Imidazoquinoline compounds that possess anti-inflammatory, antifungal, antiparasitic, and anticancer properties.

Abstract

Imidazoquinoline compounds are described that have activity against inflammation, fungi, unicellular parasitic microorganisms, and cancer.

Description

Background Art

[0001] Whether a single-celled organism or a multicellular organism including humans, most nucleated eukaryotic cells contain acidified vacuoles that are very important for cell maintenance and function. In mammalian cells, these vacuoles include lysosomes and other endosomal vesicle organelles. The pH inside lysosomes is usually about 4.5 - 5, and is maintained by vacuolar ATP-dependent proton pumps and the Donnan equilibrium effect. Lysosomes contribute to the pH buffering of the cytoplasm, protect the cell from an acidic environment, and are also a major site for decomposing and recycling the components of aged or damaged organelles, such as mitochondria, in a process known as autophagy. There are several important pathological conditions in which changes in the characteristics of lysosomes contribute to the development of diseases, and these are potential targets for drug therapy.

[0002] There is growing evidence that a common phenotypic change in invasive cancer cells is lysosomal redirection, which is involved in the destruction of surrounding cells via exocytosis of acidic contents containing enzymes. Proteolytic enzymes such as cathepsins, normally found in lysosomes but secreted by cancer cells, can degrade extracellular matrix proteins, potentially promoting tumor invasion and metastasis. Furthermore, lysosomes and other acidic vacuolar organelles often enlarge within cancer cells, which contributes to pH buffering; many solid tumors generate an acidic extracellular environment that promotes invasion, requiring cancer cells to adapt to both the generation and tolerance of low extracellular pH. Cancer cells selected in vitro for their potential for invasion are larger and have more acidic lysosomes than less aggressive cells. Cancer cells exposed to ionizing radiation undergo a defensive response involving lysosomal enlargement and acidification. The defensive response associated with cancer cells gaining a survival advantage is the activation of autophagy. Autophagy activation involves the fusion of autophagosomes containing damaged organelles or other cellular debris with lysosomes. Disruption of autophagy can impair the viability of cancer cells. Some cancer cells also sequester chemotherapeutic agents into lysosomes as a mechanism of drug resistance. Chloroquine, an antimalarial drug that accumulates in mammalian lysosomes, enhances the anticancer activity of cancer treatments with multiple classes of chemotherapeutic agents and targeted small molecules and antibodies, or restores sensitivity to them. Lysosomal-targeting fluorescent dyes, such as acridine orange, can be used to visually distinguish tumors from surrounding tissues in situ, suggesting the potential for strict differentiation of specific lysosomal-targeted cytotoxic substances for selectively killing cancer cells.

[0003] Lysosomal alterations are also a key feature of common inflammatory diseases, particularly those involving activated macrophages, and the exocytosis of lysosomal enzymes, cytokines, and certain inflammatory mediators such as HMBG1, which are processed and released via lysosomes, may be involved in tissue damage, both local and systemic. Glucocorticoid signaling is also lysosomal, so impaired lysosomal function may enhance anti-inflammatory pathways that mediate glucocorticoid effects.

[0004] Most fungi possess acidic vacuoles similar to lysosomes. These acidic vacuoles are crucial for ion and pH homeostasis, amino acid storage, autophagy, and the processing of some proteins. Vacuoles are proton pumps, including vacuolar H2 cells. + Fungi that are acidified by -ATPase, or "V-ATPase," and that possess inactivating mutations in V-ATPase subunits that cause impaired vacuolar acidification, are also known to lose virulence and exhibit reduced growth. Ergosterol, a steroid that is a major and specific membrane component of fungal membranes, is crucial for the conformation and activity of V-ATPase, and V-ATPase dysfunction is considered to be the main mechanism of antifungal activity of ergosterol synthesis inhibitors, which include some classes of existing antifungal agents.

[0005] Antifungal agents that act by binding to specific proteins, such as enzyme inhibitors, are inherently vulnerable to the development of drug resistance due to single mutations in the gene encoding the target protein. Drugs that target fungi through appropriate specific targeting and disruption of the fungal acidic vacuole by cation trapping may be less susceptible to the development of resistance due to point mutations than drugs that act by binding to specific protein targets, because impaired vacuolar acidification leads to impaired survival and virulence.

[0006] Clinically important antimalarial drugs are known to accumulate in acidic vacuoles and lysosomes, and their bioactivity is primarily mediated by concentration in acidic vacuoles not only in malaria but also in inflammatory diseases, some cancers, and non-malarial infections caused by fungi and unicellular and protozoan parasites. Quinoline analog antimalarial drugs target malaria parasites via cation traps in acidic digestive vacuoles, which can accumulate to concentrations several orders of magnitude higher than in the extracellular space. Large mole fractions of chloroquine, mefloquine, quinacrine, and some of their homologues are uncharged at normal extracellular pH of approximately 7.4 and cytoplasmic pH of 7.1, and therefore can pass through cell membranes and organelle membranes. In acidic environments such as inside lysosomes or fungal acidic vacuoles, these antimalarial drugs are primarily cationic, and therefore their free passage through the vacuolar membrane is restricted. Antimalarial drugs such as chloroquine account for much / most of the specific toxicity to malaria parasites because they impair the processing of heme from hemoglobin after hemoglobin ingested by the parasite accumulates in the phagocytic vacuole. However, chloroquine and similar quinoline analog antimalarial drugs may accumulate in mammalian lysosomes and fungal acidic vacuoles, impairing vacuolar function to a degree sufficient to produce clinical effects by partially deacidifying the vacuoles. Chloroquine is used to treat chronic autoimmune and inflammatory diseases such as systemic lupus erythematosus or rheumatoid arthritis, and has moderate efficacy. Antimalarial drugs such as chloroquine or quinacrine have been reported to have some antifungal activity, both as monotherapy and in combination with other classes of antifungal agents such as fluconazole, particularly in animal models of systemic cryptococcosis. However, their activity is suboptimal, and the inhibition of fungal growth is incomplete. Recent studies have also demonstrated moderate growth inhibitory activity of other weakly cationic drugs such as chloroquine, mefloquine, and cyramesin in animal models of cancer. Therefore, existing lysosomal-targeting agents, such as the antimalarial drug quinoline compounds, may exhibit therapeutically relevant activity in diseases in which acidic vacuoles contribute to the pathogenesis.However, the activity and efficacy of antimalarial drugs in such diseases are limited because target cells can tolerate relatively high concentrations of antimalarial drugs (the specific lethal effect of quinoline compounds in malaria is primarily due to the disruption of heme processing within the protozoan phagocytic vacuole, a cytotoxic mechanism not applicable to the fields of inflammatory diseases, cancer, or fungal infections). Despite a body of evidence suggesting the potent potential of targeting lysosomes in cancer treatment, existing drugs have not demonstrated adequate activity or therapeutic index for effectively treating cancer in humans.

