  • the compounds of the present invention may be administered to any mammal. Of all mammals, it is believed that humans will benefit the most from administration of these compounds. As such, administration to humans is preferred.
  • the compounds of the present invention are antineo-plastic agents.
  • An embodiment of the present invention provides a method of treating susceptible neoplasms in mammals, preferably humans, in need of such treatment.
  • the present compounds are useful in inhibiting the growth of neoplasms or "cancers", including, but not limited to, carcinoma, sarcoma, melanoma, colorectal, choriocarcinoma, prostate, leukemia, breast, squamous or small cell lung cancer, non-small cell lung cancer, ovarian, testicular, adenocarcinoma, epidermal, lymphosarcoma, pancreatic, head and neck, kidney, bone and liver cancer.
  • the compounds of the present invention are also antiviral agents, suitable for use in mammals, preferably humans.
  • the compounds are effective for the treatment of viral infections in general, and most particularly in the treatment of infections caused by viruses of the herpes genus.
  • the compounds of the present invention can be administered orally, parenterally, or by means of insufflation or by insertion of a suppository.
  • the compounds can be administered individually or in combination, preferably parenterally, and usually in the form of a pharmaceutical composition.
  • Parenteral routes of administration include intramuscular, intrathecal, subcutaneous, intravenous, intra-arterial, intraorbital, intracapsular, intraspinal, and intrasternal .
  • Oral dosage forms, including tablets and capsules contain from 1 to
  • Isotonic saline solutions containing 1-100 mg/mL can be used for parenteral administration .
  • compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Accordingly, the present invention also includes pharmaceutical compositions comprising as active ingredient one or more compounds of formula (II) associated with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention also includes pharmaceutical compositions comprising as active ingredient, one or more compounds of formula (II) and one or more oncolytic medicaments such as, but not limited to, gemcitabine hydrochloride, cisplatin, paclitaxel, carboplatin, 5-fluorouracil, doxorubicin, epirubicin, etoposide, vinorelbine, vincristine, vinblastine, vindesine, tamoxifen, methotrexate, and irinotecan hydrochloride, associated with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • gemcitabine hydrochloride cisplatin, paclitaxel, carboplatin, 5-fluorouracil, doxorubicin, epirubicin, etoposide, vinorelbine, vincristine, vinblastine, vindesine, tamoxifen, methotrexate, and irinotecan hydrochloride, associated with at least
  • the active ingredients are usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium silicate, microcrystalline cellulose, polyvinyl-pyrrolidinone, cellulose, water, syrup, and methyl cellulose
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxybenzoates , sweetening agents or flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions are preferably formulated in a unit dosage form with each dosage normally containing from about 0.1 milligrams per square meter of body surface area (mg/M 2 ) to about 3000 mg/M 2 , more usually about 10 mg/M 2 to about 250 mg/M 2 of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.
  • the amount of the compound actually administered per unit of time, and the frequency of administration will be determined by a physician or veterinarian in light of the relevant circumstances including the relative severity of a disease state, the choice of compound to be administered, the age, weight, and response of the individual patient, and the chosen route of administration. Therefore, the above dosage ranges are not intended to limit the scope of this invention in any way .
  • Active ingredient means one or more compounds of formula (II) .
  • Hard gelatin capsules are prepared using the following ingredients:
  • a tablet is prepared using the ingredients below:
  • Tablets each containing 60 mg of active ingredient, are made as follows:
  • the active ingredient, starch and cellulose are passed through a No . 45 mesh U.S. sieve and mixed thoroughly.
  • the aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No . 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No . 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No . 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Capsules each containing 80 mg of active ingredient, are made as follows:
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No . 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
  • Suppositories each containing 225 mg of active ingredient, are made as follows:
  • Suspensions each containing 50 mg of active ingredient per 5 L dose, are made as follows:
  • An intravenous formulation may be prepared as follows:
  • Step 1 Synthesis of 1 ' -desoxy-1 ' - ⁇ - (lH-2-oxo-4-amino- pyrimidin-1-yl) -2 ' , 2 ' -difluoro-5 ' -desoxy-5 ' -bromoribose:
  • Step 2 Synthesis of 1 ' -desoxy-1 ' - ⁇ - (lH-2-oxo-4-acetamyl- pyrimidin-1-yl) -2 ' , 2 ' -difluoro-3 ' -acetoxy-5 ' -desoxy-5 ' - bromoribose:
  • Step 3 Synthesis of 1 ' -desoxy-1 ' - ⁇ - (lH-2-oxo-4-acetamyl- pyrimidin-1-yl) -2 ' , 2 ' -difluoro-3 ' -acetoxy-5 ' -desoxyribose 5 ' -diethylphosphonate :
  • Step 4 Synthesis of 1 ' -desoxy-1 ' - ⁇ - (lH-2-oxo-4-amino- pyrimidin-1-yl) -2 ', 2 ' -difluoro-5 ' -desoxyribose 5'- diammoniumphosphonate :
  • Example 1 The compound of Example 1, Step 4 was tested against the human leukemia cell line (CCRF-CEM) according to the method described in U.S. Patent 5,464,826 (columns 19-20).
  • the IC50 was found to be 0.3 ⁇ g/ml .
  • step 4 was tested against the Herpes simpl ex virus, type I (HSV-1) and Herpes simplex virus, type II (HSV-2); using the test method described in U.S. Patent No. 4,808,614, columns 18-19.
  • the compound exhibited anti-viral activity against both HSV- 1 and HSV-2.

