+

WO2006119284A2 - Composes aromatiques conjugues utilise a des fins diagnostiques et therapeutiques - Google Patents

Composes aromatiques conjugues utilise a des fins diagnostiques et therapeutiques Download PDF

Info

Publication number
WO2006119284A2
WO2006119284A2 PCT/US2006/016824 US2006016824W WO2006119284A2 WO 2006119284 A2 WO2006119284 A2 WO 2006119284A2 US 2006016824 W US2006016824 W US 2006016824W WO 2006119284 A2 WO2006119284 A2 WO 2006119284A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
optionally substituted
lower alkyl
substituted phenyl
phenyl group
Prior art date
Application number
PCT/US2006/016824
Other languages
English (en)
Other versions
WO2006119284A3 (fr
Inventor
Lee Roy Morgan
Original Assignee
Dekk-Tec, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dekk-Tec, Inc. filed Critical Dekk-Tec, Inc.
Priority to BRPI0612330-9A priority Critical patent/BRPI0612330A2/pt
Priority to CA002606599A priority patent/CA2606599A1/fr
Priority to JP2008510132A priority patent/JP2008540428A/ja
Priority to EP06758930A priority patent/EP1888053A2/fr
Priority to MX2007013762A priority patent/MX2007013762A/es
Priority to AU2006242244A priority patent/AU2006242244A1/en
Publication of WO2006119284A2 publication Critical patent/WO2006119284A2/fr
Publication of WO2006119284A3 publication Critical patent/WO2006119284A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/78—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C251/80—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • 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
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/82—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of rings other than six-membered aromatic rings

