WO2004050665A1 - Silicon compounds - Google Patents

Silicon compounds Download PDF

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Publication number
WO2004050665A1
WO2004050665A1 PCT/GB2003/005053 GB0305053W WO2004050665A1 WO 2004050665 A1 WO2004050665 A1 WO 2004050665A1 GB 0305053 W GB0305053 W GB 0305053W WO 2004050665 A1 WO2004050665 A1 WO 2004050665A1
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WIPO (PCT)
Prior art keywords
pyrimidin
tetrahydrofuran
amino
difluoro
hydroxy
Prior art date
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PCT/GB2003/005053
Other languages
French (fr)
Inventor
John Gary Montana
William Bains
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Amedis Pharmaceuticals Ltd.
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Publication date
Priority claimed from GB0227905A external-priority patent/GB0227905D0/en
Priority claimed from GB0322011A external-priority patent/GB0322011D0/en
Application filed by Amedis Pharmaceuticals Ltd. filed Critical Amedis Pharmaceuticals Ltd.
Priority to AU2003302624A priority Critical patent/AU2003302624A1/en
Publication of WO2004050665A1 publication Critical patent/WO2004050665A1/en

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    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0834—Compounds having one or more O-Si linkage
    • C07F7/0838—Compounds with one or more Si-O-Si sequences

Definitions

  • Brain tumours are found in approximately 2% of routine autopsies and, in more than half these cases, they are metastases of tumours that originate from other sites. Although about a third of patients with central nervous system (CNS) metastases have not been previously diagnosed as having cancer, their CNS symptoms are generally the first indication of cancer.
  • CNS central nervous system
  • Gemcitabine is an example of a nucleoside analogue, a specific class of anti-metabolite.
  • Other examples of anti-cancer drugs which are nucleoside analogues include cytarabine, 5-fluorouracil, fludarabine and proguanil.
  • Gemcitabine is a DNA elongation blocker, primarily killing cells in the S phase. Under certain circumstances, gemcitabine blocks progression through the G1/S boundary. Gemcitabine promotes apoptosis, possibly by causing DNA damage and premature arrest of the cell cycle. Gemcitabine is widely used as an anti-cancer agent, e.g. for the treatment of non-small cell lung, locally-advanced pancreatic, metastatic pancreatic, breast and ovarian cancers. Gemcitabine is activated in vivo by deoxycytidine kinase.
  • a prodrug is a generally inactive compound that is converted (e.g. by metabolism) within the body into its active form.
  • Prodrugs are useful when the active form is too toxic to administer systemically, is absorbed poorly (e.g. due to BBB) or breaks down before reaching its target.
  • the prodrug functionality must modulate the release of the active drug such that it is released rapidly enough to have a therapeutic effect before it is cleared from the body, but slow enough so that it can be formulated, delivered and distributed to the target. Selection of the prodrug functionality is not straightforward and subtly depends on the chemistry of the compound.
  • Prodrugs of gemcitabine are not activated by deoxycytidine kinase, due to blocking of the 5OH group.
  • Prodrugs of gemcitabine are known, see for example WO-A-98/32762.
  • the prodrugs typically have a modified pyrimidine ring, rather than the sugar.
  • the present invention is based on the discovery that therapeutic agents can be converted into prodrug form using one or more silicon-based protecting groups. Although such groups have been used extensively in synthetic and analytical chemistry, they have rarely before been considered as suitable for use in therapeutic compounds.
  • the invention particularly concerns a particular class of compounds having one or more silicon-based protecting groups bound at an oxygen atom of the active compound, forming an -O-Si- linkage.
  • the O-Si bond readily hydrolyses, typically in timescales of minutes to days, under physiological conditions.
  • the advantages of such protecting groups are numerous. Firstly, cleavage of the O-Si bond is entirely chemical, and thus unlike conventional prodrugs, prodrugs of the invention remain effective even if the patient's physiology is abnormal.
  • silyl groups are highly lipophilic and thus enhance the penetration of the compounds across the gut wall, cell membranes and BBB.
  • a first aspect of the invention is a compound of formula (I)
  • R 1 and R 2 are -Si(R) 3 , and the other is hydrogen or -Si(R) 3 ; or R 1 is a bond, R 2 is -Si(R) 2 - or -Si(R) 2 -O-Si(R) 2 -, and R 1 O-CH 2 -CH-CH- OR 2 taken together form a ring;
  • Compounds of the invention may be prodrugs of anti-metabolites and as a consequence may have therapeutic utility in the treatment of cancer.
  • Another aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer.
  • Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.
  • each R is preferably the same or different and is methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl or a group of formula (i) as defined herein.
  • alkyl refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. "C.,- 6 alkyl” has the same meaning.
  • cycloalkyl refers to a saturated alicyclic moiety having from three to ten carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The group may be a bridged moiety.
  • heterocycloalkyl refers to a saturated heterocyclic moiety having from four to ten carbon atoms and one or more heteroatoms selected from the group N, O, S, Si and P, and includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like.
  • the group may be a bridged moiety.
  • Compounds of the invention are chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate.
  • the stereochemistry of a chiral ring atom is preferably the same as that of the corresponding atom in gemcitabine. More preferably, the stereochemistry of the compound as a whole corresponds to that of gemiciabine.
  • the compounds of the invention may be prepared in racemic form, or prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art.
  • the compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallisation and regeneration of the free base.
  • the enantiomers of the novel compounds may be separated by HPLC using a chiral column.
  • Some compounds of the formula may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention.
  • Compounds of the invention may be in the form of pharmaceutically acceptable salts, for example, addition salts of inorganic or organic acids.
  • inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid.
  • Organic acid addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2- methylpropionic acid, 1 ,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconicacid, glutamicacid, N-glycolylarsanilicacid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoicacid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric
  • a compound of the invention may be prepared by any suitable method known in the art. Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by formation of a salt if appropriate or possible under the circumstances.
