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WO1996016629A2 - Composes phosphinico-creatiniques a activite antivirale - Google Patents

Composes phosphinico-creatiniques a activite antivirale Download PDF

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Publication number
WO1996016629A2
WO1996016629A2 PCT/US1995/015121 US9515121W WO9616629A2 WO 1996016629 A2 WO1996016629 A2 WO 1996016629A2 US 9515121 W US9515121 W US 9515121W WO 9616629 A2 WO9616629 A2 WO 9616629A2
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WIPO (PCT)
Prior art keywords
phosphinic
group
creatine
compound
creatine compound
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PCT/US1995/015121
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English (en)
Inventor
Inc. Amira
Rima Kaddurah-Daouk
Wei Yuan
Gustave Bergnes
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Amira Inc
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Amira Inc
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Priority to AU42858/96A priority Critical patent/AU4285896A/en
Publication of WO1996016629A2 publication Critical patent/WO1996016629A2/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07F9/48—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof
    • C07F9/4808—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof the acid moiety containing a substituent or structure which is considered as characteristic
    • C07F9/4816—Acyclic saturated acids or derivatices which can have further substituents on alkyl
    • 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered rings
    • 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • 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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • Trifluridine (5-trifluoromethyl-2'- deoxyuridine) is a fluorinated pyrimidine deoxynucleoside that inhibits viral DNA synthesis. Trifluridine is active against herpes simplex virus, cytomegalovirus, vaccinia virus, and some strains of adenovirus.
  • Ribavirin which is an analogue of the purine precursor 5'- aminoimidazole-4-carboxamide, exhibits antiviral activity against a range of viruses, including both RNA and DNA-containing viruses.
  • viruses including both RNA and DNA-containing viruses.
  • interferons which are glycoproteins that can bind to specific cell-surface receptors and inhibit viral penetration or uncoating, synthesis or methylation of mRNA, translation of viral proteins, or viral assembly and release.
  • antiviral agents are specific for particular viruses.
  • examples of such viruses include anti-herpes virus agents such as acyclovir. a synthetic purine nucleoside analogue (9- [(2-hydroxy-ethoxy)methyl]guanine), and ganciclovir, a more toxic relative of acyclovir which is also active against cytomegalovirus.
  • acyclovir a synthetic purine nucleoside analogue (9- [(2-hydroxy-ethoxy)methyl]guanine
  • ganciclovir a more toxic relative of acyclovir which is also active against cytomegalovirus.
  • ganciclovir Because of its toxicity, ganciclovir is generally reserved for sight- or life-threatening infections with cytomegalovirus.
  • Another less potent anti-herpes virus agent is vidarabine (adenine arabinoside, ara-A), which is an analogue of adenosine. Goodman Gilman. A. et al. eds. The Pharmacological Basis of Therapeutics (Pergamon Press, New York 1990) 1 182- 1201.
  • Other anti-herpes virus agents include phosphonoformic acid (PFA. foscarnet). and phosphonoacetic acid (PAA).
  • PFA and PAA are potent and highly specific inhibitors of herpes virus DNA polymerases. And despite the drawbacks to its use, e.g.
  • HIV immunodeficiency virus
  • zidovudine as zidothymidine, also known as retrovir or AZT
  • dideoxynucleosides dideoxythymidine (ddA). dideoxycytosine (ddC). and dideoxyinosine (ddl).
  • ddA dideoxythymidine
  • ddC dideoxycytosine
  • ddl dideoxyinosine
  • zidovudine as a thymidine analogue, causes chain termination during DNA synthesis.
  • Other anti-HIV agents which are synthetic dideoxynucleosides and that act on viral DNA polymerase (reverse transcriptase) so that synthesis is inhibited and virus replication is markedly decreased are ddA. ddC, and ddl.
  • ddA dideoxynucleosides and that act on viral DNA polymerase
  • ddl reverse transcriptase
  • PMEA has been found to be a strong inhibitor of retrovirus multiplication and a selective inhibitor of HIV replication in human T-lymphocytes. Indeed, the anti-HIV activity of PMEA exceeds that of zidovudine.
  • the present invention is based, at least in part, on the discovery of novel phosphinic creatine compounds.
  • the phosphinic creatine compounds of the present invention have an anti-viral effect and are more soluble in pharmaceutically acceptable carriers than their corresponding non-phosphinic creatine compound counterparts.