Definitions

  • This invention concerns methods of monitoring and altering immune function, for example in the diagnosis and/or treatment of infectious and neoplastic disease. It also discloses methods of treating lesions, such as hyperproliferative lesions associated with infectious pathogens and/or inflammation.
  • Immunotherapy involves the modulation of a subject's immune response to improve an innate ability to retain health. It has been recognized that there is a relationship between electromagnetic fields and biological functions, such as immunity.
  • U.S. Patent No. 4,670,386 discloses that the expression of strongly antigenic tumor specific antigens is induced by exposure of tumor cells to high frequency electromagnetic radiation that produces cyclic, rapid, alternating changes of polarity in dipolar molecular components of cancer cells.
  • high frequency electromagnetic radiation that produces cyclic, rapid, alternating changes of polarity in dipolar molecular components of cancer cells.
  • one of the drawbacks of very high frequency radiation is that it causes unwanted and potentially damaging heating of biological tissue.
  • U.S. Patent No. 6,038,4708 discloses that lymphocytes can be attracted to a desired location in the body by applying electrodes to the desired location and stimulating the tissue with sufficient electric current to attract lymphocytes.
  • Low energy alternating current magnetic fields were used to induce an immune response in U.S. Patent Publication 2002/0072646.
  • WO 02/062418 discloses enhancing immune function by exposing a subject to a magnetic field, or to very high frequency electromagnetic fields that are angularly modulated.
  • biologic systems frequently have electrical activity associated with them.
  • This activity can be a constant DC electric field, a constant flux of charge-carrying particles or current, or a time-varying electric field or current associated with some time-dependent or biochemical phenomenon.
  • Bioelectric phenomena are associated with the distribution of ions or charged molecules in a biologic structure and the changes in this distribution resulting from specific processes.
  • Electromagnetic bioimpedance measurements have been used for diagnostic purposes.
  • WO 01/076475 discloses use of an alternating magnetic field to induce electrical eddy currents in biological tissue.
  • An oscillator circuit is used to generate current in a coil adjacent targeted tissue. Since the amplitude of the resultant voltage is proportional to the conductivity of the tissue, changes in bioimpedance are used to detect changes in the tissue that are associated with tumors, such as prostate tumors.
  • Another tissue impedence measuring device for differentiating tissue types is disclosed in WO 01/67098. The disclosure of both of these PCT publications (WO 01/076475 and WO 01/67098) is incorporated herein by reference.
  • Protein phosphatases are composed of at least two separate and distinct families: the protein serine/threonine phosphatases and the protein tyrosine phosphatases (PTPs).
  • Human protein tyrosine phosphatases (human PTPs) are a large and diverse family of proteins present in all eukaryotes. Each PTP is composed of at least one conserved domain characterized by an 11-residue sequence motif containing cysteine and arginine residues that are known to be essential for catalytic activities.
  • the sequences of PTP share no similarity to serine or threonine, acid or alkaline phosphatases.
  • the diversity in structure within the PTP family results primarily from the variety of non-catalytic sequences attached to the NH 2 - or COOH- termini of the catalytic domain.
  • PTPs generally are classified into two subgroups.
  • the first subgroup is made up of the low molecular weight, intracellular enzymes that contain a single conserved catalytic phosphatase domain. All known intracellular type PTPs contain a single conserved catalytic phosphatase domain. Examples of the first group of PTPs include placental PTP IB, T-cell PTP, rat brain PTP, neuronal phosphatase (STEP), and cytoplasmic phosphatases that contain a region of homology to cytoskeletal proteins.
  • the second subgroup of PTPs comprises high molecular weight, receptor-linked PTPs, termed R-PTPs.
  • the R-PTPs generally include an intracellular catalytic region, a single transmembrane segment, and a putative ligand-binding extracellular domain.
  • the structures and sizes of the putative ligand-binding extracellular "receptor" domains of R-PTPs are quite divergent, in contrast to the intracellular catalytic regions of R-PTPs which are highly homologous. All R-PTPs have two tandemly duplicated catalytic phosphatase homology domains, with the prominent exception of an R-PTP termed HPTP ⁇ , which has only one catalytic phosphatase domain. (Tsai et al., J. Biol. Chem. 266(16):10534-10543 (1991)).
  • LCA leukocyte common antigen
  • LCA is referred to in the literature by different names, including T200, B220 for the B cell form, the mouse allotypic marker Ly-5, and more recently CD45 (Cobbold et al., Leucocyte Typing III, ed. A. J. McMichael et al., pp. 788-803 (1987)). CD45 is believed to play a critical role in T cell activation. These studies are reviewed in Weiss A., Ann. Rev. Genet. 25:487- 510 (1991).
  • R-PTPs are the leukocyte common antigen related molecule (LAR) (Streuli et al., J. Exp. Med. 168:1523-1530 (1988)).
  • LAR leukocyte common antigen related molecule
  • published application W092/01050 discloses human R-PTP- ⁇ , ⁇ and ⁇ and reports on the nature of the structural homologies found among the conserved domains of these three R-PTP and other members of this protein family.
  • the extracellular PTPs are related to surface recognition and adhesion molecules of leukocyte cell surface recognition.
  • the PTPs are not only associated with human cells, but also present in prokaryotes and viruses, and bacteria.
  • the Yop2b tyrosine-specific PTP is an essential virulence determinant. Numerous studies have demonstrated the importance of PTPs in physiological processes.
  • Phenotypic defects and hyperproliferative behavior of T-and B-lymphocytes, granulocytes and macrophages are considered to be key issues in the development of cancer and autoimmune diseases.
  • the compounds have the formula
  • Ar comprises an aryl group substituted with at least one electron withdrawing group
  • X is NH, CH 2 , O, — , SO 2 , or B;
  • Y and Y' independently are selected from N, CH and B; n is O or 1; m is from 0 to 6;
  • R 1 is H, lower alkyl, optionally substituted phenyl or
  • R 4 is an optionally substituted phenyl group
  • R 2 is optionally substituted lower alkyl, aralkyl, thioalkyl, amidoalkyl, amino, amino alkyl, nitro, azido; together with Z forms an optionally substituted 4-7 membered carbocyclic or heterocyclic ring; or together with R 4 forms an optionally substituted phenyl group;
  • R 3 with R 2 forms an optionally substituted phenyl group or is an optionally substituted phenyl group
  • Z is H, lower alkyl, substituted alkyl, thioalkyl, nitrile, amino, or together with R 2 forms an optionally substituted 4-7 membered carbocyclic or heterocyclic ring.
  • the compounds are derivatized with a biomolecule, such as a carbohydrate, amino acid, peptide, fatty acid, nucleoside or nucleic acids.
  • a biomolecule such as a carbohydrate, amino acid, peptide, fatty acid, nucleoside or nucleic acids.
  • such derivatization is used to enhance a compound's solubility and/or target a compound to a particular tissue, cell or receptor.
  • an optionally substituted phenyl group as recited with respect to the general formula above, comprises such a biomolecule.
  • the disclosed compounds are resonance modulators effective to stimulate a therapeutic response.
  • a method for stimulating a therapeutic response such as an immune response
  • a resonance modulating compound that possesses resonating intramolecular dipole moments (or electron densities) that allow it to interact with biological environments.
  • Administration of the compound can take many forms, including, without limitation, topical application to a target area, insertion of pellets into the skin, placement in diseased organs, and inhalation.
  • the resonance modulating compounds are capable of stimulating an immune response characterized in part by infiltration of immune cells, such as lymphocytes, into a target region in the vicinity of the resonance modulating compound.
  • the electromagnetic properties of the target region also change as the immune cells enter the target area, and these electromagnetic changes can be detected (for example by electromagnetic signals provided by the resonance modulator) to measure the adequacy of a subject's immune response. Deficiencies of the immune response can be quickly detected in this manner, for example by the absence of an expected aggregation of immune cells, and appropriate therapeutic or preventative interventions taken.
  • One such intervention is to expose the resonance modulating compound to an external electromagnetic stimulus that enhances the immune response both locally in the target area, and remotely throughout the body. Examples of such electromagnetic stimuli are electrical current flowing across an electrical potential through the compound, an induced magnetic field, or radiant energy (such as laser energy) applied to the compound.
  • resonance modulator compounds include aryl compounds, particularly those having an aryl group substituted with electron withdrawing groups.
  • resonance modulator compounds have the general formula set forth above.
  • disclosed compounds include, for example, compounds having the formula above; wherein n is 0, such as compounds of the formula
  • R 7 and R s independently are -OR 5 , -SR 5 , -SO 2 N(R 5 ) 2 , -SO 2 CN, -SO 2 R 6 , -SO 2 N 3 , N 3 , -CN, ⁇ N(R 5 )C(O)R 6 , -R 6 ; each R 5 independently is H, lower alkyl, carbohydrate, fatty acid, amino acid, peptide, nucleoside or nucleic acid; R 6 is lower alkyl or C-glycoside; and Ar, X and Y are as described above.
  • X represents a bond.
  • Exemplary structures wherein X represents a bond include
  • the compounds have the formula wherein G represents -CH 2 -, -C(O)-, -N-, — , -O-, or -S-; n is 0 or 1; and Y', Q, Y, X, Ar, R 7 and R 8 are as set forth above.
  • R 5 is H, -OR 6 , -SR 6 , -SO 2 N(R 6 ) 2 , -SO 2 CN 3 -SO 2 R 7 , -SO 2 N 3 , N 3 , -CN, - N(R 6 )C(0)R 7 , or -R 7 ;
  • R 1 and R 6 independently are H or lower alkyl
  • R 2 and R 7 independently are lower alkyl; and Ar is an aryl group as set forth above.
  • arylhydrazones include arylhydrazones.
  • Other examples include aryl nitrohydrazones, such as phenylhydrazones, such as polyaryl mononitro- or dinitrophenylhydrazones, for example
  • R 1 is hydrogen, hydroxy, hydroxyphenyl (such as 2- or 4-hydroxyphenyl), acetate, phosphate, azido, nitrile, amino, dimethylamino, sulfate, methylsulfonate, phosphate, succinate;
  • R 2 is an unsubstituted (C 6 H 5 ) or substituted phenyl group such C 6 H 4 OH, C 6 H 4 N 3 , C 6 H 4 CN, 4-HO-C 6 H 4 -C 6 H 4 , C 6 H 4 OPO 2 OH, C 6 H 4 OSO 2 H, C 6 H 4 NH 2 , C 6 H 4 NHMe 2, C 6 H 4 OSO 2 Me, C 6 H 4 OCO(CH 2 ) X CO 2 H, or C 6 H 5 Cl;
  • Ar is nitrophenyl, such as C 6 H 3 -2,4(NO 2 ) 2 , C 6 H 4 -4(NO 2 ), C 6 H 4 -3(NO 2 ), or C 6 H 3 -2,4(NO 2 ) 2 ;
  • these compounds possess resonating intramolecular dipole movements that are believed to be capable of electrostatic interaction with biological environments, and in particular examples interact with the extracellular catalytic receptors of R-PTP, such as those found on the R-PTP CD45+ PTP subtype, or with lymphocytes in general. This interaction attracts lymphocytes (such as T-lymphocytes) to target regions to which the compound has been applied.
  • R-PTP extracellular catalytic receptors of R-PTP
  • lymphocytes such as T-lymphocytes
  • the resonance modulating compounds are capable of non-covalent affiliations, they typically lack substantial chemical reactivity and produce no local chemical reactions.
  • lymphocytes for example T-lymphocytes such as CD45+ T-lymphocytes, for example CD45RO+ or CD45RA+ lymphocytes
  • the resonance modulator compounds are also capable of stimulating the immune system at locations remote from the targeted region, for example in the spleen, by its interactions with the distributed networks of immune cells, such as those found in the lymphatic system. This mobilization of immune response can be used to treat infections or tumors.
  • the ability of the disclosed compounds to activate immune system activity remote from the site of application of the compound to the body allows the compound to act as an immune stimulator in the substantial absence of cytotoxicity or other pharmacological action (such as an estrogenic or anti-estrogenic activity) on the target cell itself. Since the compound is activating an immune response that affects the target cell, the body's natural defenses are elicited to indirectly achieve a desired therapeutic effect. Hence the drug can remain on the surface of the body (for example on the skin), and have its remote immunological effect without penetrating the skin to contact a target cell (such as a dysplastic, neoplastic, or virally infected cell).
  • a target cell such as a dysplastic, neoplastic, or virally infected cell.
  • the drug can also be dispensed in new dosage forms, such as tablets or crystals, which provide prolonged contact with an environment in which immunological stimulation is desired without necessarily bringing the drag into contact with cells that are the target of the therapeutic intervention.
  • new dosage forms such as tablets or crystals
  • Other such dosage forms include containers (such as sealed bandages or impermeable pouches) that may be affixed to the skin to exert their remote immunoactivating property without even directly contacting the body of the subject or penetrating into or through the skin, or by introducing the dosage form into the skin where it exerts its effect in solid (including crystalline) form.
  • Dosage forms can also include tablets or suppositories, which can be introduced into body cavities other than blood vessels (such as the vagina, anus or peritoneum) to dissolve in body fluids that contact a diseased tissue (such as the vaginal cervix, anal epithelium, or peritoneal metastases).
  • a diseased tissue such as the vaginal cervix, anal epithelium, or peritoneal metastases.
  • Certain embodiments of the disclosed compounds are cytotoxic.
  • Exemplary cytotoxic compounds nucleate or self-assemble at a particular tissue, cell or receptor, for example a target cell.
  • such compounds are selectively cytotoxic for a particular cell-type.
  • Targeted self- aggregation at a tumor cell in certain examples is able to achieve localized increases in activity of the drug.
  • the compound is administered by applying it to the skin of the subject, for example by applying it topically in a gel to the surface of the skin, or otherwise introducing it into the skin, for example by intradermal placement of crystals or pellets of the compound.
  • the compound can also be administered by introducing the compound into the body, for example into a diseased organ or a tumor (such as a malignant tumor or metastatic lesion), to stimulate a local immune response, mobilize lymphocytes from the lymphatic system, and direct an immune response at the target organ or tumor.
  • the compound can also be administered in an aerosol preparation for tracheobronchial or oropharyngeal administration.
  • the compound is applied topically to or adjacent a metastatic or epithelial lesion, such as a chest wall breast cancer lesion or a cervical epithelial carcinoma.
  • a metastatic or epithelial lesion such as a chest wall breast cancer lesion or a cervical epithelial carcinoma.
  • the compound is applied to the epithelial or epidermal surface of the subject on an area that is in therapeutically sufficient proximity to the lesion to stimulate the immune response in the target region.
  • a superficial lesion such as a chest wall recurrence of breast tumor or a cervical or anal epithelial cancer
  • the compound is applied directly to the lesion.
  • the compound is not applied to a cutaneous lesion (such as a primary tumor or cutaneous metastasis) but is instead placed on the body surface over a subjacent tumor within the body that the compound does not contact, such that the tumor and compound are separated by an integumentary structure through which the compound does not penetrate.
  • the compound can be applied on or over the skin of the subject to have an anti-tumor effect on neoplastic cells deeper within the body, such as metastatic cells within the lymphatic system, or tumors within organs or structures such as the uterus, breast, anus or prostate.
  • the disclosed compounds can be used to treat an internal or external body surface lesion.
  • Such lesions can include an anogenital lesion, such as a genital or anal lesion, for example a wart or malignancy, such as a primary malignancy.
  • the lesion is an internal lesion, such, as a genital wart of the female reproductive tract, such as a cervical wart.
  • the lesion is a precancerous lesion.
  • the lesion is a papillomavirus associated lesion, such as an HPV-induced lesion.
  • the lesion is a non-venereal wart, such as a plantar wart, filiform wart, flat wart or seborrheic wart.
  • the disclosed compounds can be used to exert a prophylactic effect, such as by treating a precancerous lesion and preventing or delaying neoplasia of the tissue.