  • Preferred compounds of the invention include:
  • cancer refers to any disease or condition characterised by uncontrolled, abnormal growth of cells and includes all known types of cancer, for example cancer of the bladder, breast, colon, brain, bone, head, blood, eye, neck, skin, lungs, ovaries, prostate and rectum; digestive, gastrointestinal, endometrial, hematological, AIDS-related, muscoskeletal, neurological and gynecological cancers; lymphomas, melanomas and leukaemia.
  • cancer refers to both solid and liquid tumours.
  • the active compound may be administered orally, intravenously, rectal ly, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity.
  • Intravenous administration is preferred.
  • the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration.
  • the compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art.
  • the compositions of the invention may contain 0.1-99% by weight of active compound.
  • the compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1-500 mg.
  • the excipients used in the preparation of these compositions are the excipients known in the art.
  • compositions for oral administration include known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example com starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl or n-propyl p- hydroxybenzoate
  • colouring agents for example ethyl or n-propyl p- hydroxybenzoate
  • flavouring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Suitable sweetening, flavouring and colouring agents may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1 ,3- butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as ol . eic acid, find use in the preparation of injectables.
  • the compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • compositions for topical administration are also suitable for use in the invention.
  • the pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel.
  • a suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants.
  • An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax.
  • a gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent.
  • Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. The following Examples illustrate the invention.
  • Mass spectrometry involved the use of an electrospray source operating in positive and negative ion mode.
  • the system ran at 1.5 ml/min, detection mode is through a Hexa-pole Mass Spectrometry detector and a Diode-Array detector for UV.
  • Trimethylsilyl chloride (TMSCI, 2.96 ml, 23.4 mmol) was added and the resulting mixture was stirred at room temperature for 24 h before being washed with water (200 ml) and extracted into ethyl acetate (3 x 200 ml). The combined organic extracts were then washed with saturated sodium chloride solution (200 ml), dried (magnesium sulfate, MgSO 4 ) and concentrated in vacuo. The crude material was then purified by column chromatography (silica, 1 :19-methyl alcohol-ethyl acetate) to afford the title compound in a homogeneous form (1.2 g, 24 %).
  • Example 2 4-Amino-1 -f5-f tert-butyldimethylsilyloxymethyl)-3.3-difluoro-4- hydroxy-tetrahydrofuran-2-yll-1 -pyrimidin-2-one
  • Example 3 4-Amino-1 -r5-(te/t-butyldiphenylsilyloxymethyl)-3,3-difluoro-4- hydroxy-tetrahvdrofuran-2-yl1-1f/-pyrimidin-2-one
  • 4-amino-1-[3,3-difluoro-4-hydr ⁇ xy-5- hydroxymethyl-tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one hydrochloride (2.00 g, 5.0 mmol) and imidazole (1.36 g, 20 mmol) in anhydrous DMF (29 ml) under nitrogen at 0 °C was added fe/f-butyldiphenylsilyl chloride (TBDPS-CI, 1.84 ml, 8.0 mmol).
  • Example 5 4-Amino-1 -f3,3-difluoro-5-hvdroxymethyl-4-(triethylsilyloxy)- tetrahvdrofuran-2-v ⁇ -1 -pyrimidin-2-one To a solution of 4-amino-1 -[3,3-difluoro-4-(triethylsilyloxy)-5-
  • Example 7 4-amino-1 -r3.3-difluoro-5-(ethyldimethylsilyloxymethyl)-4- hydroxy-tetrahvdrofuran-2-yl1-1 -pyrimidin-2-one This material was formed as a minor product in the synthesis of 4-amino- 1 -[4-(ethyldimethylsilyloxy)-5-(ethyldimethylsilyloxymethyl)-3,3-difluoro- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one (Example 6).
  • Example 9 4-Amino-1 -r(4-diethylmethylsilyloxy)-5-(diethylmethyl- silyloxymethyl)-3,3-difluoro-tetrahvdro-furan-2-yl1-1 -pyrimidm-2-one
  • Example 11 4-Amino-1 -r4-(diethylmethylsilyloxy)-3.3-difluoro-5-hvdroxy- methyltetrahvdrofuran-2-yll-1tf-pyrimidin-2-one

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Abstract

A compound of formula (I) wherein one of R1 and R2 is -Si(R)3, and the other is hydrogen or -Si(R)3; or R1 is a bond, R2 is -Si(R)2- or -Si(R)2 -O-Si(R)2-, and R10-CH2-CH-CH-OR2 taken together form a ring; R3 and R4 are the same or different and are each halogen; and each R is the same or different and is alkyl, aryl, cycloalkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

Description

SILICON COMPOUNDS
Field of the Invention
This invention relates to silicon compounds and their use in therapy. Background to the Invention Of the various cancers, brain tumours are among the most difficult to treat.
Furthermore, the incidence of brain tumours is increasing as a result of the increased survival rates to systemic cancers achieved using chemotherapy. Brain tumours are found in approximately 2% of routine autopsies and, in more than half these cases, they are metastases of tumours that originate from other sites. Although about a third of patients with central nervous system (CNS) metastases have not been previously diagnosed as having cancer, their CNS symptoms are generally the first indication of cancer.
The treatment of CNS tumours is often difficult because therapeutic agents do not readily enter the brain from the blood; this is attributed to a "blood- brain barrier" (BBB). This barrier is effective against many known anti-cancer agents and thus chemotherapy is of limited use. Some forms of chemotherapy, such as intravenous injection of high doses of cyclophosphamide, 5-fluorouracil or methotrexate, have been shown to be effective. However, the high dosages result in numerous, often severe side-effects throughout the body. As a result, these agents are generally injected into the cerebro-spinal fluid, either via intrathecal injection or by injection into an Ommaya reservoir, an access device that delivers the drugs to the brain ventricles. Chemotherapy is often combined with radiation therapy and, where necessary, surgery. All three treatments may result in seizures and cognitive problems (e.g. dysphasia, memory loss or personality changes).
An anti-metabolite is a compound which has a similar structure to a metabolite, but which competes with or replaces the metabolite, thus preventing or reducing its normal function in cellular metabolism. Anti-metabolites used in cancer therapy include methotrexate, analogues of nucleic acid bases such as mercaptopurine (Purinethol), azathioprine (Imuran), thioguanine, dacarbazine, nucleoside analogues, analogues of sugars such as mitobronitol, and analogues of steroid synthesis in the adrenals (e.g. mitotane). Some anti-metabolites are also used to treat other proliferative diseases such as inflammatory conditions.
