WO1998025938A1 - Novel compounds - Google Patents

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Publication number
WO1998025938A1
WO1998025938A1 PCT/SE1997/002052 SE9702052W WO9825938A1 WO 1998025938 A1 WO1998025938 A1 WO 1998025938A1 SE 9702052 W SE9702052 W SE 9702052W WO 9825938 A1 WO9825938 A1 WO 9825938A1
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alkyl
compound according
alkoxy
treatment
unbranched
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PCT/SE1997/002052
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French (fr)
Inventor
Boris Gorin
Brian Pring
Gregory Thatcher
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Astra Aktiebolag (Publ)
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Priority to AU54232/98A priority Critical patent/AU5423298A/en
Publication of WO1998025938A1 publication Critical patent/WO1998025938A1/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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4062—Esters of acids containing the structure -C(=X)-P(=X)(XR)2 or NC-P(=X)(XR)2, (X = O, S, Se)
    • C07F9/4065—Esters of acids containing the structure -C(=X)-P(=X)(XR)2, (X = O, S, Se)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative

Definitions

  • the present invention relates to novel compounds, novel methods for their preparation, novel intermediates, pharmaceutical compositions and to methods for combatting viral diseases caused by, for example, herpesviruses or retroviruses, which can occur in animals including man.
  • diseases include both common viral infections and virus-related neoplastic diseases.
  • PFA Phosphonoformic acid
  • CMV cytomegalovirus
  • HSV-2 herpes simplex virus types 1 and 2
  • HHV-6 human herpesvirus 6
  • EBV Epstein-Barr virus
  • NZV varicella-zoster virus
  • Alkyl derivatives of PFA are known from EP 0003 007 and from ⁇ oren, J.-O. et al. (J. Med. Chem. 26 (1983) 264-270) and amide derivatives of PFA are known from EP 0003 008, as are the antiviral effects in vitro and in vivo in animals of such compounds and of pharmaceutical compositions thereof. So far, however, no drug based on any of these alkyl or amide derivatives has become availiable.
  • Phosphonoformic acid hydrazides are known from US 4,308,263 as are the antiviral effects against herpesviruses in vitro of such compounds. So far, however, no drug based on any of these hydrazides has become available.
  • Lipid derivatives of phosphonoacids for liposomal incorporation are known from WO 95/13682 and from Hostetler, K. Y. et al., Antiviral Research 31 (1996), 59-67, as are the antiviral effects in vitro of such compounds on viruses such as HIN, hepatitis B virus, EBV, and VZV.
  • P-monoesters of foscamet with octadecyl substituted alditol moieties as well as with substituted derivatives of glycerol have been disclosed in WO 96/15132.
  • Ri and R 2 each independently are hydrogen, or a . 2 -alkyl, C 3 . 8 -cycloalkyl,
  • Ci . 24 -alkylthio-C ⁇ . 24 -alkyl group and each . 2 -alkyl or -alkoxy group may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and is optionally substituted with one or more hydroxy, mercapto, amino, halogen, oxo, or with Q . 24 - alkoxy, C> . 4 -alkylcarbonyloxy, Ci . 2 -alkoxycarbonyloxy, . 2 -alkylthio, Ci . 2 -alkyl- carbonylthio, Ci . 24 -alkoxycarbonylthio, .
  • Ri and R 2 each independently are carboxyl, carboxamido, aryl, aryloxy- carbonyl, or aryl-Ci . 2 -alkyl, d . 24 -alkoxycarbonyl, Ci . 24 -alkylaminocarbonyl, di-(C ⁇ . 24 - alkyl)aminocarbonyl, aryl-Ci . 24 -alkoxycarbonyl, aryl-d - 24 -alkylaminocarbonyl, Ci . 24 - alkylcarbonyloxymethoxycarbonyl, Q .2 4 -alkylcarbonyloxy-(C ⁇ .
  • R 3 and R* are the same or different and each is selected from the group consisting of hydrogen, halogen, or Ci . -alkyl, Ci . -alkoxy, Ci . 4 -acyl, Ci . -acyloxy, Ci . 4 -alkoxy- carbonyl, all of which may be branched or unbranched; or R 3 and R together form an unbranched saturated alkylene chain having 3 or 4 carbon atoms bound to adjacent positions in the phenyl ring; or R 3 and R_t together form a methylenedioxy group, a 1,1- ethylidenedioxy group, or a 1,2-ethylenedioxy group bound to adjacent positions of the phenyl ring;
  • R 1 -CH-CH-R2 form part of a C . s-carbocyclic ring which is optionally substituted with hydroxy, mercapto, amino, halogen, oxo, or with Ci . 24 -alkyl, Ci . 24 - alkoxy, d . 24 -alkylthio, Ci .24-alkylamino, di-(C ⁇ - 24 -alkyl)amino, Ci . 2 -alkylcarbonyl, d . 2 -alkylcarbonyloxy, Ci . 24 -alkoxycarbonyl, Ci .
  • Ci - 24 -alkyl- carbonylamino Ci . 24 -alkyl-(C! . 24 -alkylcarbonyl)amino, all the Ci . 24 -alkyl groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds;
  • R 1 -CH-CH-R2 form part of the furanose or pyranose ring of a sugar, e.g. D- ribose, D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-talose, D- allose, D-altrose, D-gulose, D-idose or the corresponding L-isomers, the hydroxyl groups of which may optionally be replaced by hydrogen, halogen, amino, azido, oxo, mercapto, d - 24 -alkoxy, C_ - 24 -alkylthio, Ci .24-alkylamino, di-(C ⁇ .
  • a sugar e.g. D- ribose, D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-
  • Rj and R 2 each independently are hydrogen or methyl which latter is optionally substituted with hydroxy or mercapto, or with Q . 2 - alkoxy, Ci . 24 -alkylcarbonyloxy, _ 24 -alkylthio, or Ci . 24 -alkylcarbonylthio, the Ci . 24 - alkyl and -alkoxy groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds.
  • R[ is as defined immediately above except hydrogen, and R 2 is hydrogen.
  • Ri and R 2 each independently are hydrogen or n-octadecyloxymethyl.
  • the compounds of the invention are useful in therapeutic and /or prophylactic treatment of viral infections and may be useful in therapeutic and/or prophylactic treatment of virus- related neoplastic diseases in mammals.
  • the compounds of the present invention are particularly useful for the treatment of human herpesvirus infections and human retrovirus infections. They are also useful for the treatment of viral infections associated with acquired immunodeficiency syndrome (AIDS).
  • the human herpesviruses include HSV-1 and HSV-2, VZV, CMV, EBV, human herpesvirus 6 and 7(HHV-6 and HHV-7), and human herpesvirus 8 (HHV-8) also known as Kaposi's sarcoma associated herpesvirus (KSHV).
  • Human retroviruses include human immunodeficiency virus type 1 and 2 (HTV-1 and HIN-2) and human T-cell leukaemia virus type 1 and type 2 (HTLV-1 and HTLV-2).
  • Another important area of use of the compounds of the present invention is in the treatment of infections caused by ortho- myxo viruses, e.g. influenza viruses of type A and type B.
  • a further area of use is in the treatment of infections caused by viruses such as hepatitis B virus and hepatitis C virus, papillomaviruses, adenoviruses and poxviruses.
  • compositions of the present invention are in the treatment of infections caused by picomaviruses, arboviruses, arenaviruses, coronaviruses, rhabdoviruses, paramyxoviruses and bunyaviruses.
  • the compounds according to the invention may be used for the therapeutic and prophylactic control and treatment of diseases caused by virus infections.