  • the compounds are particularly suitable for treating genital lesions caused by a variety of pathologies, including cancers of the vagina and cancers of the external genitalia, such as primary cancers of the penis or vulva.
  • the compound is applied topically to the body surface lesion or introduced into the skin, for example by injection or placement of a pellet into the lesion.
  • the agent is applied in a pad to the lesion, and the pad is left in place over the lesion for an extended period of time, such as one or more days or a week or more.
  • the lesion is a skin lesion induced by infection or inflammation.
  • the lesion may be a virally induced lesion, such as a wart, for example a papillomavirus induced wart.
  • the lesion being treated is a bacterial (for example staphylococcus) or viral (for example herpes virus) infection of the skin, or a skin neoplasm (for example a skin cancer such as a squamous or basal cell carcinoma or a primary melanoma).
  • the immune stimulating activity or PTP activating activity or immunomodulating activity of the compound can be enhanced by exposing the compound to an electromagnetic field (such as a time varying electric field, a time varying magnetic field, and/or a radiating electromagnetic field), for example a field that induces increased resonance modulation of the compound.
  • an electromagnetic field such as a time varying electric field, a time varying magnetic field, and/or a radiating electromagnetic field
  • a field that induces increased resonance modulation of the compound can be induced by placing a magnetic probe in the vicinity of the compound that has been administered to the subject, or by providing a current that flows through the compound between two electrodes, or by a laser that irradiates the compound with laser energy.
  • activity of the immune system can be conveniently up-regulated by applying the compound to a target region of the skin using a convenient patch or pellet, and inducing the electromagnetic field in a manner that increases the resonance modulation of the compound.
  • the resonance modulator on the skin surface acts as a convenient coupler between the externally applied electromagnetic field and the immune system, which can increase immune function particularly locally at the site of the resonance modulator.
  • immune function can be enhanced systemically, remote from the resonance modulating compound.
  • the ability of the compound to interact with PTPs (such as components of the immune system) also allows the compound to be used to monitor immune function.
  • PTP expressing cells such as cellular components of the immune system.
  • the attraction of the immune cells apparently occurs by electrostatically interacting with and attracting dendritic cells and other early phase lymphoid cells. These cells aggregate in the vicinity of the resonance modulator, and change electromagnetic characteristics (such as bioimpedance) in the target region in which they aggregate.
  • the changed electromagnetic characteristics are detectable, for example, as a change in amplitude of the voltage difference detectable across the target area, even in the absence of an applied voltage potential across the electrodes.
  • electrodes are placed in contact with the compound, and the inherent varying voltages are produced by resonance modulation of the compound over time. The amplitude of these varying voltage potentials is used to monitor immune function. For example, a reduction in voltage amplitude between the electrodes as compared to a normal control is an indication of impaired immune function.
  • the amplitude of the waveform may be monitored to determine a response of the subject's immune system to the compound.
  • An increase in the amplitude of the voltage over time indicates that an immune response has occurred (and that immune effector cells such as lymphocytes have migrated to the target region). If the increase in amplitude falls below a predetermined threshold (such as an expected increase of at least 10%, 25% or 50%), then further diagnostic or therapeutic interventions may be undertaken to assess or correct the reasons for the impaired immunity. For example, a rigorous search can be undertaken for infectious, toxic or neoplastic causes of the impaired immune response. Alternatively, the immune response can be upregulated by exposing the resonance modulating compound to an electromagnetic field that induces increased resonance modulation of the compound. Another approach would be to initiate treatment of the subject with appropriate anti-infective or anti-neoplastic chemotherapeutic agents.
  • the disclosed agents are particularly effective for treating a tumor, by administering the agent to the subject (for example by topical application to a target region over or adjacent a cutaneous metastasis).
  • An external electromagnetic field may then optionally be applied to the agent to increase its resonance modulation and thereby increase its immunostimulant effect.
  • the external electromagnetic field may be produced, for example, by a magnetic probe that induces a localized magnetic field, an induced external current applied across electrodes, or a laser that stimulates resonance modulation of the resonance modulating compound.
  • Resulting increased mobilization of antigen presenting cells (such as dendritic cells) and immune effector cells (such as T-cells) to the target region helps direct immunosurveillance and immune effector activity to the tumor target.
  • the agents can be used, for example, to treat a cervical, anal or vaginal carcinoma, such as a carcinoma associated with an HPV infection in which HPV has induced a malignant transformation of the cells.
  • the disclosed agents can stimulate an immune response either through or to a RPTP expressing cell, such as a CD45+ cell, such as a CD45+ T-lymphocyte or a RPTP or CD45+ expressing infected cell.
  • a RPTP expressing cell such as a CD45+ cell, such as a CD45+ T-lymphocyte or a RPTP or CD45+ expressing infected cell.
  • An example of such a cell would be a lymphocyte produced in response to a virally infected cell, such as a cell infected with papillomavirus, for example human papillomavirus (HPV), or an immunodeficiency virus (such as HIV).
  • papillomavirus for example human papillomavirus (HPV), or an immunodeficiency virus (such as HIV).
  • HPV human papillomavirus
  • HIV immunodeficiency virus
  • compound is placed in contact with the subject (for example on or in the skin
  • the compound is a resonance modulator so that the inherent resonance modulation of the compound yields characteristic waveforms of the compound.
  • the waveforms (such as alternation of voltage potentials or other electromagnetic waves) detected from the compound are monitored to detect waveforms produced by the compound that are associated with altered immune function.
  • the waveforms are monitored by detecting voltage changes in the compound over time, for example by detecting waveforms that have a decreased amplitude from an expected increase that would be seen over time.
  • a diagnostic or therapeutic intervention may be undertaken in response to the detection of the waveforms.
  • the intervention can be a diagnostic intervention designed to detect a specific feature of the altered immunity (such as decreased number or function or particular cells involved in the immune response, such as T-lymphocytes) or a cause of the altered immunity (such as infection with an immunodeficiency virus, or the presence of a neoplastic condition, such as a tumor, that alters immune function).
  • detection of altered immunity results in a therapeutic intervention, such as administration of an anti-neoplastic or anti-infectious therapy (such as an antibiotic or antiviral drug), and/or modulating resonance of the compound to enhance immune function.
  • Modulating resonance of the compound can include applying an induced electromagnetic field to the compound that enhances resonance modulation of the compound, which in turn improves immune function.
  • the improved immune function constitutes improved mobilization of T-lymphocytes (such as CD45+ T-lymphocytes) to the site of application of the resonance modulating compound.
  • the disclosed methods also include a method of treating a tumor by exposing the tumor to a therapeutically effective dose of a resonance modulating compound, and applying an external electromagnetic field to the compound to increase its resonance modulation of the compound and thereby increase an anti-tumor effect of the compound to treat the tumor.
  • the method can be used to treat an infection (such as a bacterial infection like Yersinia pestis infection or a viral infection, such as an HPV or HIV infection, or other infections in which a PTP is expressed by the pathogen) by administering a therapeutically effective amount of the compound.
  • the therapeutic amount is sufficient to interact with a PTP extracellular receptor of a cell to activate the receptor.
  • the compound is applied to the skin of the subject, or to an area of infection or neoplasia.
  • the compound may, for example, be applied as a topical gel to the skin of the subject, or to urogenital or anogenital epithelium (such as anal, vaginal or cervical epithelium) that is infected with a papillomavirus (such as HPV).
  • the epithelium is dysplastic or metaplastic epithelium, such as cervical intraepithelial or high grade or squamous intraepithelial neoplasms (CIN/HSIL), anal intraepithelial neoplasms (AIN/HSIL) or a squamous carcinoma.
  • the compound is applied as a 0.25% gel that is applied topically to the subject for a period sufficient to have a therapeutic effect, such as at least five days.
  • gel is applied daily, and/or the effective amount is at least 2 grams of a topical gel containing at least 0.25% of the compound.
  • RPTP+ cells such as lymphocytes (for example CD45+ cells, such as T-lymphocytes) can be concentrated from biological tissue (or in culture) by exposing the biological tissue (or cells) to an effective amount of the agent.
  • that agent is applied to the skin of a subject to concentrate RPTP+ cells (such as lymphocytes) at and around the site of application of the agent.
  • RPTP+ cells such as lymphocytes and/or dendritic cells, can be attracted to any target region of the body in which the agent is introduced, such as a breast, colon or prostate tumor.
  • the agent can be introduced into a tissue culture that contains RPTP+ cells such as lymphocytes and/or dendritic cells to attract them to the agent. Selective concentrations of sub-populations of cells can be achieved in this manner.
  • the agent can also be used to increase the concentration of CD45RO+ and CD45RB+ cells, for example by inducing expression of these cell surface markers. In particular embodiments, selective expression of CD45RO+ occurs, which is involved in cytotoxic activity.
  • Also disclosed herein is a method for stimulating platelet levels, for example by stimulating platelet production, for example in the treatment of thrombocytopenia.
  • One embodiment of this method includes treating a subject having reduced platelet count with a compound disclosed herein.
  • the thrombocytopenic subject has reduced platelet levels as a result of a neoplastic, autoimmune or infectious disorder.
  • the subject has an autoimmune thrombocytopenia, or toxic thrombocytopenia, for example induced by cytotoxic antineoplastic drugs.
  • FIG. 1 is a schematic illustration of the interaction between a conjugated aryl hydrazone and the CD45+ T-lymphocyte surface receptor.
  • FIG. 2 illustrates the structural formula of A-007.
  • FIG. 3 is a schematic illustration of the resonance structures of a conjugated aryl hydrazone.
  • A-007 4,4 '-dihydroxybenzophenone-2,4-dinitrophenylhydrazone
  • AMTR A-007 Magnetic Transistor Resonator An: Antigen
  • APC Antigen Presenting Cell
  • BDP-DNP 2,6-Dibenzylidenecyclohexanone-2,4-dinitrophenylhydrazone
  • DC Dendritic Cell
  • DNP Dinitrophenylhydrazone
  • PTP Protein Tyrosine Phosphatase
  • Alkyl group is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ?-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • a "lower alkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 10 carbon atoms.
  • Aryl group denotes any carbon-based aromatic group including, but not limited to, phenyl, napthyl, fluorenyl, etc.
  • aromatic also includes “heteroaryl groups.”
  • heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, without limitation, nitrogen, oxygen, sulfur, and phosphorous.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl group can be unsubstituted.
  • aralkyl refers to an aryl group having an alkyl group, as defined above, attached to the aryl group.
  • An example of an aralkyl group is a benzyl group.
  • Animal Living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds.
  • mammal includes both human and non-human mammals.
  • subject includes both human and veterinary subjects.
  • Antigen A compound, composition, or substance that can stimulate the production of antibodies or a T-cell response in an animal, including compositions that are injected or absorbed into an animal.
  • An antigen reacts with the products of specific humoral or cellular immunity, including those induced by heterologous immunogens.
  • the term "antigen" includes all related antigenic epitopes.
  • Cancerous Referring to a malignant tumor or lesion. Examples include primary cancer of the penis, vulva, vagina, uterine cervix, or integument.
  • An example of a cancer of the penis is an invasive squamous cell carcinoma.
  • One example of cancer of the vagina is squamous cell carcinoma. Any of these tumors can be treated with the methods described herein.
  • CD Markers Cluster of differentiation (CD) markers that can serve as cell surface markers for different classes of lymphocytes.
  • HLA human leukocyte antigens
  • a certain subset of CD marker is the CD45 marker, which is a leukocyte common antigen (LCA).
  • CD45 RA, CD45RB and CD45RO are restricted LCAs that are a subset of CD45+ cells, and are further described in Roitt, et al., Appendix 2.
  • Chemotaxis Movement of an organism or a single cell, such as a leukocyte, in response to a chemical compound. As used herein, chemotaxis can occur in response to any physical property of the compound, including electrostatic properties.
  • Chemotherapy; chemotherapeutic agents any chemical agent with therapeutic usefulness in the treatment of diseases, for example diseases characterized by abnormal cell growth, such as neoplasms.
  • a chemotherapeutic agent is an agent of use in treating neoplasms such as solid tumors.
  • a chemotherapeutic agent of use e.g. see Slapak and Kufe, Principles of Cancer Therapy, Chapter 86 in Harrison's Principles of Internal Medicine, 14th edition; Perry et al., Chemotherapy, Ch.
  • Derivative is used to refer to a compound or portion of a compound that is derived from or is theoretically derivable from a parent compound.
  • Dendritic cell are the principle antigen presenting cells (APCs) involved in primary immune responses. Dendritic cells include plasmacytoid dendritic cells and myeloid dendritic cells. Their major function is to identify and process antigen in tissues, migrate to lymphoid organs and present antigenic information in order to activate the T-cell cascade. Immature dendritic cells originate in the bone marrow and reside in the periphery as immature cells.
  • DCs are capable of evolving from immature, antigen-capturing cells to mature, antigen- presenting, T cell-priming cells; converting antigens into immunogens and expressing molecules such as cytokines, chemokines, costimulatory molecules and proteases to initiate an immune response.
  • a hydrazone is generally formed by the condensation of a hydrazine with a carbonyl group.
  • An aryl hydrazone is a hydrazone in which at least one of the R groups is an aryl group, for example a phenyl group (a phenylhydrazone).
  • a nitrophenylhydrazone is a phenylhydrazone having one or more NO 2 substitutions on the phenyl ring.
  • Immune response A response of an organism to a foreign (non-self) agent. An immune response to a stimulus is implemented by cells of the immune system, such as a B-lymphocyte, or a T-lymphocyte. In one embodiment, the response is specific for a particular antigen (an "antigen- specific response").
  • Infectious agent An agent that can infect a subject, including, but not limited to, viruses, bacteria, and fungi.
  • Inherent electromagnetic waveforms Waveforms that are produced as a characteristic of a compound, independent of actively induced electromagnetic phenomena, such as intentional application of electrical currents, electrical potentials, or magnetic fields.
  • An example of a waveform is the waveform produced by alternating voltages over time, for example waveforms that alternate between a positive and negative potential, often in a predictable manner (for example as defined by a sine wave).
  • Waveforms can be monitored by a variety of electromagnetic monitoring devices, such as a volt meters that measures an electrical potential across two electrodes in contact with the compound.
  • Intervention is an action taken to detect or affect a physiologic or medical state of a subject.
  • a diagnostic intervention detects the state of the subject, for example by performing a laboratory test, such as a blood test, biopsy, imaging study or physical examination.
  • a therapeutic intervention affects the state of the subject, for example by performing surgery, administering a drug or other treatment, or performing any other therapeutic procedure.