[0007] Lysosome-targeting surfactants contain a weakly cationic heterocyclic moiety supporting a single alkyl chain with approximately 10-14 carbon atoms and have been reported to exhibit potent cytotoxicity to mammalian cells and broad antifungal activity in vitro. This class of drugs accumulates in lysosomes and acidic vacuoles via the same type of cation trapping process that concentrates antimalarial drugs, and acts as a surfactant upon reaching critical micelle concentrations within the vacuole, damaging the vacuolar membrane. They exhibit characteristic sigmoid dose-response curves as a result of micelle microstructure formation. However, there is no information available regarding the in vivo activity or safety of this class of drugs in animal models of related diseases. [Overview of the project]

[0008] The present invention provides the following compound: 2-(3-phenoxybenzyl)-1H-imidazo[4,5-c]quinoline and its pharmaceutically acceptable salts.

[0009] The present invention also provides a use or method for treating or preventing a condition in a mammalian subject; the condition is selected from the group consisting of inflammatory diseases, fungal infections, single-celled parasitic infections, and neoplastic diseases; the use or method comprises administering an effective amount of the compound or salt of the present invention to the subject. Compositions comprising the compound or a salt thereof are also provided. The present invention also provides a method for inhibiting fungi ex vivo, comprising contacting a surface or fungi with the compound or salt. [Brief explanation of the drawing]

[0010] [Figure 1] This shows the survival rate of A549 cancer cells incubated with compound AF or GE for 48 hours. [Figure 2] This shows the survival rate of A549 cancer cells incubated with compound AF or GE for 72 hours. [Figure 3] This shows the survival rate of PC3 cancer cells incubated with compound AF or GE for 48 hours. [Figure 4] This shows the survival rate of PC3 cancer cells incubated with compound AF or GE for 72 hours. [Figure 5] This shows the ear thickness of mice with imiquimod-induced dermatitis treated with the compound GE. [Figure 6A] This shows the PASI cutaneous erythema score (0-4) in mice with imiquimod-induced psoriasis-like dermatitis treated with the compound GE. [Figure 6B] This shows the PASI skin thickening score (0-4) in mice with imiquimod-induced psoriasis-like dermatitis treated with the compound GE. [Figure 6C] This shows the PASI skin desquamation score (0-4) in mice with imiquimod-induced psoriasis-like dermatitis treated with the compound GE. [Figure 6D] This shows the cumulative PASI score (0-12) in mice with imiquimod-induced psoriasis-like dermatitis treated with the compound GE. [Modes for carrying out the invention]

[0011] While not wishing to be bound by theory, the present invention provides compounds and uses thereof for treating diseases characterized by pathogenic cells having disease-related changes that facilitate the accumulation of the compounds of the present invention in lysosomes or other acidic vacuoles, thereby selectively inactivating or eliminating the pathogenic cells. The compounds of the present invention are characterized by a significant improvement in potency and activity over known aminoquinoline drugs such as chloroquine, as a result of structural components that potently disrupt the integrity of the lysosomal membrane or vacuolar membrane when the compounds accumulate in the acidic vacuoles within cells. Diseases that respond at least moderately to antimalarial quinoline derivatives and analogs are generally more effectively treated with the compounds of the present invention. Such diseases broadly include inflammatory diseases, neoplastic diseases including both hematological and solid tumors, and infections by eukaryotic pathogens, such as fungi and several classes of protozoa or other single-celled parasites.

[0012] definition Certain compounds are referred to herein by their chemical names or the two-letter codes shown below. Compound GE is a compound of the present invention. Compound AF is disclosed in WO2014 / 120995A2 (Wellstat Therapeutics Corp.). GE 2-(3-phenoxybenzyl)-1H-imidazo[4,5-c]quinoline AF N-(3-phenoxybenzyl)quinoline-4-amine

[0013] As used herein, the transitional phrase “comprising” is open-ended. Claims using this term may include elements in addition to those described in such claims.

[0014] The following abbreviations are used in the chemical synthesis examples and elsewhere in this specification. DCM Dichloromethane DMAP 4-(N,N-dimethylamino)pyridine DMF (N,N-dimethylformamide) EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOH Ethanol EtOAc Ethyl acetate MeOH Methanol TEA Triethylamine TFA Trifluoroacetic acid TLC Thin layer chromatography

[0015] Use and method of treatment The present invention provides certain compounds described below for treating diseases characterized by pathogenic cells characterized by lysosomes or other acidic vacuoles having disease-related changes in which the compounds of the present invention tend to accumulate, and then selectively inactivate or remove pathogenic cells thereby.

[0016] The compounds of the present invention are characterized by a marked improvement in efficacy and activity over known aminoquinoline drugs such as chloroquine as a result of a structural moiety that potently disrupts the integrity of the lysosomal membrane or vacuole membrane when the compound accumulates in acidic vacuoles within cells. Diseases that are at least moderately responsive to antimalarial drug quinoline derivatives and analogs are generally treated more effectively with the compounds of the present invention. Such diseases widely include inflammatory diseases, neoplastic diseases including both blood cancers and solid tumors, and infections by eukaryotic pathogens such as fungi and several classes of protozoa or other single-celled parasites.

