Gallium Complexes Of 3-Hydroxy-4-Pyrones To Treat Infection By Intracellular Prokaryotes, DNA Viruse

专利摘要:
Retrovirus, and a method for treating or preventing an infection caused by a DNA virus, including herpes virus, papilloma virus, adenovirus, and hepatitis B virus. Emphasis is placed on providing methods for treating HIV disease. In addition to providing a method of treating HIV infection itself, there is provided a method of treating an HIV patient with another retrovirus, a knock-in-cell prokaryote, or a coinfection with a DNA virus. These methods include the step of administering a 3: 1 complex of 3-hydroxy-4-pyrone with gallium, for example gallium maltolate. There is also provided a treatment for administering gallium maltolate in combination with an agent used for a prokinetic prokaryote, a retrovirus, and a DNA virus pathogen. For example, in HIV-infected individuals there are multiple combination therapies designed to treat coinfection by intramedullary prokaryotes, retroviruses or DNA viruses. This multiple combination therapy can reinforce antiviral agents against HIV and other pathogens (such as herpes virus infections, including CMV retinitis and blindness, and lymphoma) in immunocompromised patients with HIV infection .
公开号:KR20020041451A
申请号:KR1020027004304
申请日:2000-10-04
公开日:2002-06-01
发明作者:로렌스 리차드 베른스타인
申请人:로렌스 리차드 베른스타인；
IPC主号:

专利说明:

Gallium Complexes of 3-Hydroxy-4-Pyrones To Treat Infection by Intracellular Prokaryotes, DNA Viruses and Retroviruses for Treatment of Infections by Intracellular Prokaryotes, DNA Viruses and Retroviruses }
[2] Gallium showed therapeutic activity for metabolic bone diseases, hypercalcemia and cancer [Bernstein (1998), " Mechanisms of therapeutic activity for gallium, " Pharmacol Rev. 50 : 665-682). In the United States, it has been approved for use as an intravenous injectable citrate-chelated gallium nitrate solution to treat hypercalcemia of malignant tumors [Warrell (1995), " Gallium for treatment of bone disease, " Handbook of Metal-Ligand Interactions in Biological Fluids, Bioinorganic Medicine , 2 : 1253-1265, New York: Marcel Dekker]. As a result of extensive clinical studies, gallium has been implicated in some lymphoma [Foster et al. (1986), "Gallium nitrate: the second metal with clinical activity," Cancer Treat Rep 70 : 1311-1319], urinary epithelial carcinoma [Einhorn et al. (1994), "Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma," J Clin Oncol 12 : 2271-2276] and non-squamous cell carcinoma of the cervix [Malfetano et al. (1995), "A Phase II trial of gallium nitrate (NSC # 15200) in nonsquamous cell carcinoma of the cervix," Am J Clin Oncol 18 : 495-497. The antiproliferative properties of gallium extend to some microorganisms, and gallium has been proposed as a potential antibiotic against certain intracellular infections, especially tuberculosis [Olakanmi et al. (1977), " Gallium inhibits growth of pathogenic mycobacteria in human macrophages by disruption of bacterial iron metabolism: a new therapy for tuberculosis and mycobacterium avium complex , J Invest Med 45 : 234A]. The therapeutic activity of gallium and its proposed mechanism are discussed in Bernstein, 1998, supra. The mechanism summarizes the inhibition of ribonucleotide reductase by displacing iron in the M2 region of the enzyme ribonucleotide reductase, possibly interfering with cellular uptake of "transperin-binding iron" by substitution of gallium (See the above-mentioned Bernstein article in 1998).
[3] Although not intended to limit the scope of the invention in any way, the main mechanism of the anti-neoplastic activity and general antiproliferative activity of gallium is to replace the iron ion in the iron transport protein transfuran (Tf) It is thought to be the ability to reduce absorption. This mechanism is based on the fact that HL 60 cells, which exhibit resistance to the antiproliferative action of Ga, also have a similar effect of the iron chelating agent diferoxamine and a monoclonal antibody blocking effect of the cell Tf receptor (which acts to absorb iron into the cell) (Chitambar et al., 1991), "Targeting iron-dependent DNA synthesis with gallium and transferrin-gallium," Pathobiology 59 (1): 3-10]. Ribonucleotide reductase is an iron-containing enzyme necessary for the synthesis of deoxyribonucleotides necessary for DNA synthesis and subsequent cell division. The activity of ribonucleotide reductase can be influenced by the intracellular concentrations of iron and gallium, and can be influenced by intracellular prokaryotic organisms (e.g., chlamydia and rickettsia), DNA viruses and viruses using reverse transcriptase (usually retroviral ) And the replication cycle. Proliferating cells require iron very much because of the increased demand for ribonucleotide reductase. Most of the iron available in the blood binds to the iron transport protein, Tf, which is also the main carrier of gallium in plasma. Because proliferating cells are highly required for iron, they overexpress Tf receptors and thus absorb large amounts of metal-containing Tf. When gallium is present on Tf, it can be rapidly absorbed into proliferating cells to deplete intracellular iron and be introduced into the M2 region of the ribonucleotide reductase. Orally administered gallium, especially gallium maltolate, has been found to lead to greater Tf binding of absorbed gallium and thus to better tissue distribution than intravenous gallium nitrate [Bernstein et al., 1998, See, for example, Stein, et al., (200), " Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability ", Metal-Based Drugs 7 (1): 33-47). Another advantage of oral administration of gallium over IV-administered gallium nitrate is that no renotoxicity or nephrotoxicity is observed with oral gall maltolate (see Bernstein et al., 1998 and 2000) .
[4] When iron is depleted at the iron-containing M2 site of the ribonucleotide reductase, the gallium makes the ribonucleotide reductase non-functional regardless of whether it is substituted or not. It also depletes the concentration of deoxyribonucleotides and, in part, by the depletion of the deoxyribonucleotide reactant and at least in part by the biologic (term " organism " including viruses) To reduce the productivity of DNA. The electron spin resonance (ESR) spectrum showed a ribonucleotide reductase iron signal that was significantly reduced in cytoplasmic extracts from gallium-treated HL 60 cells, but this spectrum and signal intensity were restored to normal by the addition of iron [Chitambar et al. (1991), " Targeting iron-dependent DNA synthesis with gallium and transferrin-gallium, " Pathobiology 59 (1): 3-10]. Cells that can not produce DNA can not be cloned, and eventually the cells can be destroyed.
[5] In a similar manner, gallium is also found in intracellular prokaryotes, DNA viruses and retroviruses, which must also produce DNA at some point in the life cycle and directly or indirectly affect the cytoplasmic iron concentration of the host cell for the activity of the ribonucleotide reductase Which will inhibit replication. Some viruses use the host's ribonucleotide reductase to produce deoxyribonucleotides, the major essential component of DNA. Retroviruses that first synthesize DNA from RNA using reverse transcriptase enzymes before generating new virus particles are particularly sensitive because they use the host's ribonucleotide reductase in the first step of their life cycle in the host cell . More complex DNA viruses, such as those belonging to the herpes virus family with their own ribonucleotide reductase, are affected by the intracellular environment generated by interfering with the iron metabolism of host cells.