  • the phosphinic creatine compounds can be used to treat a subject for viral infection and/or for reducing or eliminating the spreading of virus from cell to cell.
  • the method of the present invention involves administering an antiviral effective amount of a phosphinic creatine compound to a subject such that the subject is treated for viral infection.
  • the treatment can be of a preexisting viral infection or the treatment can be a prophylactic treatment in that it can prevent the occurrence of a viral infection within the subject.
  • the present invention even further pertains to the novel phosphinic creatine compounds and therapeutic compositions containing the compounds for treating a subject for a viral infection.
  • the therapeutic compositions contain an antiviral effective amount of a phosphinic creatine compound and a pharmaceutically acceptable carrier.
  • Another aspect of this invention is a packaged antiviral agent being a phosphinic creatine compound packaged with instructions for use of the phosphinic creatine compound as an antiviral agent.
  • Figure 1 is a graph depicting the inhibition of human cytomegalovirus (HCMV) plaque formation on human embryonic lung fibroblast cells by a phosphinic creatine compound.
  • Figure 2 is a graph depicting the inhibition of herpes simplex virus- 1 (HSV-1 ) plaque formation on human embryonic lung fibroblast cells by a phosphinic creatine compound.
  • HMV herpes simplex virus- 1
  • the present invention provides a method for treating a subject for viral infection.
  • the method involves administering an antiviral effective amount of a phosphinic creatine compound to a subject being treated for viral infection such that the subject is treated for viral infection.
  • subject is intended to include subjects susceptible to viral infection.
  • the subject can have or be susceptible to a viral infection at the time of treatment.
  • examples of subjects include humans, dogs, cats, pigs, cows, horses, rats, rabbits, and mice.
  • the language "viral infection” is intended to encompass infections caused by a virus.
  • the virus can be a DNA or an RNA virus.
  • DNA viruses intended to be encompassed by the present invention include herpes viruses, respiratory syncitial virus (RSV) and adenoviruses.
  • RNA viruses include influenza and human immunodeficiency virus (HIV).
  • herpes viruses include herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), (e.g., human cytomegalovirus (HCMV). varicella zoster virus (VZV), Epstein Barr virus (EBV).
  • HHV-6 human herpes virus type 6
  • HBV-VI human lymphotrophic virus type VI
  • adenoviruses include adenovirus 5 and adenovirus 2.
  • the term "administering" is intended to include routes of administration which allow the phosphinic creatine compound to perform its intended function of providing treatment for or protection against viral infection. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, etc.), oral, inhalation, transdermal, and rectal. The injection can be bolus injections or can be continuous infusion.
  • the phosphinic creatine compound can be coated with or in a material to protect it from natural conditions which detrimentally effect its ability to perform its intended function.
  • the phosphinic creatine compound can be administered alone or further can be co-administered with a pharmaceutically acceptable carrier. Further, the compounds can be administered as a mixture of phosphinic creatine compounds which also can be in a pharmaceutically acceptable carrier.
  • the phosphinic creatine compounds even further can be coadministered with other different reagents useful for treating viral infection, e.g., other creatine compounds or art-recognized anti-viral agents.
  • the phosphinic creatine compounds can be coadministered with at least one other anti-viral agent (for combination therapy purposes).
  • the antiviral agent can be an agent having an adverse effect on viral infection as described below for the phosphinic creatine compounds of the present invention.
  • the agent can be a material which inhibits the polymerase thereby preventing replication of the viral genome, e.g., foscarnet.
  • the agent further can be a material which becomes incorporated within or binds to the viral genome preventing replication.
  • An example of a type of antiviral agent is a nucleoside. Examples of nucleosides include acyclovir, ganciclovir, idoxoridine, trifluoridine. vidarabine, dideoxyinosine, and azidothymidine.
  • antiviral agents include antisense molecules or immunoglobulins directed against the virus.