Gemcitabine is an example of a nucleoside analogue, a specific class of anti-metabolite. Other examples of anti-cancer drugs which are nucleoside analogues include cytarabine, 5-fluorouracil, fludarabine and proguanil.
Gemcitabine is a DNA elongation blocker, primarily killing cells in the S phase. Under certain circumstances, gemcitabine blocks progression through the G1/S boundary. Gemcitabine promotes apoptosis, possibly by causing DNA damage and premature arrest of the cell cycle. Gemcitabine is widely used as an anti-cancer agent, e.g. for the treatment of non-small cell lung, locally-advanced pancreatic, metastatic pancreatic, breast and ovarian cancers. Gemcitabine is activated in vivo by deoxycytidine kinase. In systemic therapy, gemcitabine is co-administered with a wide range of other agents, including epirubicin (see WO-A-9943332), alkylating anthracyclines (see WO-A-200105382), and other alkylating agents. Together, gemcitabine and cisplatin are better tolerated than MVAC (methotrexate, vinblastine, adriamycin and cisplatin), despite their similar efficacies.
A prodrug is a generally inactive compound that is converted (e.g. by metabolism) within the body into its active form. Prodrugs are useful when the active form is too toxic to administer systemically, is absorbed poorly (e.g. due to BBB) or breaks down before reaching its target. Typically, the prodrug functionality must modulate the release of the active drug such that it is released rapidly enough to have a therapeutic effect before it is cleared from the body, but slow enough so that it can be formulated, delivered and distributed to the target. Selection of the prodrug functionality is not straightforward and subtly depends on the chemistry of the compound. Prodrugs of gemcitabine are not activated by deoxycytidine kinase, due to blocking of the 5OH group.
Prodrugs of gemcitabine are known, see for example WO-A-98/32762. The prodrugs typically have a modified pyrimidine ring, rather than the sugar. Summary of the Invention
The present invention is based on the discovery that therapeutic agents can be converted into prodrug form using one or more silicon-based protecting groups. Although such groups have been used extensively in synthetic and analytical chemistry, they have rarely before been considered as suitable for use in therapeutic compounds.
The invention particularly concerns a particular class of compounds having one or more silicon-based protecting groups bound at an oxygen atom of the active compound, forming an -O-Si- linkage. The O-Si bond readily hydrolyses, typically in timescales of minutes to days, under physiological conditions. The advantages of such protecting groups are numerous. Firstly, cleavage of the O-Si bond is entirely chemical, and thus unlike conventional prodrugs, prodrugs of the invention remain effective even if the patient's physiology is abnormal. Secondly, silyl groups are highly lipophilic and thus enhance the penetration of the compounds across the gut wall, cell membranes and BBB.
A first aspect of the invention is a compound of formula (I)
Figure imgf000004_0001
wherein one of R1 and R2 is -Si(R)3, and the other is hydrogen or -Si(R)3; or R1 is a bond, R2 is -Si(R)2- or -Si(R)2-O-Si(R)2-, and R1O-CH2-CH-CH- OR2 taken together form a ring;
R3 and R4 are the same or different and are each halogen; and each R is the same or different and is alkyl, aryl, cycloalkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof.
Compounds of the invention may be prodrugs of anti-metabolites and as a consequence may have therapeutic utility in the treatment of cancer.
Another aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer. Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.
Description of the Preferred Embodiments Certain compounds and combinations of substituents are preferred; in particular see the subclaims.
With regard to formula (I), each R is preferably the same or different and is methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl or a group of formula (i) as defined herein. More patricularly, R1 and/or R2 is preferably a group selected from trimethylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, ethyldimethylsilyl, propyldimethylsilyl, methyldiethylsilyl, cyclopropyldimethysilyl, cyclohexyldimethylsilyl and norbornyldimethylsilyl. R3 and/or R4 is preferably fluorine. When R is a group of formula (i), then it is preferred that X is -CH2CH2-, Y is -CH2- and Z is -CH2-. In formula (i), the proviso concerns the stability of the group.
The term "alkyl" as used herein refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. "C.,-6 alkyl" has the same meaning. The term "cycloalkyl" as used herein refers to a saturated alicyclic moiety having from three to ten carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The group may be a bridged moiety.
The term "heterocycloalkyl" as used herein refers to a saturated heterocyclic moiety having from four to ten carbon atoms and one or more heteroatoms selected from the group N, O, S, Si and P, and includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like. The group may be a bridged moiety.
The term "aryl" as used herein refers to optionally substituted aromatic ring systems comprising six to ten ring atoms, and optionally substituted polycyclic ring systems having two or more cyclic rings at least one of which is aromatic. This term includes for example, phenyl and naphthyl. The group may be optionally substituted with the substituents being the same or different in each occurrence and selected from halogen, alkyl, nitro and the like. The term "halogen" as used herein refers to F, Cl, Br or I. A compound of the invention may be in a protected amino form. The term "protected amino" as used herein refers to amino groups which are protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or like groups, or in the form of a phthalimido or like group.
Compounds of the invention are chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate. The stereochemistry of a chiral ring atom is preferably the same as that of the corresponding atom in gemcitabine. More preferably, the stereochemistry of the compound as a whole corresponds to that of gemiciabine.
The compounds of the invention may be prepared in racemic form, or prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art. The compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallisation and regeneration of the free base. Alternatively, the enantiomers of the novel compounds may be separated by HPLC using a chiral column.
Some compounds of the formula may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention.
Compounds of the invention may be in the form of pharmaceutically acceptable salts, for example, addition salts of inorganic or organic acids. Such inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid. Organic acid addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2- methylpropionic acid, 1 ,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconicacid, glutamicacid, N-glycolylarsanilicacid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoicacid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-toluenesulphonic acid, 10-undecenoic acid and the like.
It will be appreciated that such salts, provided that they are pharmaceutically acceptable, may be used in therapy. Such salts may be prepared by reacting the compound with a suitable acid in a conventional manner.