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Abstract

L'invention concerne des acides difluoronucléosides-phosphoniques et leurs dérivés, de formule (II), dans laquelle R est une base choisie dans le groupe constitué de (i), (ii), (iii), (iv) et (v). Dans ces formules, R1 est hydrogène, méthyle, bromo, fluoro, chloro ou iodo; R2 est hydroxy ou -NR4R5, dans laquelle R4 et R5 sont choisis indépendamment dans un groupe comprenant hydrogène, méthyle, éthyle et propyle; R3 est hydrogène, bromo, chloro ou iodo; les deux R6 sont identiques et sont soit -OR7, soit -(O?-R8), R7¿ choisi dans le groupe constitué d'hydrogène, méthyle, éthyle et isopropyle; R8 est un cation pharmaceutiquement acceptable. La présente invention concerne également des sels et des solvates pharmaceutiquement acceptables de ces acides. Lesdits acides, sels et solvates sont utilisés, conformément à l'invention, comme agents antiviraux et antinéoplasiques.
PCT/US1998/005477 1997-03-24 1998-03-19 Acides difluoronucleosides-phosphoniques et leurs derives WO1998042351A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP54582098A JP2001518931A (ja) 1997-03-24 1998-03-19 ジフルオロヌクレオシドホスホン酸とその誘導体
EP98910503A EP0994715A4 (fr) 1997-03-24 1998-03-19 Acides difluoronucleosides-phosphoniques et leurs derives
AU64730/98A AU6473098A (en) 1997-03-24 1998-03-19 Difluoronucleoside phosphonic acids and derivatives thereof
CA002284263A CA2284263A1 (fr) 1997-03-24 1998-03-19 Acides difluoronucleosides-phosphoniques et leurs derives

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US4150797P 1997-03-24 1997-03-24
US60/041,507 1997-03-24

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007112028A2 (fr) * 2006-03-23 2007-10-04 Rfs Pharma, Llc. Phosphonates de 2'-fluoronucléoside en tant qu'agents antiviraux
WO2008017515A1 (fr) 2006-08-11 2008-02-14 Resprotect Gmbh Nucléoside pour la suppression ou la réduction de la formation de résistance lors du traitement cytostatique
US8101745B2 (en) 2004-12-16 2012-01-24 The Regents Of The University Of California Lung-targeted drugs
US9775852B2 (en) 2013-03-15 2017-10-03 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US9801884B2 (en) 2014-09-15 2017-10-31 The Regents Of The University Of California Nucleotide analogs
US10377782B2 (en) 2015-09-15 2019-08-13 The Regents Of The University Of California Nucleotide analogs

