US20040224984A1

US20040224984A1 - Methods of treating inflammations and infections with pyridinium salts

Info

Publication number: US20040224984A1
Application number: US10/792,465
Authority: US
Inventors: Jeffrey Selph; John Partridge; John Reinhard
Original assignee: Mycosol Inc
Current assignee: Mycosol Inc
Priority date: 2003-03-03
Filing date: 2004-03-03
Publication date: 2004-11-11
Also published as: ATE402924T1; US20040235898A1; CA2517461A1; BRPI0407991A; JP2007525441A; MXPA05009449A; EP1601652A2; AU2004218452A1; WO2004078136A2; US20100267716A1; WO2004078136A3; JP4742028B2; US7547444B1; US7820696B2; EP1601652B1; DE602004015425D1; US7220761B2; US8124626B2; US20070213299A1; KR20050108373A

Abstract

Compounds of pyridinium salts and methods of their use in medicine, particularly in the prophylaxis and treatment of inflammatory conditions, infectious conditions, as well as immune disorders are disclosed. The present invention also relates to methods of controlling fungi and/or bacteria.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 60/480,995, filed on Jun. 23, 2003, U.S. Provisional Application No. 60/524,775, filed on Nov. 25, 2003, U.S. Provisional Application No. 60/525,075, filed on Nov. 25, 2003, U.S. Provisional Application No. 60/524,784, filed on Nov. 25, 2003, and U.S. Provisional Application No. 60/450,599, filed on Mar. 3, 2003, the disclosures of which are incorporated herein by reference in their entireties.[0001]

FIELD OF THE INVENTION

The present invention generally relates to compounds of pyridinium salts and methods of their use in medicine, particularly in the prophylaxis and treatment of inflammatory conditions, allergic conditions, infectious conditions, as well as immune disorders.

BACKGROUND OF THE INVENTION

The present invention relates to pyridinium derivatives, processes for their preparation, pharmaceutical formulations comprising them, and their use in medicine, particularly in the prophylaxis and treatment of inflammatory conditions, allergic conditions, infectious conditions, as well as immune disorders.

Stilbazium iodide is a known anthelmintic which is reported to be effective against roundworms, threadworms, and whipworms. U.S. Pat. No. 3,075,975 and U.S. Pat. No. 3,085,935 recite methods of eradicating infestations of parasitic nematodes inhabiting the intestinal tract.

The adhesion of circulating leukocytes to the vascular endothelium is a crucial event in the pathogenesis of inflammatory responses. Inflammatory, allergic, infectious and immune mediators can stimulate the adhesion process by increasing the adhesiveness of the leukocyte or the endothelial cell through the activation, up-regulation, or induction of various adhesion molecules on the cell surface.

Anti-inflammatory drugs currently available have limited efficacy, often with side effects. Monoclonal antibodies used experimentally for anti-adhesion therapies have theoretical disadvantages for treatment of chronic diseases. Therefore, the discovery and development of small molecules which specifically block or inhibit the adhesive interactions of leukocytes and the endothelium is an attractive area of therapeutic intervention.

SUMMARY OF THE PRESENT INVENTION

The present invention relates to methods and compositions comprising stilbazium. One aspect of the present invention is a composition comprising formula (I)

or a solvate thereof wherein said compound is in the E, E double bond configurations. The amino moieties may be in either the ortho, meta or para postion. X ⁻ may be an anionic salt, R₁, R₂, R₃, or R₄are independently selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), or wherein R₁and R₂or R₃and R₄taken together with the nitrogen atom to which they are attached form pyrrolidino or piperidino rings; and R₅is selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), alkynes, n-propyl, i-propyl, n-butyl, i-butyl substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties. The N—R moieties may be in the ortho, meta or para position on the aryl or benzyl moieties.

The present invention also relate to compositions comprising formula (I)

or a solvate thereof. The amino moieties may be in either the ortho, meta or para postion. X ⁻ may be an anionic salt, R₁, R₂, R₃, or R₄are independently selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), or wherein R₁and R₂or R₃and R₄taken together with the nitrogen atom to which they are attached form pyrrolidino or piperidino rings; and R₅is selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), alkynes, n-propyl, i-propyl, n-butyl, i-butyl, substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties. The substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties may include, but are not limited to lower alkyl, aryl, benzyl, acyl, amido, amino, alkoxy, carboxy, carboxy ester, alcohol, nitro, trifluoroalkoxy, trifluoroalkyl and halo.

The present invention also relates to methods of treating inflammations, infections and immune disorders comprising administering a composition comprising any of the above formulas or a solvate thereof. The present invention also relates to methods of controlling fungi and/or bacteria comprising administering a composition comprising any of the above formulas or a solvate thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1G show various compounds including a methyl on a pyridine ring at the nitrogen position. [0012]
FIGS. 2A-2G depict various compounds including a trifluoroethyl attached to the pyridine ring at the nitrogen position. [0013]
FIGS. 3A-3F illustrate compounds including an isobutyl on the pyridine ring at the nitrogen position. [0014]
FIGS. 4A-4G depict various compounds with an ethyl attached to the pyridine ring at the nitrogen position.[0015]

