WO1992009285A1 - Combinaisons de composes vanilloides et de composes phosphonates antiviraux pour le traitement d'infections par herpes - Google Patents

Combinaisons de composes vanilloides et de composes phosphonates antiviraux pour le traitement d'infections par herpes Download PDF

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Publication number
WO1992009285A1
WO1992009285A1 PCT/US1991/008678 US9108678W WO9209285A1 WO 1992009285 A1 WO1992009285 A1 WO 1992009285A1 US 9108678 W US9108678 W US 9108678W WO 9209285 A1 WO9209285 A1 WO 9209285A1
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Prior art keywords
hydroxy
compound
methyl
vanilloid
methoxyphenyl
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PCT/US1991/008678
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English (en)
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Larry Milton Brand
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The Procter & Gamble Company
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Publication of WO1992009285A1 publication Critical patent/WO1992009285A1/fr

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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

Definitions

  • the subject invention relates to a novel method for the treatment of Herpes infections.
  • the subject invention involves natural and synthetic vanilloid compounds.
  • the following references disclose vanilloid compounds and are incorporated herein by reference: U.S. Patent No. 4,313,958 issued to LaHann on February 2, 1982; U.S. Patent No. 4,401,663 issued to Buckwalter & LaHann on August 30, 1983; j 5 U.S. Patent 4,424,205 issued to LaHann & Buckwalter on January 3, 1984; U.S. Patent No. 4,443,473 issued to Buckwalter & LaHann on April 17, 1984; U.S. Patent No. 4,460,602 issued to Buckwalter & LaHann on July 17, 1984; U.S. Patent No.
  • Vanilloid compounds have been generally disclosed in the above references to have analgesic, anti-irritant and anti-in- flammatory activity. Vanilloid compounds have been disclosed to be useful in the treatment of Herpes simplex infections in European Patent Application No. 0,347,000 of O'Neill, Kasting & Cupps, published December 20, 1989.
  • the subject invention also involves phosphonate antiviral compounds.
  • Certain phosphonate antiviral compounds have been disclosed to have anti-herpetic activity.
  • Phosphonate antiviral compounds are disclosed in the following references which are incorporated herein by reference: U.S. Patent No. 3,767,795 issued to Schleicher & Roderick on October 23, 1973; U.S. Patent No. 4,016,264 issued to Clark on April 5, 1977; U.S. Patent No. 4,052,439 issued to Herrin & Fairgrieve on October 4, 1977; U.S. Patent No. 4,056,673 issued to Heimer & Nussbaum on November 1, 1977; U.S. Patent No. 4,087,522 issued to Von Esch on May 2, 1978; U.S. Patent No.
  • VZV lesion episodes usually cause severe pain and exhibit large groups of lesions distributed along the course of a sensory nerve.
  • the vesicular eruptions of Herpes zoster are often activated by systemic diseases such as Hodgkins, and immuno- suppressive therapy.
  • VZV is also the causative agent in chicken pox. Later Herpes zoster infections (or shingles outbreaks) are most common after the age of fifty. Crops of vesicles form on an erythemateous base and follow the sensory distribution of one or more posterior root ganglia. The sensory zone on the skin that is affected is usually hyperalgesic with associated severe pain.
  • Herpes zoster infections may have some similari- ty to Herpes simplex virus (HSV) infections, but several impor ⁇ tant differences between the two exist.
  • HSV Herpes simplex virus
  • Herpes simplex lesion episodes are characterized by general ⁇ ized or localized cutaneous and mucosal lesions, often with associated severe constitutional (general, not local) symptoms.
  • the virus spreads along sensory nerves and becomes established in the regional sensory ganglia, or area of neuron cell bodies.
  • HSV usually present with latent infections in the trigeminal or presacral ganglia (Type I) or dorsal root ganglia (Type II). Although VZV infections generally produce latent infections, these occur mainly in the dorsal root ganglia.
  • HSV infections are generally of two types, Type I or Type II.
  • Type I HSV infections are mainly implicated in oral or ocular Hero infections.
  • HSV Type II infections are usually genital and transmitted primarily through direct contact with Hero lesions. While Hero simplex lesions may appear anywhere on the skin or mucosa, they most frequently appear on the mouth, the lips, the conjunctiva and cornea and the genitalia.
  • Type I HSV recurrence 80%
  • Type II HSV recurrence 50%
  • Reinfection with different strains of Type II HSV may also occur.
  • Recurrent herpetic eruptions can be precipitated by conditions as broad as over exposure to sunlight, febrile illness, physical or emotional stress, or certain foods or drugs.
  • HSV vesicular eruptions
  • vesi- cular eruptions The primary lesions of HSV (vesicular eruptions) are the most painful, prolonged and widespread. During periods of vesi- cular eruption, patients often experience pain in the region of viral infection. This pain, though it may be severe, resolves upon healing of the herpetic lesions, and leaves the patient basically asymptomatic between recurrent herpetic episodes.
  • OBJECTS OF THE PRESENT INVENTION It is an object of the present invention to provide new methods which are effective for treating or preventing lesion episodes due to Herpes infections.
  • the subject invention involves methods of treating or preventing lesion epidodes in humans, due to Hero infections, comprising administering to the humans combinations of vanilloid compounds and phosphonate antiviral compounds.