A compound of the invention may be prepared by any suitable method known in the art. Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by formation of a salt if appropriate or possible under the circumstances.
Preferred compounds of the invention include:
4-amino-1-[5-(te/t-butyldiphenylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1/ -pyrimidin-2-one;
4-amino-1-[4-(te/Y-butyldiphenylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one;
4-am i no- -[Λ-(tert -butyl di phenyl si lyloxy)-5-(ferf - butyldiphenylsilyloxymethyl)-3,3-difluoro-tetrahydrofuran-2-yl]-1H-pyrimidin-2- one;
4-amino-1-[5-(fe/ιf-butyldimethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-amino-1-[4-(fetf-butyldimethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one; 4-am i no- 1 -[4-(tert-buty Id i methyl si lyloxy)-5-(ferf - butyldimethylsilyloxymethyl)-3,3-difluoro-tetrahydrofuran-2-yl]-1/-/-pyrimidin-2- one; 4-amino-1-[3,3-difluoro-4-hydroxy-5-(trimethylsilyloxymethyl)- tetrahydrofuran-2-yl]-1 /-/-pyrimidin-2-one;
4-amino-1-[3,3-difluoro-5-hydroxymethyl-4-(trimethylsilyloxy)- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one; 4-amino-1-[3,3-difluoro-4-(trimethylsilyloxy)-5-(trimethylsilyloxymethyl)- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-amino-1-[3,3-difluoro-4-hydroxy-5-(triethylsilyloxymethyl)- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one;
4-amino-1-[3,3-difluoro-5-hydroxymethyl-4-(triethylsilyloxy)- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one;
4-amino-1-[3,3-difluoro-4-(triethylsilyloxy)-5-(triethylsilyloxymethyl)- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-amino-1-[5-(ethyldimethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one; 4-amino-1-[4-(ethyldimethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1 /-/-pyrimidin-2-one;
4-amino-1-[4-(ethyldimethylsilyloxy)-5-(ethyldimethylsilyloxymethyl)-3,3- diflubro-tetrahydrofuran-2-yl]-1/--pyrimidin-2-one;
4-amino-1-[3,3-difluoro-5-(dimethylpropylsilyloxymethyl)-4-hydroxy- tetrahydrofuran-2-yl]-1 /-/-pyrimidin-2-one;
4-amino-1-[3,3-difluoro-4-(dimethylpropylsilyloxy)-5-hydroxymethyl- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one;
4-amino-1-[3,3-difluoro-4-(dimethylpropylsilyloxy)-5- (dimethylpropylsilyloxymethyl)-tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one; 4-amino-1-[5-(diethylmethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-amino-1-[4-(diethylmethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-amino-1-[4-(diethylmethylsilyloxy)-5-(diethylmethylsilyloxymethyl)-3,3- dif luoro-tetrahydrofuran-2-yl]-1 -/-pyrimidin-2-one;
3',5'-O-(dimethylsilyleηyl)-gemcitabine;
3',5'-O-(diethylsilylenyl)-gemcitabine;
3,,5'-O-[(di-terf-butyl)silylenyl]-gemcitabine; 3',5'-O-(diphenylsilylenyl)-gemcitabine;
3',5'-O-(tetramethyldisiloxanyl)-gemcitabine;
3',5'-O-(tetraethyldisiloxanyl)-gemcitabine;
3',5'-O-[(tetra-erf-butyl)disiloxanyl]-gemcitabine; 3',5'-O-(tetraphenyldisiloxanyl)-gemcitabine;
4-amino-1-[5-(cyclopropyldimethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1 /--pyrimidin-2-one;
4-amino-1-[4-(cyclopropyldimethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one; 4-amino-1 -[4-(cyclopropyldimethylsilyloxy)-5-
(cyclopropyldimethylsilyloxymethyl)-3,3-difluoro-tetrahydrofuran-2-yl]-1H- pyrimidin-2-one;
4-amino-1-[5-(cyclohexyldimethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one; 4-amino-1 -[4~(cyclohexyldimethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one;
4-amino-1 -[4-(cyclohexyldimethylsilyloxy)-5- (cyclohexyldimethylsilyloxymethyl)-3,3-difluoro-tetrahydrofuran-2-yl]-1H- pyrimidin-2-one; 4-amino-1-[5-(2-norbomyldimethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-amino-1-[4-(2-norbonyldimethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1 -/-pyrimidin-2-one; and
4-amino-1-[4-(2-norbornyldimethylsilyloxy)-5-(2- norbornyldimethylsilyloxymethyl)-3,3-difluoro-tetrahydrofuran-2-yl]-1H-pyrimidin- 2-one; the corresponding structures of which are shown below, respectively (ordered left to right):
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0003
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
The activity and selectivity of the compounds may be determined by any suitable assay known in the art.
The compounds of the invention may be used in the treatment of numerous ailments, conditions and diseases including, but not limited thereto, cancer. The term "cancer" as used herein refers to any disease or condition characterised by uncontrolled, abnormal growth of cells and includes all known types of cancer, for example cancer of the bladder, breast, colon, brain, bone, head, blood, eye, neck, skin, lungs, ovaries, prostate and rectum; digestive, gastrointestinal, endometrial, hematological, AIDS-related, muscoskeletal, neurological and gynecological cancers; lymphomas, melanomas and leukaemia. The term refers to both solid and liquid tumours.
In therapeutic use, the active compound may be administered orally, intravenously, rectal ly, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity. Intravenous administration is preferred. Thus, the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1-500 mg. The excipients used in the preparation of these compositions are the excipients known in the art.
Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the disease undergoing treatment. Compositions for oral administration include known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example com starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as ol.eic acid, find use in the preparation of injectables.
The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compositions for topical administration are also suitable for use in the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. The following Examples illustrate the invention.
In the Examples, all 1H NMR spectra were run at 400 MHz using CDCI3 as solvent unless stated otherwise. LC-MS spectra were run using Conditions A1 or A2 (described below):
Mass spectrometry involved the use of an electrospray source operating in positive and negative ion mode. The system ran at 1.5 ml/min, detection mode is through a Hexa-pole Mass Spectrometry detector and a Diode-Array detector for UV.