[0017] Use as an anti-inflammatory agent An important effect of the compounds of the present invention is anti-inflammatory activity, providing utility for treating or preventing diseases or conditions associated with excessive tissue inflammation. The present invention also provides compositions containing the compounds of the present invention, as well as the use of the compounds of the present invention for the manufacture of medicaments for the treatment or prevention of inflammatory diseases. The compounds of the present invention selectively suppress or inactivate macrophages stimulated in an inflammation-inducing state, but have little effect on unstimulated macrophages. Activated inflammation-inducing macrophages contribute to the development of a variety of inflammatory and autoimmune diseases. Macrophages are both antigen-presenting cells and effectors against tissue damage induced by autoreactive T cells, and are involved in tissue damage and dysfunction in diseases including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and atopic dermatitis. Inflammatory macrophages are involved in many systemic diseases such as autoimmune diseases, cardiovascular diseases and metabolic diseases, and neurodegenerative conditions. Activated macrophages play a major role in tissue damage associated with the instability of atherosclerotic plaques, resulting in a risk of rupture and thrombotic vascular occlusion. Activated macrophages in adipose tissue contribute to metabolic abnormalities including insulin resistance, type 2 diabetes, and other consequences of obesity. Osteoclasts are macrophage-like cells that mediate bone degeneration in osteoporosis and are involved in bone destruction and "bone pain" in cancers that have originated in bone or metastasized to bone. The compositions of the present invention are useful for treating these and other diseases in which activated macrophages contribute to the development of inflammatory diseases.

[0018] Multiple classes of topical medications are used to treat inflammatory skin conditions such as atopic dermatitis, eczema, or psoriasis. Corticosteroids are widely used, but especially with long-term use, they can cause both local and systemic toxicity. Corticosteroids cause local skin atrophy or thinning, which can lead to skin destruction and telangiectasia. Furthermore, topical corticosteroids may be absorbed systemically in amounts sufficient to cause systemic side effects. A second class of medications for treating atopic dermatitis are T-cell immunosuppressants such as tacrolimus and pimecrolimus, which are calcineurin inhibitors. Their local and systemic immunosuppressive effects raise concerns that they may reduce immune surveillance for cancers such as melanoma and lymphoma.

[0019] Vitamin D analogs, particularly calcipotriene, are known for their use in the topical treatment of psoriasis. Calcipotriene works by inhibiting the excessive proliferation of keratinocytes. Topical application to normal skin is contraindicated due to its bleaching effect and the possibility of adverse events due to systemic absorption. Skin irritation or itching are known side effects of calcipotriene. The compounds of the present invention are particularly active against macrophage precursors activated by exposure to vitamin D3. While calcipotriene treatment of psoriasis provides some improvement by inhibiting keratinocyte proliferation, it can induce a pro-inflammatory state in topical macrophages, contributing to known side effects such as irritation and potentially limiting the overall therapeutic effect. Given the ability of the compounds of the present invention to inactivate pro-inflammatory vitamin D3-stimulated macrophage precursors, topical treatment of the compounds of the present invention in combination with vitamin D analogs may offer unexpected benefits in psoriasis and psoriatic dermatitis, both in treating the excessive proliferation of inflammatory epidermis and in reducing irritation or itching as a side effect of vitamin D analogs.

[0020] The compounds of the present invention are useful in treating ocular inflammation, including keratitis caused by infection (fungus, bacteria, amoeba), corneal injury, or non-infectious triggers such as contact lenses. The compounds of the present invention are particularly suitable for fungal keratitis and are effective against both infectious fungi and concurrent inflammatory damage. The compounds of the present invention inhibit corneal neovascularization and other inflammatory changes in response to mechanical or chemical injury.

[0021] The compounds of the present invention are useful for treating a variety of inflammatory or hyperproliferative skin conditions or lesions, including but not limited to eczema, atopic dermatitis, psoriasis, and impetigo. Impetigo is a skin infection caused by superficial bacteria with inflammatory damage to the epidermis, and the compounds of the present invention have a direct inhibitory or bactericidal effect against Gram-positive bacteria, including but not limited to Staphylococcus aureus and Streptococcus pyogenes, which are the main organisms involved in impetigo and suppress inflammation together. The compounds of the present invention also inhibit pre-tumor and neoplastic skin changes, which often exhibit both inflammatory and neoplastic characteristics, including but not limited to actinic keratosis, seborrheic keratosis, and warts.

[0022] Macrophages and related cell types contribute to the pathogenesis of autoimmune diseases with adaptive immune systems, both as antigen-presenting cells and as effectors that damage tissues after inappropriate stimulation by T cells, thereby secreting interferon-gamma and other inflammatory mediators that mobilize and activate macrophages. The compounds of the present invention disrupt antigen presentation by macrophages and dendritic cells, and also inactivate macrophages as pro-inflammatory effectors that damage tissues. General guidelines indicate that the compounds of the present invention are useful in treating chronic or paroxysmal autoimmune diseases in which chloroquine, hydroxychloroquine, or other antimalarial drugs such as quinoline analogs are active in human or related animal models, and are generally more potent and active than antimalarial drugs in inflammatory and non-malarial infectious diseases. Such diseases include, but are not limited to, rheumatoid arthritis, systemic discoid lupus erythematosus, psoriatic arthritis, vasculitis, Sjögren's syndrome, scleroderma, autoimmune hepatitis, and multiple sclerosis.

[0023] Macrophage activation syndrome (MAS) is an acute complication of several autoimmune diseases, particularly in childhood-onset conditions such as idiopathic juvenile arthritis (affecting more than 10% of patients) and inflammatory bowel disease. In MAS, when macrophages are hyperactivated, they cause damage to the hematopoietic system and systemic inflammation, and MAS can sometimes be fatal. The compounds of the present invention are useful for the treatment of MAS and may be delivered orally, or by intravenous injection or infusion.

[0024] In the treatment of chronic autoimmune disorders, the compounds of the present invention are administered systemically, preferably orally. In the treatment of acute inflammatory conditions or relapses of autoimmune diseases, intravenous treatment using the compounds of the present invention is any suitable delivery route.

[0025] For the oral or intravenous treatment of autoimmune or inflammatory diseases, the compounds of the present invention are typically administered in a single dose or in two or three divided doses per day, in a dose ranging from 1 to 1000 milligrams per day, preferably in a dose ranging from 100 to 600 milligrams per day.

[0026] Use of antifungal and antiparasitic drugs The compounds of the present invention are useful for inhibiting fungal growth both in vivo and ex vivo. Therefore, the present invention also provides methods and uses for inhibiting fungal growth in mammalian subjects, such as humans. These methods can be used to treat and prevent fungal infections. Ex vivo, it is useful to treat surfaces with the compounds of the present invention to inhibit or prevent fungal growth, or in agriculture or horticulture, to prevent or treat fungi affecting beneficial plants. The present invention also provides compositions containing the compounds of the present invention, and uses of the compounds of the present invention for the manufacture of pharmaceuticals for inhibiting fungal growth.