  • alkyl means carbon-con ⁇ taining chains which may be straight, branched, or cyclic; substituted or unsubstituted; and which may be saturated, mono- unsaturated (i.e., one double or triple bond in the chain), or polyunsaturated (e.g., two or more double bonds in the chain; two or more triple bonds in the chain; one or more double and one or more triple bonds in the chain).
  • alkyl preferences alone and/or collectively, are as follows. Preferred alkyl are straight or branched chain, especially straight chain. Preferred alkyl are unsubstituted.
  • Preferred alkyl are monounsaturated, or especially saturated. Preferred alkyl are about C ⁇ C ⁇ , more preferably about C ⁇ Cu,. Preferred alkyl are lower alkyl, about C--C 6 , more preferably about C--C 4 , more preferably still C : -C 2 , especially C-. Substituted alkyl groups can be mono- or polysubstituted. Preferred is mono-, di- or trisubstituted; more preferred is monosubstituted.
  • Preferred substitutents are selected from the group consisting of halogen, hydroxy, alkoxy, aryloxy, amino, nitro, cyano, trifluoromethyl, thiol, aryl, heteroaryl and carboxylate; more preferred are halogen, hydroxy, amino, thiol, aryl and carboxylate; most preferred are hydroxy or amino, and also aryl.
  • saturated alkyl groups are referred to as "alkanyl”; unsaturated alkyl groups comprising double bonds in the chain are referred to as “alkenyl” (preferred are chains having the double bonds in the "Z” or “cis” geometric configura ⁇ tion); and unsaturated alkyl groups comprising triple bonds in the chain are referred to as “alkynyl”.
  • alkanyl unsaturated alkyl groups comprising double bonds in the chain
  • alkenyl (preferred are chains having the double bonds in the "Z” or "cis” geometric configura ⁇ tion)
  • unsaturated alkyl groups comprising triple bonds in the chain are referred to as “alkynyl”.
  • the designation " of geometric configurations for any double bonds present in com ⁇ pounds of the present invention utilizes the art-known nomencla ⁇ ture "Z” and “E”, and is fully described in Morrison and Boyd, Organic Chemistry. Third Edition (Allyn and Bacon, Inc., Boston; 1973), pp. 131-133 and
  • aryl and heteroaryl mean aryl or heteroaryl rings which may be mono-, di-, or tri-substituted or unsubstituted, preferably monosubstituted or unsubstituted. Additionally, heteroaryl rings comprise at least one heteroatom in the ring structure.
  • heteroatom means an atom other than carbon that can covalently bond to at least two other atoms and become part of a stable chemical structure. Preferred heteroatoms are nitrogen, oxygen and sulfur.
  • Preferred aryls and heteroaryls include substituted or unsubstituted phenyl, naphthyl, pyridyl, pyrimidyl, i idazolyl, furanyl, thiophenyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, tri- azinyl, pyrrolyl, indolyl and purinyl. More preferred aryls and heteroaryls include unsubstituted and substituted phenyl, pyridyl, imidazolyl, furanyl and thiophenyl. Most preferred aryl is unsubstituted or substituted phenyl.
  • Substituted aryls and heteroaryls can be mono- or polysubstituted. Preferred is mono-, di- or trisubstituted; more preferred is monosubstituted. Preferred substituents include halogen, hydroxy, alkoxy, amino, nitro, cyano, phenyl, benzyl, benzyloxy, trif1uoromethyl, formyl- amino, carboxylate and alkyl; more preferred substituents include alkyl, alkoxy, halogen, hydroxy, amino and carboxy; most pre ⁇ ferred are halogen, and especially lower alkyl. More preferred aryl or heteroaryl is unsubstituted.
  • carboxylate means an organic carboxylic acid moiety (i.e., C00H), and the salts (e.g., sodium, potassium, calcium, tetraethylammonium) and esters (e.g., methyl ester, ethyl ester) and amides (e.g., unsubstituted amide, N-methyl amide, N,N-dimethyl amide) thereof.
  • salts e.g., sodium, potassium, calcium, tetraethylammonium
  • esters e.g., methyl ester, ethyl ester
  • amides e.g., unsubstituted amide, N-methyl amide, N,N-dimethyl amide
  • Pharmaceutically-acceptable salts include ammonium salts derived from inorganic acids (e.g., HC1, HBr, NaHS0 4 , H 2 C0 3 ), and ammoni ⁇ um carboxylic acid salts derived from organic carboxylic acids (e.g., acetic acid; lactic acid; gluconic acid; citric acid; glucuronic acid; galacturonic acid; fumaric acid; gentisic acid; lactobionic acid; benzoic acid).
  • Pharmaceutically-acceptable amides include those derived from organic carboxylic acids (e.g., acetic acid amides) including amino acids (e.g., glycine amides).
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal.
  • compact- ible means that the components of a pharma ⁇ ceutical carrier are capable of being commingled with the vanilloid compounds and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.
  • Vanilloid Compounds and Compositions are natural and synthetic vanilloid compounds, and the pharmaceuti ⁇ cally-acceptable salts thereof, having the general structure:
  • n 0 or 1.
  • the -W-X- moiety is selected from -C(0)NH-, -C(S)NH-, -S(0) 2 NH-, -NHC(0)0-, -NHC(S)0-, -NHC(0)NH-, and -NHC(S)NH-.