Mobile phase: acetonitrile-water (running from 5-95% acetonitrile) with either 0.05% formic acid (Conditions A1 ) or 0.05% ammonium hydroxide (Conditions A2) added.
Intermediate 1 : Diethylmethylsilyl trifluoromethanesulphonate
To a neat quantity of cooled (ice/salt bath) stirred diethylmethylsilane (10 g, 97.79 m'mol) under nitrogen was added trifluoromethane sulphonic acid (16.14 g, 107.55 mmol). After the addition was complete the reaction was stirred at ambient temperature overnight and the crude mixture was then purified by vacuum distillation to afford the title compound (b.p. 57-62 °C at 10 mbar; 23.42 g, 96 %). 1H NMR δ 1.07 (6 H, t, J = 7.83 Hz), 0.94 (4 H, m), 0.47 (3 H, s). Example 1: 4-Amino-1-r3.3-difluoro-4-ftrimethylsilyloxy)-5- trimethylsilyloxymethyl)-tetrahvdrofuran-2-vn-1tf-pyrimidin-2-one
To a stirred suspension of 4-amino-1-[3,3-difluoro-4-hydroxy-5- hydroxymethyl-tetrahydrofuran-2-yl]-1H-pyrimidin-2-one hydrochloride (3.5 g, 11.7 mmol) in anhydrous tetrahydrofuran (THF, 27 ml) being stirred under nitrogen was added triethylamine (TEA, 6.19 ml, 46.7 mmol) and the reaction was stirred for 10 min at room temperature. Trimethylsilyl chloride (TMSCI, 2.96 ml, 23.4 mmol) was added and the resulting mixture was stirred at room temperature for 24 h before being washed with water (200 ml) and extracted into ethyl acetate (3 x 200 ml). The combined organic extracts were then washed with saturated sodium chloride solution (200 ml), dried (magnesium sulfate, MgSO4) and concentrated in vacuo. The crude material was then purified by column chromatography (silica, 1 :19-methyl alcohol-ethyl acetate) to afford the title compound in a homogeneous form (1.2 g, 24 %). Example 2: 4-Amino-1 -f5-f tert-butyldimethylsilyloxymethyl)-3.3-difluoro-4- hydroxy-tetrahydrofuran-2-yll-1 -pyrimidin-2-one
To a stirred suspension of 4-amino-1-[3,3-difluoro-4-hydroxy-5- hydroxymethyl-tetrahydrofuran-2-yl]-1H-pyrimidin-2-one hydrochloride (2.00 g, 6.67 mmol) and imidazole (1.36 g, 20 mmol) in anhydrous N,N- dimethylformamide (DMF, 29 ml) under nitrogen at 0 °C was added tert- butyldimethylsilyl chloride (TBDMSCI, 1.21 ml, 8.0 mmol). The reaction was then stirred at room temperature for 18 h before being diluted with diethyl ether (30 ml) and the resulting mixture was washed with water (20 ml). The colourless precipitate that formed in the aqueous phase was isolated by filtration and then triturated with diethyl ether and dried in vacuo to afford the title compound (954 mg, 38 %).
Example 3: 4-Amino-1 -r5-(te/t-butyldiphenylsilyloxymethyl)-3,3-difluoro-4- hydroxy-tetrahvdrofuran-2-yl1-1f/-pyrimidin-2-one To a stirred suspension of 4-amino-1-[3,3-difluoro-4-hydrόxy-5- hydroxymethyl-tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one hydrochloride (2.00 g, 5.0 mmol) and imidazole (1.36 g, 20 mmol) in anhydrous DMF (29 ml) under nitrogen at 0 °C was added fe/f-butyldiphenylsilyl chloride (TBDPS-CI, 1.84 ml, 8.0 mmol). The reaction was then stirred at room temperature for 72 h before being washed with saturated aqueous sodium chloride solution (50 ml) and extracted into ethyl acetate (50 ml). The organic extracts were then dried (MgS04) and concentrated in vacuo. The crude material was purified by column chromatography (silica, 1 :33-methyl alcohol-dichloromethane) to afford the title compound as a colourless powder (1.97 g, 81 %).
Example 4: 4-Amϊno-1-f3,3-difluoro-4-(triethylsilyloxy)-5- (triethylsilyloxymethyl)-tetrahydrofuran-2-yl]-1H-pyrimidin-2-one
To a stirred solution of 4-amino-1-[3,3-difluoro-4-hydroxy-5- (hydroxymethyl)-tetrahydrofuran-2-yl]-1H-pyrimidin-2-one (100 mg, 0.38 mmol) was added triethylsilyl chloride (TESCI, 0.13 ml, 0.79 mmol) and imidazole (135 mg, 1.99 mmol) in dry DMF (2 ml) under nitrogen at 0 °C. The mixture was stirred at room temperature for 18 h before being quenched with water (5 ml) and extracted with diethyl ether (3 x 10 ml). The ether extracts were washed with saturated sodium chloride solution before being dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography (silica, 1 :4-methyl alcohol-diethyl ether) to afford the title compound (217 mg, 99 %) as an oil, Rf (1 :4-methyl alcohol-diethyl ether) 0.92; 1H NMR δ 7.67 (1 H, d, J = 7.6 Hz), 6.26 (1 H, m), 5.79 (1 H, d, J = 7.6 Hz), 4.28 (1 H, dt, J = 11.8, 8.0 Hz), 3.92 (1 H, br d, J = 11.8 Hz), 3.84 (1 H, br d, J = 8.0 Hz), 3.77 (1 H, dd, J = 11.8, 2.0 Hz), 1.16 (1 H, d, J = 5.0 Hz), 0.94 (9 H, t, J = 8.3 Hz), 0.92 (9 H, t, J = 8.3 Hz) and 0.61 (12 H, m); LC-MS (ESI) Rt (Conditions A1 ) 4.9 min, m/z (ES+) 491 (M+).