[6] Many current drugs used to treat HIV infection (eg, AZT, ddI ddC) are nucleoside analogs that inhibit the polymerization of DNA during replication (the DNA so formed is terminated too early and is non-functional). Gallium is predicted to inhibit the ribonucleotide reductase and thus synergize with the nucleoside analogue by inhibiting the production of the nucleoside required for DNA synthesis, and the relative proportion of the nucleoside analogue to the natural nucleoside is increased And will thus further inhibit DNA. In general, inhibiting enzymes and depletion of the substrate are considered to have a synergistic effect on the rate of reduction of product production. Star player tonnes in 1999, including the literature [ "Gallium nitrate: a potent inhibitor of HIV-1 infection in vitro," Program and Abstracts, 39 th ICACC Meeting, San Francisco, 1999, pp. 74] was used alone at concentrations of 4 to 10 [mu] m to demonstrate the efficacy of gallium nitrate to inhibit in vivo replication of HIV. In addition, this document enhances the inhibitory effect of zidovudine, azidinium (AZT), dideoxyinosine (ddI) and dideoxycytosine (ddC) at subinhibitory concentrations of gallium nitrate, as expected Showed the fact. A combination of a nucleoside analog and a nucleoside analog having a non-nucleoside analog reverse transcriptase inhibitor has already been shown to be synergistic [Daluu et al. (1977), " 152U89, a novel carbocyclic nucleoside analog with potent selective anti-human immunodeficiency virus activity, " antimicrob. Agents Chemother . 41 (5): 1082-93).
[7] Antiretroviral antimicrobials (e.g., HIV protease inhibitors) that are active at different phases of the microbial life cycle than DNA polymerizations are believed to have synergistic effects achieved by the combined use of nucleoside analogs and protease inhibitors for retroviral therapy (Nucleoside analog 1592U89 and human immunodeficiency virus protease inhibitors are synergistic in vitro, " Antimicrob. Agents ", Drusano et al. Chemother. 42 (9); 2153-9), are recognized as synergistic with nucleoside analogs that affect DNA synthesis. Similarly, in Poppe et al., 1997, " Antiviral activity of the dihydropyrone PNU-140690, a novel noneptidic human immunodeficiency virus protease inhibitor, " Antimicrob. Agents Chemother. 41 (5): 1058-63) showed that structurally different non-peptide protease inhibitors synergistically interact with substrate analog protease inhibitors. Protease inhibitors are specific for treating retroviruses and only inhibit the proteases of the specific viruses so that HIV 1 protease inhibitors will have the same effect on HIV 2 and have no effect on other retroviruses. Thus, such agents that target proteins other than DNA polymerases (eg, HIV reverse transcriptase) to disrupt other lifecycle steps other than the DNA replicators may act synergistically in inhibiting DNA synthesis by inhibiting reverse transcriptase Lt; / RTI > is expected to act synergistically in combination with agents such as gallium / nucleoside analogs.
[8] Furthermore, peptides and non-macromolecular hormone biomolecules, humoral biomolecules or hormone-like biomolecules (e.g., interferon, leukotriene, interleukin, etc.) that promote an immune response, particularly a cellular immune response, Or synergistic effects when combined with an effective antimicrobial agent. These facts are described in Taylor et al., &Quot; Combined effects of interferon-alpha and acyclovir on herpes simplex type 1 DNA polymerase and alkaline DNase, " Antiviral Res . 38 (2): 95-106].
[9] In addition to the use of nucleoside analogs and other inhibitors of DNA replication and the use of hormonal or humoral biological agents to stimulate the immune system, the combination therapy for retroviruses has been used for treatment of other viruses . These agents are currently available for HIV but are expected to be available for the treatment of other retroviruses such as human T cell leukemia virus (HTLV). Thus, anti-viral cocktails effective in stopping or inhibiting the viral life cycle are used together by a synergistic combination of chemical inhibition of DNA replication, chemical degradation of any other stage of the viral life cycle, and hormonal or humoral stimulation of the immune system Is expected to lead to even greater synergism. In the case of combination therapy of retroviruses (HIV 1, HIV 2) or other viral diseases that damage the immune system (eg, Epstein-Barr virus), in order to introduce a hormonal or humoral biological agent, Lt; RTI ID = 0.0 > chemo / antiviral < / RTI > That is, in the case of immunostimulants that can exert a synergistic effect, the immune system should be able to initiate the reaction, conditions that will be present at the beginning of HIV infection or after reconstitution of specific cell-mediated immune responses by active antiretroviral therapy . Thus, it is not surprising recently that these synergies have been confirmed in patients with sufficiently high " CD4 + cell counts " (Roscoe et al., 2000 ("A randomized, controlled, phase II trial comparing escalating doses of subcutaneous interleukin -2 plus antiretrovirals versus antiretrovirals alone in human immmunodeficiency virus-infected patients with CD4 + cell counts> / = 350 / mm 3, "J. Infect Dis 181 (5):.. 1614-21)]. Recently, the addition of a protease inhibitor to a combination therapy resulted in the recovery of the HIV-specific immune response, that is, the reconstitution or recovery of the immune system predicted for the initial HIV disease treated with high-activity antiretroviral therapy (HAART) ( AIDS 14 (7): 761-70), and from this, it has been shown that the hormone-humoral response promoting immunity It can be predicted that biomolecules (e.g., leukotrienes and interferons) will be useful additives for the treatment of common HIV diseases.
[10] Oral gallium is another immune system dependent agent that enhances antiretroviral therapy and is available for other pathogens (eg DNA viruses). A recognized advantage of combination therapy is that it reduces the appearance of resistant strains because the single organism is less likely to acquire multiple mutations conferring resistance at the same time (see Drosano, 1998, supra). The greater the structural and mechanistic differences between the co-administered agents, the greater the protection from simultaneous multiple tolerance mutations due to the distance between the loci, as well as the targeting of different agent targets See the literature of 1998 by Drusano). As the mechanism of action of gallium influences the deoxyribonucleotide substrate level for DNA polymerase by affecting the iron-containing site of the ribonucleotide reductase due to the collapse of the iron absorption metabolism of the host cell, The addition or replacement of gallium in viral therapy increases the likelihood of delaying or preventing the appearance of resistant viruses. Furthermore, as the mechanism of gallium action depends heavily on non-evolving somatic host cells, gallium is essentially a drug that has a direct counter-action to viral proteins due to the mechanisms described above (e.g., protease inhibitors and nucleosides Lt; RTI ID = 0.0 > analog). ≪ / RTI >
[11] Gallium has been shown to inhibit reverse transcriptase in the in vitro Rauscher murine leukemia virus [Waalkes et al. (1974), " DNA polymerases of Walker 256 carcinoma, " Cancer Res 34 : 358-391). Since this murine retrovirus is involved in HIV, this mechanism will act on HIV and other human retroviruses associated therewith. Moreover, it is recognized that reverse transcriptase is an RNA-dependent DNA polymerase that requires deoxyribonucleotides supplied by active ribonucleotide reductase, like all DNA polymerases. Thus, any viral or non-viral intracellular microorganism that uses a DNA polymerase and thus requires deoxynucleotides as substrates may be a "microorganism" that is ultimately affected by circulating Tf-bound gallium in the cytoplasm of the host cell, Depletion / gallium abundance ". This is expected even when the organism has its own ribonucleotide reductase, such as those belonging to the herpes virus family. Additionally, as in the case of intracellular prokaryotes, the microorganism has its own protoplasm comprising the cytoplasm and nucleotides, since it is predicted that the protoplast will undergo iron depletion / gallium-rich properties of the cytoplasm of the host cell.
[12] Orally active gallium compounds have been sought as an alternative to parenterally administered gallium because they are more convenient, convenient, safe and inexpensive, and such compounds could also be used for daily administration for chronic patients. HHV-1 (HSV1), HHV-2 (HSV2), HHV-3 (VZV), HHV-4 (EBV), HHV- 8 (KSV)], retinal inflammation due to CMV (HHV-4) or other herpes virus, and treatment with HHV-8 (KSV), occasionally HHV-7 or HHV-6 and HHV- (EBV), HHV-8 (KSV), occasionally HHV-7 or HHV-7 and HHV-6 (KSV) induced by the viruses currently suspected These compounds are administered to HIV-infected individuals that have already been damaged by the immune system in order to chemically prevent the lymphomas induced by the immune system.