  • Preferred -W-X- is selected from -C(0)NH-, -C(S)NH-, -NHC(0)NH-, -NHC(S)NH- and -S(0) 2 NH-.
  • More preferred -W-X- is selected from -C(0)NH-, -C(S)NH-, and -NHC(0)NH-.
  • Most preferred -W-X- is -C(0)NH-. Either available bond of the -W-X- moiety may be bonded to the -R moiety, with the other bond being attached to the benzyl carbon atom, or directly attached to the benzene ring.
  • the -R 1 moiety is selected from hydrogen, hydroxy, lower alkyl esters of hydroxy, lower alkyl, and lower alkoxy.
  • Preferred -R 1 is selected from hydrogen, hydroxy, and methyl; most preferred -R 1 is hydrogen.
  • the -Z moiety is selected from hydrogen, hydroxy and methoxy; preferred -Z is selected from hydroxy and methoxy. Most preferred -Z is methoxy.
  • -S- and -NH- More preferred -Y- is selected from -0- and -S-; most preferred -Y- is -0-.
  • the -V moiety is selected from hydrogen, short chain alkyl, and -CR 2 2 -CR 2 2 -NH 2 .
  • Preferred -V is selected from C x to C 3 alkyl and hydrogen. Even more preferred -V is selected from hydrogen and methyl, especially hydrogen. Also more preferred is -V being -CR 2 2 -CR 2 2 -NH 2 .
  • the -R 2 moieties are each independently selected from hydro- gen; halogen; unsubstituted or substituted alkyl, the alkyl portion having from about 1 to about 6 carbon atoms; substituted or unsubstituted aryl or heteroaryl; and carboxylate; or two -R 2 moieties are covalently bonded to form a substituted or unsub ⁇ stituted alkyl, heteroalkyl, aryl or heteroaryl ring having from about 3 to about 8 atoms, preferably 3-6 atoms, in the ring, including from 0 to about 3 heteroatoms. It is preferred that no more than two -R 2 are other than hydrogen.
  • Preferred -R 2 substi ⁇ tuents other than hydrogen include unsubstituted and substituted lower alkyl (preferred substituents being hydroxy, amino and phenyl) and unsubstituted and substituted phenyl. It is pre ⁇ ferred that at least one -R 2 on the alpha carbon atom (the carbon atom bonded directly to the Y moiety) be a hydrogen. Also pre ⁇ ferred is at most only one -R 2 being other than hydrogen. Also preferred is all -R 2 being hydrogen.
  • both -R 2 on the alpha carbon atom are hydrogen and both -R 2 on the beta carbon atom (the carbon atom bonded directly to the alpha carbon atom) are unsubstituted or substituted alkyl or are covalently bonded to form a sub ⁇ stituted or unsubstituted alkyl or heteroalkyl ring having from about 3 to about 8 atoms, including from 0 to about 3 hetero ⁇ atoms, in the ring.
  • Preferred -R 2 alkyl moieties on the beta carbon atom are saturated or unsatur ⁇ ated having a single double or triple bond, more preferred is that both -R 2 on the beta carbon be unsubstituted or substituted alkanyl or covalently bonded to form an unsubstituted or sub ⁇ stituted alkanyl ring. More preferred still is that both -R 2 on the beta carbon atom are methyl or ethyl, especially methyl.
  • both -R 2 on the alpha carbon atom are hydrogen
  • one -R 2 on the beta carbon atom is hydrogen and the other is arylalkyl or heteroarylalkyl, preferably having the structure -(CH 2 ) n -Ar, wherein -Ar is aryl or heteroaryl and n is an integer from 1 to about 6; preferably n is 1 or 2, especially
  • Preferred aryl and heteroaryl moieties of this structure include unsubstituted and substituted phenyl, pyridyl, or furanyl, especially unsubstituted and substituted phenyl.
  • Preferred substitutents on the aryl or heteroaryl moiety include chloro, methyl, methoxy, nitro, fluoro, and Ci-C 6 alkyl. Most preferred aryl is phenyl, especially unsubstituted phenyl. In such compounds, the beta carbon is a chiral center; preferred compounds have the S-enantiomer structure: -V being
  • the -R moiety is a C x -C 24 alkyl moiety which may be straight, branched or cyclic chain and may be saturated, onounsaturated, or polyunsaturated, substituted or unsubstituted.
  • Preferred -R moieties are straight and branched chain alkanyl, straight and branched chain monounsaturated alkyl, straight and branched chain diunsaturated alkyl, and straight and branched chain triunsaturated alkyl. More preferred -R moieties are mono or diunsaturated or saturated, C 6 -C 24 straight or branched chain alkyls. Also more preferred are C 6 -C 14 straight chain alkyls, especially C 7 -C 10 straight chain alkanyls. Even more preferred are mono or diunsaturated alkenyls, or C 6 -C 24 straight chain alkenyls.
  • Such preferred -R moieties are prefer ⁇ ably unsubstituted.
  • Other preferred -R moieties are arylalkyls having a C ! -C 12 , more preferably Ci-Ce, most preferably C x -C 2 , alkyl portion which is preferably straight chain and also preferably alkanyl. The aryl portion is preferably unsubstituted or substituted phenyl.