  • the compounds of the invention can be used alone or with other antiviral agents, e.g. acyclovir, valacyclovir, famciclovir, penciclovir, desciclovir, brivudine, carbovir, fiacitibine, ibacitabine, ganciclovir, idoxuridine, sorivudine, trifluridine, vidarabine, cidofovir, lobucavir, afovirsen, zidovudine, didanosine, stavudine, zalcitabine, dideoxyadenosine, lamivudine, FTC, fialuridine, adefovir, adefovir dipivoxil, nevirapine, delaviridine, loviride, saquinavir, indinavir, ritanovir
  • antiinflammatory agents including steroids, in particular glucocorticoids, and non-steroid antiinflammatory drugs (NSAID's), CMN neutraGAM, regavirumab, sevirumab, interferon, and growth factors e.g. granulocyte- macrophage (GM-CSF) and granulocyte-colony stimulating factors (G-CSF).
  • steroids in particular glucocorticoids, and non-steroid antiinflammatory drugs (NSAID's)
  • CMN neutraGAM e.g. granulocyte- macrophage (GM-CSF) and granulocyte-colony stimulating factors (G-CSF).
  • GM-CSF granulocyte- macrophage
  • G-CSF granulocyte-colony stimulating factors
  • the compounds of the present invention are suitably admixed with excipients to be formulated into capsules, tablets, suppositories and other formulations, e.g. ointments, suspensions, gels and solutions.
  • the compounds of the invention may be formulated into pharmaceutical formulations for oral, parenteral, rectal and topical administration.
  • the pharmaceutical formulation contains the compound of the invention normally in combination with a pharmaceutically acceptable excipient.
  • the excipient may be in the form of a solid, semi- solid or liquid diluent.
  • the amount of active compound is between 0.1-99% by weight of the preparation.
  • the compound may be mixed with a solid, powdered carrier, e.g. lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier; stabilizing substances, e.g. alkaline compounds, e.g. bicarbonates, carbonates, and hydroxides of sodium, potassium, calcium, magnesium, as well as magnesium oxide and the like as well as with lubricating agents e.g. magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethyleneglycol waxes.
  • a solid, powdered carrier e.g. lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier
  • stabilizing substances e.g. alkaline compounds, e.g. bicarbonates, carbonates, and hydroxides of sodium, potassium, calcium, magnesium, as well as
  • the mixture may then be processed into granules or pressed into tablets.
  • Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalyzed degradation as long as the dosage form remains in the stomach.
  • the enteric coating is chosen among pharmaceutically acceptable enteric- coating materials e.g. beeswax, shellac or anionic film-coating polymers and the like, if preferred in combination with a suitable plasticizer.
  • enteric- coating materials e.g. beeswax, shellac or anionic film-coating polymers and the like, if preferred in combination with a suitable plasticizer.
  • To the coating various dyes may be added in order to distinguish among tablets or granules with different active compounds or with different amounts of the active compound present.
  • Soft gelatin capsules may be prepared with capsules containing a mixture of the active compound of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Soft gelatin capsules may also be enteric-coated as described above.
  • Hard gelatin capsules may also contain the active compound in combination with a powdered carrier as described above.
  • the hard gelatin capsules may be enteric-coated as described above.
  • Hard gelatin capsules may contain granules or enteric-coated granules of the active compound.
  • Dosage units for rectal administration may be prepared in the form of suppositories with the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatin capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules, or they may be prepared in the form of enemas, e.g. dry micro enemas, or they may be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of solutions, syrups, emulsions or suspensions, e.g.
  • liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • sustained release preparations at doses of 1 mg to 2000 mg may be formulated.
  • preparations are suitably in the form of a solution, ointment, gel, suspension cream or the like.
  • the amount of active substance may vary, for example between 0.05% to 20% by weight of the preparation .
  • Such preparations for topical application may be prepared in known manner by mixing the active substance with known carrier materials e.g. isopropanol, glycerol, paraffin, stearyl alcohol, polyethylene glycol, etc.
  • the pharmaceutically acceptable carrier may also include a known chemical absorption promotor. Examples of absorption promotors are e.g. dimethylacetamide, trichloroethanol or trifluoroethanol, certain alcohols and mixtures thereof.
  • Liposomal formulations based on lipid substances e.g. phospholipids, sphingolipids, glycolipids, and galactolipids can be used for formulations for oral, topical or parenteral administration.
  • the typical daily dose of the active substance will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, doses will be in the range of 1 mg to 2000 mg per day, preferably 5 mg to 1000 mg of active substance per day. Unit doses of 0.25 mg to 2000 mg can be given e.g. 1 to 4 times a day.
  • the compounds of the formula I may be prepared by cyclization of suitably substituted ,C-diesters of phosphonoformic acid, for example as follows.
  • the salt may be treated with an acidic ion exchange resin in a suitable solvent, e.g. ethanol or water.
  • a suitable solvent e.g. ethanol or water.
  • Ri and R 2 have the meaning given above and R5 is an electron-withdrawing group, e.g. carbomethoxy, carboethoxy, acetyl, or nitro at the ortho- orp ra-position of the phenyl ring.
  • Rja d R2 contain groups with labile hydrogen atoms, e.g. carboxyl, hydroxyl, mercapto or amino, they must first be protected with suitable protective groups which can be subsequently removed. Examples of such protective groups and methods for their introduction and removal are given in Protective Groups in Organic Synthesis, Ed. T. W. Greene and P.G. M. Wuts, John Wiley & Sons, Inc., New York, 1991.
  • * is a cation, e.g. Li + , Na + , K + , Et 3 Nir or C 5 H 5 NH + .
  • the first step of the reaction may be carried out in a suitable solvent, e.g. tetrahydrofuran or dioxane, at a temperature from 0°C to the boiling point of the solvent for 2 hours to 7 days.
  • a suitable solvent e.g. tetrahydrofuran or dioxane
  • the aryloxycarbonylphosphonic dichlorides required as starting materials are prepared by methods known per se for the synthesis of dichlorides of phosphoric acids and phosphonic acids. References for these methods are found, for example, in L.A. Slotin, Synthesis 1977. 737 and in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII/1, p. 387-406 and Band XH/2, p. 212-225.
  • the bis-trimethylsilyl ethers may be obtained by methods known er se for the trimethylsilylation of alcohols. References for these methods are found, for example, in Protective Groups in Organic Chemistry, Ed. T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1991, p. 68-71.
  • the second step of the reaction (hydrolysis of the cyclic phosphonoformate ester) may be carried out in a suitable solvent, e.g. tetrahydrofuran or dioxane, at a temperature from 0°C to the boiling point of the solvent for 5 minutes to 2 hours followed by neutralization with e.g. one equivalent of a base, e.g. sodium, potassium, or lithium bicarbonate, carbonate or hydroxide, or an amine, e.g. triethylamine or pyridine.
  • a suitable solvent e.g. tetrahydrofuran or dioxane
  • a base e.g. sodium, potassium, or lithium bicarbonate, carbonate or hydroxide
  • an amine e.g. triethylamine or pyridine.
  • the final step of the reaction may be carried out in a suitable solvent, e.g. dimethyl- formamide or dimethyl sulfoxide, in the presence of a suitable base, e.g. 1,5-diaza- bicyclo[4.3.0]non-5-ene or l,8-diazabicyclo[5.4.0]undec-7-ene, at a temperature from 0°C to 100°C for 1 hour to 48 hours.
  • a suitable solvent e.g. dimethyl- formamide or dimethyl sulfoxide
  • a suitable base e.g. 1,5-diaza- bicyclo[4.3.0]non-5-ene or l,8-diazabicyclo[5.4.0]undec-7-ene
  • Mass spectra were recorded on a Fisons VG Quatro quadrupole mass spectrometer or on a Jeol JMS-SX102 mass spectrometer.
  • the following solvents and chemicals were purified before use by heating under reflux and distillation over the appropriate drying agent: toluene and trimethyl phosphite (Na), diethyl ether and dioxane (CaH 2 ), pyridine (BaO), dichloromethane, acetonitrile and dimethylformamide (P 2 O 5 ).