[13] Gallium there is very little absorption upon oral administration to a salt such as chloride or nitrate [Cole library (Collery) 1989 Year et al., ( "Clinical pharmacology of gallium chloride after oral administration in lung cancer patients," Anticancer Res 9:. 353- (Bioavailability of gallium nitrate, Eur. J. Pharmacol . 183 : 1200), which is partially hydrolyzed to produce a low-solubility polymerized gallium oxide hydroxide in the gastrointestinal fluid . In animal and clinical studies gallium maltolate, or tris (3-hydroxy-2-methyl- 4H -pyran-4-ono) gallium (GaM) has been found to absorb about 10 times more oral gallium than gallium salts lost.
[14] Gallium maltolate is a coordination complex of trivalent gallium ions and three delocalized maltol (maltolate) groups. Maltol (2-methyl-3-hydroxy- 4H -pyran-4-one) is produced by some plants and is normally formed upon heating the sugar. This is the main cause of the scent of cotton candy and contributes significantly to the scent of many cakes, cookies and candy. Has been widely used as a food additive due to its ability to provide " freshly baked " aroma and increase sweet flavor [LeBlanc et al. (1989), " Maltol and ethyl maltol: from the larch tree to successful food additive, " Food Technology 43 : 78-84).
[15] Methods for synthesizing gallium complexes of 3-hydroxy-4-pyrone, methods for making such complexes as pharmaceuticals, and several methods of using them pharmaceutically are described in Bernstein (U.S. Patents 5,258,376, 5,574,027, 5,883,088 , 5,968,922, 5,981,518, 5,998,397, 6,004,951, 6,048,851 and 6,087,354).
[16] The use of gallium complexes of 3-hydroxy-4-pyrone to treat intracellular prokaryotic and viral infections has not been known to date. Also, the use of these complexes to treat multiple or coinfection by DNA viruses, retroviruses and intracellular prokaryotes has not been disclosed. The present invention is based on the discovery that these complexes, including gallium maltolate, are particularly useful in combination with other antiretroviral drugs, including intramuscular prokaryotes, adenoviruses, hepatitis B, herpes virus strains (human or non-human), including mycoplasmas, rickettsia and chlamydia, ≪ RTI ID = 0.0 > HIV < / RTI > and HIV < RTI ID = 0.0 > and HTLV. ≪ / RTI > Furthermore, these complexes, including gallium maltolate, are unusually effective in treating such pathogens in HIV-infected individuals with impaired immune systems. Even eukaryotic parasites that replicate their own genome in the cell are susceptible to a wide range of mechanisms of gallium action. Non-intracellular prokaryotic organisms, such as phagocytosed bacteria that do not die once internalization by macrophages (eg, Mycobacterium truberculosis, Mycobacterium leprae, Mycobacterium avium, and other mycobacterial species) Is sensitive to the Tf-bonded gallium, a Tf-receptor mediated mechanism of possible gallium compounds. The gallium compound of the present invention may also be useful in combination therapy with a more effective agent to an uninflammated infectious individual, since the strained individual of the organism resistant to phagocytosis makes the infection difficult to treat.
[17] It has also been found that gallium maltolate and its related gallium complexes of hydroxypyrone provide a safe and effective method of orally administering gallium to infected and co-infected patients. Due to the synergistic mechanism of the compounds of the present invention against other retroviral agents, in addition to nucleoside analogs that antagonize DNA viruses and bacteriocidal bacteria that act bacteriostatically against immune-stimulating biomolecules and prokaryotes, And are expected to be indispensable for the treatment of opportunistic or resistant infections in immunocompromised HIV patients.
[1] The present invention relates generally to the treatment or prevention of intracellular microbial infections, including viral infections. More specifically, the present invention relates to a method of inducing DNA viruses, including intracellular prokaryotes, hepatitis B, an inducible viral family and the herpes virus family, and neurodegenerative and acquired indigestion syndrome (AIDS) To retroviruses (e. G., Human immunodeficiency virus (HIV)) and related leukemia retroviruses and sarcoma retroviruses. Specifically, the present invention relates to a method for preparing a gallium complex of gallium (III), including gallium (3-hydroxy-2-methyl- 4H -pyran- .
[18] DISCLOSURE OF INVENTION
[19] Accordingly, the main object of the present invention is to satisfy the above-mentioned needs in the art by providing a pharmaceutical method for treating or preventing intra-articular prokaryotes, DNA viruses and retrovirus infections. These methods can be used in combination with gallium complexes of 3-hydroxy-4-pyrone, in particular, to human or other mammals that are susceptible to intraocular prokaryotes, DNA viruses or retrovirus infections, Gallium maltolate < / RTI >
[20] A second object of the present invention is to meet the specific requirements for agents that can be used in combination with therapies for different microbes that are susceptible to coinfection and which can bring about a synergistic effect. The most important objective is to strengthen the anti-HIV therapy and at the same time, by the usual non-opportunistic co-infections (eg hepatitis B and C hepatitis) and often latent and opportunistically appearing, Which is effective against opportunistic infections, which essentially result in morbidity and mortality in immune-compromised HIV patients, including those belonging to the herpesvirus lineage that cause the patient to become debilitated and eventually to die by inducing the disease.
[21] Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will be apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention.
[22] Embodiments of the present invention
[23] As described above, the present invention relates to a method for treating and preventing a retrovirus infection using a gallium complex of 3-hydroxy-4-pyrone. Before discussing the present invention in detail, the terms will first be defined. Unless otherwise stated, the terms used herein have the meaning usually understood
[24] 1. Definitions
[25] The terms used in this specification have the following meanings.
[26] &Quot; 3: 1 neutral gallium complex of 3-hydroxy-4-pyrone " means an anion form of Ga ³⁺ and 3-hydroxy-4-pyrone in an amount of 3 equivalents of an electrostatically neutral complex, [Ga ³⁺ (py ^- ) ₃ ] wherein py ^- is an anion form of 3-hydroxy-4-pyrone described later. Most of these complexes remain electrostatically neutral in such solutions, since such complexes do not dissociate to a significant extent in aqueous solutions maintained at a pH of about 5 to about 9.
[27] In this respect, these complexes are considered electrostatically neutral because of the same number of positive and negative charges in these complexes.
[28] It is also clear that the anion form of 3-hydroxy-4-pyrone acts as a chelating agent for gallium, and thus the complex is often referred to as the " neutral gallium chelate of 3-hydroxy-4-pyrone "Quot; 3: 1 neutral gallium complex of 3-hydroxy-4-pyrone ").
[29] &Quot; 3-Hydroxy-4-pyrone " represents a compound of the following formula (1).
[30]
[31] In this formula, 0 to 3 hydrogen atoms attached to the ring carbon atom are substituted with a hydrocarbon group having 1 to 6 carbon atoms.
[32] Specific compounds included in " 3-hydroxy-4-pyrone " are compounds of the following formulas (2) to (5).
[33]
[34]
[35]
[36]
[37] In the above formulas, each R is independently hydrocarbons having from 1 to 6 carbon atoms.
[38] The unsubstituted form of 3-hydroxy-4-pyrone (also referred to as pyromeconic acid of formula (2)) has three hydrogen atoms bonded to the ring carbon atom only. As noted above, any combination of these three hydrogen atoms may be substituted with a hydrocarbon group, and all possible combinations of such substitutions fall within the scope of the present invention. Some possible substitution positions are shown in formulas (3) to (5), wherein R is a hydrocarbon group including methyl, ethyl, isopropyl and n-propyl. The hydrocarbon group is preferably bicyclic and non-branched. Preference is given to groups with up to 6 carbon atoms, in particular with 1 to 3 carbon atoms, in particular methyl or ethyl. Single substitution is preferred and substitution at the 6 position or especially at the 2 position is preferred. Examples of specific compounds that form gallium complexes that can be used in the compositions of the present invention are 3-hydroxy-2-methyl-4-pyrone (formula (3), R = CH ₃ , sometimes referred to as maltol or larykic acid) 3-hydroxy-2-ethyl-4-pyrone (formula (3), R = C ₂ H ₅ , sometimes referred to as ethyl maltol or ethyl pyromeconic acid) -4-pyrone are particularly preferred for use in the present invention. In another preferred compound is 3-hydroxy-4-Piron (formula (2), sometimes referred to as fatigue methoxy acid) and 3-hydroxy-6-methyl-4-Piron (formula _{(4), R = CH 3} ) .