  • Preferred -R groups are selected from n-hexanyl, n-heptanyl, n-octanyl, n-nonanyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tri- decanyl, n-tetradecanyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, octadienyl, nonadienyl, decadienyl, undecadienyl, dodecadienyl, tridecadienyl and tetra- decadienyl.
  • More preferred -R groups are selected from n- octanyl, n-nonanyl, n-decanyl, 7-methyl-5E- or 5Z-octenyl, 9-decenyl, 8Z-undecenyl, 9Z-dodecnyl, 8Z-tridecnyl, and 9Z-tetra- decenyl.
  • Preferred compounds useful in the subject invention include 8-methyl-N-vanillyl-6-nonenamide; N-vanillylnonanamide; N-van- illy!-9-octadecenamide; N-((4-(2-aminoethoxy)-3-methoxyphenyl)- methyl)-9Z-octadecenamide; N-((4-(2-aminoethoxy)-3-methoxy- phenyl)-methyl)-nonanamide; N-((4-(2-methyl-2-aminopropoxy)- 3-methoxyphenyl)-methyl)-nonanamide; N-((4-(2-methyl-2-amino ⁇ propoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-((4-(2- amino-3-methylbutoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-((4-(2- amino
  • More preferred compounds useful in the methods of the present invention include 8-methyl-N-vanillyl-6-nonenamide; N-vanillylnonanamide; N-(9- decenyl)-4-hydroxy-3-methoxyphenylacetamide; N-(9Z-dodecenyl)- 4-hydroxy-3-methoxyphenylacetamide; N-(9Z-tetradecenyl)-4-hy- droxy-3-methoxyphenylacetamide; N-((4-hydroxy-3-methoxy- phenyl)-methyl)-9-decenamide; N-((4-hydroxy-3-methoxyphenyl)- methyl)-9Z-dodecenamide; N-((4-hydroxy-3-methoxyphenyl)-methyl)- 9Z-tetradecenamide; N-((4-(3-phenyl-2(S)-2-am ⁇ no-l-propoxy)-3- methoxyphenyl)-methyl)-
  • Vanilloid pharmaceutical compositions useful in this invention are described in the following U.S. Patents, all incorporated by reference herein: U.S. Patent No. 4,401,663, Buckwalter, et al, issued August 30, 1983; U.S. Patent No. 4,424,205, LaHann, et al, issued January 31, 1984; U.S. Patent No. 4,443,473, Buckwalter, et al, issued April 12, 1984; U.S. Patent No. 4,493,848, LaHann, et al, issued January 15, 1985.
  • Vanilloid pharmaceutical compositions preferably comprise one or more of the vanilloid compounds and a pharmaceutically-acceptable carrier.
  • Total single dosages of the vanilloid compounds present in pharmaceutical compositions useful herein are generally from about 1 ug to about 1 g.
  • Preferred single dosages are from about 10 ug to about 100 mg; more preferred are from about 100 ug to about 50 mg; and most preferred are from about 1 mg to about 10 g.
  • a pharmaceutically-acceptable carrier to be used in conjunction with the vanilloid compounds in the subject invention is largely determined by the way the compound is to be administered. Such methods include parenteral (especially subcu ⁇ taneous), oral and topical.
  • Phosphonate Antiviral compounds include antiviral compounds which are phosphonate derivatives.
  • Preferred phosphonate antiviral compounds useful in the subject invention are derivatives of phosphonoacetic acid.
  • Examples of "phosphonoacetic acid antiviral compounds" are disclosed in U.S. Patent Nos. 3,767,795, 4,016,264, 4,052,439, 4,056,673, 4,087,522, 4,092,412, 4,272,528 and 4,340,599, which have been incorporated herein by reference.
  • Preferred phosphonate antiviral compounds useful in the subject invention also include phosphonofor ic acid and deriva ⁇ tives thereof.
  • Examples of "phosphonoformate antiviral com- pounds" are disclosed in U.S. Patent Nos. 4,215,113, 4,372,894, 4,386,081, 4,536,400, 4,591,583, 4,665,062 and 4,771,041, which have been incorporated herein by reference.
  • the phosphonoformate antiviral compounds useful in the subject invention include those disclosed in U.S. Patent No. 4,215,113 issued to Erickson, Helgstrand, Mizyorni, Stenning and Strigg on July 29, 1980, being phosphonoformic acid and physio ⁇ logically-acceptable salts thereof.
  • Suitable salts include, for example, amine salts, such as dimethylamine, triethylamine, ammonium, tetrabutylammonium, cyclohexylamine and dicyclohexyl- amine; and metal salts, such as mono-, di- and trisodiu , mono-, di- and tr.i.potassium, magnesium, _. calcium and zinc.
  • the most preferred compound is foscarnet, the trisodium salt of phosphonoformic acid.
  • Phosphonate antiviral compounds include other phosphonate derivatives having antiviral activity.
  • Examples of other phos ⁇ phonate antiviral compounds are arylalkyl and aryloxyalkyl phosphonates disclosed in U.S. Patent Nos. 4,182,759 and 4,217,346, which have been incorporated herein by reference.
  • a preferred aryloxyalkylphosphonate is fosarilate having the structure:
  • the subject invention involves methods of treating Herpes infections, particularly methods of alleviating signs and symptoms associated with herpetic vesicular eruptions and the attendant pain of Herpes lesions by administering to a person a safe and effective amount of a combination of a vanilloid com ⁇ pound and a phosphonate antiviral compound.