  • the language "treated for viral infection” is intended to include treatments which result in the reduction or elimination of a symptom(s) or condition(s) associated with a preexisting viral infection or treatments which prevent the occurrence of a viral infection or significantly reduce the occurrence of a symptom(s) or condition(s) associated with a viral infection within the subject. Therefore, the present invention provides a prophylactic means of preventing viral infection from ever occurring.
  • the symptoms or conditions associated with a viral infection can vary depending on such factors as the particular virus, the immune state of the subject (e.g. immunocompromised subjects can have symptoms which vary from their non- immunocompromised counterparts), and the severity of the infection.
  • symptoms or conditions associated with viral infection include tissue damage, inflammation, edema, interruption of visual acuity (CMV retinitis). elevated body temperature, pneumonia- like symptoms, and ischemia.
  • conditions or diseases associated with viral infection which are intended to be part of this invention include retinitis. encephalitis, enteritis, interstitial, pneumonia, and hepatitis. Specific examples include cytomegalovirus chorioretinitis (CMV retinitis), e.g.
  • HCMV retinitis HCMV retinitis. and herpes simplex virus meningitis (HSV meningitis).
  • Cytomegalovirus (CMV) chorioretinitis (retinitis) is a disease or condition of the retina of the eye caused by infection with CMV.
  • HCMV retinitis is caused by HCMV. This disease or condition is prevalent in immunocompromised hosts, e.g. hosts suffering from AIDS, newborns, or transplant recipients.
  • an antiviral effective amount of a phosphinic creatine compound in the context of this invention is that amount necessary or sufficient to significantly reduce or eliminate a symptom(s) or condition(s) associated with a viral infection or necessary or sufficient to prevent the occurence of a symptom(s) or condition(s) associated with a viral infection. This amount can vary depending on such factors as, particular virus or condition, the weight of the subject and severity of the condition or symptom.
  • Creatine also known as N-(amidinomethyl-N-methylglycine, methylglycosyamine or N-methyl-guanidino acetic acid
  • Creatine also known as N-(amidinomethyl-N-methylglycine, methylglycosyamine or N-methyl-guanidino acetic acid
  • Creatine and phosphorylated creatine are generally present in the muscular tissue, brain and other organs of many vertebrates and the naturally occurring product that is commercially available is typically extracted from meat. Creatine can be chemically synthesized using conventional techniques such as by heating cyanamide with sarcosine rStrecher72. Chem. (1868.. 686; cf. Volhard - -h ⁇ iru 5,318 (1869); Paulmann, ⁇ l---L Eharm- 232, 638 (1894): Bergmann et al. Z. Phvsiol. Chem. 173, 80 (1928): and King J. Che , Soc, (1930), 2374).
  • phosphinic creatine compound is intended to include phosphinic creatine and compounds which are structurally similar to phosphinic creatine (e.g., phosphinic creatine analogs) which contain a phosphinic moiety.
  • the phosphinic creatine compounds of this invention all contain a phosphinic moiety (replacing the carboxylic acid or carboxylate moiety of its corresponding creatine compound counterpart (e.g., see creatine compounds described in commonly owned copending applications USSN 08/185,438 filed on January 21 , 1994 and USSN 08/204,995 filed on March 2, 1994).
  • the phosphinic moiety can be a phosphinic acid moiety or other moieties encompassed by the definition for "Z" set forth in formula I below.
  • Phosphinic creatine was known prior to the present invention. All other phosphinic creatine compounds described herein are novel and are part of the present invention.
  • the phosphinic creatine compounds of this invention can be used to treat a subject for viral infection, as described herein, or can be used for other purposes as previously described for their corresponding non-phosphinic creatine compound counterparts (see. e.g., the utilities described in the copending applications or issued patents cited below)
  • the language “phosphinic creatine compound” also is intended to include pharmaceutically acceptable salts of the compound.
  • phosphinic creatine compound can also include "mimics” or "inhibitors of creatine kinase” which contain a phosphinic moiety.
  • “Mimics” is intended to include compounds which may not be structurally similar to creatine but mimic the therapeutic activity of creatine or structurally similar creatine compounds.
  • the "inhibitors of creatine kinase” are compounds which inhibit the activity of the enzyme.