[39] The term " anion of 3-hydroxy-4-pyrone " refers to a compound defined in the above formulas (2) to (5) wherein the hydroxyl proton is removed to provide an anion-charged form of the compound.
[40] &Quot; Oral administration " and " oral ingestion " refer to all conventional forms for the oral delivery of pharmaceutical compositions that result in accumulation of the pharmaceutical composition in the gastrointestinal tract, including the gastric site (i. Thus, oral administration and oral ingestion include, for example, actual ingestion of a solid or liquid composition, oral gavage, and the like.
[41] By " dissociation inhibition " is meant at least 20%, preferably at least 50%, more preferably at least 80% of the complex under acidic conditions (e.g., about pH 2 to 4) Or more.
[42] An " effective amount " or " therapeutically effective amount " of a drug refers to the non-toxic or sufficient amount of a compound that provides the desired efficacy at a reasonable benefit / hazard ratio associated with any medical therapy. The desired efficacy may be indicative of a disease, alleviation of symptoms or causes, or any other desired alteration of the biological system.
[43] &Quot; Active agent ", " pharmaceutically active agent ", and " drug " are used herein to denote complexes of hydroxypyrone with gallium, especially 3: 1 neutral gallium (III) complexes of 3-hydroxy-4-pyrone.
[44] "To cure" refers to the prevention of disease (ie, avoiding the clinical symptoms of the disease), (2) inhibiting the disease, ie, the clinical symptoms And / or (3) relieving the disease, i. E. Causing the regression of clinical symptoms.
[45] An " individual " as used in the expression " used in the treatment of an individual " refers to an individual organism that is susceptible to or susceptible to an abnormality, symptom or disorder specified herein and includes both humans and animals.
[46] The term " pharmaceutically acceptable " refers to materials that are biologically or otherwise desirable. In other words, the substance may be administered to an individual with an active agent without causing unwanted biological effects or acting in a harmful manner with any other component of the pharmaceutical composition containing the active substance.
[47] &Quot; Optional " or " optionally " means that the circumstances described below may or may not occur in situations where the situation may or may not occur. For example, in the context of the present specification, the term " optionally present " includes both where the formulation contains the additive or not.
[48] "Intracellular prokaryotes" refer to living prokaryotes in a cell. The term includes " prokaryotic prokaryotes " (to be described later) and prokaryotes that can survive and are present in the actual host cells. Macrophage-like "Mycobacterium truberculosis" And "Mycobacterium leprae"Are two examples of intracellular prokaryotes that are not prokaryotic organisms.
[49] &Quot; Prokaryotic prokaryotes " means prokaryotes that must survive in the host cell. The term includes prokaryotes that resemble viruses in that they can not complete the life cycle outside the host cell. In the case of prokaryotic prokaryotes in the sense of an example rather than limiting the above definition, there are mycoplasma, chlamydia, and rickettsia, all of which are important pathogens.
[50] A "DNA virus" refers to any virus that has the genome in its infectious viral particles as DNA, and has to make DNA for replication accordingly. Adenoviruses, adeno-associated viruses, inductive viruses, and herpes viruses are examples of DNA viruses in the sense of illustration rather than limiting this definition. Specific examples of DNA viruses include, but are not limited to, hepatitis B virus, SV40, individual human-inducible viral species, and individual horses, cats, monkeys, murine, algae and human herpesvirus species [human herpes virus 1-8 (HHV- 8). The human herpesviruses are important and often opportunistic pathogens, also known as: HHV-1 is Herpes Simplex I (HSV 1), HHV-2 is Herpes Simplex II (HSV-2), HHV-3 is Herpes Varicella Zoster I HHV-6, HHV-7, and HHV-8 are currently used for Kaposi's sarcoma-related viruses (KSV ).
[51] &Quot; Retrovirus " or " retroviral " refers to a virus that has its genome in an infectious viral particle as a single stranded RNA (ssRNA) and as a reverse transcriptase Refers to any virus that makes a DNA pro virus from the ssRNA of infectious particles using a known unique RNA template-dependent DNA polymerase. The taxonomic definition of retroviruses is Retroviral (Retroviridae) And the virus belongs to. Examples of retroviruses include, but are not limited to, human spuma virus, Meisson-Pyrazza monkey leukemia virus, mouse mammary tumor virus, avian leukemia virus, murine leukemia virus, Laussian sarcoma virus, feline leukemia virus (FELV) (FIV), monkey immunodeficiency virus (SIV), hepatitis C virus, human T cell leukemia (HTLV1, 2), HIV-1 and HIV-2. Also included in the definition of retrovirus is an endogenous virus known to contain about 1-2% of the genome of an animal species. These endogenous retroviruses are usually latent and non-pathogenic to species having endogenous production and may be pathogenic to their native species. Human endogenous retrovirus (HERV) includes those that appear to be derived from cats, murines, horses, and other retroviruses from species that have come into contact with humans through evolution. Different mechanisms, including xenografts that expose xenografts to the virulent tumor virus, infections by other tumor viruses, including HIV virus, and dislocations, can evolve ERV to become a pathogen to the species or other species that the pathogen has been infected with have.
[52] &Quot; HIV infection " and " HIV infection " refer to an infection by one or more retroviruses belonging to the primate lentivirus in the genus Lentiviridae , HIV-1 and HIV-2 are examples of primate lentiviruses known to infect humans. HIV-1 infections, HIV-2 infections or HIV-1 and HIV-2 infections are included in the above definition. It is also intended that human infections by lentiviruses that are not named and different than all known HIV strains belong to the above definition.
[53] In the present specification, the singular forms include plural referents unless the context clearly dictates otherwise. Thus, for example, in the " active agent " in the formulation, the active agent also includes two or more active agents, and the carrier referred to in the carrier also includes two or more carriers.
[54] 2. Synthesis and methodology
[55] The 3: 1 complex of 3-hydroxy-4-pyrone or 3-hydroxy-4-pyrone useful in the present invention is synthesized by reacting hydroxypyrone with gallium ions and at least partially isolating the resulting complexes or complexes .
[56] Specifically, a 3: 1 neutral complex of 3-hydroxy-4-pyrone is prepared by reacting a gallium ion and 3-hydroxy-4-pyrone in solution. Gallium ions may be derived from gallium salts, such as hydrated gallium halides, especially gallium chloride or gallium nitrate compounds, especially hydrated gallium nitrate. Gallium nitrate compounds are sometimes highly desirable because they are highly irritating and react more readily with gallium halides that can react violently with many solvents, including water. As a suitable safety measure, various gallium salts can be used. This reaction is conveniently carried out in mutual solvents including, but not limited to, mixtures containing water, ethanol, methanol and chloroform. In many cases, purified water can be used. If it is desired to isolate at least a major portion of the reaction byproducts such as sodium nitrate, sodium chloride and sodium carbonate, it is a preferred method to use a mixture comprising ethanol and chloroform in approximately equal proportions with a trace amount of water. The reaction products described above have very low solubility in this mixture and are easily removable by filtration.