  • Isolated An "isolated" biological component (such as a dendritic cell or lymphocyte, or a population of those cells) has been substantially separated or purified away from other biological components in the cell of the organism in which the component naturally occurs.
  • Laboratory evidence of impaired immunity Objective laboratory data that is generally medically accepted as evidence of reduced immunity, such as a white blood cell count that is below accepted norms in a particular laboratory, reduced lymphocyte (such as T-lymphocyte) concentration, or evidence of generalized impaired activity of any cell of the immune system. In particular examples, the data demonstrate impaired cellular immunity or humoral immunity, or both.
  • Lacking chemical reactivity Certain resonance modulating compounds are electrostatically active but substantially non-reactive under physiological conditions (in the body) because of their resonance stabilization. Such lack of chemical reactivity results in the compound being excreted substantially completely unchanged after systemic (such as oral or intravenous) administration.
  • Leukocyte Cells in the blood, also termed "white cells,” that are involved in defending the body against infective organisms and foreign substances. Leukocytes are produced in the bone marrow. There are 5 main types of white blood cell, subdivided between 2 main groups: polymorphonuclear leukocytes (neutrophils, eosinophils, basophils) and mononuclear leukocytes (monocytes and lymphocytes). When an infection is present, the production of leukocytes increases.
  • Neoplasm An abnormal cellular proliferation, which includes benign and malignant tumors, as well as other proliferative disorders. .
  • Papillomavirus Papillomaviruses are small, nonenveloped viruses with an icosahedral symmetry, capsomere, and a double-strand circular DNA genome of about 8,000 bp. All papillomaviruses have a similar genetic organization. The viral genome is divided into an early region which encodes the genes required for viral DNA replication and cellular transformation, a late region that codes for the capsid proteins, and a regulatory region that contains the origin of replication and many of the control elements for transcription and replication.
  • Papillomarviruses have a high degree of species specificity. There are no known examples of natural transmission of human papillomavirus (HPV) to other species. Papillomaviruses also display a marked degree of cellular tropism, infecting only surface squamous epithelia of the skin or mucosa and producing for the most part benign epithelial tumors. Specific viral types appear to have a preference for either cutaneous or mucosal types. For example, HPV-11 does not readily infect cutaneous epithelium from other body sites but can infect mucosal epithelium of either the genital or the respiratory tract. However the papillomaviruses induce cellular proliferation and transformation that can lead to the development of invasive cancers. HPV infections have been associated with the development of cervical and anal cancers.
  • Genital warts are usually caused by HPV.
  • Papilloma viruses cause small growths (warts) on the skin and mucous membranes. Infection of the genital and anal regions with HPV can cause warts (anogenital condyloma) on the penis, vulva, urethra, vagina, cervix, and around the anus (perianal). More than fifty different types of HPV have been classified. Several types, including 6 and 11, are associated with raised, rough, easily visible genital warts (especially in women). Other types are associated with flat warts. More importantly, several types are associated with pre- malignant and malignant changes in the cervix (abnormal Pap smears). These include types 16, 18, 31, 39, 45, 51, and 52. Research also shows that the presence of both HPV and herpes virus together is a good predictor of the development of cervical cancer.
  • Papillomavirus associated lesion A lesion in which there is evidence of a papillomavirus infection, such as identification of an HPV associated with the lesion.
  • Pharmaceutical agent or drug A chemical compound or composition capable of inducing a desired therapeutic or prophylactic effect when properly administered to a subject.
  • Pharmaceutical agents include, but are not limited to, chemotherapeutic agents and anti-infective agents.
  • compositions useful in this invention are conventional. Remington 's Pharmaceutical Sciences, by E. W. Martin, Mack
  • compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed are suitable for pharmaceutical delivery of the compounds herein disclosed.
  • parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • solid compositions e.g., powder, pill, tablet, or capsule forms
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • purified does not require absolute purity; rather, it is intended as a relative term.
  • a purified preparation of lymphocytes is one in which the lymphocytes are present in a greater concentration than in its natural environment within the body.
  • Resonance Modulator A compound that possesses resonating intramolecular dipole movements (or electrical densities) that allow it to electrostatically interact with biological environments.
  • a resonance modulator is also characterized by the emission of oscillating frequency waves generated by the compound's intramolecular resonance. This resonance is believed to convey the electrical dispositions for interactions with cells of the immune system (such as dendritic cells) to up-regulate and/or enhance immunity.
  • Resonance modulators are capable of attracting immune cells, concentrating them in a target region of the peripheral immune system adjacent the resonance modulator, and in some instances have a distant effect on circulating immune cells (such as immune cells in the peripheral blood and lymphoid tissue such as a lymph node or the spleen). Many resonance modulators have a crystalline structure. Examples of assays for selecting resonance modulator candidates are disclosed in Example 14. '
  • Sigma waves that are recorded from crystals and tissue culture are waves over and above the base line of electrical energy that is generated from the heart and other biorhythms within the body. The sigma waves therefore measure voltage changes with time and amplitude increases with time after exposure to A-007.
  • Subject in need of immunostimulation A subject having a condition that would benefit from general or specific stimulation of the immune system. Examples include subjects with immune deficiencies (such as persons infected with HIV or who have recently received chemotherapy or other immunosuppressive drugs), and persons with conditions that could be improved by the stimulation of an immune response (such as subject infected with a pathogen or tumor that alters immune function, such as a lymphoma).
  • the subject is in need of immunostimulation for a condition other than a tumor, for example because of infection or immunocompromise (for example infectious or pharmaceutically induced immunodeficiency).
  • the subject in need of immunostimulation is a subject having laboratory evidence of impaired immune function.
  • Therapeutically effective dose A dose sufficient to inhibit or prevent advancement, or to cause regression of the disease, or which is capable of relieving symptoms caused by the disease, such as pain or swelling.
  • thrombocytopenia is a term for a reduced platelet (thrombocyte) count. Normal thrombocyte levels are known to those of skill in the art, and those levels are easily determined by • automated means. Normal levels differ among laboratories depending on the detection means used. However, thrombocytopenia leads to reduced clotting and pathological bleeding (for example from the gums, nose, or internal organs).
  • Waveforms associated with altered immune function Waveforms that are noted to be present in subject having an enhanced or decreased immune function.
  • the amplitude of voltage potential waveforms increases over time after a resonance modulating compound is applied to a subject.
  • the increase in amplitude is a consequence of normal immune function, and is indicative of the mobilization of immune cells (such as lymphocytes) and their migration to the site of application of the compound.
  • an increase in amplitude that is below that seen in the same subject at a baseline measurement taken during health, or an increase below a range that is statistically normal in a population of subjects can be taken as associated with altered (impaired) immune function.
  • an increase in amplitude that is greater than normal is an indication of supra-normal immune function.
  • Particular methods disclosed herein concern the use of hydrazone compounds to treat infectious, neoplastic and/or inflammatory conditions.
  • Exemplary methods include convenient and effective treatment for body surface lesions, such as infectious, neoplastic or inflammatory lesions, for example warts.
  • certain compounds act as resonance modulators and act as activators of PTPs.
  • the compound acts as an immunostimulant and/or as a coupling agent between the immune system and external monitors or modulators.
  • the compounds are believed to interact with PTPs, for example interacting with cellular components of the immune system (such as CD45+ receptor lymphocytes or dendritic cells) to promote maturation of immune cells, and recruitment of other cellular components of immunity in an immune response.
  • the ability of compounds to attract immune cells to the vicinity of the modulator also allows an immune response to be directed to a target region within the body (such as a tumor) where an immune response is needed for treatment of a localized condition.
  • the compounds also are capable of eliciting an immune response at distant sites, such as remote lymphatic tissue or metastatic lesions.
  • the compounds therefore provide a novel interface with the immune system that allows information about immune status to be collected and interventions (including manipulation of immune function) to be performed.
  • Resonance structures illustrate composite electronic structures of compounds in which electron density is delocalized. Multiple alternative formal structures are said to be resonance structures, and a molecule can be described as a resonance hybrid of these structures.
  • the conjugated aromatic compounds disclosed herein generally comprise multiple alternative formal structures having delocalized electron density.
  • A-007 2,4- di ⁇ itrophenylhydrazone
  • R 1 is OH
  • R 2 is C 6 H 4 OH
  • X is C 6 H 3 -2,4(NO 2 ) 2 .
  • resonance modulating compounds are also disclosed herein, some of which are shown in the attached FIGS. 12, 16 and 17. These include formyl and acetylbarbituric phenylhydrazone analogs. Another example is 2,6-dibenzylidenecyclohexanone-2,4-dinitrophenylhydrazone
  • X is a nitrophenyl (C 6 H 3 -2,4(NO 2 ) 2 ), R 1 is H, R 2 is unsubstituted phenyl, and R 3 is
  • the resonance modulator compounds disclosed herein including 4,4'- dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007), are particularly suitable to act as a sensor and immune modulator, because they generally have an affinity for cell membrane receptors.
  • A-007 4,4'- dihydroxybenzophenone-2,4-dinitrophenylhydrazone
  • FIG. 1 One example of this affinity for RPTP+ cell membrane receptors is the interaction between A-007 and the CD45+ T-lymphocyte surface receptor, which is illustrated in FIG. 1. These interactions are believed to induce maturation of the cells with which they interact, to promote the immune response.
  • Example 1 Resonance Modulation with Phenylhydrazones
  • This example discloses particularly suitable conjugated aromatic compounds having both modulating and sensor properties.
  • Certain such compounds include polyaryl mononitro- or dinitrophenylhydrazones, such as
  • R 1 is hydrogen, hydroxy, 2- or 4-hydroxyphenyl, acetate, phosphate, azido, nitrile, amino, dimethylamino, sulfate, methylsulfonate, phosphate, nitroso, succinate or another water soluble electrophilic group capable of hydrogen bonding;
  • R 2 is C 6 H 5 , C 6 HiOH, C 6 H 4 N 3 , C 6 H 4 CN, 4-HO- C 6 H 4 -C 6 H 4 , C 6 H 4 OPO 2 OH, C 6 H 4 OSO 2 H, C 6 H 4 NH 2 , C 6 H 4 NHMe 2, C 6 H 4 OSO 2 Me, C 6 H 4 OCO(CH 2 ) X CO 2 H, or C 6 H 5 Cl; and
  • Ar is C 6 H 3 -2,4(NO 2 ) 2 , C 6 H 4 -4(NO 2 ), C 6 H 4 -3(NO 2 ), or C 6 H 3 - 2,4(NO 2 ) 2
  • these chemical structures are able to resonate between multiple dipolar configurations of conjugated electron rich/poor areas that allows/permits migrating intermolecular hydrogen bonding, as well as nucleophilic/electrophilic attractions with complementary sites to exist for moments in time.
  • these resonating mini- dipoles are capable of attracting for example -SH, -COOH, -NH 2 -CH-NH 3 + that are present in amino acids (such as cysteine, threonine, arginine), carbohydrates (mucopolysaccharides) and glycoproteins, all of which are essential components of cellular regulators in the immune system.
  • Certain resonance modulators described herein have a sufficient "electron count” in that they have an excess of electrons for electrostatic interactions.
  • the excess allows attraction of electrophilic/nucleophilic centers that are present in proteins and other biololecules, and they do not need to react (via a transfer of electrons and covalent bond formations) for structure stabilization.
  • simple “flirtations” with the environment are believed to induce changes in other polymolecular configurations, such as the CD45+ receptor, without changing the structure of the resonance modulator.
  • a resonance modulator has the formula above, wherein R 1 is OH, R 2 is C 6 H 4 OH and X is C 6 H 3 -2,4(NO 2 ) 2 (A-007).
  • This compound is highly electronegative.
  • A-007 can be represented in several resonance forms, as illustrated in FIG. 3, as can additional compounds disclosed herein.
  • Representative oscillating frequency waves generated by the hydrazones electrostatically interact with dendritic cells and other early phase lymphoid cellular elements to promote immunity. The interactions can be incorporated into one or more Dirac equation(s) to formulate quantum molecular changes in the skin associated with influxes of potentially selective and diagnostic lymphocyte components.
  • Stabilization of certain resonance forms of the disclosed compounds is believed to occur upon binding, which results in alteration of frequency and electrical effluxes from the test areas as the resonance modulator interacts with lymphocytes.
  • the interactions typically are non-covalent interactions, such as electrostatic interactions.
  • the cycle of resonance will be disturbed by this interaction, and such interference has been monitored (for example by detecting changes in waveforms of voltage over time) and used as an indicator of activity. Variations in the waveform patterns indicate the presence of an evolving cellular immune response (such as the infiltration of dendritic cells and lymphocytes). An absence of expected waveforms or other detected patterns of interference are also useful for detecting an abnormal immune response that requires further investigation and/or treatment.
  • the resonance modulator acts as a coupling agent between immune activity and an external monitor.
  • the resonance modulator is capable not only of detecting cellular immune activity, but it also couples the immune system to external physical modulators that can be used to alter this activity.
  • a magnetic resonator probe may be used to apply a magnetic field to the surface of the skin, for example by applying the probe to or adjacent the skin surface.
  • the magnetic probe activates the resonance modulator, stimulates resonant energy efflux and promotes tissue T-cell contact.
  • AMTR Magnetic Transistor Resonator
  • Some of the disclosed methods therefore concern the use of various resonance modulators, such as hydrazones, that are able to function as quantum chemical modulators/sensors/transmitters of immune profiles. These agents are therefore useful in documenting and treating changes in epithelial surfaces (such as the skin) that are connected via biological networks with lymphatic circuits.
  • Peripheral modulation of lymphocytes and precursor cells in the skin is an early warning network for systemic lymphocytes and a natural mechanism by which living systems detect foreign changes and objects (viruses, bacteria, chemicals, cancer cells, etc). Invasion by cancer and foreign chemical/biological objects can produce electrical and emergent behavioral changes that require monitoring/alterations to insure health.
  • the ability to monitor the status of this peripheral modulation provides an important new medical diagnostic and therapeutic tool.
  • Dihydroxybenzophenone-2,4-dinitrophenylhydrazone have significant anticancer activity in anticancer trials (IND 47,470). Specifically, among fifty-three (53) people treated with topical A-007 (as a 0.25% gel), 37% objective remissions have been observed with ten complete responses.
  • Certain disclosed compounds do not act via a cytotoxic mechanism. This is evidenced, for example, by a substantial absence of A-007 induced local or systemic toxicity. Histochemical assays, from biopsies of human skin topically treated with A-007, confirmed that increased infiltrates of a variety of T-lymphocytes (CD4+, CD3+, CD8+, and CD45+) had occurred during treatment. Increased skin infiltrates of CDl lc+ dendritic cells were also observed in treated areas. Immunohistochemical (IHC) studies to date have found that immune modulation had occurred in vitro and in vivo following exposure to A-007. Hence the compounds disclosed herein can have a therapeutic effect without diffuse cytotoxicity that often causes collateral clinical harm.