  • the phosphinic compounds of the present invention are more soluble than their corresponding non-phosphinic creatine compound counterparts.
  • the phosphinic compounds preferably are five times more soluble than their corresponding non-phosphinic creatine compound counterparts, more preferably ten times more soluble, and most preferably at least twenty times more soluble using the assay described in Example 4 below.
  • the phosphinic creatine compounds can be modified versions of the creatine compounds or analogs previously described in other copending applications or issued U.S. patents.
  • Creatine compounds have previously been described in copending application Serial No. 08/204,995. entitled TheUse of Creatine Compounds for Treating Cachexia filed on March 2, 1994; copending application Serial No. 08/185.438, entitled Methods of Inhibiting Undesirable Cell Growth Using A Combination of A Creatine Compound and A Hyperplastk Inhibitory Agent filed January 21 , 1994; copending application Serial No. 07/061.677 entitled Methods of Treating Body Parts Susceptible to Ischemia Using Creatine Analogs, filed May 14. 1993; copending application Serial No.
  • B ] -B4 are each independently selected from hydrogen and OX4;
  • Xj -X4 are each independently selected from the group consisting of hydrogen, alkyl. alkenyl, alkynyl and pharmaceutically acceptable salts;
  • Y ⁇ and Y2 are each independently selected from the group consisting of a direct bond, alkylene, alkenylene, alkynylene and alkoxylene;
  • R] is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, and alkoxyl;
  • R2 - R5 are each independently selected from the group consisting of hydrogen, a phosphorus containing moiety, alkyl, alkenyl. alkynyl, alkoxy and haloalkyl, wherein A may form a ring structure with one of the nitrogens in the amidino moiety or with Y2.
  • the alkylene. alkenylene, alkynylene. alkyl. alkenyl and alkynyl groups may have straight or branched chains.
  • the unsaturated groups may have a single site of unsaturation or a plurality of sites of unsaturation.
  • the hydrocarbon groups preferably have up to about ten carbons, more preferably up to about six carbons, and most preferably up to about three carbons.
  • a hydrocarbon group having three carbon atoms or less is considered to be a lower hydrocarbon group.
  • an alkyl group having three carbon atoms or less is a lower alkyl.
  • Examples of lower hydrocarbon groups which may be used in the present invention include methyl, methylene, ethyl, ethylene, ethenyl, ethenylene, ethynl, ethynylene, propyl, propylene, propenyl, propenylene, propynyl. and propynylene.
  • Examples of higher hydrocarbon groups include butyl, t-butyl, butylene, butenyl, butenylene. and butynyl, butynylene, nonyl. nonylene. nonenyl, nonenylene. nonynyl, and nonynylene.
  • the alkoxy. haloalkyl. alkoxyene. and haloalkylene groups are alkyl or alkylene groups substituted with one or more oxygen or halogen atoms.
  • the alkoxy and haloalkyl groups also may be straight or branched chain and preferably are made up of up to about ten atoms (including carbon, oxygen or halogen), preferably up to about six atoms, and most preferably up to about three atoms.
  • the term halogen is art-recognized and includes chlorine, fluorine, bromine, and iodine. Examples of substituted hydrocarbon groups which are useful within this invention are similar to the examples of the hydrocarbon groups set forth above except for the incorporation of oxygen(s) or halogen(s) into the groups.
  • pharmaceutically acceptable salt is intended to include pharmaceutically acceptable salts capable of being solvated under physiological conditions.
  • examples of such salts include sodium, e.g. disodium, potassium, e.g. dipotassium, and hemisulfate.
  • the term further is intended to include lower hydrocarbon groups capable of being solvated under physiological conditions, i.e. alkyl esters, e.g. methyl, ethyl and propyl esters.
  • the nitrogens in this moiety can form a ring structure with A or with X2.
  • the ring can be a hydrocarbon ring or a hetero ring containing atoms such as O, N or S.
  • the ring structure further can be a single ring or alternatively can be a fused ring system.
  • the preferred ring structures are single rings having five, six or seven ring members and most prefereably five membered rings such as those present in cyclocreatine- or carbocreatine-like compounds.
  • the phosphinic creatine compounds of this invention preferably possess inherent characteristics enhancing their ability to perform their intended function of preventing viral infection.