  • Tetrahydrofuran (THF) was purified by treatment overnight with KOH, heating under reflux and distilling from potassium.
  • ⁇ H (CDC1 3 ): 1.37 (t, 3H, OC 2 H 5 ); 4.04 (d, 6H, 2 x OCH 3 , Jp H 11); 4.35 (q, 2H, OC 2 H 5 ); 7.15 (dd, 1H, 3-CH); 7.35 (dt, 1H, 4-CH); 7.58 (dt, 1H, 5-CH) and 8.08 (dd, 1H, 6-CH).
  • ⁇ H (CDC ): 1.34 (t, 3H, OC 2 H 5 ); 4.32 (q, 2H, OC 2 H 5 ); 4.67 (d, 4H, J PH 9.5, -CH 2 CH 2 -); 7.16 (d, IH, arom. 3-CH); 7.38 (t, IH, arom. 4-CH); 7.59 (t, IH, arom. 5-CH) and 8.08 (d, IH, arom. 6-CH).
  • ⁇ P (CDCl 3 ): 13.15 (s).
  • Example 6 The compounds in the following Examples 6 - 8 were prepared in a similar manner to that described in Example 5 from [(2-ethoxycarbonylphenoxy)carbonyl]phosphonic dichloride and the appropriate bis(trimethylsilyl) ether.
  • the starting bis(trimethylsilyl) ether, l,2-bis(trimethylsilyloxy)-3-dodecanoyloxypropane was prepared by silylation of 3-dodecanoyloxy-l,2-propanediol by conventional methods.
  • the starting bis(trimethylsilyl) ether, l,2-bis(trimethylsilyloxy)-3-octanoylthiopropane was prepared by silylation of 3-octanoylthio-l,2-propanediol by conventional methods.
  • the starting bis(trimethylsilyl) ether, l,2-bis(trimethylsilyloxy)-3-dodecanoylthiopropane was prepared by silylation of 3-dodecanoylthio-l,2-propanediol by conventional methods.
  • Example 14 The compounds in the following Examples 14 - 16 were prepared in a similar manner to that described in Example 13.
  • Example 14 The compounds in the following Examples 14 - 16 were prepared in a similar manner to that described in Example 13.
  • the starting bis(trimethylsilyl) ether, l,2-bis(trimethylsilyloxy)-3-octadecyloxypropane was prepared by silylation of 3-octadecyloxy-l,2-propanediol (batyl alcohol) by conventional methods.
  • the antiviral activity of the compounds of the invention may be determined according to the method of Wahren, B. et al., J. Virol. Methods 6 (1983) 141-149.
  • confluent human lung fibroblast cells are infected with Herpes simplex virus type 1 (HSV-1). After absorption for one hour at 37°C, virus is removed and the compounds of the invention diluted in cell media were added, at concentrations of 800 ⁇ M down to 3 ⁇ M. Cells are incubated at 37°C in a humidified atmosphere of 5% CO 2 in air until a characteristic cytopathic effect is seen in control wells (24-48 h).
  • Cells are lysed by addition of Triton X- 100, and viral antigen content of the supernatants measured by enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody.
  • ELISA enzyme-linked immunosorbent assay

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Abstract

The present invention pertains to novel compounds which are derivatives of phosphonoformic acid, processes for their synthesis and their use as antiviral agents.

Description

NOVEL COMPOUNDS
Field of the invention
The present invention relates to novel compounds, novel methods for their preparation, novel intermediates, pharmaceutical compositions and to methods for combatting viral diseases caused by, for example, herpesviruses or retroviruses, which can occur in animals including man. Such diseases include both common viral infections and virus-related neoplastic diseases.
Background of the invention
Phosphonoformic acid (PFA) is a well known compound having antiviral activity. Pharmaceutical formulations of PFA for the treatment of viral diseases have been described in U.S. Patent Nos. 4,215,113; 4,339,445; 4,665,062 and 4,771,041. PFA inhibits replication of all known herpesviruses in vitro including cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSN-1, HSV-2), human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV) and varicella-zoster virus (NZV) as well as certain retroviruses including the human immunodeficiency virus (HIV) types 1 and 2 (HIN-1 and HIV-2).
Alkyl derivatives of PFA are known from EP 0003 007 and from Νoren, J.-O. et al. (J. Med. Chem. 26 (1983) 264-270) and amide derivatives of PFA are known from EP 0003 008, as are the antiviral effects in vitro and in vivo in animals of such compounds and of pharmaceutical compositions thereof. So far, however, no drug based on any of these alkyl or amide derivatives has become availiable.
Phosphonoformic acid hydrazides are known from US 4,308,263 as are the antiviral effects against herpesviruses in vitro of such compounds. So far, however, no drug based on any of these hydrazides has become available. Lipid derivatives of phosphonoacids for liposomal incorporation are known from WO 95/13682 and from Hostetler, K. Y. et al., Antiviral Research 31 (1996), 59-67, as are the antiviral effects in vitro of such compounds on viruses such as HIN, hepatitis B virus, EBV, and VZV.
P-monoesters of foscamet with octadecyl substituted alditol moieties as well as with substituted derivatives of glycerol have been disclosed in WO 96/15132.
Treatment of CMV infections in AIDS patients infected with herpesvirus with foscamet, i.e. trisodium phosphonoformate hexahydrate, is at present by intravenous injections. This mode of treatment is burdensome where foscamet must be administered daily. Doses in the range of grams per day need to be administered. The development of a more effective drug is therefore very desirable since it would offer a more convenient method of treatment and result in improved quality of life for the patient.
Description of the invention
According to the invention we provide compounds of formula I
Figure imgf000004_0001
I wherein Ri and R2 each independently are hydrogen, or a .2 -alkyl, C3.8-cycloalkyl,
C3.8-cycloalkyl- .24-alkyl, d .24-alkoxy, .24-alkylthio, .24-alkoxy-Cι .24-alkyl,
Ci .24-alkylthio-Cι .24-alkyl group and each .2 -alkyl or -alkoxy group may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and is optionally substituted with one or more hydroxy, mercapto, amino, halogen, oxo, or with Q .24- alkoxy, C> . 4-alkylcarbonyloxy, Ci .2 -alkoxycarbonyloxy, .2 -alkylthio, Ci .2 -alkyl- carbonylthio, Ci .24-alkoxycarbonylthio, .2 -alkylamino, di-(Cι , 2 -alkyl)amino, Ci .24- alkylcarbonylamino, .24-alkyl-(Cι .24-alkylcarbonyl)amino, . 4-alkoxycarbonylamino, C! .2 -alkyl-(C! .24-alkoxycarbonyl)amino, and each Ci .24 -alkyl or -alkoxy group may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds;
or wherein Ri and R2 each independently are carboxyl, carboxamido, aryl, aryloxy- carbonyl, or aryl-Ci .2 -alkyl, d .24-alkoxycarbonyl, Ci .24-alkylaminocarbonyl, di-(Cι .24- alkyl)aminocarbonyl, aryl-Ci .24-alkoxycarbonyl, aryl-d - 24-alkylaminocarbonyl, Ci .24- alkylcarbonyloxymethoxycarbonyl, Q .24-alkylcarbonyloxy-(Cι .4-alkyl)methoxycarbonyl, d .24-alkoxycarbonyloxymethoxycarbonyl, Q .24-alkoxycarbonyloxy-(Cι .4-alkyl)- methoxycarbonyl, all the d .24-alkyl groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds and all the Ci - -alkyl groups of which may be branched or unbranched and saturated or unsaturated, and where each aryl group has the formula H
Figure imgf000005_0001
π
wherein R3 and R* are the same or different and each is selected from the group consisting of hydrogen, halogen, or Ci . -alkyl, Ci . -alkoxy, Ci .4-acyl, Ci . -acyloxy, Ci .4-alkoxy- carbonyl, all of which may be branched or unbranched; or R3 and R together form an unbranched saturated alkylene chain having 3 or 4 carbon atoms bound to adjacent positions in the phenyl ring; or R3 and R_t together form a methylenedioxy group, a 1,1- ethylidenedioxy group, or a 1,2-ethylenedioxy group bound to adjacent positions of the phenyl ring;
or wherein R1-CH-CH-R2 form part of a C . s-carbocyclic ring which is optionally substituted with hydroxy, mercapto, amino, halogen, oxo, or with Ci .24-alkyl, Ci .24- alkoxy, d .24-alkylthio, Ci .24-alkylamino, di-(Cι - 24-alkyl)amino, Ci .2 -alkylcarbonyl, d .2 -alkylcarbonyloxy, Ci .24-alkoxycarbonyl, Ci .2 -alkylcarbonylthio, Ci - 24-alkyl- carbonylamino, Ci .24-alkyl-(C! .24-alkylcarbonyl)amino, all the Ci .24-alkyl groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds;
or wherein R1-CH-CH-R2 form part of the furanose or pyranose ring of a sugar, e.g. D- ribose, D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-talose, D- allose, D-altrose, D-gulose, D-idose or the corresponding L-isomers, the hydroxyl groups of which may optionally be replaced by hydrogen, halogen, amino, azido, oxo, mercapto, d - 24-alkoxy, C_ - 24-alkylthio, Ci .24-alkylamino, di-(Cι .24-alkyl)amino, Ci .2 -alkyl- carbonyloxy, Ci .24-alkylcarbonylthio, Ci .2 -alkylcarbonylamino, .2 -alkyl-(Cι .24-alkyl- carbonyl)amino the d .24-alkyl groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds;
and physiologically acceptable salts and optical isomers thereof.