  • the methods of the subject invention include the prevention of recurrent Herpes simplex lesion episodes and/or the reduction in number and/or severity of Herpes simplex or Hero zoster vesicular eruptions that manifest in a lesion episode.
  • a "safe and effective amount" means an amount of compounds or compositions high enough to significantly positively modify the condition to be treated, but low enough to avoid serious side effects (at a reasonable bene ⁇ fit/risk ratio), within the scope of sound medical judgment.
  • the safe and effective amount of compounds or compositions will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concur ⁇ rent therapy, the specific compounds or compositions employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
  • the vanilloid compounds and the phosphonate antiviral compounds useful in the subject invention may be administered to a person together in a single composition or separately in different compositions. When administered separately in dif- ferent compositions, the compounds may be administered by the same or different routes of administration, and may be admin ⁇ istered at about the same time or at different times.
  • Daily dosages of vanilloid compounds preferably range from about 0.01 mg/kg of body weight to about 200 mg/kg of body weight. More preferred daily dosages are from about 0.1 mg/kg to about 10 mg/kg of body weight; still more preferred daily dosages are from about 0.2 mg/kg to about 1 mg/kg of body weight. Up to about 6, preferably from about 1 to about 4, single dosages per day may be administered.
  • Preferred routes of administration of vanilloid compounds include topical, peroral, and parenteral; more preferred are topical and peroral; most preferred is topical.
  • Topical admini ⁇ stration can be used by directly laying on or spreading a safe and effective amount of a vanilloid composition on epidermal or epithelial tissue, including outer skin and oral, anal, vaginal and gingival tissue.
  • the amount of the pharmaceutical composi- tion to be topically administered may vary from about 1 mg/cm 2 to about 20 mg/cm 2 , and if a patch is worn over the affected area possibly higher amounts, depending upon such factors as the sensitivity, type and location of tissue to be treated, the composition and carrier to be administered, and the particular compound to be administered.
  • the vanilloid compound When administered topically, the vanilloid compound is preferably administered between lesion episodes to tissue in areas where lesions previously occurred and/or are likely to occur, especially on the face or in the genital region.
  • the vanilloid compound is preferably administered topically for from about 1 to about 60 days at a frequency of about weekly to about yearly, more preferably for from about 2 days to about 30 days at a frequency of from about biweekly to about twice yearly, more preferably still for from about 3 days to about 15 days at a frequency of from about monthly to about thrice yearly, most preferably from about 4 days to about 7 days at a frequency of from about bimonthly to about trimonthly.
  • Preferred routes of administration of phosphonate antiviral compounds are peroral, topical, and parenteral (especially intravenous); preferred routes of administration are peroral and topical, especially peroral.
  • Daily dosages of phosphonate antiviral compounds preferably range from about 0.01 mg/kg of body weight to about 20 mg/kg of body weight. More preferred daily dosages are from about 0.1 mg/kg to about 15 mg/kg of body weight; still more preferred daily dosages are from about 1 mg/kg to about 10 mg/kg of body weight; more preferably still from about 5 mg/kg to about 8 mg/kg of body weight. Up to about 8, preferably from about 1 to about 6, more preferably from about 2 to about 4, single dosages per day may be administered.
  • the phosphonate antiviral compound is preferably administered everyday, although less frequent admini ⁇ stration is often effective.
  • Combination Compositions The subject invention also includes pharmaceutical composi ⁇ tions comprising one or..more vanilloid. compounds, one or more phosphonate antiviral compounds, and a pharamaceutically-accept- able carrier.
  • Preferred combination compositions of the subject invention comprise one vanilloid compound, one phosphonate antiviral compound and a carrier formulated for topical, peroral or parenteral administration.
  • Preferred combination compositions of the subject invention are for topical administration.
  • administered topically means placing the compounds, whether vanilloid, phosphonate antiviral, or combina- tions thereof, in contact with the skin, mucous membrane, or body cavity. It thus includes epidermal, intraoral, intravaginal, intraanal, and intraaural administration. Preferred methods of the subject invention involve topical administration of one or both of the active compounds. Suitable pharmaceutically-accept ⁇ able carriers for topical application include those suited for use in lotions, creams, solutions, gels, ointments, tapes and the like.
  • Suitable carriers for topical administration preferably remain in place on the skin as a continuous film and resist being washed off easily by perspiration or by immersion in water.
  • the carrier is either organic in nature or an aqueous emulsion and capable of having the vanilloid compound dispersed or dissolved therein.
  • the carrier may include pharmaceutically- acceptable emollients, skin penetration enhancers, coloring agents, fragrances, emulsifiers, thickening agents, and solvents. A more detailed description of such forms follows: Suitable carriers for topical administration preferably remain in place on the skin as a continuous film and resist being washed off easily by perspiration or by immersion in water.
  • the carrier is either organic in nature or an aqueous emulsion and capable of having the vanilloid compound dispersed or dissolved therein.
  • the carrier may include pharmaceutically- acceptable emollients, skin penetration enhancers, coloring agents, fragrances, emulsifiers, thickening agents, and solvents.