[0027] This invention is at least partially based on the finding that the compounds of the present invention are effective in inhibiting the growth of various fungal species, as shown in the following biological activity examples. While not bound by any particular theory, the compounds of this disclosure are thought to exploit the vulnerability of fungal acidic vacuoles. The compounds of this disclosure are thought to exert antifungal activity by accumulating in acidic vacuoles via cation trapping and further disrupting the structure and function of the acidic vacuoles.

[0028] According to the present invention, fungal growth is generally inhibited. Examples of fungi that can be inhibited include, but are not limited to, Candida, Saccharomyces, Trichophyton, Cryptococcus, Aspergillus, and Rhizopus. In more specific embodiments of the present invention, the fungi include Candida albicans, Candida glabrata, Saccharomyces cerevisiae, Trichophyton rubrum, Cryptococcus neoformans, such as serotypes D and A of Cryptococcus neoformans, and Aspergillus fumigatus.

[0029] The present invention also provides methods for treating and preventing parasitic infections. Due to the ability of the compounds of the present invention to enter and accumulate in the acidic vacuoles of cells, the compounds of the present invention are useful in treating infections caused by parasitic microorganisms present in the acidic vacuoles of macrophages and other cell types. Tuberculosis (mycobacteria), Listeria or Staphylococcus (Gram-positive bacteria), Cryptococcus (fungus), as well as Leishmania and Trypanosoma (amoebas), Coxiella burnetii (Gram-negative bacteria), and Plasmodium species (some of which cause malaria) are not limited examples of such important infectious organisms, and the presence of these organisms in macrophages can protect them from cellular or humoral immunity, or reduce the effectiveness of drug therapy.

[0030] The compounds of this invention, which carry a lipophilic portion and are generally partially neutral at physiological pH (7.3), can freely migrate to acidic vacuoles harboring parasites. There, they are concentrated and captured due to ionization in an acidic environment (pH 4-6.5). These compounds disrupt the structure and function of acidic vacuoles, which are a comfortable site for parasites, and also possess direct antiparasitic activity due to the presence of acidic vacuoles in many parasites.

[0031] Parasites whose survival rate or pathogenicity depends on the integrity and function of their acidic vacuoles are also vulnerable to the compounds of the present invention, which are similar in basis to their antifungal activity. The acidic vacuoles of the malaria parasite provide an environment for the concentration of the compounds of the present invention. Similarly, trypanosomes also have large acidic vacuoles necessary for utilizing environmental nutrients. The compounds of the present invention are useful in the treatment or prevention of malaria and trypanosomiasis infections. More broadly, parasitic protozoa generally use acidified digestive vacuoles for food acquisition and digestion, and are therefore susceptible to the antiparasitic effects of the compounds of the present invention.

[0032] Chloroquine, an antimalarial drug, has been reported to have antiparasitic activity against a variety of organisms, including but not limited to Mycobacterium tuberculosis, Cryptosporidium, Leishmania, and Cryptococcus, which reside in or possess acidic vacuoles in host cells. Generally, chloroquine acts by accumulating in acidic vacuoles via cation traps. Therefore, while chloroquine activity is an indicator of the estimated activity of the compounds of the present invention, the compounds of the present invention are substantially more potent and highly active than chloroquine. Although published reports have shown that chloroquine can improve survival in animal models of cryptococcosis, it has shown an upper limit of approximately 40% inhibition of C. neoformans proliferation in vitro. In contrast, the compounds of the present invention are substantially more potent than chloroquine and can cause 100% inhibition of Cryptococcus proliferation by effectively disrupting the membrane of the acidic vacuoles where each drug accumulates.

[0033] For the treatment of fungal or parasitic infections, the compounds of the present invention are administered by vehicle via a route of administration appropriate to the nature and location of the infection. For skin or nail infections, the compounds of the present invention are applied topically in the form of a lotion, ointment, solution, suspension, or spray. For fungal infections of the eye, the compounds of the present invention are formulated as eye drops. For systemic infections, the compounds of the present invention are administered orally in the form of tablets, capsules, sugar-coated tablets, solutions, or suspensions, or systemically by injection in saline, lipid emulsion, liposomes, or other standard parenteral vehicles. Lung infections, particularly those involving organisms present in alveolar macrophages, may be treated by inhalation delivery of the compounds of the present invention and appropriate excipients known to be acceptable for inhalation drug delivery. For intravenous or oral administration to treat systemic infections, the compounds of the present invention are administered in doses ranging from 10 to 2000 milligrams per day, preferably from 200 to 1000 milligrams per day.

[0034] Other classes of antifungal agents in clinical use include inhibitors of ergosterol synthesis ("azole" antifungal agents including, but not limited to, fluconazole, ketoconazole, and voriconazole, and allylamines including, but not limited to, terbinafine), polyene antifungal agents that act by binding to fungal membrane components, particularly ergosterol (including, but not limited to, amphotericin B or nistatin), echinocandin inhibitors of glucan synthesis (including, but not limited to, caspofungin), and other agents known as active antifungal agents in medical practice. The compounds of the present invention act by a distinct mechanism of action compared to existing clinically important antifungal agents and may be administered in combination with one or more other antifungal agents to improve the overall antifungal treatment. The compounds of the present invention may be administered in combination as separate pharmaceutical formulations or formulated as combined single drug products. The combination of the compounds of the present invention with azole antifungal agents is particularly advantageous as a completely oral regimen for use against cryptococcosis, which otherwise generally requires injection or infusion of amphotericin B for initial induction. The compounds of the present invention may also be administered in combination with amphotericin B. Some formulations of amphotericin B involve its incorporation into lipids containing the liposome membrane. Since many of the compounds of the present invention carry a lipophilic moiety that penetrates the lipid membrane, the compounds of the present invention are favorably incorporated into liposomes, either as monotherapy or in combination with amphotericin B or other known polyene antifungal agents.