  • IHC Immunohistochemical
  • there are at least three unique moieties present in A-007 that may contribute to its overall biological activity - a dihydroxy-diphenylmethane, a hydrazone and a dinitrophenyl moiety.
  • A-007 substantially lacks chemical reactivity under physiological conditions in the human body.
  • the NH on the hydrazone group might ordinarily be predicted to undergo in vivo methylation or acylation, but such modifications are substantially absent when A-007 is administered to a human subject. Indeed, the drug is excreted substantially unchanged.
  • A-007 is very insoluble in body fluids and is not extensively absorbed into the blood. A-007 has not been detected in the blood from any of the subjects who have been treated with topical A-007. Plasma assays of A-007 verify its stability.
  • the lymphatic system includes lymphatic vessels that communicate with other structures and organs that contain lymphatic tissue in a specialized form of reticular connective tissue.
  • Lymphatic vessels include lymph capillaries, which combine into larger lymph vessels (lymphatics) that resemble veins in structure, but have thinner walls and more valves.
  • Lymph nodes are distributed throughout the body, with the most intense concentration in the face and neck, axillae, thoracic cavity, intestines, groin, elbows and knees. Shallow lymphatic channels of the skin generally follow veins, while deeper lymphatics generally follow arteries. These lymphatics function to network lymph fluid throughout the body, but they are also an important distributed aspect of the immune system that functions in surveillance and defense against foreign cells, such as microbes and cancer cells.
  • lymphatic system contains numerous types of lymphocytes. Some of these lymphocytes are T-cells that destroy foreign cells directly or indirectly by releasing cytotoxic substances. Other lymphocytes are B-cells that differentiate into plasma cells that secrete antibodies against antigens to help eliminate them. The lymph nodes filter foreign material carried by the lymph fluid, so that segregated foreign material can then be destroyed by phagocytosis.
  • the spleen, thymus and tonsils are other lymphatic organs that produce B-cells, T-cells, and other lymphocytes.
  • dendritic cells from the lymph system interact with the tumor cells, and recruit other immune effector cells (such as T-Iymphocytes) from lymphatics.
  • T-Iymphocytes immune effector cells
  • CD45+ surface receptors are present on lymphoendothelial cells, and in particular on dendritic cells.
  • Dendritic cells are antigen-presenting cells (APCs) involved in the initiation of the immune response. Serving as immune system sentinels, DCs are responsible for antigen (An) acquisition and subsequent transport to T-lymphocyte rich areas.
  • the DCs are present in lymphatic tissues, such as peripheral cutaneous tissue, as well as in lymphoid organs. Once immature DCs interact with an antigen and become activated, the mature APCs are capable of specific immune responses.
  • the agents disclosed herein, including A-007 are organic molecules, that are sufficiently electrically endowed to act as a hapten/ An, and/or through electromagnetic field effects (EFE), to modulate or up-regulate emergent lymphocyte networks.
  • EFE electromagnetic field effects
  • the disclosed compounds include a new class of renaissance molecules referred to herein as resonance modulators. It is believed that up-regulation of the CD45+ receptor is one initiation site for the A-007-induced immune modulations that are observed in patients with cancer.
  • CD45+ is expressed on dendritic cells, lymphocytes, monocytes, and leukocytes, as well as some neoplastic cells, as a protein tyrosine phosphatase (PTP), which together with other members of the PTPs, are responsible for phosphorylating tyrosine residues.
  • PTP protein tyrosine phosphatase
  • Blockade of the CD45+ receptor sites with anti-CD45 antibodies inhibits T-cell activation and prevents mitogen (lectin) activation of naive T-cells.
  • CD45+ receptor surfaces contain arginine, serine/threonine and cysteine moieties, which can bind to and/or transfer natural ligands to the surface of APCs, as well as hydrolyze tyrosyl phosphates.
  • A-007 do not inhibit or block CD45+, but up-regulate CD45+ lymphocytes and dendritic cells (to APCs) via electrostatic/non-covalent binding with Arg, Cys, Ser/ Threo, etc as illustrated in FIG. 1.
  • Different resonance states of A-007 are capable of interacting with different immune cells.
  • A-007-activated DCs are capable of initiating mitotic events with naive human blood peripheral mononuclear cells (PBMC) and up-regulating both CD45+ and CD 11 c+ receptors in human peripheral dendritic cells.
  • Dendritic cells in cancer tissue are up-regulated from CD45RA+ to CD45RO+/CD45RB+ following exposure to topical A-007 during topical treatment of skin lesions.
  • A-007 is not an inhibitor of CD45+, but an up-regulator or modulator of the molecular sites.
  • A-007 crystal or implanted skin pellet of A-007 to increase both local and more remote immune cell populations (such as splenic dendritic cell populations), and increase concentrations of immune effector cells, such as CD8+ cytotoxic lymphocytes (CTL).
  • CTL cytotoxic lymphocytes
  • A-007 has the ability to interact peripherally in the skin and other epithelial surfaces with dendritic cells to induce maturation of the antigen presenting cell
  • APC cell surface receptor
  • CD45+ cell surface receptor
  • APCs and other early recognition cells are capable of being sensed and modulated with maturation of the lymphocyte recognition cascade - CD4+, CD8+, etc. and associated cytokines.
  • A-007 Some of the unusual properties of A-007 that make it suitable as an immune modulator are illustrated by the ability of its crystals to align in an unusual pattern when evaporated on a glass slide between two electrical wires through which a current was introduced. This arrangement of the crystals was obtained by evaporating an alcoholic (5%) solution of A-007 in air on a glass slide between two wires respectively connected to the positive and negative leads of a 9 volt battery. The A-007 condenses in a circumferential pattern at the positive pole, rather than as a diffuse "spot" over the entire field. When evaporation of the alcoholic solution occurs in a magnetic field, a single line of tightly agglutinated crystals forms down the middle of the slide. Hence A-007 has electromagnetic properties that interact with induced electromagnetic fields. This characteristic can also be used as a screening test for other resonance modulators.
  • A-007 unusual electromagnetic properties of A-007 are further illustrated by the conductance of this compound. This was measured from A-007 crystals, to which two microelectrodes were attached using the magnification of a dissecting microscope. The electrodes were separated by about 1.5 - 2 mm on the crystal surface and the energy was measured from the contact. The Fluke ScopeMeter was used to record the frequency (Hz) generated. No external applied current was involved; hence the measured frequencies represent a natural physical property of the crystals. These excursions from the baseline frequency are believed to be a translational type of energy that is accumulated from the environment and intermittently released. The baseline frequency is likely from ambient electromagnetic radiation.
  • Excursions from the baseline frequency of at least 30-40 Hz is generated by the resonance of the crystals by the intermittent excursions (indicated by the peaks in frequency) from the baseline frequency of about 60 Hz.
  • This ability to emit natural frequencies of energy for example at a frequency of at least 20 Hz from baseline, for example to between 30-40 Hz
  • at least once every five minutes is another example of a characteristic of a resonance modulator that allows resonance modulators to be screened and selected for further testing.
  • naive human lymphocytes obtained from peripheral blood
  • lymphocytes and dendritic cells aggregate around the crystal or pellet.
  • Crystals (0.5 mg) of A-007 were placed into RPMI media containing 5% bovine serum albumin, antibiotic preservatives penicillin/streptomycin, and naive lymphocytes obtained from the buffy coat of blood from a healthy person. After contact with the crystal of A-007, there is agglutination and increased mitotic activity, as well as colonization of activated dendritic cells into the area of the A-007 resonance modulator agent.
  • the ability of an agent to induce aggregation of naive lymphocytes in culture around a test agent is another factor to be considered in determining whether the agent is a resonance modulator suitable for use in the methods disclosed herein.
  • the ability to induce aggregation within one hour is a particularly strong indication that the compound is suitable for further investigation.
  • “Aggregation” refers to a substantial increase in the number of lymphocytes, such as an increase visible by microscopy.
  • Another unusual electromagnetic characteristic of the resonance modulator is that an increase in amplitude of an electromagnetic wave (such as current) can be measured as lymphocytes mature and agglutinate around the crystal.
  • an electromagnetic wave such as current
  • A-007 was condensed on to sterile glass microscope slides, as shown in Fig 4.
  • the dried slide was immersed into a petri dish with RPMI (5% bovine albumin), and a pair of sterile microelectrodes were inserted into the media (about 5 cm apart) and placed in contact with the opposite ends of the line of A-007 and the voltage recorded.
  • the A-007 is not soluble in the media and remains on the slide with continuity. No induction currents were present; hence the measured currents were an inherent characteristic of the resonance modulating compound.
  • After 1-hour of exposure to A-007 there was an increase in amplitude of the measured voltage over time as the lymphocytes migrate to and attach to the A-007 crystals.
  • the crystals do not dissolve, they remain available for continuous interactions. In vitro, the lymphocytes eventually die after about 24 hours from lack of cytokines needed for cellular perpetuation.
  • another characteristic that can be used to select resonance modulators is an ability to increase the amplitude of alternating voltages in an inherent current produced by the resonance modulator when the compound is placed in culture with naive lymphocytes.
  • the compounds described herein can be used to monitor electrical activity associated with the immune system.
  • Exemplary compounds can be used as an analytical device to measure and control immune characteristics, in which there is a linear relationship between T-lymphocyte and frequency responses.
  • the microbalance that exists is due to the fact that mass sensitivity of a 50 Hz A-007 crystal is approximately 0.057 HzCm 2 Hg "1 , which is approximately 50 times higher than that of an electronic fine-balance with a sensitivity of 0.1 ⁇ g.
  • the crystals can be used to measure electromagnetic properties of cellular elements.
  • crystals are chosen the have a mass sensitivity of at least about 0.01, 0.03 or 0.05 HzcnAig "1 .
  • the crystals can be combined with quartz micro-crystals to amplify the electrical interactions (piezoelectric resonator effects) and improve transmission.
  • the quartz microcrystals would be provided in an amount of 10-50% of the total weight of the composition.
  • the crystals are therefore capable of readily transforming interactions between RPTP+ cell (such as lymphocyte) populations and equivalent electrical circuits of the cutaneous tissues which permit a complete description of the oscillations in the presence of the hydrazones and other resonance modulators.
  • the resonance modulators serve as a resonator of dipolar movements and electrostatic interactions with cellular elements, such as cells of the tissue and peripheral immune system. The resonance modulator allows these interactions to be monitored for diagnostic purposes, and altered for therapeutic interventions.
  • the ability to use resonance modulating compounds to monitor immune function permits early diagnosis of a subject's altered ability to recognize a biological insult, such as a toxin or foreign antigen. For example, a subject who has been exposed to a foreign chemical or biological agent may not recognize the exposure and may therefore not respond appropriately. However if the resonance modulator detects a change in function of the immune system, this altered immune status serves as a sentinel event that alerts the subject to a possible unknown toxic exposure. Similarly, subjects exposed to environmental stresses (such as virus/bacteria and traumatic events) may have dendritic cells that do not recognize foreign viruses, chemicals or cancer. Functional impairment of the dendritic cells may allow significant penetration of immune defenses and a threat to life via emergent behavior mechanisms.
  • a biological insult such as a toxin or foreign antigen
  • the resonance modulators may be used in methods to detect and quantitate changes in cellular profiles of the skin that are associated with normal body immunity and natural surveillance activity.
  • Animal studies and human studies have shown that a resonance modulator such as A-007 is not absorbed from the skin but will attract and peripherally activate populations of dendritic cells, CD8+ cytotoxic lymphocytes and other cellular populations that are needed for the natural modulation toward foreign exposure or irritation.
  • aggressive health monitoring and therapies may be pursued.
  • the monitoring device can take the form of a patch that maintains the resonance modulator in contact with the skin of a subject.
  • the patch can be periodically attached to a voltage meter, for example a voltage meter that provides output in the form of a waveform tracing of the type obtained from an oscilloscope.
  • the amplitude of voltage changes over time is then evaluated to determine how the amplitude changes compare to changes that are observed in healthy subjects.
  • the amplitude of the voltage waveforms would be expected to increase by a predetermined value (for example at least 10% or 25%) in the presence of the resonance modulator.
  • An amplitude change that is less than the predetermined value is taken as an indicator of a pathologic insult, such as exposure to a toxin or pathogen.
  • the abnormal test can prompt the initiation of therapy (or more aggressive therapy), such as the administration of chemotherapeutic agents.
  • a piezoelectric crystal may be introduced into the resonance modulator compound to provide maximum A-007 transmission through a transducer effect.
  • Example 5 Additional Examples of Compounds
  • a variety of compounds having immunomodulatory and/or antineoplastic activity are disclosed herein, many of these compounds also have resonance modulating properties. These compounds are capable of treating body surface lesions such as warts and cancers, such as anogenital, genital, reproductive tract, or skin cancers.
  • the compounds have the general formula wherein Ar comprises an aryl group substituted with at least one electron withdrawing group;
  • X is NH, CH 2 , O, — , SO 2 , or B;
  • Y and Y' independently are selected from N, CH and B; n is O or 1; m is from O to 6; R 1 is H, lower alkyl, optionally substituted phenyl or
  • R 4 is an optionally substituted phenyl group
  • R 2 is optionally substituted lower alkyl, aralkyl, thioalkyl, amidoalkyl, amino, amino alkyl, nitro, azido; together with Z forms an optionally substituted 4-7 membered carbocyclic or heterocyclic ring; or together with R 4 forms an optionally substituted phenyl group;
  • R 3 with R 2 forms an optionally substituted phenyl group or is an optionally substituted phenyl group
  • Z is H, lower alkyl, substituted alkyl, thioalkyl, nitrile, amino, or together with R 2 forms an optionally substituted 4-7 membered carbocyclic or heterocyclic ring.
  • Certain embodiments include compounds of the formula above, wherein n is 1 or more. In one embodiment, such compounds are represented by the formula
  • R 5 and R 6 independently are -OR 7 , -SR 7 , -SO 2 N(R 7 ) 2 , -SO 2 CN, -SO 2 R 8 , -SO 2 N 3 , N 3 , -CN, -N(R 7 )C(O)R 8 , -R 7 ;
  • R 7 is H, lower alkyl, carbohydrate, fatty acid, amino acid, peptide, nucleoside or nucleic acid; and R 8 is lower alkyl or C-glycoside.
  • a compound has the formula
  • the compounds having the general formula set forth above have n equal O. Certain examples of such compounds have the formula
  • R 7 and R 8 independently are -OR 5 , -SR 5 , -SO 2 N(R 5 ) 2 , -SO 2 CN, -SO 2 R 6 , -SO 2 N 3 , N 3 , -CN, -N(R 5 )C(O)R 6 , -R 6 ; each R 5 independently is H or lower alkyl; R 6 is lower alkyl; and Ar, X and Y are as described above.
  • R 5 is H, -OR 6 , -SR 5 , -SO 2 N(R 6 ) 2 , -SO 2 CN, -SO 2 R 7 , -SO 2 N 3 , N 3 , -CN, - N(R 6 )C(O)R 7 , or -R 7 ;
  • R 1 and R 5 independently are H or lower alkyl
  • R 2 and R 7 independently are lower alkyl; and Ar is an aryl group as set forth above.
  • the compound is a mono or polyaryl mononitro- or dinitrophenylhydrazone such as
  • R 1 is hydrogen, hydroxy, 2- or 4-hydroxyphenyl, acetate, nitroso, phosphate, azido, nitrile, amino, dimethylamino, sulfate, methylsulfonate, phosphate, succinate or another water soluble electrophilic group capable of hydrogen bonding;
  • R 2 is C 6 H 4 OH, C 6 H 4 N 3 , C 6 H 4 CN, 4-HO-C 6 H 4 - C 6 H 4 , C 6 H 4 OPO 2 OH, C 6 H 4 OSO 2 H, C 6 H 4 NH 2 , C 6 H 4 NHMe 21 C 6 H 4 OSO 2 Me, C 6 H 4 OCO(CH 2 ) X CO 2 H, or C 6 H 5 Cl; and