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The foregoing and other aspects of the present invention will now be described in more detail with respect to other embodiments described herein. It should be appreciated that the invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. [0016]
The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the invention and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. [0017]
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. [0018]
All publications, patent applications, patents and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and/or paragraph in which the reference is presented. [0019]
The present invention relates to pyridinium derivatives, processes for their preparation, methods of their use and compositions comprising such derivatives. Stilbazium iodide is a known anthelmintic which is reported to be effective against roundworms, threadworms, and whipworms. U.S. Pat. No. 3,075,975 and U.S. Pat. No. 3,085,935 recite methods of eradicating infestations of parasitic nematodes inhabiting the intestinal tract. It was both surprising and unexpected to find that this compound may be used to treat inflammations, infections, immune disorders, fungi and/or bacteria. [0020]
The present invention comprises a compound comprising formula (I) [0021]
or a solvate thereof, wherein X[0022] ⁻ is an anionic salt, wherein R₁, R₂, R₃, or R₄are independently selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), or wherein when R₁and R₂or when R₃and R₄are taken together with the nitrogen atom to which they are attached, they form pyrrolidino or piperidino rings. X⁻ can be selected from the group including fluoride, chloride, bromide, iodide halide, mesylate, tosylate, napthylate, nosylate, para-aminobenzoate, lauryl sulfate, 2,4-dihydroxy benzophenone, 2-(2-hydroxy-5′-methylphenyl) benzotriazole, benzenesulfonate, besylate, ethyl 2-cyano-3,3-diphenyl acrylate and 5-butyl phenyl salicylate. R₅can be selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), alkynes, n-propyl, i-propyl, n-butyl, i-butyl, substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties. R₅may also be an organometallic compound such as organotin, organosilicon, or organogermanium. Additionally, R₅may be (CH₂)_n-MR₆, wherein n is a number from 1 to 6, M is an organometallic compound such as tin, silicon, or germanium, and wherein R₆is a selected from the group consisting of propyl, butyl, or any alkyl compound. The present compound is more commonly known as stibazium. One of the embodiments of formula I is 2,6,-bis (p-pyrrolidinostyryl) pyridine methiodide.
Alternatively, the NR[0023] ₁R₂moiety may be in various positions as evidenced in the compounds below.
Formula II illustrates the NR[0024] ₁R₂moiety in one meta position and NR₃R₄is in one para position.
Formula III illustrates the NR[0025] ₁R_2andNR₃R₄moieties in both para positions.
may be an anionic salt, R[0026] ₁, R₂, R₃, or R₄are independently selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), or wherein when R₁and R₂or when R₃and R₄are taken together with the nitrogen atom to which they are attached, they form pyrrolidino or piperidino rings. R₅is selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), alkynes, n-propyl, i-propyl, n-butyl, i-butyl, substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties.
Additionally, the present invention may include compounds of the following general formula IV: [0027]
or a solvate thereof, wherein n is a number from 1 to 5, wherein Z can be present at multiple positions on the phenyl ring and is selected from the group consisting of C, N, O, S and halogen, wherein X[0028] ⁻ is an anionic salt, wherein R₁, R₂, R₃, or R₄are independently selected from the group consisting of nothing, hydrogen, methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), nitriles, benzenes, pyridines, benzothiophenes, trifluoroalkyls, difluoroalkyls, substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties, or wherein when R₁and R₂or when R₃and R₄are taken together with the nitrogen atom to which they are attached, they form pyrrolidino or piperidino rings. X⁻ can be selected from the group including fluoride, chloride, bromide, iodide halide, mesylate, tosylate, napthylate, nosylate, para-aminobenzoate, benzenesulfonate, besylate, lauryl sulfate, 2,4-dihydroxy benzophenone, 2-(2-hydroxy-5′-methylphenyl) benzotriazole, ethyl 2-cyano-3,3-diphenyl acrylate and 5-butyl phenyl salicylate. R₅is selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), alkynes, n-propyl, i-propyl, n-butyl, i-butyl, substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties. R₅may also be an organometallic compound such as organotin, organosilicon, or organogermanium. Additionally, R₅may be (CH₂)_n-MR₆, wherein n is a number from 1 to 6, M is an organometallic compound such as tin, silicon, or germanium, and wherein R₆is a selected from the group consisting of propyl, butyl, or any alkyl compound. FIGS. 1-4 illustrate various combinations of the compounds that may be formed according to the present invention. These compounds can be in the E, E configuration and can be used for any of the methods or uses disclosed in the present application.
The compounds of the present invention are capable of existing as geometric isomers. All such isomers, individually and as mixtures, are included within the scope of the present invention for their industrial and agricultural uses. The present invention is the first time the compound of formula I has been characterized as an E,E isomer. The E,E isomer is the preferred configuration of the invention, and both the cisoid and [0029] transoid 2,6-conformations may be possible. Furthermore, it was both surprising and unexpected to find that this compound may be used to control fungi and/or bacteria in both industrial and agricultural settings.
X[0030] ⁻ may be an anionic salt, R₁may be selected from the group consisting of methyl, ethyl, alkyl, dimethyl, diethyl, dialkyl, pyrrolidino and piperidino, and R₂may be selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties. Again, the NR moieties may be in any ortho, meta or parra position for the transoid or cisoid conformation.
Some of the embodiments of the present invention include 1-ethyl-(E-E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium chloride, also known as 1-ethyl-(E-E)-2,6-bis[p-(1-pyrrolidinostyryl]pyridinium chloride, and 1-methyl-(E-E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium chloride, also known as 1-methyl-(E-E)-2,6-bis[p-(1-pyrrolidinostyryl]pyridinium chloride. [0031]
Other embodiments include, but are not limited to a composition comprising: [0032]
or a solvate thereof and wherein the NR[0033] ₁R₂and NR₃R₄moieties are in the ortho, meta or para positions; wherein X⁻ is an anionic salt; wherein R₁, R₂, R₃, or R₄are independently selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), or wherein R₁and R₂or R₃and R₄taken together with the nitrogen atom to which they are attached form pyrrolidino or piperidino rings; and wherein R₅is selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), alkynes, n-propyl, i-propyl, n-butyl, i-butyl, substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties. X⁻ can be selected from the group including fluoride, chloride, bromide, iodide halide, mesylate, tosylate, napthylate, nosylate, para-aminobenzoate, lauryl sulfate, 2,4-dihydroxy benzophenone, 2-(2-hydroxy-5′-methylphenyl) benzotriazole, benzenesulfonate, besylate, ethyl 2-cyano-3,3-diphenyl acrylate and 5-butyl phenyl salicylate.
These compounds have been found to inhibit one or more of the enzymes 5-lipoxygenase, cyclooxygenase, and lyso-PAF: acetyl-CoA acetyltransferase. Additionally, this series of pyridinium derivative were surprisingly found to inhibit the expression of adhesion molecules on human umbilical endothelial cell monolayers at low concentrations and are therefore indicative of being able to treat inflammations, allergic conditions, infections and immune disorders. [0034]
Examples of inflammatory conditions, allergic conditions, infectious conditions or immune disorders are those of the lungs, throat, mouth, joints, eyes, nose, bowel, and skin; particularly those associated with the infiltration of leucocytes into inflamed tissue and/or release of allergic-induced leukotrienes. Conditions of the lung include asthma, adult respiratory distress syndrome, bronchitis and cystic fibrosis (which may additionally or alternatively involve the bowel or other tissues. Conditions of the thoat include laryngitis and orophoryngeal mucositis. Conditions of the mouth include gingivitis and periodontitis. Conditions of the joint include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions. Inflammatory eye conditions include uveitis (including iritis) and conjunctivitis. Inflammatory nose conditions include rhinitis and chronic rhinosinusitis. Inflammatory bowel conditions include Crohn's disease, ulcerative colitis and distal proctitis. Skin diseases include those associated with cell proliferation, such as psoriasis, eczema and dermatitis, and allergic-induced pruritis, such as prurigo. Other inflammatory conditions and immune disorders include tissue necrosis in chronic inflammation. [0035]
Additionally, the present invention provides a method for the prophylaxis or treatment of an inflammatory condition, allergic condition or immune disorder in a mammal, such as a human, which comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable solvate thereof. [0036]
In another embodiment of the present invention, there is also provided a compound of formula (I), or a pharmaceutically acceptable solvate thereof for use in medical therapy; particularly, for use in the prophylaxis or treatment of an inflammatory condition, allergic condition or immune disorder in a mammal, such as a human. [0037]