[0035] Use of anticancer drugs This invention provides compounds useful for systemic cancer treatment based on consistent lysosomal changes that characterize invasive cancer. Lysosomal changes in cancer, including lysosome expansion and acidification, promote the survival of cancer cells in an extracellular acidic environment and increase the ability of cancer cells to invade surrounding tissues through exocytosis of lysosomal contents, including proteases and polysaccharides that can degrade extracellular matrix components. However, these typical changes in lysosomal properties can make cancer cells vulnerable to lysosomal disruptors that selectively accumulate in cancer cells compared to normal tissue and possess physicochemical properties suitable for damaging their lysosomes.

[0036] The compounds of the present invention accumulate in lysosomes in cancer cells, disrupting their integrity and thereby exhibiting potent selective cytotoxic activity against cancer cells both in vivo and in vitro.

[0037] Since one of the main mechanisms of cancer cell resistance to various chemotherapeutic agents is the sequestration of cancer cells into lysosomes and other acidic vesicle compartments, the compounds of the present invention can repair or enhance the sensitivity of cancer cells to various classes of anticancer agents, including antimetabolites, tyrosine kinase inhibitors, anticancer antibodies against growth factor receptors, anthracyclines, platinum compounds, alkylating agents, and antibodies. The compounds of the present invention typically do not exhibit dose-limiting toxicity overlapping with that of most anticancer agents, and enable combinations of the compounds of the present invention with other classes of anticancer agents, resulting in net improvements in efficacy and therapeutic index.

[0038] Cancer cells exposed to sublethal doses of ionizing radiation undergo a protective response that increases their resistance to subsequent irradiation. This protective response involves the formation of enlarged lysosomes or other acidifying vacuolar organelles. Inhibition of vacuolar ATPases involved in lysosome acidification using bafilomycin A prevents this protective response in sublethally irradiated cells, thereby sensitizing cancer cells to ionizing radiation. Lysosome damage is a key mediator of radiation-induced death in cancer cells. The compounds of the present invention are useful in reducing the resistance of cancer cells to therapeutic ionizing radiation and enhancing the anticancer efficacy of ionizing radiation therapy by disrupting the integrity of the lysosomal membrane. The compounds of the present invention may be administered as radiosensitizers before ionizing radiation therapy for cancer (whether using external beam radiation or antibody-targeted radioisotope administration), or after irradiation to attack surviving cancer cells that have undergone a protective response to nonlethal irradiation, involving the formation or enlargement of acidic vacuoles.

[0039] One mechanism that confers selective survival and proliferation advantages in some cancers is the upregulation of autophagy, a process in which damaged organelles or other cellular fragments are engulfed by autophagosomes, which then fuse with lysosomes to digest and recycle their constituent molecules. The compounds of the present invention impair autophagy in cancer cells by concentrating within lysosomes and disrupting them, thereby reducing the survival rate of cancer cells and their resistance to other anti-cancer therapies.

[0040] In cancer treatment, the compounds of the present invention are administered orally or intravenously at doses of 10 to 2000 milligrams per day. The compounds of the present invention are administered as monotherapy or, since the toxicity that would generally necessitate substantial dose reduction does not overlap with that of other classes of anticancer agents, they are administered in combination with other cancer therapies suitable for specific types of cancer, at doses generally used when such agents are used alone.

[0041] Pharmaceutical composition The present invention provides pharmaceutical compositions comprising a biologically active agent and a pharmaceutically acceptable carrier as described herein. Further embodiments of the pharmaceutical compositions of the present invention include any one of the embodiments of the biologically active agents described herein. Each such agent and group of agents is incorporated herein as if they were repeated, but is not repeated for the benefit of avoiding unnecessary redundancy.

[0042] Preferably, the composition can be adapted for oral administration in the form of, for example, tablets, coated tablets, sugar-coated tablets, hard or soft gelatin capsules, solutions, emulsions, or suspensions. Generally, the oral composition contains 10 to 1000 mg of the compound of the present invention. It is convenient for the subject to swallow one or two tablets, coated tablets, sugar-coated tablets, or gelatin capsules per day. However, the composition can also be adapted for administration by any other conventional means of systemic administration, including, for example, rectal administration in the form of suppositories, parenteral administration in the form of injection solutions, or nasal administration.

[0043] Biologically active compounds can be processed with pharmaceutically inert inorganic or organic carriers for the production of pharmaceutical compositions. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, for example, can be used as such carriers for tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules.

[0044] Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solids, and liquid polyols. However, depending on the properties of the active ingredient, in the case of soft gelatin capsules, carriers other than soft gelatin itself are usually not required. Suitable carriers for the production of solutions and syrups include, for example, water, polyols, glycerol, and vegetable oils. Suitable carriers for suppositories include, for example, natural oils or hydrogenated oils, waxes, fats, semi-liquids, or liquid polyols.

[0045] The pharmaceutical composition may further contain preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts for altering osmotic pressure, buffers, coatings, or antioxidants. The pharmaceutical composition may also contain other therapeutically beneficial substances acting by mechanisms other than those underlying the effects of the compounds of the present invention, particularly anti-inflammatory or antifungal agents (depending on whether the patient is being treated for an inflammatory disease, fungal infection, or cancer).

[0046] In the treatment of cancer, further preferred drugs that can be advantageously co-administered or concurrently formulated with the compounds of the present invention include orally active anticancer agents. Because the compounds of the present invention act by a unique mechanism not shared with other anticancer drugs, they are compatible with a wide variety of combination therapies, including antimetabolites, anthracyclines, tyrosine kinase inhibitors, platinum drugs, or alkylating agents. When such drugs are orally active, they are administered or concurrently formulated to deliver a drug dose that has been determined to be effective and appropriately tolerable in previous clinical trials.

[0047] For the systemic treatment of diseases including certain cancers, inflammatory conditions, and fungal or protozoan infections, the compounds of the present invention may be administered by intravenous injection or infusion. For intravenous administration, the compounds of the present invention are dissolved in a suitable intravenous formulation as a solution or in a lipid emulsion, using standard excipients known in the art as well-tolerated intravenous formulation components and compositions. Depending on the specific requirements of the compound and the disease state determined in clinical trials, a suitable volume and concentration are selected to deliver 10 to 2000 milligrams (miligrams) of the compound of the present invention per day.