  • emollients preferably from about 0.001% to about 5%, more ⁇ preferably from about 0.1% to about 1%) of a vanilloid compound; from 1% to 50%, preferably from 3% to 15%, of an emollient; the balance being water, a C 2 or C 3 alcohol, or a mixture of water and the alcohol.
  • emollients are known.
  • emollients are as fol- 1ows: a. Hydrocarbon oils and waxes. Examples are mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, and perhydrosqualene. b. Silicone oils, such as dimethylpolysiloxanes, methyl- phenylpolysiloxanes, water-soluble and alcohol-soluble silcone- glycol copolymers. c. Triglyceride fats and oils such as those derived from vegetable, animal and marine sources. Examples include castor oil, safflower oil, cotton seed oil, corn oil, olive oil, cod liver oil, almond oil, avocado oil, palm oil, sesame oil, and soybean oil .
  • Acetoglyceride esters such as acetylated monoglycer- ides.
  • Ethoxylated glycerides such as ethoxylated glyceryl monostearate.
  • Examples include hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, isopropyl yristate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate, diisopropyl adipate, diisohexyl adipate, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate, yristyl lactate, and cetyl lactate.
  • Examples thereof include oleyl myristate, oleyl stearate, and oleyl oleate.
  • Fatty acids having 9 to 22 carbon atoms include pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachi- donic, behenic, and erucic acids.
  • i Fatty alcohols having 10 to 22 carbon atoms.
  • Lauryl, myristyl, cetyl, hexadecyl , stearyl, isostearyl, hydroxystearyl , oleyl, ricinoleyl, behenyl, erucyl, and 2-octyl dodecyl alcohols are examples of satisfactory fatty alcohols.
  • Ether-esters such as fatty acid esters of ethoxylated fatty alcohols.
  • Lanolin and derivatives Lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated lanolin, acetylated lanolin alcohols, lanolin alcohols linoleate, lanolin alcohols ricinoleate, acetate of lanolin alcohols ricinoleate, 5 acetate of ethoxylated alcohols-esters, hydrogenolysis of lano ⁇ lin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semisolid lanolin absorption bases are illustrative of emollients derived from lanolin.
  • polyal ylene glycols and derivatives polyal ylene glycols and derivatives, hexylene glycol (2-methyl-2,4-pentanediol), 1,3-butylene glycol, 1,2,6- hexanetriol, ethohexadiol USP (2-ethyl-l,3-hexanediol) C 15 -C 18
  • Wax esters such as beeswax, spermaceti, myristyl myrist- ir
  • Beeswax derivatives e.g., polyoxyethylene sorbitol beeswax. These are reaction products of beeswax with ethoxylated sorbitol of varying ethylene oxide content, forming a mixture of ether-esters.
  • Vegetable waxes including carnauba and candelilla waxes, r. Phospholipids such as lecithin and derivatives.
  • Sterols. Cholesterol, cholesterol fatty acid esters are examples thereof.
  • Amides such as fatty acid amides, ethoxylated fatty acid amides, solid fatty acid alkanolamides.
  • the lotions further preferably comprise from 1% to 10%, more preferably from 2% to 5%, of an emulsifier.
  • the emulsifiers can be nonionic, anionic or cationic. Examples of satisfactory nonionic emulsifiers include fatty alcohols having 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbon atoms con ⁇ densed with 2 to 20 moles of ethylene oxide or propylene oxide, alkyl phenols with 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono- and di-fat ⁇ ty acid esters of ethylene oxide, mono- and di-fatty acid esters of ethylene glycol wherein the fatty acid moiety contains from 10 to 20 carbon atoms, diethylene glycol, polyethylene glycols of molecular weight 200 to 6000, propylene glycols of molecular weight 200 to 3000, glycerol, sorbitol, sorbitan, polyoxyethylene sorbi
  • Suitable anionic emulsifiers include the fatty acid soaps, e.g. sodium, potassium and triethanolamine soaps, wherein the fatty acid moiety contains from 10 to 20 carbon atoms.
  • Other suitable anionic emulsifiers include the alkali metal, ammonium or substi ⁇ tuted ammonium alkyl sulfates, alkyl arylsulfonates, an alkyl ethoxy ether sulfonates having 10 to 30 carbon atoms in the alkyl moiety.
  • the alkyl ethoxy ether sulfonates contain from 1 to 50 ethylene oxide units.
  • Satisfactory cationic emulsifiers are the quaternary ammonium, morpholiniu and pyridinium compounds. Certain of the emollients described in preceding paragraphs also have emulsifying properties. When a lotion is formulated con ⁇ taining such an emollient, an additional emulsifier is not needed, though it can be included in the composition.
  • the balance of the lotion is water or a C 2 or C 3 alcohol, or a mixture of water and the alcohol.
  • the lotions are formulated by simply admixing all of the components together.
  • the compound of the present invention is dissolved in the mix ⁇ ture.
  • Conventional optional components can be included.
  • One such additive is a thickening agent at a level from 1% to 10% of the composition.
  • suitable thickening agents include: cross-linked carboxypolymethylene polymers, ethyl cellulose, polyethylene glycols, gum tragacanth, gum kharaya, xanthan gums and bentonite, hydroxyethyl cellulose, and hydroxypropyl cellu ⁇ lose.
  • the creams comprise an effective amount (preferably from about 0.001% to about 5%, more preferably from about 0.1% to about 1%) of a vanilloid compound; from 5% to 50%, preferably from 10% to 25%, of an emollient; the balance being water.