Additionally, the compound of formula I was found to have anti-infective activity against certain bacteria, yeast and fungi. Such activity was un-anticipated and suggests utility for the treatment of topical bacterial, yeast and fungal infections with the compound of formula I. Such infections include [0038] Staphylococcus aureus and Streptococcus strains, e.g. pyogenes as well as the yeast strains Candida albicans, Candida tropicalis and Saccharomyces cervisciae and also include the following fungal strains: Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Rhizopus arrihizus, Fusarium solani, Microsporidium canis, Microsporidium gypseum, Trichophyton equinium, Trichophyton mentagrophyt, Trichophyton rubrum and Epidermophyton floccsum.
The amount of a compound of formula (I) or pharmaceutically acceptable solvate thereof, which is required to achieve the desired biological effect will depend on a number of factors such as the use for which it is intended, the means of administration, and the recipient. A typical daily dose for the treatment of septic shock, for instance, may be expected to lie in the range of 0.005 mg/kg-100 mg/kg, preferably 0.05-50 mg/kg, and most preferably 0.5-20 mg/kg. This dose may be administered as a single unit dose or as several separate unit doses or as a continuous infusion. An intravenous dose may be expected to lie in the range of 0.0025 mg/kg to 50 mg/kg and would typically be administered as an infusion. Similar dosages would be applicable for the treatment of other disease states. For administration to the lungs of a subject by aerosol an amount of the compound should be used sufficient to achieve concentrations on the airway surface liquid of the subject of about 2 to 1000 mu mol. [0039]
Thus, in another aspect of the present invention, there are provided pharmaceutical compositions comprising, as active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutical carrier or recipient. These pharmaceutical compositions may be used in the prophylaxis and treatment of inflammatory conditions, allergic condition, infectious conditions, and immune disorders. The carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or liquid and is preferably formulated as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredients. If desired other physiologically active ingredients—may also be incorporated in the pharmaceutical compositions of the invention. [0040]
Possible formulations include those suitable for oral, buccal, rectal, topical including dermal, intranasal and inhalation administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the condition being treated and on the nature of the active compound, but where possible, topical administration would be preferred for treatment of topical dermatitis or pruritis, for instance. For the treatment of a condition such as asthma, however, inhalation, would be the preferred route of administration. [0041]
Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. [0042]
Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically a flavored base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose acacia. [0043]
Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient in one or more solid carriers forming the suppository base, for example, cocoa butter. [0044]
Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, DMSO and combinations thereof. The active ingredient is typically present in such formulations at a concentration of from 0.1 to 15% w/w. [0045]
Formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound with liquids or finely divided solid carriers or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape. [0046]
For example a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by molding an intimate mixture of powdered active ingredient and inert liquid diluent. [0047]
Aqueous solutions are typically prepared by dissolving the active ingredient in saline to which cyclodextrin has been added. [0048]
Suitable formulations for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulisers, or insufflators. [0049]
For pulmonary administration via the mouth, the particle size of the powder or droplets is typically in the range 0.5-10 μm, preferably 1-5 μm, to ensure delivery into the bronchial tree. For nasal administration, a particle size in the range 10-500 μm is preferred to ensure retention in the nasal cavity. [0050]
Metered dose inhalers are pressurized aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquefied propellant. During use, these devices discharge the formulation through a valve adapted to deliver a metered volume, typically from 10 to 150 μl, to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more co-solvents, for example, ethanol as well as fatty acid surfactants, such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavouring agents. [0051]
Nebulisers are commercially available devices that transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas typically air or oxygen, through a narrow venturi orifice, or by means of ultrasonic agitation. Suitable formulations for use in nebulisers consist of the active ingredient in a liquid carrier and comprising up to 40% w/w of the formulation, preferably less than 20% w/w. The carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if the formulation is not prepared sterile, for example, methyl hydroxy-benzoate, anti-oxidants, flavoring agents, volatile oils, buffering agents and surfactants. [0052]
Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff. In the insufflator, the powder is contained in capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically comprises from 0.1 to 100 w/w of the formulation. [0053]
Therefore, according to a further aspect of the present invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for the prophylaxis or treatment of an inflammatory condition, allergic condition or immune disorder. [0054]
Further, the present invention can provide microcapsules having an ultraviolet absorber and as required an organic solvent enclosed therein, which have capsule wall film of synthetic resin and mean particle size of 0.1 to 3 μm. These absorber may block or inhibit ultraviolet rays. [0055]
The following are examples of ultraviolet absorbers that may be used in the present invention. [0056]
Phenyl salicylate, p-tert-butylphenyl salicylate, p-octylphenyl salicylate and like salicylic acid type ultraviolet absorbers; 2,4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-octyloxybenzophenone, 2-hydroxy-4-dodecyloxybenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone, 2,2,′-dihydroxy-4,4′-dimethoxybenzophenone, 2-hydroxy-4-methoxy-5-sulfobenzophenone and like benzophenone type ultraviolet absorbers; 2-ethylhexyl 2-cyano-3,3-diphenyl-acrylate, ethyl 2-cyano-3,3-diphenylacrylate and like cyanoacrylate type ultraviolet absorbers; bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate, bis(2,2,6,6-tetramethyl-4-piperidyl) succinate, bis(1,2,2,6,6-pentamethyl-4-piperidyl) 2-(3,5-di-tert-butyl-4-hydroxybenzyl)-2-n-butyl malonate and like hindered amine type ultraviolet absorbers; 2-(2′-hydroxyphenyl)benzotriazole, 2-(2′-hydroxy-5′-methylphenyl)benzotriazole, 2-(2′-hydroxy-5-tert-butylphenyl)benzotriazole, 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)benzotriazole, 2-(2′-hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazole, 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)-5-chlorobenzotriazole, 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)-5-tert-butylbenzotriazole, 2-(2′-hydroxy-3′,5′-di-tert-amylphenyl)benzotriazole, 2-(2′-hydroxy-3′,5′-di-tert-amylphenyl)-5-tert-amylbenzotriazole, 2-(2′-hydroxy-3′,5′-di-tert-amylphenyl)-5-methoxybenzotriazole, 2-[2′-hydroxy-3′-(3″,4″,5″,6″1-tetrahydrophthalimido-methyl)-5′-methylpheny]benzotriazole, 2-(2′-hydroxy-5′-tert-octylphenyl)benzotriazole, 2-(2′-hydroxy-3′-sec-butyl-5′-tert-butylphenyl)benzotriazole, 2-(2′-hydroxy-3′-tert-amyl-5′-phenoxyphenyl)-5-methylbenzotriazole, 2-(2′-hydroxy-5′-n-dodecylphenyl)benzotriazole, 2-(2′-hydroxy-5′-sec-octyloxyphenyl)-5-phenylbenzotriazole, 2-(2′-hydroxy-3′-tert-amyl-5′-phenylphenyl)-5-methoxybenzotriazole, 2-[2′-hydroxy-3′,5′-bis(dimethylbenzyl)phenyl]benzotriazole and like benzotriazole type ultraviolet absorbers which are solid at ordinary temperature; 2-(2′-Hydroxy-3′-dodecyl-5′-methylphenyl)-benzotriazole, 2-(2′-hydroxy-3′-undecyl-5′-methylphenyl)-benzotriazole, 2-(2′-hydroxy-3′-tridecyl-5′-methylphenyl)-benzotriazole, 2-(2′-hydroxy-3′-tetradecyl-5′-methylphenyl)-benzotriazole, 2-(2′-hydroxy-3′-pentadecyl-5′-methylphenyl)-benzotriazole, 2-(2′-hydroxy-3′-hexadecyl-5′-methylphenyl)-benzotriazole, 2-[2′-hydroxy-4′-(2″-ethylhexyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(2″-ethylheptyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(2″-ethyloctyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(2″-propyloctyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(2″-propylheptyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(2″-propylhexyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(1″-ethylhexyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(1″-ethylheptyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(1″-ethyloctyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(1″-propyloctyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(1″-propylheptyl)oxyphenyl]-benzotriazole, 2-[2′-hydroxy-4′-(1″-propylhexyl)oxyphenyl]-benzotriazole, 2-(2′-hydroxy-3′-sec-butyl-5′-tert-butylphenyl-5-n-butylbenzotriazole, 2-(2′-hydroxy-3′-sec-butyl-5′-tert-butylphenyl)-5-tert-pentyl-benzotriazole, 2-(2′-hydroxy-3′-sec-butyl-5′-tert-butylphenyl)-5-n-pentyl-benzotriazole, 2-(2′-hydroxy-3′-sec-butyl-5′-tert-pentylphenyl)-5-tert-butylbenzotriazole, 2-(2′-hydroxy-3′-sec-butyl-5′-tert-pentylphenyl)-5-n-butylbenzotriazole, 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)-5-sec-butylbenzotriazole, 2-(2′-hydroxy-3′,5′-di-tert-pentylphenyl)-5-sec-butylbenzotriazole, 2-(2′-hydroxy-3′-tert-butyl-5′-tert-pentylphenyl)-5-sec-butylbenzotriazole, 2-(2′-hydroxy-3′,5′-di-sec-butylphenyl)-5-chlorobenzotriazole, 2-(2′-hydroxy-3′,5′-di-sec-butylphenyl)-5-methoxybenzotriazole, 2-(2′-hydroxy-3′,5′-di-sec-butylphenyl)-5-tert-butylbenzotriazole, 2-(2′-hydroxy-3′,5′-di-sec-butylphenyl)-5-n-butylbenzotriazole, octyl 5-tert-butyl-3-(5-chloro-2H-benzotriazole-2-yl)-4-hydroxybenzene-propionate, condensate of methyl 3-[3-tert-butyl-5-(2H-benzotriazole-2-yl)-4-hydroxyphenyl]propionate and polyethylene glycol (molecular weight: about 300) and like benzotriazole type ultraviolet absorbers which are liquid at ordinary temperature. Of course, the ultraviolet absorber is not limited to thereabove and can be used as required in a mixture of at least two of them. The ordinary temperature means about 20° C. [0057]