[0048] The compounds of the present invention may be incorporated into liposomal formulations. The lipophilic portion of the compounds of the present invention allows for their direct incorporation into the lipid layer of liposomes. In certain conditions, liposomes are advantageous for intravenous administration due to improved efficacy and milder infusion reactions compared to non-liposomal formulations. Liposomes are also suitable for inhalation delivery to treat fungal or parasitic infections of the lungs or inflammation of the lungs and airways. In some embodiments, the compounds of the present invention are incorporated into liposomal delivery formulations together with other drugs, including but not limited to antifungal agents such as liposomal amphotericin B, or anticancer agents such as liposomal doxorubicin.

[0049] For the treatment of inflammatory skin conditions or fungal infections of the skin, nails, or nasal cavity, the compounds of the present invention are applied topically in pharmaceutically acceptable formulations. Topical compositions may be in various forms, including but not limited to liquid suspensions, lotions, or creams, solutions, sprays, gels, hydrogels, lotions, creams, ointments, pastes, or emulsions. Compositions may also be applied by skin patches or bandages, which can be applied to the affected area as needed, to allow the skin to be exposed to the pharmaceutical for an extended period. In such formulations, appropriate standard topical pharmaceutical excipients and vehicles are suitable for delivering the compounds of the present invention. Standard components for topical formulations are known in the art and are suitable as vehicles for the compounds of the present invention. The ointment base may contain one or more of the following: hydrocarbons (paraffin wax, soft paraffin, microcrystalline wax, or ceresin), absorbent bases (wool fat or beeswax), macrogol (polyethylene glycol), or vegetable oils. The lotions and creams are water-in-oil or oil-in-water emulsions, and the oily components may include long-chain fatty acids, alcohols, or esters, and may also contain biocompatible nonionic surfactants. The compounds of the present invention are incorporated into a topical vehicle at a concentration ranging from 0.01% to 5%, preferably 0.02% to 1%. The compounds of the present invention are applied to the skin lesions once to three times per day for a duration depending on the rate of recovery.

[0050] Inhalation formulations of the compounds of the present invention are suitable for the treatment of fungal infections or certain lung infections, including those involving parasites present in alveolar macrophages. Excipients and inhalation drug delivery devices are known in the art and are useful for delivering the compounds of the present invention to treat lung infections, including cryptococcal infections and tuberculosis.

[0051] The compounds of the present invention are advantageously formulated co-formulated with other antifungal or anti-inflammatory agents for topical or systemic administration, particularly when both drugs are appropriately administered via the same route and schedule. The compounds of the present invention are compatible with standard formulations and excipients used for other topical or systemic antifungal or anti-inflammatory agents, including but not limited to ointments and tablets or capsules. A class of drugs advantageous for combination in anti-inflammatory topical formulations includes corticosteroids, calcineurin inhibitors and vitamin D analogs, as well as other agents known to have independent therapeutic activity in inflammatory skin conditions.

[0052] The present invention will be better understood by referring to the following examples, which illustrate, and do not limit, the present invention as described herein. [Examples] Chemical Synthesis Examples [Examples]

[0053] Synthesis of 2-(3-phenoxybenzyl)-1H-imidazo[4,5-c]quinoline Step 1: 3-Nitroquinoline-4-ol

[0054] [ka]

[0055] A 70% aqueous nitric acid solution (6.1 mL) was added dropwise to a mixture of 4-hydroxyquinoline (10 g, 69 mmol) and acetic acid (100 mL) that had been heated under reflux. After 15 minutes, the mixture was cooled to room temperature. Dilution with EtOH formed a precipitate, which was filtered and washed sequentially with EtOH, H2O, and EtOH. The filtrate was dried under vacuum to obtain 4.62 g of a pale yellow powder. 1 H NMR (400 MHz, DMSO-d6) δ 9.2 (s, 1H), 8.3 (d, 1H), 7.9-7.7 (m, 2H), 7.5 (m, 1H).

[0056] Step 2: 4-Chloro-3-Nitroquinoline

[0057] [ka]

[0058] 2.5 mL of phosphorus oxychloride (27 mmol) was added dropwise to a mixture of 3-nitroquinoline-4-ol (4.6 g, 24 mmol) and 100 mL of DMF. The mixture was heated at 100°C for 15 minutes and then poured onto stirred ice. The slurry was neutralized with solid NaHCO3, the precipitate was filtered, and washed with saturated NaHCO3 and H2O. The filtrate was dissolved in DCM, dried on anhydrous Na2SO4, and concentrated to obtain 2.3 g of solid.

[0059] Step 3: N-(tert-butyl)-3-nitroquinoline-4-amine

[0060] [ka]

[0061] A mixture of 4-chloro-3-nitroquinoline (6.30 g, 30.2 mmol), tert-butylamine (6.40 mL, 60.5 mmol), TEA (8.50 mL, 60.6 mmol), and 40 mL of DCM was heated under reflux for 5 hours until the starting materials were consumed. The mixture was stirred overnight at room temperature. The mixture was separated into DCM and saturated NaHCO3, and the organic phase was dried over anhydrous Na2SO4 and concentrated to obtain the product.

[0062] Step 4: N 4 -(tert-butyl)quinoline-3,4-diamine

[0063] [ka]

[0064] The previously obtained N-(tert-butyl)-3-nitroquinoline-4-amine, 10% Pd-C (630 mg), 1.5 mL of TEA, and 50 mL of MeOH were stirred under a hydrogen atmosphere until the starting materials were consumed. The hydrogen was replaced with nitrogen, and the mixture was filtered through a Celite pad and concentrated. The residue was dissolved in toluene spiked with 1:1:1 MeOH, DCM, and 0.5 mL of TEA, then concentrated to obtain 7.37 g of material. Rf 0.50 (7.5% MeOH / DCM + 1% TEA)

[0065] Step 5: N-(4-(tert-butylamino)quinoline-3-yl)-2-(3-phenoxyphenyl)acetamide

[0066] [ka]

[0067] EDC (6.5g, 33.8 mmol) in 60mL of 1:1 DMF / DCM, N 4-(tert-butyl)quinoline-3,4-diamine (4.91 g, 22.2 mmol), 3-phenoxyphenylacetic acid (5.2 g, 22.8 mmol), HOBt (3.49 g, 22.8 mmol), and DMAP (0.60 g, 4.9 mmol) were added to a mixture. After 17.5 hours, TLC of a fixed volume of the mixture showed that the starting material had not been consumed, so additional EDC (2.12 g, 11.0 mmol) and DMF (15 mL) were added, the mixture was heated to 45°C, and the DCM was removed by boiling. After 68 hours, the mixture was cooled and separated into SiO (3 × 250 mL), 5% Na₂CO₃ (2 × 150 mL), and brine (150 mL). The organic phase was dried over anhydrous Na₂SO₄ and concentrated to obtain the product.