[57] In order to prepare the preferred neutral 3: 1 hydroxypyrone / gallium complex, the hydroxypyrone and gallium ions are preferably added in an amount which is preferably slightly above the 2: 1 and 1: 1 complexes so that the 3: Hydroxypyrone in a molar ratio of 3: 1. The ratio of the specific complex formed depends on the pH of the solution. When a gallium salt such as a halide or nitrate is dissolved, the resulting solution will generally have a low pH. A pH of 5 to 9, preferably 7 to 8 is used to predominantly form the desired neutral 3: 1 complex. If a more acidic solution is used, the less preferred 2: 1 complex and 1: 1 complex will predominantly form, even in the presence of excess hydroxypyrone. Under very basic conditions, almost insoluble gallium hydroxide may precipitate. It is desirable to adjust the pH with a substance other than hydroxide such as sodium hydroxide, which would lead to the precipitation of undesirable, almost insoluble gallium hydroxide when using hydroxides, and by this precipitation the pH is buffered to an undesired level . It is preferred to use a carbonate, especially sodium carbonate, in adjusting the pH. For example, if sodium carbonate is used in a solvent mixture containing ethanol and chloroform, it can lead to precipitation of the filterable sodium nitrate to assist in the purification of the solution which is very slightly soluble in the mixture and, if desired, contains the desired pharmaceutical composition.
[58] The reaction to form the hydroxypyrone-gallium complex is usually completed in about 5 minutes at about 20 < 0 > C. Some stirring or other stirring of the solution promotes a uniform and rapid reaction. If necessary, the reaction time can be made longer. If desired, after isolating reaction byproducts such as sodium nitrate, sodium chloride and sodium carbonate (depending on the solvent and reactants used), the reaction mixture may be evaporated slowly in air or, for example, by using a rotary evaporator or by freeze drying It can be evaporated quickly. After drying, the gallium complex (s) will remain in solid form. If desired, recrystallization may be achieved using a suitable solvent, including, but not limited to, chloroform, alcohols (e.g., ethanol and methanol), ether, water, acetone, and mixtures including such solvents. Suitable solvents may vary depending on whether the particular gallium complex (s) and impurities are present, the impurities to be isolated, temperature and other physical conditions.
[59] It should be noted that the above method is not the only way to prepare complexes of hydroxypyrone and hydroxypyrone with gallium, and that other alternative methods obvious to those skilled in the art may be used. Additionally, in preparing neutral 3: 1 complexes of 3-hydroxy-4-pyrone and gallium, it is possible to use 3-hydroxy-4-pyrone alone or to use a mixture of 4-hydroxy- . However, it is preferable to use 3-hydroxy-4-pyrone alone.
[60] When preparing 3-hydroxy-4-pyrone used as a starting material in the preparation of the neutral 3: 1 complex of 3-hydroxy-4-pyrone and gallium, some of these compounds occur naturally, Can be prepared by extraction. For example, maltol can be used as a raw material in the shell and pine leaves of Larix decidua Mill , chicory, wood tar and oil, and roasted malt (Merch Index, 9 ^th Edition, pp. 741-742, Rahway, Co., 1976). Some of 3-hydroxy-4-pyrone, including maltol and ethyl maltol, are commercially available. Others can be prepared using pyromeconic acid, which can be derived by decarboxylation of meconic acid, as the starting material. Methods for preparing such 3-hydroxy-4-pyrone are well known in the art. In addition, it is well known that maltol and ethyl maltol are widely used as food flavorings and aroma enhancers and have very low toxicity when administered orally.
[61] 3. Pharmaceutical composition
[62] The method of the present invention is accomplished using a pharmaceutical composition comprising a 3: 1 neutral complex of 3-hydroxy-4-pyrone and gallium. The compounds may be formulated for administration as tablets containing one or more pharmaceutically acceptable conventional nontoxic carriers, for example orally, parenterally (including subcutaneous, intravenous and intramuscular injection), transdermal, rectal, intranasal, buccal, , Topical, and intravenous administration.
[63] The pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions and the like, May be present in unit dosage form. The compositions usually need not be administered with a pharmaceutically acceptable carrier, but may contain an effective amount of an active agent and may also include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.
[64] In the case of solid compositions, conventional non-toxic carriers may include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like. A pharmaceutically acceptable liquid composition can be prepared, for example, by forming a solution or suspension by dissolving, dispersing, or the like, any of the above-described active agents and any pharmaceutical adjuvant in an excipient such as water, saline, aqueous dextrose, glycerol, can do. If desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate and the like. Actual methods of preparing such dosage forms will be apparent to or well known, or one skilled in the art [for example, the literature of Leamington (The Science and Practice of Pharmacy, 19 ^th Ed, Easton PA:. Mack Publishing Co. , 1995).
[65] For oral administration, the compositions may take the form of tablets or capsules, or may be aqueous or non-aqueous solutions, suspensions or syrups. Tablets and capsules are the preferred dosage forms. Oral tablets and capsules usually comprise one or more conventional carriers (e.g., lactose and corn starch). Lubricants (e. G., Magnesium stearate) are also topically added. When a liquid suspension is used, the active agent may be combined with an emulsifying agent and a suspending agent. If desired, flavors, colorants and / or sweeteners may also be added. Other optional components for introduction into the oral preparation of the present invention may include preservatives, suspending agents, thickening agents and the like, but are not limited to these components. Particularly preferred oral formulations in the present invention are sustained release formulations (e.g., enteric coated tablets) as described in detail below.
[66] Parenteral administration is generally characterized by injection. The injectable formulations may be prepared in conventional forms, as liquid solutions or suspensions suitable for solution or suspension in liquid prior to injection, as a solid, or as an emulsion. The injectable sterile suspension is preferably formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Injectable sterile preparations may also be injectable sterile solutions or suspensions in a parenterally acceptable non-toxic diluent or solvent. Acceptable vehicles and solvents that may be used include Ringer's solution and sodium chloride isotonic solution. In addition, sterile, nonvolatile solutions are commonly used as solvents or suspending media.
[67] In addition, the compounds of the present invention can be delivered through the skin or mucosa using conventional " transdermal " -type patches containing the drug in a lamellar structure that serves as a drug delivery device fixed to the skin. In such a structure, the drug composition is contained in the layer below the upper backing layer, or in the storage layer. The stacked structure may contain a single storage layer or may contain multiple storage layers. In one embodiment, the storage layer comprises a polymer matrix of a pharmaceutically acceptable contact adhesive material that acts to immobilize the system on the skin during drug delivery. Suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, and the like. Alternatively, the drug-containing storage layer and the skin contact adhesive are present in distinct distinct layers, which may be the polymeric matrix described above, or may be a liquid or hydrogel storage layer, or under the storage layer, which may take any other form, .
[68] Alternatively, the pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration. They can be prepared by mixing the drug with a non-irritating excipient that is liquid at a solid or rectal temperature at room temperature and therefore dissolves in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[69] The pharmaceutical compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmacy and may be prepared using benzyl alcohol or other suitable preservatives, absorption enhancers to increase biocompatibility, injecting agents (e.g., hydrocarbons or nitrogen) and / or other conventional solubilizing or dispersing agents Can be made into a brine solution.
[70] Preferred formulations for topical drug delivery are ointments and creams. Ointments are typically semi-solid preparations based on petrolatum or other petrolatum derivatives. Creams containing the selected active agent are viscous liquid or semi-solid emulsions, water-in-water or water-in-oil types well known in the art. The cream base is washable with water and may contain oil phase, emulsifier and water phase. It is also common that the oil phase, sometimes referred to as the internal phase, contains petroleum jelly and fatty acids (cetyl or stearyl alcohol) and that the water phase does not necessarily exceed the oily phase but contains a humectant It is common. Emulsifiers in cream formulations are usually nonionic, anionic, cationic or amphoteric surfactants. As is well known to those skilled in the art, the particular ointment or cream substrate that is to be used is one that provides optimal drug delivery. The ointment substrate should be inert, stable, non-irritating and non-sensitive, like any other carrier or vehicle.