Although the amount of ultraviolet absorber to be used in a heat sensitive recording material is not limited specifically, it is desirable to adjust the amount preferably to 10 to 500 parts by weight, more preferably to 20 to 250 parts by weight, per 100 parts by weight of the basic dye present in the heat sensitive recording layer. [0058]
The microcapsules for use in the present invention can be prepared by various known methods. They are prepared generally by emulsifying and dispersing the core material (oily liquid) comprising an ultraviolet absorber and, as required, an organic solvent in an aqueous medium, and forming a wall film of high-molecular-weight substance around the resulting oily droplets. [0059]
Examples of useful high-molecular-weight substances for forming the wall film of microcapsules are polyurethane resin, polyurea resin, polyamide resin, polyester resin, polycarbonate resin, aminoaldehyde resin, melamine resin, polystyrene resin, styrene-acrylate copolymer resin, styrene-methacrylate copolymer resin, gelatin, polyvinyl alcohol, etc. Especially, microcapsules having a wall film of a synthetic resin, particularly polyurea resin, polyurethane resin and aminoaldehyde resin among other resins have excellent retainability of an ultraviolet absorber and high heat resistance and accordingly exhibit the outstanding additional effect to serve the function of a pigment which is to be incorporated in the protective layer for preventing sticking to the thermal head. Moreover, microcapsules having a wall film of polyurea resin or polyurethane resin are lower in refractive index than microcapsules with wall films of other materials and usual pigments, are spherical in shape and are therefore usable favorably because even if present in a large quantity in the protective layer, they are unlikely to reduce the density of record images (so-called whitening) owing to irregular reflection of light. Further, polyurea resin and polyurethane resin are more elastic than aminoaldehyde resin and therefore polyurea resin and polyurethane resin are preferably used as a wall film for microcapsules which are used under a condition of high pressure. On the other hand, microcapsules having a wall film made from aminoaldehyde resin have a merit that the wall film can be controlled in thickness without depending on particle size of emulsion because the microcapsules can be prepared by adding a wall-forming material after emulsification of a core material. [0060]
The present invention may also include organic solvent together with an ultraviolet absorber. The organic solvent is not particularly limited and various hydrophobic solvents can be used which are used in a field of pressure sensitive manifold papers. Examples of organic solvents are tricresyl phosphate, octyldiphenyl phosphate and like phosphates, dibutyl phthalate, dioctyl phthalate and like phthalates, butyl oleate and like carboxylates, various fatty acid amides, diethylene glycol dibenzoate, monoisopropylnaphthalene, diisopropylnaphthalene and like alkylated naphthalenes, 1-methyl-1-phenyl-1-tolylmethane, 1-methyl-1-phenyl-1-xylylmethane, 1-phenyl-1-tolylmethane and like alkylated benzenes, isopropylbiphenyl and like alkylated biphenyls, trimethylolpropane triacrylate and like acrylates, ester of polyol and unsaturated carboxylic acid, chlorinated paraffin and kerosene. These solvents can be used as required in a mixture of at least two of them. Among these hydrophobic media having a high boiling point, tricresyl phosphate and 1-phenyl-1-tolylmethane are desirable since they exhibit high solubility in connection with the ultraviolet absorber to be used in the present invention. Generally, the lower the viscosity of the core material, the smaller is the particle size resulting from emulsification and the narrower is the particle size distribution, so that a solvent having a low boiling point is conjointly usable to lower the viscosity of the core material. Examples of such solvents having a low boiling point are ethyl acetate, butyl acetate, methylene chloride, etc. [0061]
The amount of organic solvent to be used should be suitably adjusted according to the kind and amount of ultraviolet absorber to be used and the kind of organic solvent and is not limited specifically. For example in case of using an ultraviolet absorber which is liquid at ordinary temperature, an organic solvent is not necessarily used. However, in case of using an ultraviolet absorber which is solid at ordinary temperature, since it is desired that the ultraviolet absorber be in a fully dissolved state in the microcapsules, the amount of organic solvent, for example in case of microcapsules of polyurea resin or polyurethane resin, is adjusted preferably to usually 10 to 60 wt. %, more preferably to 20 to 60 wt. %, based on the combined amount of organic solvent, ultraviolet absorber and wall-forming material. Further, in case of microcapsules of aminoaldehyde resin, the amount of organic solvent is adjusted to usually 50 to 2000% by weight, preferably 100 to 1000% by weight of ultraviolet absorber. [0062]
While the amount of capsule wall-forming material to be used is not limited specifically either, preservation for a long period of time is likely to permit the organic solvent in the microcapsules to ooze out to decrease contemplated effects or give adverse effects to a heat sensitive recording material and other materials having microcapsules used, so that it is desired to use a larger amount of wall-forming material than is the case with usual microcapsules used in a pressure sensitive recording material, etc. Thus, for example in case of using microcapsules of polyurea resin or polyurethane resin, the wall-forming material is used preferably in an amount of 20 to 70 wt. %, more preferably 25 to 60 wt. %, based on the combined amount of the three components, i.e., the organic solvent which is used as required, ultraviolet absorber and wall-forming material. In case of using microcapsules of aminoaldehyde resin, the wall-forming material is used usually in an amount of 30 to 300% by weight, preferably 35 to 200% by weight of the core material containing as main components ultraviolet absorber and as required organic solvent. [0063]
Additionally, an absorber may be utilized. An absorber should be selected which reduces the sensitivity of the microcapsule in those portions of its spectral sensitivity range which interfere with the exposure of microcapsules at other wavelengths (its inactive range) without overly reducing the sensitivity of the microcapsule in those portions of the spectral sensitivity range in which the microcapsule is intended to be exposed (its active range). In some cases it may be necessary to balance the absorption characteristics of the absorber in the active range and the inactive range to achieve optimum exposure characteristics. Generally absorbers having an extinction coefficient greater than about 100/M cm in the inactive range and less than about 100,000/M cm in the active range of the microcapsule are preferred. When the absorber is directly incorporated into the photosensitive composition, ideally, it should not inhibit free radical polymerization, and it should not generate free radicals upon exposure. [0064]
The absorbers used in the present invention can be selected from among those absorbers which are known in the photographic art. Examples of such compounds include dyes conventionally used as silver halide sensitizing dyes in color photography (e.g., cyanine, merocyanine, hemicyanine and styryl dyes) and ultraviolet absorbers. A number of colored dyes which absorb outside the desired sensitivity range of the microcapsules and do not absorb heavily within the range could also be used as absorbers in the present invention. Among these, Sudan I, Sudan II, Sudan III, Sudan Orange G, Oil Red O, Oil Blue N, and Fast Garnet GBC are examples of potentially useful compounds. [0065]
Additionally ultraviolet absorbers that may be desirable include those selected from hydroxybenzophenones, hydroxyphenylbenzo-triazoles and formamidines. The absorbers may be used alone or in combination to achieve the spectral sensitivity characteristics that are desired. [0066]
Representative examples of useful hydroxybenzophenones are 2-hydroxy-4-n-octoxybenzophenone (UV-CHEK AM-300 from Ferro Chemical Division, Mark 1413 from Argus Chemical Division, Witco Chem. Corp., and Cyasorb UV-531 Light Absorber from American Cyanamid), 4-dodecyl-2-hydroxybenzophenone (Eastman Inhibitor DOBP from Eastman Kodak), 2-hydroxy-4-methoxybenzophenone (Cyasorb UV-9 Light Absorber from American Cyanamid), and 2,2′-dihydroxy-4-methoxybenzophenone (Cyasorb UV-24 Light Absorber from American Cyanamid). Representative examples of useful hydroxybenzophenyl benzotriazoles are 2-(2′-hydroxy-5′-methylphenyl)benzotriazole (Tinuvin P from Ciba-Geigy Additives Dept.), 2-(3′,5′-ditert-butyl-2′hydroxyphenyl)-5-chlorobenzotriazole (Tinuvin 327 from Ciba-Geigy), and 2-(2-hydroxy-5-t-octylphenyl)benzotriazole (Cyasorb UV-5411 Light Absorber from American Cyanamid). Representative examples of useful formamidines are described in U.S. Pat. No. 4,021,471 and include N-(p-ethoxy-carbonylphenyl)-N′-ethyl-N′-phenylformamidine (Givsorb UV-2 from Givaudan Corp.). The optimum absorber and concentration of absorber for a particular application depends on both the absorption maximum and extinction coefficient of the absorber candidates and the spectral sensitivity characteristics of the associated photoinitiators. [0067]
Additionally, the microcapsules, photosensitive compositions, image-forming agents, developers, and development techniques described in U.S. Pat. Nos. 4,399,209 and 4,440,846, the contents of which are incorporated and may be used in the present invention. [0068]
The present invention is explained in greater detail in the Examples that follow. These examples are intended as illustrative of the invention and are not to be taken are limiting thereof. [0069]