[0068] Step 6: N-(4-aminoquinoline-3-yl)-2-(3-phenoxyphenyl)acetamide

[0069] [ka]

[0070] N-(4-(tert-butylamino)quinoline-3-yl)-2-(3-phenoxyphenyl)acetamide was mixed with TFA / DCM in a 1:1 ratio at room temperature for 2 hours. The volatile components were evaporated, the residue was dissolved in DCM, washed with 5% Na2CO3, and the organic phase was dried over anhydrous Na2SO4 and then concentrated. The product was purified by flash chromatography (5% MeOH / DCM + 1% TEA) to obtain a solid. The product was recrystallized from MeOH. MW369 was confirmed by LC-MS. Rf 0.25 (10% MeOH / DCM)

[0071] Step 7: 2-(3-phenoxybenzyl)-1H-imidazo[4,5-c]quinoline

[0072] [ka]

[0073] A mixture of N-(4-aminoquinoline-3-yl)-2-(3-phenoxyphenyl)acetamide (1.76 g, 4.77 mmol) and NH4Cl (21 mg, 0.39 mmol) in 25 mL of anisole was heated under reflux for 4.5 hours. The volatile material was evaporated, and the solid residue was separated into DCM and 5% Na2CO3. The organic phase was dried over anhydrous Na2SO4 and concentrated. Purification by flash chromatography (5% MeOH / DCM) yielded 1.60 g of the product as a foamy solid. MW351 was confirmed by LC-MS. Rf 0.46 (10% MeOH / DCM). 1 H NMR (400 MHz, CDCl3) δ 9.04 (br s, 1H), 8.25 (br s, 1H), 8.14 (d, 1H, J=8.7 Hz), 7.62-7.58 (m, 1H), 7.52 (br s, 1H), 7.27-7.22 (m, 3H), 7.18-7.14 (m, 1H), 7.08-7.04 (m, 1H), 6.97-6.95 (m, 1H), 6.90-6.86 (m, 3H), 6.81-6.79 (m, 1H), 4.34 (s, 2H).

[0074] Examples of biological activity Example A: In vitro anticancer activity Compound AF has already been identified as a potent lysosomal-targeting agent with anticancer activity against several cancer cell lines. The relative potencies of Compounds (GE) and AF were compared in two cancer cell lines with very different genetic abnormalities and oncogene drivers underlying their tumorigenic characteristics.

[0075] PC3 (prostate cancer) and A549 (lung cancer) cell lines were cultured in a medium consisting of a 90% F-12K nutrient mixture (modified Kaighn) containing L-glutamine and 10% hydroxyl fetal bovine serum. No antibiotics were used in the culture medium.

[0076] PC3 and A549 cells were seeded in 96-well plates at densities of 20,000 and 10,000 cells per well, respectively, in a volume of 0.1 ml per well. Twenty-four hours after seeding, the culture medium was replaced with 0.1 ml of medium containing either AF or GE compound. The AF compound was tested at concentrations of 1, 0.5, 0.25, and 0.1 micromoles. The GE compound was tested at concentrations of 0.1, 0.05, 0.025, and 0.01 micromoles. The cells were then cultured for 72 hours, and cell viability was evaluated at 48 and 72 hours using the WST-1 assay.

[0077] Regarding cell viability, the absorbance obtained in the WST-1 assay of cells exposed to the compound was expressed as a percentage of the absorbance in the wells of cells incubated in the absence of the compound. All measurements are expressed as the mean of three wells ± SEM.

[0078] Figures 1-4 show the cancer cell survival rates as a function of dose (concentration) of GE and AF. Compound GE reduced cancer cell survival in both A549 lung cancer cells (Figures 1 and 2) and PC3 prostate cancer cells (Figures 3 and 4) at approximately 1 / 10 the dose required for a similar reduction in cell survival by compound AF.

[0079] Example B. Anti-inflammatory effect of compound GE on psoriasis-like dermatitis in mice Topical imiquimod (IMQ), a toll-like receptor agonist, was established as a model for inflammatory skin diseases, including psoriasis and atopic dermatitis, to predict clinical activity in human subjects. Skin inflammatory changes and gene expression in mice treated with topical imiquimod mimic human psoriasis-like dermatitis (van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen F, Mus AM, Florencia E, Prens EP, Lubberts E. (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23 / IL-17 axis. J Immunol. 182(9):5836-45). The effect of compound GE of the present invention was tested in a mouse model of imiquimod-induced dermatitis.

[0080] Compound GE was dissolved in ethanol at a concentration of 0.1%, and then mixed with 9 volumes of petrolatum (melted in a water bath heated at 50°C) to obtain an ointment containing 0.01% of the active drug. Petrolatum containing 10% ethanol was used as a control or vehicle treatment.

[0081] Female Balb / C mice weighing approximately 20 grams were randomized and divided into three groups of five animals each. The mice were fitted with polyethylene collars to prevent them from easily scratching their ears.

[0082] 5% imiquimod was applied daily to both ears of each mouse for 5 days (20 microliters per ear), and then every 2 days for the entire duration of the study. Inflammatory changes, including increased ear thickness, were evident by day 5. Treatment with compound GE was initiated on day 5 after the start of imiquimod. Both ears of each mouse were treated with the test ointment.

[0083] Ear thickness and PASI assessment (Psoriasis Area and Severity Index, a standard psoriasis scoring system that captures swelling, erythema, and scaling) were recorded twice a week throughout the study.

[0084] result Treatment with imiquimod resulted in significant inflammatory changes, including increased ear thickness (Figure 5) and changes in PASI scores. Control ears reached the maximum possible score on the PASI scoring system (12 points, i.e., reflecting severe swelling, erythema, and scaling on a scale of 0–4 points each) (Figures 6A–D). Compound GE, applied topically in an ointment base, reduced imiquimod-induced inflammatory damage to mouse ears, as assessed by caliper thickness measurements and appearance-based PASI scoring, and reduced all three aspects of skin inflammation captured by the PASI scoring system. Compound GE was effective at a concentration of 0.01% and demonstrated high efficacy in this psoriasis-like dermatitis model.