  • Ar represents an aryl group substituted with one or more nitro moiety.
  • Ar comprises C 6 H 3 -2,4(NO 2 ) 2 , C 6 H 4 -4(NO 2 ), C 6 H 4 -3(NO 2 ), or C 6 H 3 -2,4(NO 2 ) 2 .
  • R 1 is OH
  • R 2 is C 6 H 4 OH
  • X is C 6 H 3 -2,4(NO 2 ) 2 .
  • useful compounds are represented by the structure:
  • Ri is hydrogen, hydroxyl, 2- or 4-hydroxyphenyl, acetate, phosphate, azido, nitrile, amino, dimethylamino, sulfate, methylsulfonate, phosphate, succinate or another water soluble electrophilic group capable of hydrogen bonding;
  • R 2 is C 6 H 5 , C 6 H 4 OH, C 6 H 5 , C 6 H 4 N 3 , C 6 H 4 CN, 4-HO-C 6 H 4 -C 6 H 4 , C 6 H 4 OPO 2 OH, C 6 H 4 OSO 2 H, C 6 H 4 NH 2 , C 6 H 4 NHMe 21 C 6 H 4 OSO 2 Me, C 6 H 4 OCO (CH 2 ) X CO 2 H, or C 6 H 5 Cl;
  • X is C 6 H 3 -2,4(NO 2 ) 2 , C 6 H 4 -4 (NO 2 ), C 6 H 4 -3 (NO 2 ), or C 6 H 3 -2,4(NO 2
  • Ri is hydrogen, hydroxyl, 2- or 4-hydroxyphenyl, acetate, phosphate, azido, nitrile, amino, dimethylamino, sulfate, methylsulfonate, phosphate, succinate or another water soluble electrophilic group capable of hydrogen bonding;
  • R 2 is C 6 H 4 OH, C 6 H 4 N 3 , C 6 H 4 CN, CH 3 , 4-HO-C 6 H 4 -C 6 H 4 , C 6 H 4 OPO 2 OH, C 6 H 4 OSO 2 H, C 6 H 4 NH 2 , C 6 H 4 NHMe 21 C 6 H 4 OSO 2 Me, C 6 H 4 OCO(CH 2 ) X CO 2 H, or C 6 H 5 Cl;
  • X is C 6 H 3 -2, 4(NO 2 ) 2 , C 6 H 4 -4(NO 2 ), C 6 H 4 -3(NO 2 ), or C 6 H 3 -2, 4(NO 2 ) 2 ;
  • G represents -CH 2 -, -C(O)-, -N-, — , -0-, or -S-; n is O or 1 ;
  • R 7 and R 8 independently are -OR 5 , -SR 5 , -SO 2 N(R 5 ) 2 , -SO 2 CN, -SO 2 R 6 , -SO 2 N 3 , N 3 , -CN, -N(R 5 )C(O)R 6 , - R 6 ;
  • Ar comprises an aryl group substituted with at least one electron withdrawing group;
  • X is NH, CH 2 , O, SO 2 , or B;
  • Y and Y' independently are selected from N, CH and B; each R 5 independently is H or lower alkyl; and R 6 is lower alkyl.
  • R 2 is H, lower alkyl or optionally substituted phenyl
  • R 3 is H, or together with R 2 forms an optionally substituted heterocyclic or carbocyclic ring, which optionally is fused to an aryl group
  • R 4 , R 5 and R 6 independently are selected from H, -OH and -OR 7 .
  • the agents can be provided in many forms, such as a crystal, pellet or gel/cream.
  • the agent can be implanted, for example, subcutaneously or applied to an epithelial surface of the patient whose immune system maybe impaired, or who may have come in contact with a lethal or toxic material capable of down-regulating their immune system.
  • the agent can be incorporated into any form (such as a patch, or a two-dimensional or three-dimensional matrix) that brings it into electromagnetic contact with a target site. "Electromagnetic contact” refers to a sufficient proximity to exert its immune modulating effect as described herein.
  • the agent is applied to or over a lesion (such as a tumor or dysplastic epithelium) that is being treated.
  • the agents can also be chemically modified if desired, for example to form polymers.
  • the agent is also useful to detect changes in immune function that are associated with cancer, in which there is a loss of auto- modulation of the immune system.
  • a pellet of A-007 was prepared by pressing 50 mg of the pure compound and sizing it to 16-gauge.
  • Bulk A-007 was prepared using GLP/GMP procedures, with no additives.
  • additives stearic acid, povidone, etc
  • Pellets may be manufactured, for example, in 25 mg, 50 mg and 75 mg doses. Adjustments in pellet concentrations may be made according to the observed physical properties (such as dissolution rates) and animal toxicity.
  • Therapeutically effective doses can be determined by known means, and doses to be administered can be varied depending on the condition being treated, or the severity of a disease.
  • the agents can also be provided in the form of a gel, such as a preparation of propylene glycol/methyl cellulose, for application to a target area (such as a portion of the body) in which it is desired to focus an immune response.
  • the gels may be provided in a tube, such as 50 mg of the active agent suspended in the gel. These gels are particularly convenient for application to the skin or other epithelial surface (for example skin of the chest wall, back, skin of the foot, face or anogenital area, or cervical mucosa).
  • the gel is dispensed from an elongated applicator tube (such as a rectal or vaginal applicator), for example to apply it rectally or intravaginally.
  • the pellet can be inserted into a target region, such as the chest wall.
  • the agent is suspended in tetrahydrofuran (THF) or another non-toxic aerosol, and introduced into to the tracheobronchial or oropharyngeal area to treat cancer of the oral cavity or upper respiratory tract.
  • THF tetrahydrofuran
  • the pellet stimulates the deposition of uric acid crystals, which can result in painful nodules.
  • Application to the surface of the skin is therefore more preferred than insertion into the skin, but either approach will produce the immune modulation described herein.
  • the described agents can both monitor and/or up-regulate immune profiles in the presence of emergent behavioral alterations that are associated with pathological conditions.
  • the monitor is a device for detecting changes in electromagnetic properties of the agent, such as a resonance modulator, as it interacts with a biological system.
  • the interaction can be observed either in vitro or in vivo.
  • the monitor can be applied to a subject, or to biological samples taken from the subject (such as a tissue culture), for further analysis.
  • the resonance modulating agent (A-007) is present on the skin of a patient with lymphoma, as a 0.25% propylene glycol/methyl cellulose gel (0.5 g). Although shown as a gel, it could also be applied as a cream or simple crystals (50 mg) or a pellet (50 - 100 mg) that can be applied on to or inserted into the epithelial surface or the skin (or other surface) with a 16-gauge trochar needle. In one embodiment, the agent is applied to the skin as an orange gel, and covered with a 2 x 3 Tegaderm ® patch with two spaced apart attached skin surface electrode tabs of the type used as electrocardiogram leads.
  • the electrodes are positioned on either side of the gel, in a position that allows them to measure a voltage potential across the gel.
  • the two probes of a voltage meter are then contacted, one probe to each electrode tab.
  • the voltage meter preferably is associated with an oscilloscope that measures changes in voltage over time, so that the amplitude of the detected voltage over time can be seen.
  • the voltage meter is a Fluke® Scopemeter 192/196/199 having software that permits the voltage waveforms to be filtered to remove background voltages, and to be viewed, recorded, measured and analyzed on a computer. Changes in the amplitude of voltage over time are then observed to monitor immune response to the resonance modulator.
  • the electrodes are then subsequently attached to the oscilloscope to monitor amplitude and frequency of electrical transmission from the test site.
  • the amplitude of the voltage changes over time will increase.
  • the tips of the voltmeter probes were again attached to the electrode leads, and the changes in voltage over time were recorded.
  • a measurement was made of the electrical activity associated with agglutination and increased mitotic activity brought about by migration of activated dendritic cells into the target area of the patch.
  • the amplitude of the waveform (as measured from zero) increased by about 25%, from 3 volts to 4 volts.
  • electrodes could also be sensed with an external laser beam sensor that detects changes in local chemical - cellular interactions. Since the chemical is capable of conducting electrical energy via resonance, the chemical will provide signals of stages of cellular interaction associations.
  • a molecular scanner such as a laser could be used to excite the chemical or assay at its absorption wavelength, which is 404 nm for A-007.
  • One such molecular scanner is an Edmund Industrial Optics solid state tunable laser (wave length 425 nm) that is programmed to record or generate specific excitations associated with A-007 resonance and cellular interactions. These high- performance lasers may be programmed to recognize A-007 spectral characteristics on a nano scale much like a bar code scanner.
  • Example 8 Enhancement of Immune Function Modulation The disclosed compounds also provide a relatively simple method to enhance immune function, for example in subjects suffering from impaired immunity.
  • Such subjects may, for example, have an immunodeficiency disease (such as HIV/AIDS) or a toxin induced immune defect (such as leucopenia induced by an antineoplastic chemotherapy drug or an environmental toxin).
  • Other subjects may have an impaired immunity of the kind often seen in subjects with malignant tumors.
  • the subject may have objective laboratory evidence of impaired immunity, regardless of whether the ultimate cause of the impaired immunity is known.
  • the compound can act as a coupling agent or interface with the immune system that allows the immune system to be not only monitored, but also therapeutically manipulated.
  • a targeted immune response can be directed to a target region (such as the vicinity of a tumor) by introducing the agent into or adjacent the target area.
  • Exposing the resonance modulator to an electromagnetic field that stimulates the electromagnetic properties of the agent then stimulates the resonance modulator.
  • the agent can be exposed to an external magnetic or electrical field.
  • One example of such an electromagnetic field is one that signals or tunes the frequency that would provide the highest concentration of a resonant form of the resonance modulator (such as one of the forms of A-007 shown in FIG. 3) to provide maximum interface with cellular receptor surfaces.
  • a laser would be chosen to apply an electromagnetic field in the form of laser energy that possesses similar wave lengths (400-450) to those demonstrated by A- 007.
  • A-007 does not have lasing properties, a programmed laser could recognize its spectra characteristics.
  • a simple magnetic field generated by 2 AA or 3 V batteries could non-specifically activate a surface gel of A-007 or 9 V for a subcutaneous pellet.
  • a more specific tunable laser would be able to scan the area and be more specific about the optimal electromagnetic field to apply. Selecting a desired frequency will increase the amplitude of the voltage changes over time seen in the resonance modulator, and in turn enhance or activate an immune response.
  • a conjugated aromatic compound is applied to the surface of the skin over a target area that contains the tumor.
  • the compound will attract dendritic cells and lymphocytes into the target area, tumors can often evade normal immune surveillance, and it is helpful to further stimulate the immune response by heightening activation of the resonance modulator.
  • a magnetic probe positioned over the area where the compound has been applied to the skin can provide such heightened activation.
  • the magnetic probe is connected to a device that includes an oscillator circuit, a frequency counter, a voltage supply, and an oscilloscope.
  • the device is activated to apply a magnetic pulse to the compound to enhance its resonance modulating properties.
  • An example of a suitable magnetic pulse generator is The Magnetic Pulser, which is a High
  • the Magnetic Pulser (MPG5) is designed to generate an intense ( ⁇ 43,133 Gauss), momentary ( ⁇ 2.5mS) pulsed DC magnetic field that can be used to stimulate the resonance modulator compound.
  • the magnetic pulse can be applied for a sustained period of time, sufficient to enhance the activity of the compound. For example, the pulsed DC magnetic field could be applied for 5-60 minutes or longer.
  • a simple magnetic field generated by 2 AA or 3 V batteries would activate a surface gel of A-007, or a 9 V battery would activate a subcutaneous pellet.
  • a more specific tunable laser would be able to scan the area (such as an area to which the compound has been topically applied) to provide a more specific indication of the electromagnetic field that is to be applied. Selecting a desired frequency of the field applied would maximize the amplitude of the energy produced by the resonance modulator. The duration of time for which the electromagnetic field is applied will depend on the subject's immune status; longer periods of stimulation would be helpful for subject's having a poorer immune status.
  • a general magnetic field may be used
  • a preferred approach is to use a wavelength or energy specific tunable transmitter for wide regions of treatment. The effect of the treatment can be assessed by monitoring immune status with easily available modalities, such as peripheral T-cell flow cytometry analysis. These readily available and convenient tests provide additional guidance in the selection of characteristics of an applied electromagnetic field for a particular resonance modulator.
  • the applied electromagnetic stimulus is an electric field of the type applied in U.S. Patent No. 6,190,893, which is incorporated by reference.
  • the device for electrical stimulation includes a gold wire cathode extending along one edge of the target area, and a silver wire anode positioned along an opposing edge of the target area.
  • An EG&G Princeton Applied Research Potentiostat/Galvostat Model 263 A (Oakridge, TN) is used as the source of constant potential.
  • the electrical stimulus can be applied for a period of at least one hour, at a steady potential of 100 mV.
  • PCT Publication WO 02/102457 which is incorporated herein by reference, discloses such an apparatus that includes a transducer and a generator to apply an AC signal to the transducer, such that an electromagnetic field is generated with a basic frequency between 0.1 Hz and 4000 Hz.
  • a similar device is also shown in U.S. Patent No. 5,968,527, which is incorporated by reference.
  • a bioimpedance device In some situations it is desirable to use a bioimpedance device to both provide a stimulus to the resonance modulator, and monitor the electrical properties of the target area to which the resonance modulator has been applied.
  • Direct bioimpedance measuring systems use a current generator to generate a continuous, constant amplitude and frequency current through a human or animal body segment, for the purpose of measuring tissue conductance. Frequencies in the range of 30KHz-30 MHz have typically been used. Impedence to the continuous current flow in the body segment generates a voltage difference across the body segment, and a bioimpedance meter measures the impedence in the body segment. Examples of bioimpedance devices are shown in WO 01/76475; U.S. Patent No. 4,805,621; and U.S. Patent No.
  • the bioimpedance probe is placed over the target area to which the resonance modulator has been applied, and the voltage difference is introduced across the target area. Changes in bioimpedance are also used to monitor the status of the subject's immune system. It is believed that an increased bioimpedance would be seen as immune status improves.
  • Example 9 Use of the Disclosed Compounds in Treatment of Lymphoma
  • An A-007 0.25% gel (0.5 g) was applied to the skin of a 42 year old patient with lymphoma, as described in Example 7, and there was improvement in the patient's peripheral lymphocyte profile (as measured by a total lymphocyte count) as well as an increase in amplitude of the sigma waves, indicating that there was increased activity in the skin associated with A-007.
  • the sensoring was conducted with a Fluke ® ScopeMeter oscilloscope and a PC program (192/196/199) capable of recording and sorting environmental background noise.
  • the 25% increase in voltage amplitude was considered a positive modulation of immunity in this particular example, which was consistent with the improvement in the lymphocyte profile.
  • PTPs Human protein tyrosine phosphatases
  • Each PTP is composed of at least one conserved domain characterized by an 11 -residue sequence motif containing cysteine and arginine residues, the latter are known to be essential for catalytic activities.
  • the sequences of PTP share no similarity to serine or threonine, acid or alkaline phosphatases.
  • the diversity in structure within the PTP family results primarily from the variety of non-catalytic sequences attached to the NH 2 - or COOH- termini of the catalytic domain.
  • the extracellular-PTPs are one class of PTP receptors that are related to surface recognition and adhesion molecules of leukocyte cell surface recognition.
  • the PTPs are not only associated with human cells, but also present in prokaryotes and viruses, and bacteria.
  • the Yop2b tyrosine-specific PTP is an essential virulence determinant.
  • A-007 fits well into extracellular catalytic receptors of CD45+ PTP subtype.
  • Cervical cancer cells undergo cell death in the presence of crystals of A-007; supporting A-007's ability, through its resonance to catalyze HS - SH dimerization of cysteine residues up-grading the receptor and death. This has been verified in patients with cervical cancer (Table 2).
  • a topical gel with 0.25% of A-007 was administered intravaginally in a dose of 2 grams daily for 5 days.
  • A-007 induced cell death was not observed with benign fibroblasts or healthy epithelial cells that did not contain or had not been transformed by HPV.