EXAMPLE 1

Synthesis of 1-Ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium Chloride (6)

[0070]
Step a: Reaction of 2,6-Lutidine (1) and Iodoethane (2) to [0071] Form 2,6-Lutidine Ethiodide (3). A total of 69.7 grams (0.65 mole) of 2,6-lutidine (1) was combined with 202.8 grams of ethyl iodide (2) and the mixture was heated at 100° C. overnight. The reaction mixture was then cooled and the precipitated 2,6-lutidine ethiodide (3) was collected by filtration. The filtrate was reheated to 100° C. overnight, then cooled and filtered to recover a second crop of solid 2,6-lutidine ethiodide (3). These two crops were combined, dissolved in hot absolute ethanol and recrystallized. This resultant solid was dissolved in hot ethanol and recrystallized a second time. The purified 2,6-lutidine ethiodide (3) was air dried to constant weight to yield 107.5 grams of desired product. The ¹H-NMR was consistent with the desired material and the uncorrected melting point was determined to be 205-206° C.
Step b: Conversion of Z 6-Lutidine Ethiodide (3) to 2,6-Lutidine Ethochloride (4). The 107.5 grams of 2,6-lutidine ethiodide was dissolved in 2.0 liters of methanol and the solution was chilled in an ice-water bath. A total of 220 grams of anhydrous hydrogen chloride gas was slowly added to the solution via a gas bubbler. An ice-water bath was used to keep the reaction temperature below 30° C. during the hydrogen chloride addition. After all the hydrogen chloride had been added, the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to near dryness and then re-dissolved in 1.0 liter of methanol. A total of 103 grams of anhydrous hydrogen chloride gas was then bubbled into the mixture. After stirring for 10 minutes, the reaction mixture was concentrated to dryness under vacuum to yield 94.3 grams of the desired 2,6-lutidine ethochloride (4). [0072]
Step c: Reaction of Z 6-Lutidine Ethochloride (4) and 4-Pyrrolidinobenzaldehyde (5) to Produce 1-Ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium Chloride (6). [0073]
A mixture of 30.6 grams (0.22 mole) of 2,6-lutidine ethochloride (4), 75 grams (0.54 mole) of 4-pyrrolidinobenzaldehyde (5), 12 mL piperidine and ca. 2 liters of methanol was heated at reflux overnight. The [0074] ¹H NMR indicated that no reaction had occurred. No reaction occurred after heating the reaction mixture for an additional 96 hours at reflux. An additional 12 mL of piperidine was added and heating at reflux continued. After a total of 120 hours of heating at reflux, some solids began precipitating but ¹H NMR indicated that the desired reaction was still incomplete. Another 12 mL of piperidine catalyst was added and the reaction mixture was heated at reflux for an additional 24 hours. The ¹H NMR spectrum now indicated the desired reaction was carried to completion. The reaction mixture was slowly cooled to room temperature and the precipitated solid containing 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium chloride (6) was collected by filtration. The solid was triturated and washed with three 100 ml portions of ethyl ether to remove impurities and residual methanol solvent. The solid was air dried and dried under vacuum to constant weight to yield 32.6 grams of red crystalline 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium chloride (6)−high performance liquid chromatography area percent (HPLC Area %)=98.1%, ¹H NMR (DMSO, d₆); ppm 8.16-8.14 (t,1H); 8.08-8.07 (d,2H); 7.71-7.68 (d,1H); 7.69-7.67 (d,2H,J=8.8 Hz); 7.23-7.20 (d,1H); 6.61-6.59 (d,2H,J=8.8 Hz); 4.75-4.74 (m,2H); 3.31 (m,2H); 1.98-1.96 (m,2H); 1.48-1.45 (t,3H).
The reaction filtrate was concentrated to approximately one-half the original volume, 10 mL of piperidine was added and the dark reaction filtrate was heated at reflux for 24 hours. [0075] ¹H NMR spectral analysis indicated that more 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium chloride (6) had formed, possibly by olefinic isomer equilibration. The heat was removed and the reaction mixture was allowed to stir at room temperature for 48 hours, during which time a precipitate formed. The solid was collected by filtration and was triturated and washed with three 100 ml portions of ethyl ether to remove impurities and residual methanol solvent. The red crystalline solid was air dried and dried under vacuum to constant weight to yield 19.2 grams of additional 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium chloride (6)−HPLC Area %=97.4%, ¹H NMR was consistent with the first crop of product (6).