Preferred are compounds of formula I wherein Rj and R2 each independently are hydrogen or methyl which latter is optionally substituted with hydroxy or mercapto, or with Q .2 - alkoxy, Ci .24-alkylcarbonyloxy, _ 24-alkylthio, or Ci .24-alkylcarbonylthio, the Ci .24- alkyl and -alkoxy groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds.
More preferred are compounds of formula I wherein R[ is as defined immediately above except hydrogen, and R2 is hydrogen. Also more preferred are compounds of formula I wherein Ri and R2 each independently are hydrogen or n-octadecyloxymethyl.
Especially preferred are compounds of formula I wherein Ri is n-octadecyloxymethyl and R2 is hydrogen.
Particularly preferred is the compound of formula I wherein Ri is n-octadecyloxymethyl, R2 is hydrogen and the configuration is (R).
The compounds of the invention are useful in therapeutic and /or prophylactic treatment of viral infections and may be useful in therapeutic and/or prophylactic treatment of virus- related neoplastic diseases in mammals.
The compounds of the present invention are particularly useful for the treatment of human herpesvirus infections and human retrovirus infections. They are also useful for the treatment of viral infections associated with acquired immunodeficiency syndrome (AIDS). The human herpesviruses include HSV-1 and HSV-2, VZV, CMV, EBV, human herpesvirus 6 and 7(HHV-6 and HHV-7), and human herpesvirus 8 (HHV-8) also known as Kaposi's sarcoma associated herpesvirus (KSHV). Human retroviruses include human immunodeficiency virus type 1 and 2 (HTV-1 and HIN-2) and human T-cell leukaemia virus type 1 and type 2 (HTLV-1 and HTLV-2). Another important area of use of the compounds of the present invention is in the treatment of infections caused by ortho- myxo viruses, e.g. influenza viruses of type A and type B. A further area of use is in the treatment of infections caused by viruses such as hepatitis B virus and hepatitis C virus, papillomaviruses, adenoviruses and poxviruses.
Other possible areas of use of the compounds of the present invention are in the treatment of infections caused by picomaviruses, arboviruses, arenaviruses, coronaviruses, rhabdoviruses, paramyxoviruses and bunyaviruses. Pharmaceutical formulations
The compounds according to the invention may be used for the therapeutic and prophylactic control and treatment of diseases caused by virus infections. The compounds of the invention can be used alone or with other antiviral agents, e.g. acyclovir, valacyclovir, famciclovir, penciclovir, desciclovir, brivudine, carbovir, fiacitibine, ibacitabine, ganciclovir, idoxuridine, sorivudine, trifluridine, vidarabine, cidofovir, lobucavir, afovirsen, zidovudine, didanosine, stavudine, zalcitabine, dideoxyadenosine, lamivudine, FTC, fialuridine, adefovir, adefovir dipivoxil, nevirapine, delaviridine, loviride, saquinavir, indinavir, ritanovir, nelfinavir, 141W94, ribavirin, amantidine, rimantidine, sICAM-1, pirodavir, GG167, 1263W94, fomivirsen, GEM-132, RS-79070, SR-3775, or with immunological agents e.g. antiinflammatory agents including steroids, in particular glucocorticoids, and non-steroid antiinflammatory drugs (NSAID's), CMN neutraGAM, regavirumab, sevirumab, interferon, and growth factors e.g. granulocyte- macrophage (GM-CSF) and granulocyte-colony stimulating factors (G-CSF).
The compounds of the present invention are suitably admixed with excipients to be formulated into capsules, tablets, suppositories and other formulations, e.g. ointments, suspensions, gels and solutions.
For clinical use the compounds of the invention may be formulated into pharmaceutical formulations for oral, parenteral, rectal and topical administration. The pharmaceutical formulation contains the compound of the invention normally in combination with a pharmaceutically acceptable excipient. The excipient may be in the form of a solid, semi- solid or liquid diluent. Usually the amount of active compound is between 0.1-99% by weight of the preparation.
In the preparation of pharmaceutical formulations containing the compounds of the present invention in the form of dosage units for oral administration the compound may be mixed with a solid, powdered carrier, e.g. lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier; stabilizing substances, e.g. alkaline compounds, e.g. bicarbonates, carbonates, and hydroxides of sodium, potassium, calcium, magnesium, as well as magnesium oxide and the like as well as with lubricating agents e.g. magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethyleneglycol waxes. The mixture may then be processed into granules or pressed into tablets. Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalyzed degradation as long as the dosage form remains in the stomach. The enteric coating is chosen among pharmaceutically acceptable enteric- coating materials e.g. beeswax, shellac or anionic film-coating polymers and the like, if preferred in combination with a suitable plasticizer. To the coating various dyes may be added in order to distinguish among tablets or granules with different active compounds or with different amounts of the active compound present.
Soft gelatin capsules may be prepared with capsules containing a mixture of the active compound of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Soft gelatin capsules may also be enteric-coated as described above.
Hard gelatin capsules may also contain the active compound in combination with a powdered carrier as described above. The hard gelatin capsules may be enteric-coated as described above. Hard gelatin capsules may contain granules or enteric-coated granules of the active compound.
Dosage units for rectal administration may be prepared in the form of suppositories with the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatin capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules, or they may be prepared in the form of enemas, e.g. dry micro enemas, or they may be reconstituted in a suitable solvent just prior to administration. Liquid preparations for oral administration may be prepared in the form of solutions, syrups, emulsions or suspensions, e.g. containing from 0.1% to 50% by weight of the active ingredient and the remainder consisting of for example sugar or an alditol and/or a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharin or carboxymethyl cellulose or other thickening agents. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
In addition, using known pharmaceutical procedures, sustained release preparations at doses of 1 mg to 2000 mg may be formulated.
For topical application, especially for the treatment of herpes virus infections on skin, genitals and in mouth and eyes the preparations are suitably in the form of a solution, ointment, gel, suspension cream or the like. The amount of active substance may vary, for example between 0.05% to 20% by weight of the preparation . Such preparations for topical application may be prepared in known manner by mixing the active substance with known carrier materials e.g. isopropanol, glycerol, paraffin, stearyl alcohol, polyethylene glycol, etc. The pharmaceutically acceptable carrier may also include a known chemical absorption promotor. Examples of absorption promotors are e.g. dimethylacetamide, trichloroethanol or trifluoroethanol, certain alcohols and mixtures thereof.