  • Topical application of the compounds, including resonance modulators such as A-007 to cervical/vaginal epithelial membranes in subjects infected with HPV results in elimination of cancer cells, as well as the elimination of virus particles, and an up-regulation of CD45RO+CD4+ and CD8+ T-lymphocytes.
  • the ultimate therapeutic effect of the topical application of A-007 was induction of cell death in HIV infected cells (Table 2 and FIGS 10 and 13).
  • A-007 increased the presence of T-lymphocytes, and particularly CD45+, CDl 23+, CD4+ and CD8+ cells.
  • an increase in CD45+, CD4+ and CD8+ cells was particularly noted.
  • increases of CD45RO+, CD45RA+ and CD45RB+ were noted.
  • the disclosed compounds could also be applied as a cream or simple crystals (50 mg) or a pellet (50 - 100 mg) that can be applied on to or inserted into the epithelial surface or the skin (or other surface) with a 16-gauge trochar needle for short-term treatments.
  • HeLa cancer cells undergo necrobiosis and death when incubated with crystals of A-007 for 24 hours. Clear healthy cancer cells migrate to the crystal. Then through cell membrane chemical interphase and modulation of the PTP receptors the cells down regulate, darken with pyknotic changes associated with DNA agglutination resulting in death (lower clumped dark staining cells). The attraction that the crystals have for the cells is associated with intramolecular resonance and associated magnetic patterns.
  • Naive T-lymphocytes are also activated in the presence of A-007 with agglutination of activated lymphocytes+.
  • A-007 and other disclosed compounds can play a unique role in not only sensitizing HPV positive epithelial cells to attack by activated T-cells (Table 2) but also has direct effects on HPV positive cells and A-007 resulting in cell and virus death (Table 2).
  • Table 2 shows that the agent has anti-viral properties as well.
  • A-007 has both up-regulation of CD45+ activities in T-lymphocytes, as well as extracellular membrane deregulation and elimination of cells infected with HIV.
  • HPV infected cervical epithelial cells and T-lymphocytes contain extracellular membrane bound PTPs with which the disclosed agents, including A-007 can interact.
  • the HPV virus may contain an active extracellular PTP receptor, which when exposed to the compounds disclosed herein can undergo a deregulation and death. Regardless of the actual mechanism, the disclosed compounds have been found to have effective anti-viral activity against HPV.
  • T-lymphocytes are activated by a resonance modulator, such as A-007, to promote the presence of surface membrane CD45+RO PTPs, which is believed to occur through HS - SH formation within the catalytic receptor site.
  • CD45+RA T-lymphocytes represent resting or naive cells that are not capable of attacking foreign cells, hence the conversion to CD45+RO markers represents an activation of the cytotoxic arm of the cellular immune system.
  • the resonance modulator had substantial anti-viral (anti-HPV) and anti-neoplastic activity.
  • the proportion of CD45+RO cells increases substantially after treatment with the agent.
  • PTPs such as Yersinia pestis pathogens, or PTP+ cells that are infected with pathogens (such as HPV infected epithelial cells) can also agglutinate with A-007. This agglutination is believed to occur by oxidation of cysteine and disulfide bond formation. This bond formation disrupts cell integrity and cell death - releasing virus.
  • viral PTP cell membrane auto-oxidation occurs with viral inactivation.
  • Most of the patients in Table 1 also possessed HPV+ hyperplastic cervical cells containing HPV induced intranuclear changes (CIN) that cleared with A-007 therapy.
  • CIN HPV induced intranuclear changes
  • the disclosed compounds including resonance modulators such as A-007, have the ability to destroy benign and hyperplastic cells infected with HPV, as well as malignant cells.
  • Anticancer and antiviral activities for hydrazone analogs such as 2,6- dibenzylidenecyclohexaone-2, 4-dinitrophenyl hydrazone, which has improved binding affinities and up-regulation for the PTP CD45 receptor is also potentiated through exposure to ultraviolet light.
  • Ultraviolet light induces Diels-Alder reactions between A-007 and arginine's diimine moiety and adduct formation with cysteine's HS- moiety resulting in up-regulation of the CD45 receptor (FIG. 1).
  • the immune modulating, anti-viral and anti-tumor activities of such resonance modulators can be enhanced by exposing the compound to ultraviolet light.
  • A-007 4,4'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone
  • Table 3 A topical gel containing 0.25% of A-007 (2 grams per day of gel) was applied intra-anally daily for five days, and the observed results are shown in Table 3.
  • BDP-DNP 2,6-Dibenzylidenecyclohexanone-2, 4-dinitrophenylhydrazone
  • compounds disclosed herein provide both a diagnostic and therapeutic interface with the immune system, and which independently have anti- tumor and anti-viral activities (particularly against HPV and HPV infected cells, such as vaginal and cervical cancers associated with HPV infection.
  • CD45+ lymphocytes for example CD45RO+ and CD45RA+ lymphocytes
  • CD45RO+ lymphocytes for example CD45RO+ and CD45RA+ lymphocytes
  • Upregulation of CD45RA+ to CD45RO+ lymphocytes for example when applied to an epithelium of a subject.
  • Possession of inherent electromagnetic properties for example the ability to form a single line of agglutinated crystals between positively and negatively charged points when the crystals are evaporated, or the emission of electromagnetic energy.
  • Possession of properties that affect lymphocyte migration for example inducing aggregation of naive lymphocytes in culture.
  • Certain examples of the compounds are also characterized by an ability to increase the amplitude of alternating voltages waves measured from the compound after it is applied to the skin of an individual.
  • the increased amplitude is reduced in subjects having impaired immunity, such as impaired lymphocyte function.
  • substantially no absorption through the skin is observed when the compound is applied to the skin.
  • such compounds do not satisfy LipinsM's "Rule of 5.” When applied to the skin such compounds may substantially completely remain on the surface of the skin, without transdermal flux.
  • Potential resonance modulators can also be selected based on chemical structures that suggest resonance modulation, namely the structural characteristics described earlier in this specification.
  • polyaryl compounds with electronegativity can be selected, such as Casodex®, Naprelan®, Eulexin®, and Bextra®.
  • lymphocyte blastogenesis Once candidates have been selected as potential resonance modulators, they can be easily assayed to determine whether they induce lymphocyte blastogenesis and activate lymphocytes. Such an assay is found in Morgan et al., Anticancer Research 13:1763-1768 (1993), which is incorporated by reference. See also Janossy et al., Clin. Exp. Immunol. 14:581-596 (1973). Briefly, uptake of [ 3 H]thymidine was measured for lymphocytes in culture. Lymphocytes were cultured in RPMI-1640 tissue culture medium supplemented with 10% fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • tritiated thymidine (2-20 ⁇ Ci/ml, specific activity 2 Ci/mmol) was added to the cells and incubated with them.
  • the uptake of [ 3 H]thymidine was stopped by the addition of cold 10% trichloroacetic acid after a selected period of time, and the radioactivity of the samples measured in a scintillation counter.
  • the % lymphoblast was determined by counting the number of blasts per high powered field (hpf) while % activation was determined by uptake of the rritiated thymidine.
  • the increase voltage was measured with an oscilloscope as in Example 7.
  • This procedure illustrates a correlation between increased amplitude of voltage signals with enhanced activation of lymphocytes.
  • greater increases in amplitude were observed with more vigorous enhancement of lymphocyte activation.
  • This assay can be used to quickly screen resonance modulating agent candidates for immune activating activity. For example, using this assay, an increased voltage amplitude of at least 20% (for example an increased amplitude of at least 50%) can be used as a measure of resonance modulation activity on the immune system. Resonance modulation candidates satisfying such criteria (for example an increase in amplitude of at least 20%) are then selected for further use and study.
  • Example 15 Topical Preparations
  • the compounds disclosed herein can be prepared as topical preparations for application to the skin as immunomodulators, anti-viral agents, or anti-neoplastic preparations.
  • the compound comprises 2,6-Dibenzylidenecyclohexanone-2, 4- dinitrophenylhydrazone (BDP-DNP). It is placed in a topical preparation for application to an epithelial surface, for example by application to malignant epithelium, such as a urogenital neoplasm, such as an anal, vaginal or cervical neoplasm, such as cervical CIN.
  • the compound can be used in methods of treating a tumor (neoplasm) by administering to an affected subject a therapeutically effective amount of the agent to induce regression or elimination of the tumor cells.
  • administering the BDP-DMP comprises applying the BDP-DNP topically to the tumor, although it can also include other forms of administration, such as oral, inhalational, injected or subcutaneous administration.
  • the compound (in this example A-007) in tetrahydrofuran (THF) in 5% solution was aerosoled into the respiratory system of mice under 15 psi of pressure for 30 sec. By releasing the aerosol into a closed chamber in which the mice were present. The treatment resulted in no deaths among the treated mice. Five days later the mice were sacrificed and the pulmonary system was examined by resecting the trachea and lungs en block. Histological examination of the specimens revealed that the bronchial epithelium had increased lymphocyte infiltration (CD8+ and CD4+). Identical patterns of T-cell modulation were seen as with topical applications to the cervix and skin. Controls were treatment with the THF alone with no increases in lymphocyte infiltration observed.
  • Example 17 Active Agent-Receptor Interactions This example describes modeling studies used to evaluate the binding of compounds disclosed herein with receptors, such as CD45. These studies were conducted with Sybyl 6.9.2 (Tripos Inc, St Louis, MO). The models of the compounds were made from Sybyl fragments and then optimized using the MMFF94 force field (with MMFF94 charges). These models were then docked into the IBZC crystal structure active site using FlexX 1.13 and the Drug Score scoring function. FlexX does an incremental fragment based docking where various base fragments of the ligand are docked and then the rest of the ligand is built up from this base fragment placement. Thus, all possible orientations and conformations of the ligand are sampled. Figure 19 illustrates the docking of the compound
  • the illustrated compound has a better binding score than A-007 largely because it is held tighter by ARG 47 at the entrance to the pocket with close contacts to the dihydroxybiphenyl moiety of the compound illustrated above.
  • the illustrated compound has also been found to aggregate where it binds to CD45 and exert a direct cytotoxic activity.
  • Example 18 General procedure for preparation of hydrazones Method 1 : Substituted phenylhydrazines (0.148 mol) were suspended in MeOH (300 mL) at 5O 0 C and concentrated sulfuric acid (20 mL) added with stirring at 5O 0 C. After the hydrazine dissolved, the substituted the substituted benzophenone or aryl ketone (0.1 mol) in MeOH (300 mL) was added with stirring at 5O 0 C over 10 minutes and then stirred for another 30 min. The solvent was evaporated (75%), water (500 mL) added, and the precipitate washed with 3% aqueous NaHCO 3 . Recrystallizations were from EtOH, MeOH, or acetic acid. Complete elemental and spectral analysis were conducted on all products.
  • Method 2 A second general method proceeds as follows: Substituted aryl hydrazines (2.7 mmol) were dissolved in 15 mL MeOH and 2.1 mmol of the ketone added with stirring. Dowex 50W- 50X2-100 cation exchange resin (0.5 g) [Dow Corp., Baton Rouge, LA] was added. The suspension was refluxed for 1 h at 75 0 C on a water bath. The mixture was filtered hot under water vacuum pressure and the resin washed with 3 x 0.5 mL of MeOH. The contents of the collection flask were allowed to cool to room temperature and 20 mL of distilled water added. The colored precipitates were filtered, dried and recrystallized from ETOH or MeOH.
  • A-007 Another unexpected property of the disclosed compounds, such as resonance modulators, for example A-007, is their ability to increase platelet production in subjects who are administered the drugs.
  • subjects receiving A-007 have been found to have enlarged spleens and increased platelet production.
  • This increase in platelet production is particularly advantageous for subjects suffering from thrombocytopenia, for example induced by immune or neoplastic disease or cytotoxic drugs used in the treatment of such diseases.
  • A-007 or resonance modulators or other compounds disclosed herein that are capable of stimulating platelet production are administered to a subject in need of such stimulation.
  • the drugs are administered in any manner described herein.
  • mice that have received A-007 in accordance with the disclosed methods have been found to have enlarged spleens (splenomegaly) and elevated platelet production.
  • the compounds disclosed herein are therefore capable of providing extramedullarly megakaryocyte and platelet production (outside of the bone marrow).
  • the agents disclosed herein can be used in the treatment of a broad variety of body surface lesions, such as warts, HSV blisters, psoriasis and skin cancers. These lesions are treated by applying the agent topically to the lesion for a sufficient period of time to induce disappearance or regression of the lesions. For example, the agent is applied to the surface of the lesion in a 0.25% gel, in a dose of 2 g per day, for 3-10 days. The treatment can be repeated as needed until resolution of the lesion has been achieved. Other treatment regimens can be used. For example, a higher or lower dosage of the active ingredient can be used as clinically appropriate. Therapeutically effective amounts of the drag can be determined by clinicians depending on the clinical circumstances.
  • a total dose of 1-10 g, 2-5 g, or 2-3 g can be administered topically during a treatment regimen.
  • Dosage regimens can be once a day (for example nightly), twice a day, or more often.
  • the total duration of treatment can vary depending on the clinical circumstances (for example daily for 3-10 days, for example daily for 5 days), and the treatment regimens can be repeated at intervals as necessary.
  • treatment can be administered daily for 5 days followed by 25 days of no treatment followed by another course of daily treatment for 5 days.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • AIDS & HIV (AREA)
  • Molecular Biology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés, des compositions et des méthodes permettant d'utiliser ces composés et ces compositions dans le traitement de maladies hyperprolifératives, notamment des maladies précancéreuses et cancéreuses. Dans un mode de réalisation, ces composés contiennent des composés modulant la résonance qui peuvent être utilisés dans lesdites méthodes en tant qu'agent de couplage capable d'interagir avec le système immunitaire afin de surveiller ou de stimuler la fonction immunitaire. Ces modulateurs de résonance présentent des propriétés électromagnétiques inhérentes qui attirent les cellules immunes vers une zone cible sur laquelle l'agent modulant la résonance a été appliqué. Les propriétés électromagnétiques (telles que l'amplitude de tension) de la zone cible sont modifiées en présence du modulateur de résonance et servent d'indicateur de la fonction immune. Un stimulus externe (tel qu'un champ magnétique électromagnétique appliqué) peut également être appliqué au modulateur de résonance afin d'améliorer sa stimulation immune et ses propriétés d'attraction. L'invention décrit des exemples particuliers de modulateurs de résonance et ces substances possèdent généralement des moments dipolaires intramoléculaires de résonance qui sont capables d'interaction électrostatique des environnements biologiques. Dans certains exemples, les composés s'agrègent sur des sites d'action thérapeutique afin d'améliorer l'activité thérapeutique. Dans d'autres exemples, les composés stimulent la production de plaquettes.
PCT/US2006/016824 2005-05-04 2006-05-03 Composes aromatiques conjugues utilise a des fins diagnostiques et therapeutiques WO2006119284A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BRPI0612330-9A BRPI0612330A2 (pt) 2005-05-04 2006-05-03 compostos aromÁticos conjugados para diagnàsticos e terapia
CA002606599A CA2606599A1 (fr) 2005-05-04 2006-05-03 Composes aromatiques conjugues utilise a des fins diagnostiques et therapeutiques
JP2008510132A JP2008540428A (ja) 2005-05-04 2006-05-03 診断と治療のための共役芳香族化合物
EP06758930A EP1888053A2 (fr) 2005-05-04 2006-05-03 Composes aromatiques conjugues utilise a des fins diagnostiques et therapeutiques
MX2007013762A MX2007013762A (es) 2005-05-04 2006-05-03 Compuestos aromaticos conjugados para diagnostico y terapia.
AU2006242244A AU2006242244A1 (en) 2005-05-04 2006-05-03 Conjugated aromatic compounds for diagnosis and therapy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US67808905P 2005-05-04 2005-05-04
US60/678,089 2005-05-04