EXAMPLE 2

Synthesis of 1-Ethyl-(E,E)-2,6-bis[2-[4-(dimethylamino)phenyl]ethenyl]pyridinium Chloride

[0076]
A mixture of 9.0 grams (0.07 mole) of 2,6-lutidine ethochloride, 23.6 grams (0.16 mole) of 4-dimethylaminobenzaldehyde, 14 mL piperidine and 350 mL methanol was heated at reflux for 77 hours. After 77 hr at reflux, high performance liquid chromatography—mass spectral analysis (LC/MS analysis) indicated that the desired product was present in the reaction mixture. The reaction mixture was slowly cooled to effect precipitation and the precipitated solids were collected by filtration. The solids were triturated and washed with three 100 ml portions of ethyl ether to remove impurities and residual methanol solvent. The solid was air dried and dried under vacuum to constant weight to yield 2.8 grams of red crystalline 1-ethyl-(E,E)-2,6-bis[2-[4-(dimethylamino)phenyl]ethenyl]pyridinium chloride−high performance liquid chromatography area percent (HPLC Area %)=99.5%, [0077] ¹H NMR (DMSO, d₆) consistent with the desired product.
The reaction filtrate was concentrated to approximately one-half the original volume. A total of 10 mL of piperidine catalyst was added and the dark solution was heated at reflux for an additional 24 hours. At this point high performance liquid chromatography area percent analysis (HPLC A % analysis) indicated that more product had formed and the 2,6-lutidine ethochloride starting material was almost gone. The heat was removed and the reaction was concentrated under vacuum to yield a heavy slurry. The precipitated solid was collected by filtration, washed with three 100 ml portions of ethyl ether and the resulting solid was air dried and vacuum dried overnight to yield 13.6 grams of red crystalline 1-ethyl-(E,E)-2,6-bis[2-[4-(dimethylamino)phenyl]ethenyl]pyridinium chloride−HPLC Area %=99%, [0078] ¹H NMR was consistent with the desired product.

EXAMPLE 3

Synthesis of 1-Ethyl-(E,E)-2,6-bis[2-[4-(diethylamino)phenyl]ethenyl]pyridinium Chloride

[0079]
A mixture of 9.0 grams (0.07 mole) of 2,6-lutidine ethochloride, 28.1 grams (0.16 mole) of 4-diethylaminobenzaldehyde, 14 mL piperidine and 350 mL methanol was heated to reflux for 96 hours at which time LC/MS analysis indicated that the desired product was present. The reaction mixture was cooled and concentrated under vacuum to produce a slurry. The solid was collected by filtration and was triturated and washed with three 50 ml portions of ethyl ether. The resulting purified solid was air dried and vacuum dried to yield 17.3 grams of red crystalline 1-ethyl-(E,E)-2,6-bis[2-[4-(diethylamino)phenyl]ethenyl]pyridinium chloride−high performance liquid chromatography area percent (HPLC Area %)=95%, [0080] ¹H NMR (DMSO, d₆) was consistent with the desired material and a trace of the starting 4-diethylaminobenzaldehyde present.

EXAMPLE 4

Synthesis of 1-Ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium 4-Aminobenzoate Salt

[0081]
A total of 52.8 g (0.12 mole) of 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium chloride and 18.6 grams (0.12 mole) of the sodium salt of 4-aminobenzoic acid (sodium salt of p-aminobenzoic acid, Na[0082] ⁺ PABA⁻) were dissolved in 1.3 liters of methanol and this mixture was allowed to stir at room temperature for 4 days during which time a precipitate formed. The reaction mixture was then filtered and the solid salt was air dried and vacuum dried to yield a first crop of 28.0 grams of 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium 4-aminobenzoate salt (also termed the PABA salt). The filtrate was concentrated under vacuum to produce more precipitate. Isolation of the second crop was effected by filtration followed by air drying and vacuum drying of the solid to afford a second crop of 42.6 grams of 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium 4-aminobenzoate salt (also termed the PABA salt)−high performance liquid chromatography area percent (HPLC A %) first crop=99.6% excluding PABA; HPLC A % second crop=99.9% excluding PABA; ¹H NMR and Mass Spectral analyses for both crops were consistent with structure of the desired material 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium 4-aminobenzoate salt. This product is also named 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium p-aminobenzoate salt or 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium PABA salt.
By the methods demonstrated in Examples 1-3, substituted and unsubstituted aromatic aldehydes or substituted and unsubstituted heteroaromatic aldehydes are reacted with substituted and unsubstituted lutidine ethochloride salts, lutidine isobutochloride salts, lutidine methochloride salts, [0083] lutidine 1,1,1-trifluoroethochloride salts and the like and with secondary amine catalysts such as piperidine and pyrrolidine in polar protic solvents such as methanol, ethanol, 2-propanol and the like or polar aprotic solvents such as acetonitrile (ACN), dimethyl acetamide (DMA), dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) and the like to yield any possible combination of compounds as noted throughout the application and the claims. Applicants have additionally provided numerous compounds shown in FIGS. 1-4 to illustrate some of the possible combinations of the present invention.
In the following Examples, the “active ingredient” may be any compound of formula (I) as recited above or a pharmaceutically acceptable salt or solvate thereof. [0084]

EXAMPLE 5

(1) Tablet Formulations

(i) Oral

mg/tablet

		A	B	C

Active Ingredient	25	25	25
Avicel ™	13	0	7
Starch (maize)	0	9	0
Starch (pregelatinised, NF15	0	0	32
Sodium starch glycollate	5	0	0
Povidone ™	3	3	0
Magnesium stearate	1	1	1

[0086]

(ii) Sublingual

mg/tablet

D E

Active Ingredient 25 25

Avicel ™ 0 10

Lactose 0 36

Mannitol 51 75

Sucrose 0 3

Acacia 0 3

Povidone ™ 3 0

Magnesium Stearate 1 1
Formulations A to E may be prepared by wet granulation of the first six ingredients with the povidone.TM., followed by addition of the magnesium stearate and compression. [0087]

(iii) Buccal

mg/tablet

Active Ingredient 25

Hydroxypropylmethylcellulose (HPMC) 25

Polycarbophil ™ 39

Magnesium Sterate 1
The formulation may be prepared by direct compression of the admixed ingredients. [0088]
(2) Capsule Formulations [0089]

(i) Powder

mg/Capsule

F G

Active Ingredient 25 25

Avicel ™ 45 0

Lactose 153 0

Starch (1500 NF) 0 117

Sodium starch glycollate 0 6

Magnesium Sterate 2 2
Formulations F and G may be prepared by admixing the ingredients and filling two-part hard gelatin capsules with the resulting mixture. [0090]

(ii) Liquid fill

mg/Capsule

H I

Active ingredient 25 25

Macrogol ™. 4000 BP 200 0

Lecithin 0 100

Arachis oil 0 100
Formulation H may be prepared by melting the Macrogol™. 4000 BP dispersing the active ingredient in the melt and filling two-part hard gelatin capsules therewith. Formulation I may be prepared by dispersing the active ingredient in the lecithin and arachis oil and filling soft, elastic gelatin capsules with the dispersion. [0091]

(iii) Controlled release

mg/tablet

Active Ingredient 25

Avicel 123

Lactose 62

Triethyl citrate 3

Ethyl cellulose 12
The formulation may be prepared by mixing and extruding the first four ingredients and spheronising and drying the extrudate. The dried pellets are coated with ethyl cellulose as a release controlling membrane and filled into two-part, hard gelatin capsules. [0092]
Powder Capsules for Inhalation [0093]

Active Ingredient (0.5-7.0 μm powder) 1.0 mg

Lactose (30-90 μm powder) 49.0 mg
The powders were mixed until homogeneous and filled into suitably sized hard gelatin capsules (50 mg per capsule). [0094]

Inhalation Aerosol



Active Ingredient (0.5-7.0 μm powder)	50	mg
Sorbitan trioleate	100	mg
Saccharin Sodium (0.5-7.0 μm powder)	5	mg
Menthol
2	mg
Trifluoromethane	4.2	g
Dichlorodifluoromethane	Qs to 10	mL