Liposomal formulations based on lipid substances, e.g. phospholipids, sphingolipids, glycolipids, and galactolipids can be used for formulations for oral, topical or parenteral administration.
The typical daily dose of the active substance will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, doses will be in the range of 1 mg to 2000 mg per day, preferably 5 mg to 1000 mg of active substance per day. Unit doses of 0.25 mg to 2000 mg can be given e.g. 1 to 4 times a day.
Methods of preparation of the compounds
The compounds of the formula I may be prepared by cyclization of suitably substituted ,C-diesters of phosphonoformic acid, for example as follows.
Reacting a suitably substituted aryloxycarbonylphosphonic dichloride with the bis- trimethylsilyl ether of a v c-diol to give a cyclic triester of phosphonoformic acid (a 1,3,2- dioxaphospholane) according to the formula:
Figure imgf000011_0001
ffl
followed by hydrolysis with one equivalent of water and subsequent neutralization, e.g. by addition of one equivalent of a base according to the formula:
Figure imgf000012_0001
m iv and finally by cyclization to give a salt of a compound of the formula I.
In order to liberate the free acid, the salt may be treated with an acidic ion exchange resin in a suitable solvent, e.g. ethanol or water.
Ri and R2 have the meaning given above and R5 is an electron-withdrawing group, e.g. carbomethoxy, carboethoxy, acetyl, or nitro at the ortho- orp ra-position of the phenyl ring. However, if Rja d R2 contain groups with labile hydrogen atoms, e.g. carboxyl, hydroxyl, mercapto or amino, they must first be protected with suitable protective groups which can be subsequently removed. Examples of such protective groups and methods for their introduction and removal are given in Protective Groups in Organic Synthesis, Ed. T. W. Greene and P.G. M. Wuts, John Wiley & Sons, Inc., New York, 1991. * is a cation, e.g. Li+, Na+, K+, Et3Nir or C5H5NH+.
The compounds of formulas III and IV are novel and are comprised in the scope of the present invention.
The first step of the reaction may be carried out in a suitable solvent, e.g. tetrahydrofuran or dioxane, at a temperature from 0°C to the boiling point of the solvent for 2 hours to 7 days. The aryloxycarbonylphosphonic dichlorides required as starting materials are prepared by methods known per se for the synthesis of dichlorides of phosphoric acids and phosphonic acids. References for these methods are found, for example, in L.A. Slotin, Synthesis 1977. 737 and in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII/1, p. 387-406 and Band XH/2, p. 212-225. The bis-trimethylsilyl ethers may be obtained by methods known er se for the trimethylsilylation of alcohols. References for these methods are found, for example, in Protective Groups in Organic Chemistry, Ed. T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1991, p. 68-71.
The second step of the reaction (hydrolysis of the cyclic phosphonoformate ester) may be carried out in a suitable solvent, e.g. tetrahydrofuran or dioxane, at a temperature from 0°C to the boiling point of the solvent for 5 minutes to 2 hours followed by neutralization with e.g. one equivalent of a base, e.g. sodium, potassium, or lithium bicarbonate, carbonate or hydroxide, or an amine, e.g. triethylamine or pyridine.
The final step of the reaction may be carried out in a suitable solvent, e.g. dimethyl- formamide or dimethyl sulfoxide, in the presence of a suitable base, e.g. 1,5-diaza- bicyclo[4.3.0]non-5-ene or l,8-diazabicyclo[5.4.0]undec-7-ene, at a temperature from 0°C to 100°C for 1 hour to 48 hours.
Experimental part
General experimental procedures
1H, 3IP and 13C NMR spectra were recorded on a Bruker AC-F200 (1H = 200 MHz), on a Bruker AM 400 (1H = 400 MHz), or on a Jeol GSX-270 (1H=270 MHz) spectrometer. The spectra were referenced to tetramethylsilane (1H), 85% H3PO4 (31P), CDC13 or DMSO-d6 (13C). 31P and 13C NMR spectra were 1H decoupled, unless otherwise stated. Coupling constants are given in Hz. Mass spectra were recorded on a Fisons VG Quatro quadrupole mass spectrometer or on a Jeol JMS-SX102 mass spectrometer. The following solvents and chemicals were purified before use by heating under reflux and distillation over the appropriate drying agent: toluene and trimethyl phosphite (Na), diethyl ether and dioxane (CaH2), pyridine (BaO), dichloromethane, acetonitrile and dimethylformamide (P2O5). Tetrahydrofuran (THF) was purified by treatment overnight with KOH, heating under reflux and distilling from potassium. A detailed description of the synthesis of the intermediate and final compounds according to the present invention follows. The title compound of each example was obtained according to the description.
Example 1
2-EthoxycarbonyIphenyI chloroformate:
A mixture of 16.6 g (0.1 mol) ethyl salicylate and 7.9 g (0.1 mol) dry pyridine in 50 ml of dry toluene was added dropwise to a solution of phosgene (12g, 0.12 mol) in 120 ml of dry toluene at -5° C with stirring for 1 h. The reaction mixture was stirred for 2 h at room temperature, cooled to 0° C and 15 ml of chilled 10% aq. HCl was added dropwise. The organic layer was separated, dried over CaCfe and distilled in vacuo to give 17.8 g (78%) colourless liquid (b.p. 114° C at 5 mm Hg). δH (CDC13): 1.42 (t, 3H, OC2H5); 4.42 (q, 2H, OC2H5); 7.27 (dd, 1H, arom. 3-CH); 7.41 (dt, 1H, arom. 4-CH); 7.58 (dt, 1H, arom. 5-CH) and 8.08 (dd, 1H, arom. 6-CH).
Example 2
Dimethyl [(2-ethoxycarbonylphenoxy)carbonyl]phosphonate:
A solution of 2.29 g (10 mmol) 2-ethoxycarbonylphenyl chloroformate and 1.24 g (10 mmol) trimethyl phosphite in 10 ml toluene was heated under reflux with stirring for 3 h under argon and left overnight at room temperature. Toluene was removed at reduced pressure and the residue was kept for 16 h at 1 mm Hg and room temperature. A clear colourless liquid resulted, yield 2.54 g (84%). δH (CDC13): 1.37 (t, 3H, OC2H5); 4.04 (d, 6H, 2 x OCH3, JpH 11); 4.35 (q, 2H, OC2H5); 7.15 (dd, 1H, 3-CH); 7.35 (dt, 1H, 4-CH); 7.58 (dt, 1H, 5-CH) and 8.08 (dd, 1H, 6-CH). δP (CDC13): -2.39 (s). δc (CDCI3): 13.58 (s, OCHzCHs); 54.46 (d, JPC 5.5, 2 x OCH3); 60.38 (s, OCH2CH3); 122.89 (s, aromatic CH); 126.47 (s, aromatic CH); 131.32 (s, aromatic CH); 133.55 (s, aromatic CH); 148.65 (d, JPC 6.5, aromatic CH); 163.04 (s, C=O) and 164.41 (d, JPC 273.2, C=O).
Example 3
Bis(trimethylsilyl) [(2-ethoxycarbonyIphenoxy)carbonyl]phosphonate
Bromotrimethylsilane (6.12 g, 40 mmol) was added dropwise within 1 h to 6.04 g (20 mmol) of dimethyl [(2-ethoxycarbonylphenoxy)carbonyI]phosphonate with stirring at room temperature under argon. After stirring for an additional 4 h, volatiles were removed at reduced pressure (1 h at 1 mm Hg). The resulting colourless liquid was used without further purification. Yield 8.2 g (98%). δH (CDC13): 0.39 (s, 18H, 2 x SiMe3); 1.38 (t, 3H, OC2H5); 4.34 (q, 2H, OC2H5); 7.13 (d, IH, arom. 3-CH); 7.32 (t, IH, arom. 4-CH); 7.52 (t, IH, arom. 5-CH) and 8.02 (d, IH, arom. 6-CH). δP (CDCl3): -22.62 (s).