Example 5: 4-Amino-1 -f3,3-difluoro-5-hvdroxymethyl-4-(triethylsilyloxy)- tetrahvdrofuran-2-vπ-1 -pyrimidin-2-one To a solution of 4-amino-1 -[3,3-difluoro-4-(triethylsilyloxy)-5-
(triethylsilyloxy-methyl)-tetrahydrofuran-2-yl]-1H-pyrimidin-2-one (164 mg, 0.33 mmol) in diethyl ether (1.5 ml) at 0 °C was added an aqueous solution of trifluoroacetic acid (20 %, 50 μl). The mixture was stirred at this temperature for 10 min before the solution was treated with water (1 ml) and extracted with diethyl ether (3 x 5 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography (silica, 1 :4-methyl alcohol in diethyl ether) to afford the title compound (88 mg, 70 %) as an oil, Rf (1 :4-methyl alcohol in diethyl ether) 0.52; 1H NMR δ (CD3OD) 7.83 (1 H, d, J = 7.6 Hz), 6.18 (1 H, d, J = 8.0 Hz), 5.88 (1 H, . d, J = 7.6 Hz), 4.39 (1 H, m), 3.90 (1 H, br d, J = 12.6 Hz), 3.86 (1 H, m), 3.71 (1 H, dd, J = 12.6, 2.7 Hz), 0.97 (9 H, t, J = 8.0 Hz) and 0.66 (6 H, q, J = 8.0 Hz); LC-MS (ESI) Rt (conditions A1 ) 1.9 min, m/z (ES+) 377 (M+). Example 6: 4-Amino-1-f4-(ethyldimethylsilyloxy)-5- (ethyldimethylsilyloxymethyl)-3.3-difluoro-tetrahvdrofuran-2-yπ-1H- pyrimidin-2-one To a stirred solution of 4-amino-1-[3,3-difluoro-4-hydroxy-5-
(hydroxymethyl)-tetrahydrofuran-2-yl]-1H-pyrimidin-2-one (200 mg, 0.66 mmol) in dry DMF (7 ml) under nitrogen at 0 °C was added dimethylethylsilyl chloride (0.48 ml, 3.16 mmol) and imidazole (270 mg, 3.98 mmol). The mixture was stirred at room temperature for 20 h before being quenched with water (5 ml) and extracted with ether (3 x 15 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography (silica, 1 :4-methyl alcohol in diethyl ether) to afford the title compound as an oil (186 mg, 65 %), Rf (1 :4-methyl alcohol in diethyl ether) 0.81 ; 1H NMR δ (CD3OD) 7.70 (1 H, d, J = 7.6 Hz), 6.04 (1 H, m), 5.73 (1 H, d, J = 7.6 Hz), 4.20 (1 H, dt, J = 12.1 , 8.0 Hz), 3.84 (1 H, br d, J = 11.8 Hz), 3.76 (1 H, dt, J = 8.3, 2.0 Hz), 3.65 (1 H, dd, J = 11.8, 2.2 Hz), 0.84 (3 H, t, J = 7.8 Hz), 0.81 (3 H, t, J = 7.8 Hz), 0.48 (4 H, m) and -0.01 (12 H, s); LC-MS (ESI) Rt (Conditions A1 ) 4.1 min, m/z (ES+) 435 (M+). Example 7: 4-amino-1 -r3.3-difluoro-5-(ethyldimethylsilyloxymethyl)-4- hydroxy-tetrahvdrofuran-2-yl1-1 -pyrimidin-2-one This material was formed as a minor product in the synthesis of 4-amino- 1 -[4-(ethyldimethylsilyloxy)-5-(ethyldimethylsilyloxymethyl)-3,3-difluoro- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one (Example 6). Rf (1 :4-methyl alcohol in diethyl ether) 0.64; 1H NMR δ (CD3OD) 7.77 (1 H, d, J = 7.6 Hz), 6.04 (1 H, t, J = 7.0 Hz), 5.71 (1 H, d, J = 7.6 Hz), 4.07 (1 H, dt, J = 12.6, 8.8 Hz), 3.86 (1 H, br d, J = 11.8 Hz), 3.76 (1 H, dt, J = 8.8, 2.7 Hz), 3.70 (1 H, dd, J = 11.8, 2.5 Hz), 0.99 (1 H, d, J = 6.0 Hz), 0.84 (3 H, t, J = 8.0 Hz), 0.51 (2 H, q, J = 8.0) and - 0.001 (6 H, s); LC-MS (ESI) Rt (Conditions A1 ) 3.0 min, m/z (ES+) 349 (M+). Example 8: 4-amino-1-f3,3-difluoro-4-(ethyldimethylsilyloxy)-5- hydroxymethyl-tetrahvdrofuran-2-yπ-1 -pyrimidin-2-one
To a solution of 4-amino-1 -[3,3-difluoro-5-(ethyldimethylsilyloxymethyl)-4- (ethyldimethylsilyloxy)-tetrahydrofuran-2-yl]-1 -/-pyrimidin-2-one (82 mg, 0.18 mmol) in diethyl ether (2.0 ml) at 0 °C was added an aqueous solution of trifluoroacetic acid (12 μl, 20 %). The mixture was stirred at this temperature for 10 min before being diluted with water (1 ml) and extracted with ether (3 x 5 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography (silica, 1 :4-methyl alcohol in diethyl ether) to afford the title compound (13 mg, 21 %) as an oil, Rf (1 :4-methyl alcohol in diethyl ether) 0.67; 1H NMR (CD3OD) δ 7.67 (1 H, d, J = 7.6 Hz), 6.04 (1 H, dd, J = 8.0, 7.8 Hz), 5.74 (1 H, d, J = 7.6 Hz), 4.22 (1 H, dt, J = 11.8, 8.0 Hz), 3.75 (1 H, br d, J = 12.6 Hz), 3.70 (1 H, dt, J = 8.0, 2.5 Hz), 3.55 (1 H, dd, J = 12.6, 2.7 Hz), 0.97 (1 H, d, J = 6.0 Hz), 0.81 (3 H, t, J = 8.0 Hz), 0.48 (2 H, q, J = 8.0) and -0.00 (6 H, s); LC-MS (ESI) Rt(Conditions A1 ) 3.6 min, m/z (ES+) 349 (M+).