The sorbitan trioleate and methanol are dissolved in the trichloro-fluoromethane. The saccharin sodium and active ingredient are dispersed in the mixture which is transferred to a suitable aerosol canister and the dichlorofluoromethane is injected through the valve system. This composition provides 0.5 mg of active ingredient in each 100 μl dose. [0096]
Topical solution. [0097]

Component Amount

Formula I 200 mg

Ethyl alcohol, USP (95% v/v) 100 mL
The compound of formula I is dissolved directly in the alcohol and placed in amber glass vials. Application to the skin of the resulting 0.2% solution may be attained through application by cottom swab or through a permeable, absorbent cap, applied to the affected epidermis. [0098]
Aqueous cream for external (dermal), vaginal and rectal application [0099]
The compound of formula I [0100]

Component Amount

Formula I 500 mg

Butanediol 100 mL
The compound of formula I is suspended in butane by mixing and the resulting cream is applied topically. [0101]

EXAMPLE 6

Biological Activity [0102]
Carrageenan Pleurisy Assay [0103]
The anti-inflammatory activity of compounds of the invention was determined by the procedure of Vinegar, R, et al., Proc. Soc. Exp. Biol. Med., 1981, 168, 24-32, using male Lewis rats of 150.+−0.20 grams. The carrageenan dose was 0.075 mg/rat. Pleural exudate was harvested four hours after injection of carrageenan. Acute antiinflammatory activity was determined by inhibition of pleural edema and inflammatory cells (neutrophils) from a negative (vehicle) control group. [0104]
2) Acetic Acid Colitis Assay [0105]
Anti-inflammatory activity of compounds of the invention was determined in the Acetic Acid Colitis rat model using the procedure of Fretland, D., et al., 1990, 255:572-576 in male Lewis rats 275+25 grams. Compounds were administered either orally or rectally 24, 16 and 4 hours prior to the 40 second instillation of 3% acetic acid solution in the proximal 6 cm of the colon under light anesthesia. The colon was immediately washed with 5 cc of saline. 24 hours later the rats were sacrificed and 6 cm of the proximal colon was excised weighed for edema. Neutrophil inflammation was determined by measuring MPO levels in the scraped colonic mucosa from these rats. Anti-inflammatory activity was determined by inhibition of edema formation and mucosal MPO levels compared to the negative control group (vehicle). [0106]
3) Antibacterial Activity [0107]
Solutions of formula I (1% dimethylsulfoxide) were diluted further with sterile water, using serial half-step dilutions. Forty microliters of each dilution were pipetted onto seeded Mueller-Hinton agar plates. The agar plates were then incubated for 24 hours at 35° C. and zones of inhibition were then recorded. The Minimum Inhibitory Concentration (MIC) was the lowest concentration of the test material which produced a zone of inhibition against the organism. The MIC for formula I against a series of organisms is listed in Table 2 below. [0108]
4) Antifungal Activity [0109]

Fungal strains (obtained from ATCC) were grown in Mueller-Hinton broth for 18 hours at 35° C. Plates were then seeded with the broth culture and allowed to air-dry at room temperature (22° C.) for about 10-15 minutes. Forty microliters of formula I (in 1% dimethylsulfoxide) and serial half-step dilutions in water were then pipetted onto the seeded Mueller-Hinton agar plates. The plates were then incubated for 24 hours at 35° C. and zones of inhibition were then recorded. The Minimum Inhibitory Concentration (MIC) was the lowest concentration of formula I which produced a zone of inhibition against the organism. Below, table 3 lists the antifungal activity of formula I against various fungal strains.

TABLE 1


Comparison of Formula I to other anti-inflammatory drugs
in the carrageenan pleurisy assay in male, Lewis rats

	Dose (μg/rat;		% Inhibition
Compound	intrapleural)	% Inhibition WBC	Exudate

Formula I	0.2	32	25
Formula I	1.0	41	40
Formula I	5.0	76	60
Dexamethasone	2.0	8	10
Dexamethasone	10.0	29	41
Dexamethasone	50.0	68	83
Prednisolone	50	23	25
Prednisolone	250	32	30
Prednisolone	1250	97	55

Results are expressed as % inhibition of the infiltration of white blood cells (wbc) and exudates volume resulting from the intrapleural instillation of carrageenan. Drugs were administered 1 hour after carageenan; measurements were performed 4 hours later

TABLE 2


Anti-bacterial activity of formula I

	Strain	MIC

	Streptococcus pyogenes	1.0
	Streptococcus faecalis	1.0
	Streptococcus algalactia	1.0
	Staphylococcus aureus	0.3
	Bordella bronchiseptica	1.0
	Vibrio cholerae	10.0
	Pasturella multocida	3.0
	E. coli	>100
	Pseudomonas aerugenosa	>100

The data represent the minimal inhibitory concentrations of formula I, in μg/mL, for inhibition of bacterial growth, cultured in vitro. [0112]

TABLE 3

Comparison of Formula I to other anti-inflammatory drugs

in the Acetic Acid Colitis assay in male, Lewis rats

% Inhibition Tissue % Inhibition

Compound Dose (mg/kg (po) swelling (edema) MPO (u/cm)

Formula I 5 36 39

Formula I 20 47 37

Sulfasalazine 100 10 20

Sulfasalazine 300 14 16

Prednisolone 3 44 41

Prednisolone 12 40 46
[0113]

TABLE 4

Comparison of Formula I and another anti-fungal drug for

treating vaginal candidiasis in female Charles River mice.

Compound Cleared Improved

Diluent (butanediol) 4/10 0/10

Formula I 9/10 1/10

Chlortrimazole 7/10 2/10

Mice, infected vaginally with Candida albicans, were treated with 0.025 mL of the above treatments, commencing 6 hours post-infection, daily for 4 days. The concentration of formula I was 0.5% (w/v) and chlortrimazole was 1% (w/v).

TABLE 5


Inhibition of yeast and fungal growth by Formula I in vitro

	Organism	MIC

	Candida albicans	<0.006
	Candida tropicalis	<0.4
	Cryptococcus neoformans	<0.4
	Saccharomyces cervisciae	<0.4
	Aspergillus fumigatus	<0.006
	Aspergillus flavus	6.25
	Fusarium solani	<0.4
	Rhizopus arrihizus	6.25
	Microsporidium canis	1.6
	Microsporidium gypseum	1.6
	Trichophyton equinium	1.6
	Trichophyton mentagrophyt	1.6
	Trichophyton rubrum	1.6
	Epidermophyton floccsum	1.6

The data represent the minimal inhibitory concentrations of formula I, in μg/mL, for inhibition of bacterial growth, cultured in vitro.