[71] However, as noted above, the preferred compositions in the present invention are oral formulations, particularly preferred oral formulations are extended forms. It has been found that the 3: 1 neutral complex of 3-hydroxy-4-pyrone and gallium transfers gallium from the blood to the gastrointestinal tract, but can be partially dissociated under acidic conditions (generally pH below about 4). Such acidic conditions may be present above. The dissociation may result in a less absorbable 2: 1 and 1: 1 complex with the free hydroxypyrone and the ionic gallium. Thus, in order to maintain the oral delivery of gallium in a highly absorbable form in the gastrointestinal tract, means for inhibiting dissociation of the complex upon exposure to the above acidic conditions may be included in the pharmaceutical composition of the present invention.
[72] Means for suppressing or preventing dissociation of the complex of the present invention upon exposure to the above acidic conditions include the following preferred methods.
[73] (1) a sufficient amount of a pharmaceutically acceptable buffer to make the gastric pH about 5 to 9, preferably about 6 to 7, so that the gastric juice no longer destroys the 3: 1 hydroxypyrone: Ga complex 3: 1 complex.
[74] Pharmacologically compatible buffers are those that act as buffers but do not significantly alter the ability of the neutral 3: 1 gallium complex to transfer gallium to the patient's blood, and are not toxic, either alone or in combination with neutral gallium complexes. It is not important that any substance is specifically used as a pharmaceutically compatible buffer. However, examples of pharmacologically compatible buffering agents include calcium carbonate (CaCO ₃ ), sodium bicarbonate (NaHCO ₃ ) and the like. On the other hand, aluminum hydroxide [Al (OH) ₃ ] and other aluminum-containing compounds should be avoided. Other pharmaceutically acceptable buffering agents are well known in the art and are described, for example, in standard drug manufacture literature, such as The Science and Practice of Pharmacy, supra.
[75] (2) an excess of free hydroxypyrone (or a salt thereof containing a physiologically acceptable cation), especially a 3: 1 complex, is added to the pharmaceutical composition containing the 3: 1 complex. Such mixtures have the effect of shifting the equilibrium so that the 3: 1 complexes in the 1: 1, 2: 1 and 3: 1 complexes at the time of dissolution dominate. In this embodiment, the weight of the hydroxypyrone introduced into the formulation is preferably 0.1 to 100 times, more preferably 0.1 to 10 times the weight of the 3: 1 complex used in the formulation. Although this method is not very preferable in itself, it can be used in combination with other methods for suppressing dissociation.
[76] (3) The pharmaceutical composition containing the 3: 1 complex is formulated in a sustained release form so that the predominant complex is released by reaching the intestinal tract. One example of such a composition is to prepare a 3: 1 complex with a gel, preferably a hydrogel (e.g., a polymerized polyethylene glycol hydrogel) that adsorbs the 3: 1 complex and then slowly releases it while in the uptake . The preparation of such sustained release formulations, especially those using hydrogels, is well known in the art.
[77] (4) Most preferably, the 3: 1 complex is formulated or encapsulated in a manner that prevents or inhibits the release of the 3: 1 complex until the intestinal tract reaches a basic condition or a less acidic condition.
[78] (a) encapsulating the 3: 1 complex with a material that most preferably dissolves dissociation until it reaches the intestinal tract using an enteric coated tablet or capsule or using enteric coated granules, It inhibits or prevents the release of 3: 1 complex until pH is reached. Coatings for tablets, capsules, and granules are well known in the art.
[79] (b) microencapsulate 3: 1 complexes in liposomes (preferably made from phospholipids) which dissociate under the above acidic conditions but release 3: 1 complexes at higher pH conditions in the intestinal tract. Such liposomes are also known in the art.
[80] The most preferred methods, enteric coated tablets, granules or especially capsules are well known in the art.
[81] Preferred materials for enteric coating include cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinylacetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate , Carboxymethylethylcellulose, hydroxpropylmethylcellulose acetate succinate, and acrylic acid and acrylic esters as polymer and copolymer [referably acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and Or ethyl methacrylate (commercially available under the trade name Eudragit), of which cellulose acetate phthalate is preferred. When coating capsules, a plasticizer should be used to minimize brittleness in the coating and to prevent cracking of the coating. Tablets and granules can also be used.
[82] In the case of enteric coated tablets, the core portion of the coated formulation will generally contain other materials such as binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, colorants and the like. If desired, additional active agents may be included.
[83] It is common for the core portion of the formulation to contain, but not necessarily, about 5 to 95% by weight of the active agent and the remainder of the core portion to include the binder and other materials as described above.
[84] In addition, two or more means of inhibiting the dissociation of these complexes may be used in combination to increase the level of inhibition. That is, a pharmaceutically compatible buffer and an excessive amount of free 3-hydroxy-4-pyrone can be used in combination.
[85] A preferred oral dosage form of the present invention is a solid unit dosage form (e.g., the coated tablets described above) in which each unit dosage form contains a therapeutically effective amount of an active agent. Because the capsule itself serves as a means of inhibiting dissociation of the complex, it is also possible to use a sustained-release capsule which is capable of encapsulating the active agent in the presence or absence of additional hydroxypyrone, buffer or other active ingredient without carrier or the like.
[86] Oral preparations comprising a pharmaceutically inert, liquid carrier (e.g., water) may also be considered for oral administration, and the formulation preferably comprises a pharmaceutically compatible buffer, preferably the use of CaCO ₃ or NaHCO ₃ Lt; RTI ID = 0.0 > 3: 1 < / RTI > complex in acidic conditions above. The use of such buffers is well known in the art.
[87] The practice of the present invention will employ the ordinary skill of those skilled in the art, unless otherwise indicated. Such techniques are described in the aforementioned Leamington (The Science and Practice of Pharmacy, 19 th Ed, Easton PA:. Mack Publishing Co., 1995) and literature (The Pharmacological Basis ofTherapeutics, 9 in Goodman And Gilman (Goodman & Gilman) ^th Ed., New York; McGraw-Hill, 1996).
[88] 4. Pharmacological treatment
[89] One embodiment of the present invention comprises administering a therapeutically effective amount of gallium to a mammalian subject in the form of a complex of gallium and hydroxypyrone as hereinbefore defined. The complex is essentially a neutral 3: 1 (hydroxypyrone: gallium) complex, wherein the hydroxypyrone is unsubstituted or substituted with one to three C ₁ -C ₆ alkyl substituents which may be the same or different But is preferably, but not necessarily. In addition, the therapeutically effective amount is such that sufficient plasma gallium concentration is provided for the treatment or prevention of an intracellular prokaryote, a DNA virus or a retroviral disease. A highly preferred complex is a complex of maltol with a gallium (3-hydroxy-2-methyl-4-pyrone): tris (3-hydroxy-2-methyl-4H- Also referred to as gallium maltolate. Another preferred complex is gallium (3-hydroxy-2-methyl-4-pyrone): tris (3-hydroxy-2-ethyl-4H- As the complex, it is also called gallium ethyl maltolate.
[90] In a preferred embodiment of the invention, the complex is orally administered to a solid dosage form such as a tablet or capsule containing one or more pharmaceutically acceptable carriers. Orally or by other means, for example, by injection, transdermal, rectal, nasal, oral, intravenous, sublingual, topical, local, vaginal, or inhalation, in association with one or more pharmaceutically acceptable carriers. ≪ / RTI >
[91] For oral administration, the therapeutic plasma level is about 1 to 5,000 ng / mL, especially about 200 to 1000 ng / mL. Oral doses of complexes to achieve such therapeutic levels are from about 10 to 2,500 mg per day, especially from about 250 to 750 mg per day. The complex is preferably administered in a single formulation, but may be administered multiple times per day. The complex is preferably administered at least one hour prior to meals and at least two hours after meals, although other schedules are possible.