Example 9: 4-Amino-1 -r(4-diethylmethylsilyloxy)-5-(diethylmethyl- silyloxymethyl)-3,3-difluoro-tetrahvdro-furan-2-yl1-1 -pyrimidm-2-one
To a stirred mixture of 4-amino-1 -[3,3~difluoro-4-hydroxy-5- (hydroxymethyl)-tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one hydrochloride (1.0 g, 3.8 mmol) and 2,6-lutidine (2.21 ml, 19 mmol) in dry DMF (15 ml) under nitrogen with cooling (ice/water bath) was added Intermediate 1 (2.44 ml, 11.4 mmol) in a dropwise manner. After stirring at this temperature for 2 hours the reaction was quenched with water (50 ml) and extracted with diethyl ether (3 x 50 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 25:1 to 5:1 methyl alcohol in diethyl ether) to afford the title compound (1.21 g, 69 %) as an off-white foam. 1H NMR δ 7,80 (1 H, d, J = 7.3 Hz), 6.34 (1 H, m), 5.75 (1 H, d, J = 7.3), 4.31 (1 H, m), 3.94 (2 H, m), 3.79 (1 H, d, J = 11.4), 0.98 (12 H, m), 0.65 (8 H, m), 0.14 (6 H, s). LC-MS (ESI) Rt 4.67 min (Conditions A1 ) m/z (ES+) 464 (M+H+). Example 10: 4-Amino-1 -r(5-diethylmet ylsilyloxymethyl)-3.3-difluoro-4- hydroxy-tetrahvdro-furan-2-yl1-1H-pyrimidin-2-one
This compound was isolated as a minor product in the above procedure for Example 9 (51 mg, 3.6 %). 1H NMR δ 7.87 (1 H, d, J = 7.6 Hz), 6.23 (1 H, t, J = 8.1 Hz), 5.94 (1 H, d, J = 7.6 Hz), 4.41 (1 H, m), 3.92 (2 H, m), 3.79 (1 H, dd, J = 12.6, 3.0 Hz), 1.17 (1 H, d, J = 6.1 Hz), 1.01 (6 H, t, J = 8.08 Hz), 0.68 (4 H, m), 0.17 (3 H, s).
Example 11 : 4-Amino-1 -r4-(diethylmethylsilyloxy)-3.3-difluoro-5-hvdroxy- methyltetrahvdrofuran-2-yll-1tf-pyrimidin-2-one
To a cooled solution (ice/water bath) of 4-amino-1 -[(4- diethylmethylsilyloxy)-5-(diethylmethylsilyloxymethyl)-3,3-difluoro-tetrahydro- furan-2-yl]-1 H-pyrimidin-2-one (150 mg, 0.32 mmol) in diethyl ether (1.5 ml) with stirring under nitrogen was added an aqueous solution of trifluoroacetic acid (20% v/v in water, 50 μL). The progress of the reaction was monitored carefully and after approximately 1.8 h a significant quantity of product had formed (as determined by thin layer chromatography analysis on silica plates using 1:19 methyl alcohol diethyl ether as eluent). The reaction mixture was then treated with aqueous sodium bicarbonate solution (50 %, 2.5 ml) and extracted into diethyl ether (3x 10 ml), dried (MgSO4) and evaporated under reduced pressure. The crude mixture was resolved by column chromatography (silica, 19:1-4:1 diethyl ether-methyl alcohol) to afford the title compound (66 mg, 56 %). 1H NMR δ 7.87 (1 H, d, J = 7.6 Hz), 6.22 (1 H, t, J = 7.8 Hz), 5.95 (1 H, br d, J = 6.6), 4.41 (1 H, m), 3.92 (2 H, m), 3.75 (1 H, dd, J = 12.6, 3.0), 1.01 (6 H, t, J = 7.6), 0.68 (4 H, m), 0.17 (3 H, s). LC-MS (ESI) Rt 3.42 min (Conditions A1 ) m/z (ES+) 364 (M+H+).

Claims

1. A compound of formula (I)
Figure imgf000023_0001
wherein one of R and R2 is -Si(R)3, and the other is hydrogen or -Si(R)3; or R1 is a bond, R2 is -Si(R)2- or -Si(R)2-O-Si(R)2-, and R1O-CH2-CH-CH- OR2 taken together form a ring;
R3 and R4 are the same or different and are each halogen; and each R is the same or different and is alkyl, aryl, cycloalkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R1 is -Si(R)3.
3. A compound according to claim 1 or claim 2, wherein R2 is -Si (R)3.
4. A compound according to claim 1 , wherein R1 is a bond and R2 is -Si(R)2- or -Si(R)2-O-Si(R)2-
5. A compound according to any preceding claim, wherein R3 and/or R4 is fluorine.
6. A compound according to any preceding claim, wherein each R is the same or different and is methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl or a group of formula (i)
Figure imgf000023_0002
wherein
X and Y are the same or different and are each oxygen, -O-(CH2)n- N(R5)-, -N(R5)-(CH2)n- or -(CH2)n-; Z is -(CH2)n-;
R5 is hydrogen alkyl or aryl; and each n is the same or different and is 1 , 2 or 3; with the proviso that when one of X and Y is oxygen or -N(R4)-, the other is not oxygen or -N(R4)-.
7. A compound according to claim 6, wherein X is -CH2CH2-, Y is -CH2- and Z is -CH2-.
8. A compound according to claim 6 or claim 7, wherein R1 and/or R2 is a group selected from trimethylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, triethylsilyl, ethyldimethylsilyl, propyldimethylsilyl, methyldiethylsilyl, cyclopropyldimethylsilyl, cyclohexyldimethylsilyl and norbornyldimethylsilyl.