Publications (2)

Publication Number Publication Date
WO2006119284A2 true WO2006119284A2 (fr) 2006-11-09
WO2006119284A3 WO2006119284A3 (fr) 2007-01-11

Family

ID=36954402

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/016824 WO2006119284A2 (fr) 2005-05-04 2006-05-03 Composes aromatiques conjugues utilise a des fins diagnostiques et therapeutiques

Country Status (9)

Country Link
EP (1) EP1888053A2 (fr)
JP (1) JP2008540428A (fr)
KR (1) KR20080015426A (fr)
CN (1) CN101262859A (fr)
AU (1) AU2006242244A1 (fr)
BR (1) BRPI0612330A2 (fr)
CA (1) CA2606599A1 (fr)
MX (1) MX2007013762A (fr)
WO (1) WO2006119284A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007025186A3 (fr) * 2005-08-26 2007-06-28 Dekk Tec Inc Traitement de lesions cutanees a base d'hydrazones

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4805621A (en) 1986-06-16 1989-02-21 Siemens Aktiengesellschaft Apparatus for measuring impedance of body tissue
WO1992001050A1 (fr) 1990-07-11 1992-01-23 New York University Nouvelle phosphotyrosine phosphatase de type recepteur
WO1994005276A1 (fr) 1992-09-08 1994-03-17 Morgan Lee R Composes cytotoxiques
US5529072A (en) 1995-03-17 1996-06-25 Sramek; Bohumir System for detection of electrical bioimpedance signals
US5968527A (en) 1997-02-27 1999-10-19 Catholic University Of America, The Protection of living systems from the adverse effects of stress
US6190893B1 (en) 1998-09-18 2001-02-20 Massachusetts Institute Of Technology Electroactive materials for stimulation of biological activity of bone marrow stromal cells
WO2001076475A2 (fr) 2000-04-07 2001-10-18 The Johns Hopkins University Detecteur de tumeur de la prostate chez l'homme
WO2002102457A1 (fr) 2001-06-14 2002-12-27 Georges Vanroy Dispositif destine a appliquer un champ electromagnetique au corps d'un etre vivant

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4732904A (en) * 1984-12-24 1988-03-22 Morgan Lee R Antiestrogenic hydrazones
WO2004078174A1 (fr) * 2003-02-28 2004-09-16 Morgan Lee R Modulateur a resonance pour le diagnostic et la therapie

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4805621A (en) 1986-06-16 1989-02-21 Siemens Aktiengesellschaft Apparatus for measuring impedance of body tissue
WO1992001050A1 (fr) 1990-07-11 1992-01-23 New York University Nouvelle phosphotyrosine phosphatase de type recepteur
WO1994005276A1 (fr) 1992-09-08 1994-03-17 Morgan Lee R Composes cytotoxiques
US5529072A (en) 1995-03-17 1996-06-25 Sramek; Bohumir System for detection of electrical bioimpedance signals
US5968527A (en) 1997-02-27 1999-10-19 Catholic University Of America, The Protection of living systems from the adverse effects of stress
US6190893B1 (en) 1998-09-18 2001-02-20 Massachusetts Institute Of Technology Electroactive materials for stimulation of biological activity of bone marrow stromal cells
WO2001076475A2 (fr) 2000-04-07 2001-10-18 The Johns Hopkins University Detecteur de tumeur de la prostate chez l'homme
WO2002102457A1 (fr) 2001-06-14 2002-12-27 Georges Vanroy Dispositif destine a appliquer un champ electromagnetique au corps d'un etre vivant

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Molecular Biology and Biotechnology: a Comprehensive Desk Reference", 1995, VCH PUBLISHERS, INC.
"The Encyclopedia of Molecular Biology", 1994, BLACKWELL SCIENCE LTD.
BENJAMIN LEWIN: "Genes V,", 1994, OXFORD UNIVERSITY PRESS
CHARBONNEAU ET AL., PROC. NATL. ACAD. SCI., vol. 85, 1988, pages 7182 - 7186
COBBOLD ET AL.: "Leucocyte Typing III", 1987, pages: 788 - 803
RALPH, S. J., EMBO J., vol. 6, 1987, pages 1251 - 1257
STREULI ET AL., J. EXP. MED., vol. 168, 1988, pages 1523 - 1530
TSAI ET AL., J. BIOL. CHEM., vol. 266, no. 16, 1991, pages 10534 - 10543
WEISS A., ANN. REV. GENET, vol. 25, 1991, pages 487 - 510

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007025186A3 (fr) * 2005-08-26 2007-06-28 Dekk Tec Inc Traitement de lesions cutanees a base d'hydrazones

Also Published As

Publication number Publication date
CA2606599A1 (fr) 2006-11-09
JP2008540428A (ja) 2008-11-20
BRPI0612330A2 (pt) 2009-01-27
CN101262859A (zh) 2008-09-10
KR20080015426A (ko) 2008-02-19
EP1888053A2 (fr) 2008-02-20
AU2006242244A1 (en) 2006-11-09
MX2007013762A (es) 2008-03-14
WO2006119284A3 (fr) 2007-01-11

Similar Documents

Publication Publication Date Title
US8486697B2 (en) Inducing cell death by inhibiting adaptive heat shock response
JPH07179351A (ja) リンホカイン生産刺激剤
US20070049514A1 (en) Resonance modulator for diagnosis and therapy
CN114940679B (zh) Sting激动剂前药化合物及其制备方法和应用
Chen et al. Sono-immunotherapy mediated controllable composite nano fluorescent probes reprogram the immune microenvironment of hepatocellular carcinoma
da Conceição et al. Structural design, synthesis, and anti-Trypanosomatidae profile of new Pyridyl-thiazolidinones
WO2006119284A2 (fr) Composes aromatiques conjugues utilise a des fins diagnostiques et therapeutiques
US20090247641A1 (en) Hydrazone agents to treat cutaneous lesions
RU2369402C1 (ru) Химерный пептид для лечения эпителиальных и мезенхимальных злокачественных новообразований
JP2001513070A (ja) レチノイドおよびその使用方法
Ramachandran et al. An in vitro study of electroporation of leukemia and cervical cancer cells
CN114014862A (zh) 一种治疗脑胶质瘤的新化合物及其制备和应用
CN116675693A (zh) 苯并二咪唑类化合物及其制法和药物用途
US20240066008A1 (en) Device and Antitumor Drug for the Treatment of Neoplastic Cells
KR20090090460A (ko) 이미다조퀴놀린을 함유하는 대장암 항암제 및 방사선항암치료 보조제
CN119219708A (zh) 一种四价铂类自噬诱导剂及其制备方法与应用
TW202345936A (zh) 藉由使用TTFields活化STING途徑以降低癌細胞生存力的方法
JP2022527296A (ja) 卵巣の悪性ラブドイド腫瘍および卵巣高カルシウム血症型小細胞がんを処置する方法
Li et al. Design, Synthesis and Biological Evaluation of Dual JMJD3 and HDAC Inhibitors for Potential Cancer Therapy
CN114699416A (zh) 葫芦素b在抗结膜黑色素瘤中的应用
KASZUBA-ZWOINSKA et al. E. ROKITA 2, J. MARCINKIEWICZ 3, W. ZARASKA 4, P. THOR 1 PULSATING ELECTROMAGNETIC FIELD STIMULATION PREVENTS CELL DEATH OF PUROMYCIN TREATED U937 CELL LINE

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200680020751.3

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 12007502385

Country of ref document: PH

ENP Entry into the national phase

Ref document number: 2606599

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2008510132

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/a/2007/013762

Country of ref document: MX

Ref document number: 4194/KOLNP/2007

Country of ref document: IN

Ref document number: 2006242244

Country of ref document: AU

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2006242244

Country of ref document: AU

Date of ref document: 20060503

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: RU

WWE Wipo information: entry into national phase

Ref document number: 2006758930

Country of ref document: EP

Ref document number: 1020077028299

Country of ref document: KR

ENP Entry into the national phase

Ref document number: PI0612330

Country of ref document: BR

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载