TABLE 6


In Vivo Pharmacological and Toxicological Actions of Stilbazium Salts

	Active
Assay, Species, Route of Admin.,	Dose
Injection Volume	(Conc.)	Signs of Toxicity	Comment

Candida Vaginitis, Mouse, Local, 25 ul.	100	uM	None, normal	No infection at 100 uM
			histology
Allergic Pleuritis, Rat, Local, 250 ul.	12	uM	None	Inhibition of exudate
				formation & LTs
Candida Vaginitis, Mouse, Local, 25 ul.	100	uM	None, normal	No infection at 100 uM
			histology
Allergic Pleuritis, Rat, Local, 250 ul.	12	uM	None	Inhibition of exudate
				formation & LTs
	82	uM	None	Inhibition of late response
				(neutrophil)
Allergic Synovitis, Rat, Local, 5 uL	230	uM	None	Reduced # of neutrophils
				in joints
Anti-Inflammatory Activity, Rat Hindlimb,	0.5%		None	Inhibition of neutrophil-
Topical Application, 100 ul.				mediated
				edema formation.
Anthelminthic Active Human, oral capsule	1-10	mg/kg	Mild Gastric Irritation	No adverse systemic affects
Mast Cell Release, Rat, Intradermal, 100 ul.	2	mM	Mild edema
Leukotriene Synthesis, Rat Pleural cells,	0.008	mg/kg	None	ED₅₀Dose
Local, 25 ul
Eye Irritation, Rabbit, Local, 30 ul	2	mM	No irritation

[0116]

TABLE 7

Efficacy of Stibazium salts +/− Prednisolone in Rodent

Inflammation Models

%

% Inhibition

Dose Inhibition Neu-

Compounds mg/kg Edema trophils

4 Hour Carrageenan Pleuritis

Prednisolone 0.02 31 21

STIBAZIUM 0.0004 38 18

SALT

Prednisolone + STIBAZIUM 0.02 + 0.0004 67 56

SALT

Outcome Additive Additive

4 Hour Allergic Pleuritis

Prednisolone 0.004 33 25

STIBAZIUM 0.002 19 10

SALT

Prednisolone + STIBAZIUM 0.004 + 0.002 57 40

SALT

Outcome Additive Additive

4 Hour Allergic Synovitis

Prednisolone 0.05 36 37

STIBAZIUM 0.002 24 28

SALT

Prednisolone + STIBAZIUM 0.05 + 0.02 67 72

SALT

Outcome Additive Additive
In the specification, there has been disclosed typical preferred embodiments of the invention and, although specific terms are employed, they are used in a generic and descriptive sense only and not for purposes of limitation of the scope of the invention being set forth in the following claims. [0117]

Claims

What is claimed is:

1. A method for treating an inflammation in a subject comprising:

topically administering a composition comprising formula (I)

or a solvate thereof and

wherein the NR₁R₂and NR₃R₄moieties are in the ortho, meta or para positions;

wherein X⁻ is an anionic salt;

wherein R₁, R₂, R₃, or R₄are independently selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), or wherein R₁and R₂or R₃and R₄taken together with the nitrogen atom to which they are attached form pyrrolidino or piperidino rings; and

wherein R₅is selected from the group consisting of methyl, ethyl, C_1-10alkyl (linear or branched), alkenes (linear or branched), alkynes, n-propyl, i-propyl, n-butyl, i-butyl, substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties,

to a subject in need thereof.

2. The method according to claim 1 wherein the N—R moiety is in the para position, X is Cl⁻ and R₅is methyl or ethyl.

3. The method according to claim 1, wherein said inflammation is selected from the group consisting of allergic rhinitis, otitis externa, uveitis, sinusitis, asthma, adult respiratory distress syndrome, bronchitis, laryngitis, thrush and cystic fibrosis.

4. The method according to claim 1, wherein R₅is (CH₂)_n-MR₆, wherein n is a number from 1 to 6, M is an organometallic compound selected from the group consisting of tin, silicon, and germanium, and wherein R₆is a selected from the group consisting of propyl, butyl, and alkyl, substituted or unsubstituted.

5. The method according to claim 1, wherein R₅is a ultraviolet blocker or an ultraviolet absorber.

6. A method for treating an infection in a subject comprising:

administering a composition comprising formula (I)

or a solvate thereof and

wherein X⁻ is an anionic salt;

to a subject in need thereof.

7. The method according to claim 6, wherein said infection is selected from the group consisting of allergic rhinitis, otitis extema, uveitis, sinusitis, asthma, adult respiratory distress syndrome, bronchitis, laryngitis, thrush and cystic fibrosis.

8. The method according to claim 6, wherein said composition is administered to the skin or mucous membranes of the subject.

9. The method according to claim 6, wherein R₅is (CH₂)_n-MR₆, wherein n is a number from 1 to 6, M is an organometallic compound selected from the group consisting of tin, silicon, and germanium, and wherein R₆is a selected from the group consisting of propyl, butyl, and alkyl, substituted or unsubstituted.

10. The method according to claim 6, wherein R₅is a ultraviolet blocker or an ultraviolet absorber.

11. A method for treating an immune disorder in a subject comprising:

administering a composition comprising formula (I)

or a solvate thereof and

wherein X⁻ is an anionic salt;

to a subject in need thereof.

12. The method according to claim 11, wherein said immune disease is selected from the group consisting of allergic rhinitis, otitis externa, sinusitis, asthma, adult respiratory distress syndrome, bronchitis, laryngitis, thrush, cystic fibrosis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, uveitis, conjunctivitis, inflammatory bowel conditions, Crohn's disease, ulcerative colitis, distal proctitis, psoriasis, eczema, dermatitis, allergic prurigo, topical fungal infections, gingivitis, periodontitis, coronary infarct damage, chronic inflammation, asthma, adult respiratory distress syndrome, rhinitis, chronic rhinosinusitis, orophoryngeal candidiasis, bronchitis, laryngitis, cystic fibrosis and smooth muscle proliferation disorders.

13. The method according to claim 11, wherein said composition is administered to the skin or mucous membranes of the subject.

14. The method according to claim 11, wherein R₅is (CH₂)_n-MR₆, wherein n is a number from 1 to 6, M is an organometallic compound selected from the group consisting of tin, silicon, and germanium, and wherein R₆is a selected from the group consisting of propyl, butyl, and alkyl, substituted or unsubstituted.

15. The method according to claim 11, wherein R₅is a ultraviolet blocker or an ultraviolet absorber.

16. A method for treating a fungal infection in a subject comprising:

administering a composition comprising formula (I)

or a solvate thereof and

wherein X⁻ is an anionic salt;

to a subject in need thereof.

17. The method according to claim 16, wherein said fungal infection is selected form the group consisting of tinea pedis, tinea capitis, tinea corporis, tinea versicolor, nail fungal diseases, scalp disorders, tinea cruris, candidiasis, otitis externa, eye fungal diseases, rhinosinusitis and allergic rhinitis.

18. The method according to claim 16, wherein said composition is administered to the skin or mucous membranes of the subject.

19. The method according to claim 16, wherein R₅is (CH₂)_n-MR₆, wherein n is a number from 1 to 6, M is an organometallic compound selected from the group consisting of tin, silicon, and germanium, and wherein R₆is a selected from the group consisting of propyl, butyl, and alkyl, substituted or unsubstituted.

20. The method according to claim 16, wherein R₅is a ultraviolet blocker or an ultraviolet absorber.

21. A method for treating a bacterial infection in a subject comprising:

administering a composition comprising formula (I)

or a solvate thereof and

wherein X⁻ is an anionic salt;

to a subject in need thereof.

22. The method according to claim 21, wherein said bacterial infection is selected form the group consisting of acne, uveitis, otitis externa, rhinosinusitis and allergic rhinitis.

23. The method according to claim 21, wherein said composition is administered to the skin or mucous membranes of the subject.

24. The method according to claim 21, wherein R₅is (CH₂)_n-MR₆, wherein n is a number from 1 to 6, M is an organometallic compound selected from the group consisting of tin, silicon, and germanium, and wherein R₆is a selected from the group consisting of propyl, butyl, and alkyl, substituted or unsubstituted.

25. The method according to claim 21, wherein R₅is an ultraviolet blocker or an ultraviolet absorber.