  • the phosphinic creatine compounds preferably have a solubility which allows them to be delivered in a pharmaceutically acceptable formulation.
  • a saturated solution is not considered to be a pharmaceutically acceptable formulation.
  • the phosphinic creatine compounds further can be selected based on their ability to act as a substrate for creatine kinase. Some of the phosphinic creatine compounds which are useful in this invention are listed in Table 1 below
  • the phosphinic creatine compounds can be synthezized as described in Example 1 below . It should be understood that the ordinarily skilled artisan would know to make modifications to the synthesis method of Example 1 for the purpose of making a different phosphinic creatine compound. For example, a different starting material can be used. Even further, creatine can be used as the starting material for synthesizing at least some of the compounds encompassed by formula I.
  • Appropriate synthesis reagents e.g. alkylating. alkenylating or alkynylating agents can be used to attach the respective groups to target sites, e.g. a nitrogen in the guanidino moiety.
  • Appropriate protecting groups can be employed to prevent reaction at undesired sites in the molecules.
  • the phosphinic creatine compound contains a ring structure, i.e. one of the nitrogens in the amidino moiety forms a ring with "A” or "YV. then the compound can be synthesized in a manner analogous to that described for cyclocreatine (Wang, T.. J. Org. Chem. 39:3591-3594 (1974)).
  • the various "R". "X” groups can be introduced before or after the ring is formed and "Y” group can be introduced before the ring is formed.
  • Phosphinic creatine compounds having the phosphinic moiety attached to an alpha carbon can be made in a manner analogous to that described in Example 1 below.
  • Phosphinic creatine compounds having the phosphinic moiety attached to a beta carbon can be made by introducing a halogen group which subsequently is involved in the phosphinilation step. Further, the phosphinic creatine compounds can be made in an analogous manner to their corresponding phophonic counterparts.
  • the phosphinic creatine compounds of this invention can be synthesized chemically or enzymatically.
  • the chemical conversion of the prephosphagens (see Table 1 ) to the respective phosphagens can be done in the same manner as that descibed by Annesley et al. .Biochem. Biophvs. Res. Commun. (1977) 74: 185-190).
  • Disodium salts, e.g. disodium salts, of the phosphinc creatine compounds can be prepared as described in aforementioned copending application Serial No.
  • Kaddurah-Daouk si s (WO92/08456) also provide citations for the synthesis of a plurality of creatine compounds (see Examples 2 and 3 including Table 4).
  • the contents of the entire Kaddurah-Daouk et al. published patent application including the contents of any references cited therein also are expressly incorporated by reference.
  • phosphinic creatine compounds of the present invention include phosphinic cyclocreatine (PhCCr), phosphinic CCr phosphate, phosphinic creatine. phosphinic creatine phosphate, and phosphinic homocyclocreatine.
  • the present invention further pertains to a therapeutic composition for treating a subject for viral infection.
  • the therapeutic composition contains an antiviral effective amount of a phosphinic creatine compound and a pharmaceutically acceptable carrier.
  • antiviral effective amount and "phosphinic creatine compound” are as defined above.
  • pharmaceutically acceptable carrier is intended to include substances capable of being coadministered with the phosphinic creatine compound(s) and which allow the compound to perform its intended function of treating a viral infection.
  • examples of such carriers include solutions, solvents, dispersion media, delay agents, emulsions and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media and agent compatible with the phosphinic creatine analog can be used within this invention.
  • the present invention even further pertains to packaged antiviral agents containing a phosphinic creatine compound as defined above packaged with instructions for using the phosphinic creatine analog as an antiviral agent.
  • the instructions would provide such information as the appropriate dose of the phosphinic creatine compound for treating a particular virus.
  • Reagent-grade chemicals were used as purchased from Aldrich Chemical Company. Inc. unless otherwise stated. Absolute alcohol was purchased from Commercial
  • Chloromethylphosphinic acid was prepared using the route described by E. Uhing. et al.( J.