  • the emollients above described can also be used in the cream composi ⁇ tions.
  • the cream form contains a suitable emulsifier, as previously described. When an emulsifier is included, it is in the composition at a level from 3% to 50%, preferably from 5% to 20%. 3. Solutions
  • the solution form comprises an effective amount (preferably from about 0.001% to about 5%, more preferably from about 0.1% to about 1%) of a vanilloid compound; the balance being water and/or a suitable organic solvent.
  • suitable organic materials useful as the solvent or a part of a solvent system are as follows: propyl ⁇ ene glycol, polyethylene glycol (M.W. 200-600), polypropylene glycol (M.W. 425-2025), glycerine, sorbitol esters, 1,2,6-hexa- netriol, ethanol, isopropanol, diethyl tartrate, butanediol, and mixtures thereof.
  • solvent systems can also contain water.
  • compositions in solution form can be applied to the skin as is, or else can be formulated into an aerosol and applied to the skin as a spray-on.
  • the aerosol compositions further com ⁇ prise from 25% to 80%, preferably from 30% to 50%, of a suitable propellant.
  • propellants are the chlorinated, fluorinated and chlorofluorinated lower molecular weight hydro ⁇ carbons. Nitrous oxide, carbon dioxide, butane, and propane are also used as propellant gases. These propel!ants are used at a level sufficient to expel the contents of the container.
  • Gel compositions can be formulated by simply admixing a suitable thickening agent to the previously described solution compositions.
  • suitable thickening agents have been previously described with respect to the lotions.
  • the gelled compositions comprise an effective amount (pref ⁇ erably from about 0.001% to about 5%, more preferably from about 0.1% to about 1%) of a vanilloid compound; from 5% to 75%, preferably from 10% to 50%, of an organic solvent as previously described; from 0.5% to 20%, preferably from 1% to 10% of the thickening agent; the balance being water.
  • compositions of solid forms have use as stick-type composi ⁇ tions intended for application to the lips or other parts of the body.
  • Such compositions comprise an effective amount (preferably from about 0.001% to about 5%, more preferably from about 0.1% to about 1%) of a vanilloid compound, and from 50% to 98%, prefer- ably from 60% to 90%, of the previously described emollients.
  • This composition can further comprise from 1% to 20%, preferably from 5% to 15%, of a suitable thickening agent, and optionally emulsifiers and water. Thickening agents previously described with respect to lotions are suitable herein.
  • Compositions used in the subject invention can be adminis ⁇ tered in a wide variety of vehicles, especially in the genital region.
  • infections in the genital area can be treated using vaginal, anal or uretheral suppositories; vaginal pessaries; vaginal or rectal tablets or inserts; catamenial and non-catamenial tampons; ointments; enemas; cones; emulsions; and douches.
  • Additives commonly found in topical compositions such as preservatives, e.g., methyl and ethyl-paraben, dyes and perfume can be included in any of the previously described topical compo- sitions.
  • Topical compositions of the subject invention preferably comprise from about 0.1% to about 5%, more preferably from about 0.2% to about 2%, more preferably still from about 0.5% to about 1% of a vanilloid compound, and from 0% to about 10%, more preferably from about 0.2% to about 5%, more preferably still from about 0.5% to about 2% of a phosphonate antiviral compound.
  • Topical compositions are formulated according to Examples 1-14 by blending the listed ingredients according to conventional processes for making such compositions.
  • Example 16 100 100 genital Herpes simplex infection, one gram of the topical compo- sition of any of Examples 1, 3, 5, 7, 9, 11 or 13 is applied to the skin of the genital region for five consecutive days at the beginning of each month. The person also ingests a 500 mg capsule of acyclovir twice daily. The person remains free of the recurrence of Herpes simplex lesions.
  • Example 16 100 100 genital Herpes simplex infection, one gram of the topical compo- sition of any of Examples 1, 3, 5, 7, 9, 11 or 13 is applied to the skin of the genital region for five consecutive days at the beginning of each month. The person also ingests a 500 mg capsule of acyclovir twice daily. The person remains free of the recurrence of Herpes simplex lesions.
  • Example 16 100 100 genital Herpes simplex infection, one gram of the topical compo- sition of any of Examples 1, 3, 5, 7, 9, 11 or 13 is applied to the skin of the
  • Example 17 After a lesion episode has subsided in a person having an oral Hero simplex infection, one-half gram of the topical composition of any of Examples 1, 3, 5, 7, 9, 11 or 13 is applied to the skin of the oral region once a week. The person also ingests one 500 mg capsule of acyclovir daily. The person remains free of the recurrence of Hero simplex lesions.
  • Example 18 In addition to the post lesion episode dosing of Examples 15-17, the same dosage of each composition is applied or ingested during the lesion episode, resulting in a lesion episode of less severity and shorter duration.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention se rapporte à des procédés curatifs ou préventifs de lésions chez les humains, provoquées par des infections par Herpès comprenant l'administration au patient d'une combinaison d'un composé vanilloïde et d'un composé phosphonate antiviral.