Example 4
[ (2-Ethoxycarbonylphenoxy)carbonyl] phosphonic dichloride
To 4.18 g ( 10 mmol) of bis(trimethylsilyl) [(2-ethoxycarbonylphenoxy)carbonyIj- phosphonate, freshly distilled thionyl chloride (5 ml) was added and the reaction mixture was heated under argon at 70° C for 4 h. Excess thionyl chloride and chlorotrimethylsilane were distilled off and the residue was kept under vacuum (1 mm Hg) at 80° C for 2 h. A clear yellowish liquid resulted, yield 2.95 g (94%). δH (CDC13): 1.33 (t, 3H, OC2H5); 4.28 (q, 2H, OC2H5); 6.83 (dd, IH, arom. 3-CH); 7.08 - 7.23 (m, 2H arom. 4-CH, 5-CH); 8.05 (dd, IH, arom. 6-CH). δP (THF): 10.54 (s). δP (CDC13): 12.06 (s). Example 5
2-[(2-Ethoxycarbonylphenoxy)carbonyI]-l,3,2-dioxaphosphoIane-2-oxide
A solution of 1.03 g (5 mmol) l,2-bis(trimethylsilyloxy)ethane in 10 ml of dry THF was added dropwise to a stirred solution of 1.56 g (5 mmol) [(2-ethoxycarbonylphenoxy)- carbonyl]phosphonic dichloride in 10 ml of dry THF at room temperature under argon. The reaction mixture was stirred for an additional 1 h, then solvent and chlorotrimethylsilane were removed under reduced pressure under dry conditions to give a clear viscous liquid (1.41 g, 94%). δH (CDC ): 1.34 (t, 3H, OC2H5); 4.32 (q, 2H, OC2H5); 4.67 (d, 4H, JPH 9.5, -CH2CH2-); 7.16 (d, IH, arom. 3-CH); 7.38 (t, IH, arom. 4-CH); 7.59 (t, IH, arom. 5-CH) and 8.08 (d, IH, arom. 6-CH). δP (CDCl3): 13.15 (s).
The compounds in the following Examples 6 - 8 were prepared in a similar manner to that described in Example 5 from [(2-ethoxycarbonylphenoxy)carbonyl]phosphonic dichloride and the appropriate bis(trimethylsilyl) ether.
Example 6
2-[(2-Ethoxycarbonylphenoxy)carbonyI]-4-dodecanoyloxymethyI-l,3,2-dioxa- phospholane-2-oxide
The starting bis(trimethylsilyl) ether, l,2-bis(trimethylsilyloxy)-3-dodecanoyloxypropane, was prepared by silylation of 3-dodecanoyloxy-l,2-propanediol by conventional methods.
Two diastereomers were obtained in the ratio 1:1 as racemates. δP (CDCl3): 11.89 (s) and 12.25 (s). Example 7
2-[(2-Ethoxycarbonylphenoxy)carbonyl]-4-octanoylthiomethyl-l,3,2-dioxa- phospholane-2-oxide
The starting bis(trimethylsilyl) ether, l,2-bis(trimethylsilyloxy)-3-octanoylthiopropane, was prepared by silylation of 3-octanoylthio-l,2-propanediol by conventional methods.
Two diastereomers were obtained in the ratio 1:1 as racemates. δP (CDC13): 11.96 (s) and 12.32 (s).
Example 8
2-[(2-Ethoxycarbonylphenoxy)carbonyI]-4-dodecanoyIthiomethyl-l,3,2-dioxa- phospholane-2-oxide
The starting bis(trimethylsilyl) ether, l,2-bis(trimethylsilyloxy)-3-dodecanoylthiopropane, was prepared by silylation of 3-dodecanoylthio-l,2-propanediol by conventional methods.
Two diastereomers were obtained in the ratio 1 : 1 as racemates. δP (CDC13): 11.88 (s) and 12.25 (s).
Example 9
Sodium 2-hydroxyethyl [(2-ethoxycarbonylphenoxy)carbonyl]phosphonate
2-[(2-Ethoxycarbonylphenoxy)carbonyl]-l,3,2-dioxaphospholane-2-oxide (1.5 g, 5 mmol) was dissolved in 20 ml dioxane containing 0.090 g (5 mmol) of water with stirring at room temperature, then 5 ml of 1M aqueous sodium bicarbonate was added dropwise. The solvents were evaporated and the residue was dried in vacuo (1 mm Hg) for 6 h giving a colourless glass (1.6 g, 95%). δH (DMSO-d6): 1.29 (t, 3H, OC2H5); 3.52 (dt, 2H, CH2OH); 3.89 (dt, 2H, JPH 12, POCH2); 4.25 (q, 2H, OC2H5); 7.11 (d, IH, arom. 3-CH); 7.38 (t, IH, arom. 4-CH); 7.62 (t, IH, arom. 5-CH) and 7.86 (d, IH, arom. 6-CH). δP (dioxane, DMSO- άβ insert): -5.52 (s).
The compounds in the following Examples 10 - 12 were prepared in a similar manner to that described in Example 9.
Example 10
Sodium 3-dodecanoyloxy-2-hydroxypropyl [(2-ethoxycarbonyIphenoxy)- carbonyl] phosphonate
Starting material: 2-[(2-Ethoxycarbonylphenoxy)carbonyI]-4-dodecanoyloxymethyl-l,3,2- dioxaphospholane-2-oxide.
Yield 92%. δP (acetone, DMSO-dβ as external standard): -3.22 (s).
Example 11
Sodium 3-octanoylthio-2-hydroxypropyl [(2-ethoxycarbonyIphenoxy)- carbonyl] phosphonate
Starting material: 2-[(2-Ethoxycarbonylphenoxy)carbonyI]-4-octanoylthiomethyl- 1,3,2- dioxaphospholane-2-oxide
Yield 84% (after washing with acetone). δP (DMSO-dό): -5.72 (s). Example 12
Sodium 3-dodecanoylthio-2-hydroxypropyl [(2-ethoxycarbonyIphenoxy)- carbonyl] phosphonate
Starting material: 2-[(2-Ethoxycarbonylphenoxy)carbonyI]-4-dodecanoylthiomethyl- 1 ,3,2- dioxaphospholane-2-oxide
Yield 92%. δP (DMSO-dδ): -5.82.
Example 13
Sodium 2-hydroxy-l,4,2-dioxaphosphorinane-2,3-dioxide
Sodium 2-hydroxyethyl [(2-ethoxycarbonylphenoxy)carbonyI]phosphonate ( 1.7 g, 5 mmol) was dissolved in 10 ml dry DMF and 30 mg l,8-diazabicyclo[5.4.0]undec-7-ene was added to the solution. The reaction mixture was stirred for 6 h at room temperature, then poured into 200 ml of dry ether. The precipitate was filtered and washed with acetone (2 x 50 ml) resulting in 1.4 g (81%) of a white crystalline powder. δH (D2O): 4.28 (ddt, 2H, JPH 13.74, JH6HS 4.57, JH6H6- 1.71, 6-H); 4.43 (dt, 2H, JH5H64.55, JH5H5- 2.28, 5-H). δP (D2O): -7.84 (s). δc (D2O): 65.82 (d, JPC 6.2, 6-C) and 70.84 (d, JPC 5.6, 5-C); m/z: 157.2 (M- Na+).