9. A compound according to claim 1 , selected from 4-amino-1-[5-(fe/f-butyldiphenylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one; 4-amino-1 -[4-(te/t-butyldiphenylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-am in o-1 -[4-(ferf-butyldi phenyl silyl oxy)-5-(ferf - butyldiphenylsilyloxymethyl)-3,3-difluoro-tetrahydrofuran-2-yl]-1/-/-pyrimidin-2- one; 4-amino-1-[5-(fe/f-butyldimethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one;
4-amino-1-[4-(fe f-butyldimethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1 /-/-pyrimidin-2-one;
4-amino-1 -[4-(ferf-butyldimethylsilyloxy)-5-(ferf- butyldimethylsilyloxymethyl)- 3,3-difluoro-tetrahydrofuran-2-yl]-1 H-pyrimidin-2- one;
4-amino-1-[3,3-difluoro-4-hydroxy-5-(trimethylsilyloxymethyl)- tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one;
4-am ino-1 -[3, 3-difluoro-5-hydroxymethyl-4-(tri triethylsilyl oxy)- tetrahydrofuran-2-yl]-1 /-/-pyrimidin-2-one;
4-amino-1-[3,3-difluoro-4-(trimethylsilyloxy)-5-(trimethylsilyloxymethyl)- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-amino-1-[3,3-difl.uoro-4-hydroxy-5-(triethylsilyloxymethyl)- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one; 4-amino-1 -[3,3-difluoro-5-hydroxymethyl-4-(triethylsilyloxy)- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one;
4-amino-1-[3,3-difluoro-4-(triethylsilyloxy)-5-(triethylsilyloxymethyl)- tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one; 4-amino-1 -[5-(ethyldimethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-amino-1 -[4-(ethyldimethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1 /-/-pyrimidin-2-one;
4-amino-1-[4-(ethyldimethylsilyloxy)-5-(ethyldimethylsilyloxymethyl)-3,3- difluoro-tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one;
4-amino-1 -[3,3-difluoro-5-(dimethylpropylsilyloxymethyl)-4-hydroxy- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-amino-1 -[3,3-difluoro-4-(dimethylpropylsilyloxy)-5-hydroxymethyl- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one; 4-a m i n o- 1 -[3 , 3-d if l u o ro -4 - ( d i m et h y l p ro py l s i iy l oxy) -5-
(dimethylpropylsilyloxymethyl)-tetrahydrofuran-2-yl]-1H-pyrimidin-2-one.
4-amino-1 -[5-(diethylmethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one;
4-amino-1 -[4-(diethylmethylsilyloxy)-3,3-difluorό-5-hydroxymethyl- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one;
4-amino-1-[4-(diethylmethylsilyloxy)-5-(diethylmethylsilyloxymethyl)-3,3- difluoro-tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
3',5'-O-(dimethylsilylenyl)-gemcitabine;
3',5'-O-(diethylsilylenyl)-gemcitabine; 3',5'-O-[(di-tet -butyl)silylenyl]-gemcitabine;
3',5'-O-(diphenylsilylenyl)-gemcitabine;
3',5'-O-(tetramethyldisiloxanyl)-gemcitabine;
3',5'-O-(tetraethyldisiloxanyl)-gemcitabine;
3',5'-O-[(tetra-fer---butyl)disiloxanyl]-gemcitabine; and S^δ'-O-^etraphenyldisiloxany -gemcitabine.
10. A compound according to claim 1 , selected from:
4-amino-1-[5-(cyclopropyldimethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one;
4-amino-1-[4-(cyclopropyldimethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one;
4-amino-1 -[4-(cyclopropyldimethylsilyloxy)-5- (cyclopropyldimethylsilyloxymethyl)-3,3-difluoro-tetrahydrofuran-2-yl]-1/-/- pyrimidin-2-one; 4-amino-1-[5-(cyclohexyldimethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one;
4-amino-1-[4-(cyclohexyldimethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one;
4-amino-1 -[4-(cyclohexyldimethylsilyloxy)-5- (cyclohexyldimethylsilyloxymethyl)-3,3-difluoro-tetrahydrofuran-2-yl]-1H- pyrimidin-2-one;
4-amino-1-[5-(2-norbornyldimethylsilyloxymethyl)-3,3-difluoro-4-hydroxy- tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one;
4-amino-1-[4-(2-norbonyldimethylsilyloxy)-3,3-difluoro-5-hydroxymethyl- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one; and
4-amino-1 -[4-(2-norbornyldimethylsilyloxy)-5-(2- norbomyldimethylsilyloxymethyl)-3,3-difIuoro-tetrahydrofuran-2-yl]-1H-pyrimidin- 2-one.
11. A compound according to any preceding claim, in the form of a single enantiomer or diastereoisomer.
12. A compound according to any preceding claim, for therapeutic use.
13. A pharmaceutical composition comprising a compound of any of claims 1 to 11 and a pharmaceutically acceptable diluent or carrier.
14. Use of a compound of any of claims 1 to 11, for the manufacture of a medicament for the treatment of cancer.
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WO2007117760A3 (en) * 2006-02-06 2007-12-06 Reddys Lab Ltd Dr Preparation of gemcitabine
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Cited By (11)

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Publication number Priority date Publication date Assignee Title
WO2007117760A3 (en) * 2006-02-06 2007-12-06 Reddys Lab Ltd Dr Preparation of gemcitabine
EP3204121A4 (en) * 2014-10-08 2018-05-09 Epigenetics Pharma LLC Silylated pyrimidine prodrugs and methods of their use
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WO2017183217A1 (en) 2016-04-21 2017-10-26 大原薬品工業株式会社 Sugar moiety silyl ether derivative of 5-azacytidine
US9901641B2 (en) 2016-04-21 2018-02-27 Ohara Pharmaceutical Co., Ltd. Silyl etherified derivatives of 5-azacytidines in carbohydrate moiety
KR20180134835A (en) * 2016-04-21 2018-12-19 오하라 야꾸힝 고교 가부시키가이샤 (Saccharide) silyl ether derivatives of 5-azacytidines
US10227374B2 (en) 2016-04-21 2019-03-12 Ohara Pharmaceutical Co., Ltd. Silyl etherified derivatives of 5-azacytidines in carbohydrate moiety
EP3543249A1 (en) 2016-04-21 2019-09-25 Ohara Pharmaceutical Co., Ltd. Sugar moiety silyl ether derivative of 5-azacytidine
KR102579485B1 (en) 2016-04-21 2023-09-20 오하라 야꾸힝 고교 가부시키가이샤 Sugar moiety silyl ether derivatives of 5-azacytidines
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