[92] Complexes may be administered with other antiretroviral agents, particularly those used in the treatment of AIDS, including, but not limited to, nucleoside analogs such as zidovudine (AZT), ddI and ddC, protease inhibitors such as Ritonavir, indinavir, and nelfinavir, and non-nucleoside reverse transcriptase inhibitors such as nevirapine and delavirdine. The present invention also includes formulations containing active agents other than gallium complexes.
[93] Some representative examples of dosing schedules for treating patients infected with HIV-1 include, but are not limited to, the scope of the invention in any way:
[94] (a) 500 mg of gallium maltolate once a day, plus 200 mg of AZT twice a day, plus 200 mg of ddI twice a day, plus 800 mg of indinavir every 8 hours; (b) 400 mg gallium maltolate twice a day, plus 200 mg AZT twice daily, plus 0.75 mg ddC three times daily, plus 600 mg ritonavir twice a day; (c) 250 mg of gall maltolate once a day, plus 40 mg of d4T twice a day, plus 200 mg of ddI twice a day, plus 750 mg of nelfinavir three times a day. These examples are for individuals weighing 60 kg and can be adjusted for other weights.
[95] Infections that can be treated by the methods of the present invention include retroviral infections and DNA virus infections. Retroviral infections include those associated with AIDS, such as HIV-1 infection and the associated retroviral infection of the primate family, Lentiviridae. Other treatable retroviral infections include, but are not limited to, human T-cell leukemia (HTLV), tropical flaccid paraparesis and chicken leukemia virus, bovine leukemia virus, murine mammary tumor virus, murine leukemia virus, And infections caused by the Mason-Pfizer monkey virus. ≪ RTI ID = 0.0 > Other treatable retroviral infections that primarily affect non-human animals include, but are not limited to, non-primate lentiviruses such as cats, horses, cows and sheep / goat lentiviruses.
[96] HHV-1 (HSV-1), HHV-2 (HSV2), HHV-3 (VZV), and human hepatitis B virus infections that can be treated by the method of the present invention include hepatitis B, human papilloma, And herpes viruses such as HSV-4 (EBV), HSV-5 (CMV), HSV-6, HSV-7 and HSV-8 (KSV).
[97] Intracellular prokaryotes are sensitive to the mechanism of the gallium compounds of the present invention. Macrophage-phagocytic bacteria, such as the Mycobacteria species Mycobacterium tuberculosis and Mycobacterium leprae, which can survive in macrophages, are also shown It is sensitive to gallium medicines of the invention. Absolute intracellular prokaryotes such as Mycoplasma species, Rickettsia species and Chlamidia species are entirely susceptible to the effects of the present invention in inhibiting microbial-static, for example replication, replication .
[98] While the invention has been described with reference to preferred embodiments, it is to be understood that the foregoing description and the following examples are intended to illustrate and not limit the invention. Other aspects, advantages, and modifications will be apparent to those skilled in the art to which the invention pertains.
[99] The following examples are intended to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the compounds of the present invention and are not intended to limit the scope of the invention as contemplated by the inventors. Efforts have been made to ensure accuracy with respect to numbers (eg, quantity, temperature, etc.), but some errors and deviations should be taken into account. Unless otherwise indicated, parts are parts by weight, temperatures are in 占 폚, and pressures are at or near atmospheric. All solvents were purchased at HPLC or reagent grade and, where appropriate, purity of solvent and reagent was analyzed using conventional techniques.
[100] In the present embodiment, the following abbreviations have the following meanings:
[101] Å = Angstrom (0.1 nm)
[102] C = Celsius temperature
[103] kg = kilogram
[104] M = molar concentration
[105] mg = milligrams
[106] ml = milliliters
[107] mm = millimeter
[108] N = normal concentration
[109] nm = nanometer
[110] Further, in the X-ray fluorescence and diffraction data shown in Example 1, the number in parentheses after the report value represents the estimated standard deviation of the last digit.
[111] Example 1
[112] Preparation of gallium ethyl maltolate
[113] A 1.5 M solution of ethyl maltol in chloroform was mixed with a 0.5 M solution of gallium nitrate nonohydrate in the same volume of ethanol to obtain a mixture of ethyl maltol to gallium ion in a molar ratio of 3: 1. The mixture was stirred at 22 < 0 > C for 7 minutes. Then, 10 molar excess of solid anhydrous sodium carbonate was added and stirring was continued for a further 10 minutes. When sodium carbonate is added, it may be necessary to add a small amount of water to accelerate the reaction (which is proved by some boiling). The mixture was then filtered and the filtrate was evaporated to give a 3: 1 solid complex of ethyl maltol and gallium.
[114] This is a complex prepared x- ray fluorescence analysis _{Ga (C 7 H 6 O 3} ) is a gallium content of 14.3 (1)% by weight of which is estimated to. This material forms a white to light beige monoclinic and the unit cell parameters based on powder x-ray diffraction analysis are approximately a = 7.899 (1), b = 8.765 (1), c = 31.626 , = 103.253 (7), and V = 2131 ³ . The solubility measurement results for this compound are about 5 millimoles in distilled water deionized at 23 占 폚. Crystallization in other solvents or in other conditions can produce different crystal structures. Under some conditions, water or other solvents may be incorporated into this structure.
[115] Example 2
[116] Preparation of gallium maltol
[117] The maltol was dissolved in chloroform to form a 0.75 M solution and the gallium nitrate nonohydrate was dissolved in ethanol to form a 0.5 M solution. 20 ml of a 0.75 M maltol solution in chloroform was slowly added with continued stirring to 10 ml of the above 0.5 M solution of gallium nitrate nonohydrate in ethanol. The resulting solution was stirred at 23 < 0 > C for 5 minutes. Approximately 5.5 grams of powdered anhydrous sodium carbonate was added and stirring was continued for another 12 minutes. The mixture was filtered to remove all solids, and the filtrate was evaporated in a rotary evaporator. The remaining crystalline solid is a 3: 1 maltol gallium composition. The composition was analyzed by powder x-ray diffraction and the result was that the unit cell dimensions were approximately a = 18.52 (1) Å, b = 16.94 (1) Å, and c = 12.02 (1) Å . The result of measuring the solubility of this composition is about 24 moles in distilled water deionized at 23 占 폚.
[118] The solubilities of neutral 3: 1 maltol: gallium complexes were studied in aqueous solutions of various pH values. The complexes were studied at two concentrations of deionized double distilled water, 2.5x10 ^-6 M and 1.0x10 ^-2 M. By the addition of 1N HCl or 1N Na ₂ CO ₃ to adjust the pH. The solubility of the complex was determined by ultraviolet spectroscopy for the region of 200-450 nm at 25 캜. Several absorption peaks were observed in this region including peaks at about 212-217 nm, 248 nm, 273 nm, 318 nm, and 385 nm. An isobosorbing point occurred for a number of these pH ranges at about 290 nm. In a very dilute solution (2.5 x 10 ^-6 M), the neutral 3: 1 complex appeared stable at pH 4.5 to 9.5. For the less dilute solution (1.0 x 10 ^-2 M), the measurement was more difficult because the absorbance was very high. The solubility area was very similar to the solubility of the very dilute solution, but seemed slightly wider.
[119] Example 3
[120] Preparation of Enteric Coated Capsule Formulations
[121] A 3: 1 malt: gallium composition was prepared as described in Example 2. 40 mg of the 3: 1 maltol: gallium composition, 10 mg of maltol, and about 190 mg of starch were added to a hard gelatine capsule of standard size 3 (about 15.5 mm in length and 5.8 mm in diameter). The capsules were closed and then transferred to a cellulose acetate phthalate / diethyl phthalate layer using a pilot scale method as described in Jones (1970), " Production of enteric coated capsules, " Manufacturing Chemist & Aerosol News 41: 43-57, Respectively. Using acetone as a solvent, a coating having a thickness of about 35 micrometers was obtained. Such a capsule inhibits the release of its containing component (3: 1 maltol: gallium composition) in the above acidic state and releases it in the small intestine with a pH greater than about 5.5.