  • the crude N-(2-aminoethyl)aminomethylphosphinic acid was transferred, with the aid of 200 mL of water, to a 50 liter round bottom flask, which contained a teflon coated stirring bar and was equipped with a thermometer and a 500 mL addition funnel.
  • Sodium hydroxide pellets 140.60g, 3.00 mol
  • 240 mL of water were added to the reaction flask and the mixture was cooled with stirring to a temperature of 0°C using an isopropanol/dry ice bath.
  • 322.7 g (3.05 mol) of cyanogen bromide dissolved in approximately 350 mL of methanol was then transferred to the addition funnel.
  • the cyanogen bromide solution was added dropwise to the chilled reaction mixture with efficient stirring while the temperature of the reaction solution during the addition period was kept between 5 and 10°C.
  • the addition funnel was then rinsed with a total of 140 mL of methanol, and the washings were added to the reaction flask.
  • the solution was stirred overnight, and the methanol solvent was removed on a rotary evaporator. Residual water was then removed using a rotary evaporator attached (in series) to a trap cooled on dry ice, a trap cooled on dry ice/acetone, and a vacuum pump to get a thick ochre yellow product.
  • This crude product was extracted with 3.2 L of boiling methanol and suction filtered to remove sodium halide salts which were washed with 100 mL of hot methanol. 1.4 L of diethyl ether was added to the amber-red filtrate, and the mixture was allowed to sit overnight. An additional 700 mL of ether was then added to precipitate more solid which was suction filtered, washed with 200 mL of ether and air dried. This crude material (86.1 g), 1 L of methanol and 100 mL of water were brought to a boil with stirring, and the fine white solid present (13.0 g) was suction filtered and dried over KOH in vacuo.
  • Compound Phosphinic cyclocreatine was evaluated for substrate activity using a coupled assay (see (a) Stauffer Chemical Co.; Brit. 934,090 (Cl. C. 07f); Aug. 14. 1963.
  • K m ,V max and k cat values were graphically determined by the standard manner using double reciprocal plots.
  • Creatine kinase from rabbit muscle (creatine phosphokinase, Sigma. 60 units/mg prot., Cat. No. C-6638) was used for enzyme assays. Kinetic data were collected and processed on a Beckman DU 70 UV/visible spectrophotometer. Assays were run at 37°C with the disappearance of NADH monitored at 340 nm. Assay solutions contained 0.1 M HEPES (pH 7.3), 6 mM Mg(OAc)2- 0.1 M KOAc. 3 M ATP. 0.65 M PEP, 0.39 M NADH. 0.2 mg/mL pyruvate kinase (Sigma). 0.2 mg/mL lactate dehydrogenase (Sigma), and 1.6 ⁇ g/mL creatine kinase.
  • HCMV Human cytomegalovirus
  • AD 169 ATCC
  • HSV-1 herpes simplex virus type 1
  • ATCC herpes simplex virus type 1
  • MRC-5 human embryonic lung fibroblast cells were purchased from ATCC.
  • the cells were grown to confluence in twenty four well plates and infected with a known amount of PFU (Plaque Forming Units; approximately 50 PFU/well) suspended in EMEM JRH Biosciences) containing 2% FBS (Fetal Bovine Serum, JRH Biosciences).
  • PFU Protein Forming Units
  • FBS Fetal Bovine Serum, JRH Biosciences
  • the virus was allowed to adsorb for one hour at 37°C. and then media containing a range of concentrations of PhCCr was added to the wells. This was done in triplicate for each concentration of PhCCr.
  • the plates were incubated at 37°C under 5% CO2 until plaques were identified in the control wells (approximately 7 days post-infection for HCMV and 2 days post-infection for HSV-1 ).
  • PhCCr acts as an antiviral agent against both HCMV and HS V- 1.
  • phosphinic cyclocreatine and cyclocreatine (CCr) were determined.
  • the solubility of each compound was assessed in phosphate buffered saline (PBS) and two temperatures were selected (room temperature and 4 °C). Both compounds were dissolved in IX PBS (JRH BioSciences).
  • the stock solution of CCr was made at 20 mg/mL which went into solution by incubating briefly at 65 °C and vortexing. Further dilutions of CCr were done in PBS to give additional final concentrations of 15. 12.5 and 10 mg/mL.
  • the CCr solutions were colorless.
  • PhCCr was made in a concentrated solution of 385 mg/mL, by heating briefly at 65 °C and vortexing. The PhCCr solution was the color of amber. The 385 mg/mL PhCCr precipitated out of solution when incubated briefly on ice and for a longer period at room temperature. The non-chemical particulate fibers present in the 385 mg/mL solution were removed by filtering with a syringe 0.45 um glass filter. Solutions of 300, 250, 200, 150, and 100 mg/mL PhCCr were made by dilution into PBS. One set each of the CCr and PhCCr solutions were placed at room temperature and at 4 °C. The solutions were checked for precipitates at four hours, three days, six days, and nine days after preparation.