PCT/US1991/008678 1990-11-27 1991-11-25 Combinaisons de composes vanilloides et de composes phosphonates antiviraux pour le traitement d'infections par herpes WO1992009285A1 (fr)

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US61874390A 1990-11-27 1990-11-27
US618,743 1990-11-27

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016915A1 (fr) 2003-08-14 2005-02-24 Glaxo Group Limited Derives carboxamides de piperidine/cyclohexane destines a etre utilises comme modulateurs du recepteur vanilloide
US7482488B2 (en) 2002-08-29 2009-01-27 Temple University - Of The Commonwealth System Of Higher Education Aryl and heteroaryl propene amides, derivatives thereof and therapeutic uses thereof
EP2033953A1 (fr) 2002-02-15 2009-03-11 Glaxo Group Limited Modulateurs des récepteurs vanilloides
EP2036902A2 (fr) 2001-09-13 2009-03-18 Glaxo Group Limited Dérivés de l'urée actifs comme antagonistes des récepteurs vanilloides
US7576099B2 (en) 2005-02-28 2009-08-18 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
US7943166B2 (en) 2003-04-10 2011-05-17 Neurogesx, Inc. Methods and compositions for administration of TRPV1 agonists
US8088826B2 (en) 2002-12-06 2012-01-03 Xention Limited Tetrahydro-naphthalene derivatives
WO2012045729A1 (fr) 2010-10-05 2012-04-12 Glaxo Group Limited Dérivés d'imidazo[1,2-a]pyridine et de pyrazolo[1,5-a]pyridine en tant qu'antagonistes du trpv1
WO2012072512A1 (fr) 2010-11-29 2012-06-07 Glaxo Group Limited Carboxamides de n-cyclo-butylimidazopyridine ou de n-cyclo-pyrazolopyridine comme antagonistes de trpv1
WO2012139963A1 (fr) 2011-04-11 2012-10-18 Glaxo Group Limited N-cyclobutyl-imidazopyridine-méthylamine à titre d'antagoniste des trpv1

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1983002723A1 (fr) * 1982-02-12 1983-08-18 Smith, Kendall, O. Compositions anti-virales
EP0347000A2 (fr) * 1988-06-17 1989-12-20 The Procter & Gamble Company Utilisation de dérivés de la vanilline pour la fabrication d'un médicament utile dans le traitement de l'infection de l'herpes simplex

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1983002723A1 (fr) * 1982-02-12 1983-08-18 Smith, Kendall, O. Compositions anti-virales
EP0347000A2 (fr) * 1988-06-17 1989-12-20 The Procter & Gamble Company Utilisation de dérivés de la vanilline pour la fabrication d'un médicament utile dans le traitement de l'infection de l'herpes simplex

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8063078B2 (en) 2001-09-13 2011-11-22 Glaxosmithkline Llc Urea-compounds active as vanilloid receptor antagonists for the treatment of pain
EP2036902A2 (fr) 2001-09-13 2009-03-18 Glaxo Group Limited Dérivés de l'urée actifs comme antagonistes des récepteurs vanilloides
EP2033953A1 (fr) 2002-02-15 2009-03-11 Glaxo Group Limited Modulateurs des récepteurs vanilloides
US7482488B2 (en) 2002-08-29 2009-01-27 Temple University - Of The Commonwealth System Of Higher Education Aryl and heteroaryl propene amides, derivatives thereof and therapeutic uses thereof
US8088826B2 (en) 2002-12-06 2012-01-03 Xention Limited Tetrahydro-naphthalene derivatives
US8173841B2 (en) 2002-12-06 2012-05-08 Xention Limited Tetrahydro-naphthalene derivatives
US7943166B2 (en) 2003-04-10 2011-05-17 Neurogesx, Inc. Methods and compositions for administration of TRPV1 agonists
US8734770B2 (en) 2003-04-10 2014-05-27 Acorda Therapeutics, Inc. Methods and compositions for administration of TRPV1 agonists
US10653647B2 (en) 2003-04-10 2020-05-19 Grt Us Holding, Inc. Methods and compositions for administration of TRPV1 agonists
US9750707B2 (en) 2003-04-10 2017-09-05 Acorda Therapeutics, Inc. Methods and compositions for administration of TRPV1 agonists
US8263093B2 (en) 2003-04-10 2012-09-11 Neurogesx, Inc. Methods and compositions for administration of TRPV1 agonists
US8273390B2 (en) 2003-04-10 2012-09-25 Neurogesx, Inc. Methods and compositions for administration of TRPV1 agonists
WO2005016915A1 (fr) 2003-08-14 2005-02-24 Glaxo Group Limited Derives carboxamides de piperidine/cyclohexane destines a etre utilises comme modulateurs du recepteur vanilloide
US7576099B2 (en) 2005-02-28 2009-08-18 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
WO2012045729A1 (fr) 2010-10-05 2012-04-12 Glaxo Group Limited Dérivés d'imidazo[1,2-a]pyridine et de pyrazolo[1,5-a]pyridine en tant qu'antagonistes du trpv1
WO2012072512A1 (fr) 2010-11-29 2012-06-07 Glaxo Group Limited Carboxamides de n-cyclo-butylimidazopyridine ou de n-cyclo-pyrazolopyridine comme antagonistes de trpv1
WO2012139963A1 (fr) 2011-04-11 2012-10-18 Glaxo Group Limited N-cyclobutyl-imidazopyridine-méthylamine à titre d'antagoniste des trpv1

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