[0085] (References) van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen F, Mus AM, Florencia E, Prens EP, Lubberts E. (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23 / IL-17 axis. J Immunol. 182(9):5836-45.

Claims

1. 2-(3-phenoxybenzyl)-1H-imidazo[4,5-c]quinoline and its pharmaceutically acceptable salts A compound selected from the group consisting of the following.

2. The compound according to claim 1, for use in the treatment or prevention of a condition selected from the group consisting of inflammatory diseases and neoplastic diseases in mammals.

3. Use of the compound according to claim 1 in the manufacture of a pharmaceutical product for treating or preventing a condition selected from the group consisting of inflammatory diseases and neoplastic diseases in mammals.

4. A composition comprising the compound according to claim 1 for use in the treatment or prevention of a condition selected from the group consisting of inflammatory diseases and neoplastic diseases in mammals.

5. The compound for use according to claim 2, wherein the mammalian target is a human target.

6. The compound for use according to claim 2, wherein the condition is an inflammatory disease.

7. The compound for use according to claim 6, wherein the inflammatory disease is an inflammatory skin condition.

8. The compound for use according to claim 7, wherein the inflammatory skin condition is selected from the group consisting of psoriasis, psoriatic dermatitis, eczema, atopic dermatitis, and impetigo.

9. The compound for use according to claim 6, wherein the inflammatory disease is a systemic autoimmune disorder.

10. The compound for use according to claim 9, wherein the systemic autoimmune disorder is selected from the group consisting of rheumatoid arthritis, systemic discoid lupus erythematosus, psoriatic arthritis, vasculitis, Sjögren's syndrome, scleroderma, autoimmune hepatitis, and multiple sclerosis.

11. The compound for use according to claim 2, wherein the condition is a neoplastic disease.

12. The compound for use according to claim 11, wherein the neoplastic disease is a blood cancer or a solid tumor.

13. The compound for use according to claim 11, wherein the neoplastic disease is lung cancer and / or prostate cancer.

14. The compound for use according to claim 2, wherein the compound is for local or systemic administration to a subject, and the systemic administration is optionally oral, rectal, parenteral, or nasal administration.

15. The use according to claim 3, wherein the target of mammals is human.

16. The use according to claim 3, wherein the condition is an inflammatory disease.

17. The use according to claim 16, wherein the inflammatory disease is an inflammatory skin condition.

18. The use according to claim 17, wherein the inflammatory skin condition is selected from the group consisting of psoriasis, psoriatic dermatitis, eczema, atopic dermatitis, and impetigo.

19. The use according to claim 16, wherein the inflammatory disease is a systemic autoimmune disorder.

20. The use according to claim 19, wherein the systemic autoimmune disorder is selected from the group consisting of rheumatoid arthritis, systemic discoid lupus erythematosus, psoriatic arthritis, vasculitis, Sjögren's syndrome, scleroderma, autoimmune hepatitis, and multiple sclerosis.

21. The use according to claim 3, wherein the condition is a neoplastic disease.

22. The use according to claim 21, wherein the neoplastic disease is a blood cancer or a solid tumor.

23. The use according to claim 21, wherein the neoplastic disease is lung cancer and / or prostate cancer.

24. The use according to claim 3, wherein the compound is for local or systemic administration to a subject, and the systemic administration is optionally oral, rectal, parenteral, or nasal administration.

25. The composition according to claim 4, wherein the mammalian target is a human target.

26. The composition according to claim 4, wherein the condition is an inflammatory disease.

27. The composition according to claim 26, wherein the inflammatory disease is an inflammatory skin condition.

28. The composition according to claim 27, wherein the inflammatory skin condition is selected from the group consisting of psoriasis, psoriatic dermatitis, eczema, atopic dermatitis, and impetigo.

29. The composition according to claim 26, wherein the inflammatory disease is a systemic autoimmune disorder.

30. The composition according to claim 29, wherein the systemic autoimmune disorder is selected from the group consisting of rheumatoid arthritis, systemic discoid lupus erythematosus, psoriatic arthritis, vasculitis, Sjögren's syndrome, scleroderma, autoimmune hepatitis, and multiple sclerosis.

31. The composition according to claim 4, wherein the condition is a neoplastic disease.

32. The composition according to claim 31, wherein the neoplastic disease is a blood cancer or a solid tumor.

33. The composition according to claim 31, wherein the neoplastic disease is lung cancer and / or prostate cancer.

34. The composition according to claim 4, wherein the compound or composition is for local or systemic administration to a subject, and the systemic administration is optionally oral, rectal, parenteral, or nasal administration.

35. The composition according to claim 4, further comprising a pharmaceutically acceptable carrier.

36. A method for producing 2-(3-phenoxybenzyl)-1H-imidazo[4,5-c]quinoline, (a) Adding nitric acid to a solution containing 4-hydroxyquinoline and acetic acid under conditions for producing 3-nitroquinoline-4-ol; (b) Adding phosphorus oxychloride to the 3-nitroquinoline-4-ol under conditions for producing 4-chloro-3-nitroquinoline; (c) Mixing the 4-chloro-3-nitroquinoline with tert-butylamine under conditions for producing N-(tert-butyl)-3-nitroquinoline-4-amine; (d) The above N-(tert-butyl)-3-nitroquinoline-4-amine, ４ Mixing with Pd-C under conditions for producing -(tert-butyl)quinoline-3,4-diamine; (e) The above N ４ Mixing -(tert-butyl)quinoline-3,4-diamine with 3-phenoxyphenylacetic acid under conditions that form N-(4-(tert-butylamino)quinoline-3-yl)-2-(3-phenoxyphenyl)acetamide; (f) Mixing the N-(4-(tert-butylamino)quinoline-3-yl)-2-(3-phenoxyphenyl)acetamide with trifluoroacetic acid (TFA) to form N-(4-aminoquinoline-3-yl)-2-(3-phenoxyphenyl)acetamide; (g) The above N-(4-aminoquinoline-3-yl)-2-(3-phenoxyphenyl)acetamide is ammonium chloride (NH ４ To mix with Cl, thereby forming the aforementioned 2-(3-phenoxybenzyl)-1H-imidazo[4,5-c]quinoline. The method, including the method described above.

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