Citations (2)

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US4808614A (en) * 1983-03-10 1989-02-28 Eli Lilly And Company Difluoro antivirals and intermediate therefor
US5464826A (en) * 1984-12-04 1995-11-07 Eli Lilly And Company Method of treating tumors in mammals with 2',2'-difluoronucleosides

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Publication number Priority date Publication date Assignee Title
CA2004695C (fr) * 1988-12-12 1999-08-10 Rosanne Bonjouklian Phospholipide nucleosides

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Publication number Priority date Publication date Assignee Title
US4808614A (en) * 1983-03-10 1989-02-28 Eli Lilly And Company Difluoro antivirals and intermediate therefor
US5464826A (en) * 1984-12-04 1995-11-07 Eli Lilly And Company Method of treating tumors in mammals with 2',2'-difluoronucleosides

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Title
See also references of EP0994715A4 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8101745B2 (en) 2004-12-16 2012-01-24 The Regents Of The University Of California Lung-targeted drugs
US8318700B2 (en) 2004-12-16 2012-11-27 The Regents Of The University Of California Lung-targeted drugs
WO2007112028A2 (fr) * 2006-03-23 2007-10-04 Rfs Pharma, Llc. Phosphonates de 2'-fluoronucléoside en tant qu'agents antiviraux
WO2007112028A3 (fr) * 2006-03-23 2008-03-06 Rfs Pharma Llc Phosphonates de 2'-fluoronucléoside en tant qu'agents antiviraux
US8895531B2 (en) 2006-03-23 2014-11-25 Rfs Pharma Llc 2′-fluoronucleoside phosphonates as antiviral agents
WO2008017515A1 (fr) 2006-08-11 2008-02-14 Resprotect Gmbh Nucléoside pour la suppression ou la réduction de la formation de résistance lors du traitement cytostatique
KR101113029B1 (ko) * 2006-08-11 2012-06-05 레스프로텍트 게엠베하 세포증식 억제 요법에서 저항의 발생을 억제 또는 감소하기위한 뉴클레오시드
US8492537B2 (en) 2006-08-11 2013-07-23 Resprotect Gmbh Nucleosides for suppressing or reducing the development of resistance in cytostatic therapy
US10076532B2 (en) 2013-03-15 2018-09-18 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US9775852B2 (en) 2013-03-15 2017-10-03 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US10076533B2 (en) 2013-03-15 2018-09-18 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US10195222B2 (en) 2013-03-15 2019-02-05 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US10449207B2 (en) 2013-03-15 2019-10-22 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US9801884B2 (en) 2014-09-15 2017-10-31 The Regents Of The University Of California Nucleotide analogs
US10213430B2 (en) 2014-09-15 2019-02-26 The Regents Of The University Of California Nucleotide analogs
US10702532B2 (en) 2014-09-15 2020-07-07 The Regents Of The University Of California Nucleotide analogs
US11344555B2 (en) 2014-09-15 2022-05-31 The Regents Of The University Of California Nucleotide analogs
US10377782B2 (en) 2015-09-15 2019-08-13 The Regents Of The University Of California Nucleotide analogs
US11014950B2 (en) 2015-09-15 2021-05-25 The Regents Of The University Of California Nucleotide analogs
US11572377B2 (en) 2015-09-15 2023-02-07 The Regents Of The University Of California Nucleotide analogs

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EP0994715A4 (fr) 2001-08-08
AU6473098A (en) 1998-10-20
EP0994715A1 (fr) 2000-04-26
CA2284263A1 (fr) 1998-10-01
JP2001518931A (ja) 2001-10-16

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