The compounds in the following Examples 14 - 16 were prepared in a similar manner to that described in Example 13. Example 14
Sodium 2-hydroxy-5-dodecanoyloxymethyl-l,4,2-dioxaphosphorinane-2,3-dioxide
Starting material: Sodium 3-dodecanoyloxy-2-hydroxypropyl[2-ethoxycarbonyl- phenoxy)carbonyl]phosphonate
Yield 64%. δP (DMSO-de): -9.54 (s). δH (D2O/DMSO-d6): 0.88 (t, 3H, CH3); 1.25 (br m, 16H, (CH2)8); 1.57 (m, 2H, COCH2CH2); 2.25 (t, 2H, COCH2); 3.33 (dt, 2H, CH2OCO); 4.05 - 4.40 (m, 3H, 5-H & 6-H).
Example 15
Sodium 2-hydroxy-5-octanoylthiomethyl-l,4,2-dioxaphosphorinane-2,3-dioxide
Starting material: Sodium 3-octanoylthio-2-hydroxypropyl [(2- ethoxycarbonylphenoxy)carbonyI|phosphonate
Yield 72%. δP(D2O): -8.15 (s). δH (D2O): 0.98 (t, 3H, CH3); 1.38 (br s, 8H, 4 x CH2); 1.77 (m, 2H, COCH2CH2); 2.75 (t, 2H, COCH2); 3.42 (d, 2H, SCH2); 4.43 - 4.68 (m, 2H, 6-H) and 4.96 (m, IH, 5-H). δc (D2O): 12.98 (s, CH3); 21.58; 24.56; 27.83; 28.03; 28.22; 30.83 (6s, (CH2)6); 42.92 (s, SCH2); 66.11 (d, JPC 4.5, 6-C); 77.73 (s, 5-C); 172.79 (d, JPC 205.7, 3-C) and 199.21 (s, SCO).
Example 16
Sodium 2-hydroxy-5-dodecanoylthiomethyl-l,4,2-dioxaphosphorinane-2,3-dioxide
Starting material: Sodium 3-dodecanoylthio-2-hydroxypropyl [(2- ethoxycarbonylphenoxy)carbonyI]phosphonate Yield 84%. δP (DMSO-de): -9.57 (s). δH (DMSO-d*): 0.87 (t, 3H, CH3); 1.22 (br s, 16H, (CH2)8); 1.54 (m, 2H, COCH,CH2): 2.62 (t, 2H, COCH2); 3.13 (t, 2H, SCH2); 3.96 - 4.18 (m, 2H, 6-CH2) and 4.63 (m, IH, 5-CH). δc (DMSO-d6): 13.91 (s, CH3); 22.06; 24.96; 28.17; 28.41; 28.59; 28.66; 28.78; 28.93; 29.00; 31.26 (10 s, (CH2)ιo); 65.43 (d, JPC 6.0, 6- C); 76.29 (s, 5-C); 174.56 (d, JPC 196.2, 3-C) and 197.94 (s, SCO).
Example 17
2-[(2-EthoxycarbonyIphenoxy)carbonyI]-4-octadecyIoxymethyl-l,3,2-dioxaphos- pholane-2-oxide
The starting bis(trimethylsilyl) ether, l,2-bis(trimethylsilyloxy)-3-octadecyloxypropane, was prepared by silylation of 3-octadecyloxy-l,2-propanediol (batyl alcohol) by conventional methods.
A solution of 3.5 g (7.1 mmol) l,2-bis(trimethylsilyloxy)-3-octadecyloxypropane in 15 ml of dry THF was added dropwise to a stirred solution of 2.23 g (7.1 mmol) [(2- ethoxycarbonylphenoxy)carbonyI]phosphonic dichloride in 10 ml of dry THF at room temperature under argon. The mixture was stirred for a further 1 h, then concentrated under reduced pressure to give a clear oil. The product was used directly in the following Example 18.
Example 18
Sodium 3-octadecyloxy-2-hydroxypropyI [(2-ethoxycarbonylphenoxy)carbonyl]- phosphonate
The product of Example 17, 2-[(2-ethoxycarbonylphenoxy)carbonyl]-4-octadecyloxy- methyl-l,3,2-dioxa-phospholane-2-oxide, was dissolved in 30 ml dioxane containing 0.13 ml (7.1 mmol) of water with stirring at room temperature, then 7.1 ml of 1M aqueous sodium bicarbonate was added dropwise during 30 min. The solvents were evaporated and the residue was dried under reduced pressure to give a dry foam (4.29 g), which was extracted twice by stirring with warm ether. After cooling the ether extracts, the product was collected by filtration to give 2.91 g (76%) of a solid product. δP (DMSO-dό): -5.98 (s).
Example 19
Sodium 2-hydroxy-5-octadecyloxymethyl-l,4,2-dioxaphosphorinane-2,3-dioxide
Sodium 3-octadecyloxy-2-hydroxypropyl [(2-ethoxycarbonylphenoxy)carbonylj- phosphonate (1.5 g, 2.78 mmol) was dissolved in 6 ml dry DMF and 17 mg 1,8-diaza- bicyclo[5.4.0]undec-7-ene was added. The reaction mixture was stirred for 6 h at room temperature, then poured into 120 ml dry ether. The precipitate was filtered off to afford 0.9 g (88%) of a white crystalline powder. δP(DMSO-d< : -9.91 (s). FAB-MS: m/z 457.37 (M + H+).
Tests for antiviral activity
The antiviral activity of the compounds of the invention may be determined according to the method of Wahren, B. et al., J. Virol. Methods 6 (1983) 141-149. Thus confluent human lung fibroblast cells are infected with Herpes simplex virus type 1 (HSV-1). After absorption for one hour at 37°C, virus is removed and the compounds of the invention diluted in cell media were added, at concentrations of 800 μM down to 3 μM. Cells are incubated at 37°C in a humidified atmosphere of 5% CO2 in air until a characteristic cytopathic effect is seen in control wells (24-48 h). Cells are lysed by addition of Triton X- 100, and viral antigen content of the supernatants measured by enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody. Some of the compounds of the invention were tested according to this test method for antiviral activity and were all found to be active.

Claims

Claims
1. A compound of the formula I
Figure imgf000024_0001
wherein R\ and R2 each independently are hydrogen, or a Cj .24-alkyl, C3.8-cycloalkyl, C3.8-cycloalkyl-Cι .24-alkyl, Ct .24-alkoxy, d .24-alkylthio, Ct .24-alkoxy-d .24-alkyl, Ci .24-alkylthio-Cι .24-alkyl group and each d .2 -alkyl or -alkoxy group may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and is optionally substituted with one or more hydroxy, mercapto, amino, halogen, oxo, or with d .24- alkoxy, d .24-alkylcarbonyloxy, d .24-alkoxycarbonyloxy, Ci .2 -alkylthio, d .2 -alkyl- carbonylthio, C_ - 24-alkoxycarbonylthio, .24-alkylamino, di-(C! .24-alkyl)amino, d .24- alkylcarbonylamino, d . 4-alkyl-(Cι .24-alkylcarbonyl)amino, Ci .24-alkoxycarbonylamino, d .24-alkyl-(d .24-alkoxycarbonyl)amino, and each C1.24 -alkyl or -alkoxy group may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds;
or wherein Rt and R2 each independently are carboxyl, carboxamido, aryl, aryloxy- carbonyl, or aryl-Ci .2 -alkyl, Ci .24-alkoxycarbonyl, Ci .24-alkylaminocarbonyl, di-(d .24- alkyl)aminocarbonyl, aryl-Ci . 4-alkoxycarbonyl, aryl-d - 24-alkylaminocarbonyl, d .24- alkylcarbonyloxymethoxycarbonyl, Q .24-alkylcarbonyloxy-(Cι - -alkyl)methoxycarbonyl, C 1.24-alkoxycarbonyloxymethoxycarbonyl, Q .2 -alkoxycarbonyloxy-(Cι - - alkyl)- methoxycarbonyl, all the Ci .24-alkyl groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds and all the Ci - 4-alkyl groups of which may be branched or unbranched and saturated or unsaturated, and where each aryl group has the formula II
Figure imgf000025_0001
wherein R3 and 1^ are the same or different and each is selected from the group consisting of hydrogen, halogen, or Ci .4-alkyl, Ci .4-alkoxy, Ci . -acyl, Ci .4-acyloxy, d .4-alkoxy- carbonyl, all of which may be branched or unbranched; or R3 and R4 together form an unbranched saturated alkylene chain having 3 or 4 carbon atoms bound to adjacent positions in the phenyl ring; or R3 and R4 together form a methylenedioxy group, a 1,1- ethylidenedioxy group, or a 1,2-ethylenedioxy group bound to adjacent positions of the phenyl ring;
or wherein R.-CH-CH-R2 form part of a C4.8-carbocyclic ring which is optionally substituted with hydroxy, mercapto, amino, halogen, oxo, or with Ci .24-alkyl, Ci .24- alkoxy, d .24-alkylthio, Ci .24-alkylamino, di-(d .24-alkyl)amino, d - 24-alkylcarbonyl, d .24-alkylcarbonyloxy, d - 24-alkoxycarbonyl, Ci .24-alkylcarbonylthio, Ci .24-alkyl- carbonylamino, Ci .2 -alkyl-(Cι .24-alkylcarbonyl)amino, all the d .24-alkyl groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds;
or wherein R1-CH-CH-R2 form part of the furanose or pyranose ring of a sugar, e.g. D- ribose, D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-talose, D- allose, D-altrose, D-gulose, D-idose or the corresponding L-isomers, the hydroxyl groups of which may optionally be replaced by hydrogen, halogen, amino, azido, oxo, mercapto, Ci .24-alkoxy, Ci .24-alkylthio, Ci .24-alkylamino, di-(Cι .24-alkyl)amino, Ci .24-alkylcarbonyloxy, Ci .24-alkylcarbonylthio, Ci .24-alkylcarbonylamino, Ci .2 -alkyl- (Ci .2 -alkylcarbonyl)amino the .24-alkyl groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds;
and physiologically acceptable salts and optical isomers thereof.