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Abstract

La présente invention concerne de nouveaux composés phosphinico-créatiniques. L'invention concerne également un procédé de traitement d'un sujet souffrant d'une infection virale consistant en l'administration au sujet d'une dose efficace sur le plan antiviral d'un composé phosphinico-créatinique. Ces composés peuvent s'administrer sous forme de compositions thérapeutiques contenant une dose antivirale efficace d'un composé phosphinico-créatinique et un excipient acceptable d'un point de vue pharmaceutique.
PCT/US1995/015121 1994-11-18 1995-11-20 Composes phosphinico-creatiniques a activite antivirale Ceased WO1996016629A2 (fr)

Priority Applications (1)

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AU42858/96A AU4285896A (en) 1994-11-18 1995-11-20 Phosphinic creatine compounds having antiviral activity

Applications Claiming Priority (2)

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US34208994A 1994-11-18 1994-11-18
US8/342,089941118 1994-11-18

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WO1996016629A2 true WO1996016629A2 (fr) 1996-06-06

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000004884A1 (fr) * 1998-07-20 2000-02-03 Hartmut Osswald Preparations medicamenteuses pour traitement topique d'infections herpetiques cutaneo-muqueuses et de l'herpes de la keratite de l'oeil
WO2000045851A3 (fr) * 1999-02-04 2000-12-28 Joern Bullerdiek Agent pour prevenir et/ou traiter les modifications tissulaires d'origine mesenchymateuse
WO2000044358A3 (fr) * 1999-01-26 2001-03-15 Hassan Jomaa Utilisation de composes organophosphores pour la prophylaxie et le traitement des infections
EP1115388A1 (fr) * 1998-09-22 2001-07-18 Hassan Jomaa Utilisation de composes organophosphores pour la production de medicaments pour le traitement therapeutique et prophylactique d'infections ou en tant que fongicide, bactericide ou herbicide pour vegetaux

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000004884A1 (fr) * 1998-07-20 2000-02-03 Hartmut Osswald Preparations medicamenteuses pour traitement topique d'infections herpetiques cutaneo-muqueuses et de l'herpes de la keratite de l'oeil
EP1115388A1 (fr) * 1998-09-22 2001-07-18 Hassan Jomaa Utilisation de composes organophosphores pour la production de medicaments pour le traitement therapeutique et prophylactique d'infections ou en tant que fongicide, bactericide ou herbicide pour vegetaux
WO2000044358A3 (fr) * 1999-01-26 2001-03-15 Hassan Jomaa Utilisation de composes organophosphores pour la prophylaxie et le traitement des infections
WO2000045851A3 (fr) * 1999-02-04 2000-12-28 Joern Bullerdiek Agent pour prevenir et/ou traiter les modifications tissulaires d'origine mesenchymateuse

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Publication number Publication date
AU4285896A (en) 1996-06-19

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