2. A compound according to claim 1 wherein Ri and R2 each independently are hydrogen or methyl which latter is optionally substituted with hydroxy or mercapto, or with Q .2 - alkoxy, d .24-alkylcarbonyloxy, Ci .2 -alkylthio, or Ci .24-alkylcarbonylthio, the Ci .2 - alkyl and -alkoxy groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds.
3. A compound according to either of claims 1 or 2 wherein Ri is methyl which is optionally substituted with hydroxy or mercapto, or with d .2 -alkoxy, Ci .24-alkyl- carbonyloxy, Ci .2 -alkylthio, or Ci .2 -alkylcarbonylthio, the Ci .24-alkyl and -alkoxy groups of which may be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and R2 is hydrogen.
4. A compound according to either of claims 1 or 2 wherein Ri and R2βach independently are hydrogen or n-octadecyloxymethyl.
5. A compound according to any of claims 1 to 4 wherein Ri is n-octadecyloxymethyl and R2 is hydrogen.
6. A compound according to claim 5 with the (R)-configuration.
7. A process for the preparation of a compound according to claim 1, characterized by cyclization of a compound of the formula IN
Figure imgf000027_0001
rv
wherein Ri and R2 have the meaning given in claim 1 and R5 is an electron withdrawing group at the ortho- or /?αra-position of the phenyl ring and IVT is a cation.
8. A process for the preparation of a compound of the formula IV
Figure imgf000027_0002
IV
characterized by hydrolysis of a compound of the formula IH
Figure imgf000028_0001
m
wherein Rj, R2, R5 and M have the same meaning as given above in claim 7.
9. A compound of the formula III
Figure imgf000028_0002
m
wherein Ri, R2 and R5 have the meaning given in claim 7.
10. A compound of the formula IV
Figure imgf000029_0001
IN
wherein Ri, R2, R5 and Ivf" have the meaning given in claim 7.
11. A compound according to any of the claims 1 to 6 for use in therapy.
12. A compound according to any of the claims 1 to 6 for use in the treatment of viral infections in mammals.
13. A compound according to any of the claims 1 to 6 for use in the treatment of human herpesvirus or human retrovirus infections.
14. A compound according to any of the claims 1 to 6 for use in the treatment of viral infections in humans caused by HSN- 1 , HSN-2, VZV, CMV, EB V, HHV-6, HHV-7, HHV-8, HIN-1, HIV-2, HTLV-1 or HLTV-2.
15. Use of a compound according to any of the claims 1 to 6 in the manufacture of a pharmaceutical formulation for the treatment of viral infections in mammals.
16. Use of a compound according to any of the claims 1 to 6 in the manufacture of a pharmaceutical formulation for the treatment of human herpesvirus or human retrovirus infections.
17. Use of a compound according to any of the claims 1 to 6 in the manufacture of a pharmaceutical formulation for the treatment of viral infections in humans caused by HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, HHV-7, HHV-8, HIV-1, HIV-2, HTLV-1 or HLTV-2.
18. A pharmaceutical composition containing as an active ingredient a compound as defined in any one of claims 1 to 6.
19. A pharmaceutical composition according to claim 17 which is suitable for oral administration.
20. A pharmaceutical composition according to claim 17 which is suitable for parenteral administration.
21. A pharmaceutical composition according to claim 17 which is suitable for rectal administration.
22. A pharmaceutical composition according to claim 17 which is suitable for topical administration
23. A method of treatment of vims infections wherein a therapeutically effective amount of a compound according to any of the claims 1 to 6 is administered to a patient in need of such treatment.
24. A method of treatment of human herpesvirus or human retrovims infections wherein a therapeutically effective amount of a compound according to any of the claims 1 to 6 is administered to a patient in need of such treatment.
25. A method of treatment of viral infections in humans caused by HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, HHV-7, HHV-8, HIV-1, HIV-2, HTLV-1 or HLTN-2 wherein a therapeutically effective amount of a compound according to any of the claims 1 to 6 is administered to a patient in need of such treatment.
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US6329356B1 (en) 1998-04-10 2001-12-11 Neurochem, Inc. Phosphono-carboxylate compounds for treating amyloidosis
US6440952B2 (en) 1998-04-10 2002-08-27 Queen's University At Kingston Phosphono-carboxylate compounds for treating amyloidosis
WO2000030653A2 (en) * 1998-11-25 2000-06-02 Jomaa Pharmaka Gmbh Use of phosphonoformic acid derivatives for treating infections
DE19854310A1 (en) * 1998-11-25 2000-06-29 Hassan Jomaa Use of phosphonoformic acid derivatives for the therapeutic and prophylactic treatment of infections
WO2000030653A3 (en) * 1998-11-25 2000-11-16 Hassan Jomaa Use of phosphonoformic acid derivatives for treating infections
US6562836B1 (en) 1999-05-24 2003-05-13 Queen's University Of Kingston Methods and compounds for inhibiting amyloid deposits
US7393875B2 (en) 1999-05-24 2008-07-01 Neurochem (International) Limited Methods and compounds for inhibiting amyloid deposits
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US9499480B2 (en) 2006-10-12 2016-11-22 Bhi Limited Partnership Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US10238611B2 (en) 2006-10-12 2019-03-26 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US10857109B2 (en) 2006-10-12 2020-12-08 Bellus Health, Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US11020360B2 (en) 2006-10-12 2021-06-01 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
EP2473038A1 (en) * 2009-09-04 2012-07-11 United Paragon Associates Inc. Compounds for treating disorders or diseases associated with neurokinin 2 receptor activity
US20120190743A1 (en) * 2009-09-04 2012-07-26 United Paragon Associates Inc. Compounds for treating disorders or diseases associated with neurokinin 2 receptor activity
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US8420850B2 (en) 2010-05-14 2013-04-16 Iberhospitex, S.A Compounds for the synthesis of biostable polyurethane, polyurea or polyurea urethane polymers
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