[122] Other materials known in the art can also be used for enteric coating of capsules by simply replacing the cellulose acetate phthalate / diethyl phthalate used in Example 3 above. Such other materials include, for example, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, poly (vinyl acetate phthalate), hydroxypropylmethylcellulose acetate succinate, poly (meth) acrylate, and the like.
[123] Example 4
[124] Preparation of Capsules Containing Pharmacologically Acceptable Buffers
[125] The purpose of this example is to prepare oral pharmaceutical compositions containing neutral complexes of gallium and 3-hydroxy-4-pyrone, using a pharmaceutically acceptable buffer as a means of inhibiting the dissociation of complexes in the acidic state above . Specifically, 40 mg of a 3: 1 maltol: gallium composition, about 50 to 1000 mg (preferably 500 mg) of calcium carbonate, and balance starch were placed in a standard gelatin capsule and the capsules were closed to obtain a composition of the present invention. These capsules will inhibit dissociation of the 3: 1 maltol: gallium composition in the acidic state by raising the pH of the liquid in the stomach.
[126] From the above, other neutral complexes of gallium and 3-hydroxy-4-pyrone are also prepared according to the method described above by simply using another 3-hydroxy-4-pyrone instead of the maltol and ethyl maltol used in the above examples It will be possible. Likewise, other means of preventing the dissociation of the neutral complex may be used by simply substituting the means illustrated above with other means.
[127] Specifically, about 50 to about 1000 mg of another pharmaceutically acceptable buffer may be used in place of calcium carbonate in the capsule of Example 4. Such other pharmaceutically acceptable buffer solutions include, for example, sodium bicarbonate, sodium carbonate, and the like.
[128] Example 5
[129] Clinical evaluation of gall maltolate for the treatment of HIV infection
[130] The efficacy of gallate maltolate in the treatment of HIV infection was evaluated clinically. The method of Kirk et al. (1999), "Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial," AIDS 13 (1) 9-16. HIV-infected patients were treated with a gelatin capsule containing 250 mg of gallium maltolate once a day. Patients were randomized to receive either 0 (placebo), 250, or 400 mg / day gallium maltolate for approximately 6 months, with AZT 300 mg twice daily, ddI 200 mg twice daily, and indinavir 800 mg once every 8 hours. 500, or 750 mg at random. During the study period, the patients were observed for HIV infection symptomatically. Serum samples were also obtained from patients at 0, 30, 90, and 180 days, and the number of CD4 T-cells by conventional methods and the Roche AMPLICOR Ultra assay (Sun et al. (1998), "Ultrasensitive reverse transcription- HIV-1 RNA (viral load analysis) was assayed using an assay for quantitation of human immunodeficiency virus type 1 RNA in plasma, "J. Clin. Microbiol. 36 (10): 2964-2969). As a result of conducting experiments according to literature methods, the gallium maltolate and related compounds of the present invention were found to be effective in treating HIV infection.
[131] Example 6
[132] Clinical Evaluation of Gall Maltolate for the Treatment of Hepatitis B Infection
[133] The efficacy of gallate maltolate in the treatment of hepatitis B infection was evaluated clinically. (1999), " Treatment of Chronic Hepatitis B: New Antiviral Therapies, " Curr. Gastroenterol. Rep. 1 (1): 20-26); [Hoofnagle et al. (1997), " New therapies for chronic hepatitis B, " J. Viral Hepat. 4 Suppl., 1 : 41-50] was used for the above evaluation. Patients infected with hepatitis B were treated once a day with gelatin capsules containing gallium maltolate. Patients were randomly divided into two approximately equal groups of approximately equal 4 subgroups taking 0 (placebo), 250, 500, or 750 mg gallium maltolate per day for approximately 6 months. The first four groups received gallium maltolate once daily with 5 million IU interferon injections. The second four groups received 5 million IU interferon once daily and gallium maltolate with 150 mg ramomundine twice daily. Patients should also be aware of liver disease, including medical examination of hepatic function tests and medical symptoms of hepatitis B infection during the study period, as well as careful attention to the possibility that the drug itself may cause liver disease and elevate liver function tests received. Such liver function tests were performed on week 1, week 2 and every two weeks thereafter. Also, liver biopsy samples obtained from the patients at 0, 30, 90, and 180 days were analyzed by biopsy and immunochromatography, and liver histopathology using in situ hybridization for appropriate antigens and nucleic acids Study. Blood analysis was performed by conventional methods on appropriate antigens including the hepatitis B surface antigen (HbsAg) and the " e " antigen (HbeAg) every first week, second week and every two weeks thereafter. In the case of successful treatment, patients with chronic hepatitis B can be converted from the cloned state (HBeAg positive) to the non-cloned state (HBeAg negative), and some patients may be healed by the complete loss of HbsAg .
[134] Example 7
[135] Clinical Evaluation of Gallium Maltolate for Infection with Mycoplasma Pneumonia in HIV-infected Patients
[136] Pneumonia caused by mycoplasma pneumonia is called "walking pneumonia" and it often takes patients with HIV infection, but it also affects immune competent individuals. Although often treated with a bactericide, bacteriostatic systems such as tetracycline are used for the treatment. The action of gallium seems to be a little closer to bacterium than to sterilization. Gallium can be used with tetracycline in refractory mycoplasma pneumonia, but this seems to be the case only for HIV patients, since antimicrobial therapy for prokaryotes does not use a fungicide and a bacterium together. Because tetracycline inhibits protein synthesis in prokaryotic ribosomes, a synergistic effect is expected by the dramatically different mechanism of action of gallium. Since the therapeutic pathway for HIV disease is much longer than the usual successful treatment route for gait pneumonia, gallium therapy is a powerful tool to help rebuild the immune system by enhancing the HIV-affecting or highly active antiretroviral therapy (HAART) There will be little impact.
[137] HIV patients with mycoplasma pneumonia undergoing the same HAART treatment (except gallium) as described in Example 5 were randomly and randomly divided into two nearly equivalent groups. The two groups were then equally randomly divided into four subgroups, each with a different gallium dose (including the placebo dose). Each group was then treated the same as gallium maltolate as described in Example 5. Group 1 received tetracycline 500 mg four times a day to treat pneumonia in addition to gallium. Group 2 received only gallium in addition to standard HAART. Experiments conducted according to literature procedures show that the gallium maltolate and related compounds of the present invention are effective in treating mycoplasma pneumonia in HIV patients. As expected, the combined use of gallium and tetracycline was more effective than using only one drug, and MacSynergy II Synergistic effects have been demonstrated by several computational data analysis techniques, including methods based on computer programs.
[138] Example 8
[139] Clinical evaluation of gall maltolate for the treatment of herpes simplex (I or II) infection and recurrence
[140] Clinical evaluation of the efficacy of gallate maltolate in treating herpes simplex infection of HIV negative individuals with no indication of any type of immune dysfunction. Patients infected with herpes simplex were treated with gelatin capsules once a day with gallium maltolate. The population of patients was divided into subgroups infected with recurrent herpes simplex and acute herpes simplex. These different subgroups were randomly divided into two nearly equal groups with approximately equal 4 subgroups receiving 0 (placebo), 250, 500, or 750 mg gallium maltolate per day for about 6 months. Group 1 of each subgroup received cyanoboryl 500 mg twice daily with gallium maltolate. Group 2 of each subgroup received cyanoboryl chloride 500 mg twice daily with gallium maltolate. During the study period, patients were observed, including a partial recurrence of latent herpes simplex infection or medical observations of the medical symptoms of acute herpes simplex infection, including in situ hybridization of dermatosis of HSV DNA. Also, for the group infected with acute herpes simplex, sera samples were obtained from patients on days 0, 3, 7, and 10, and HSV particles by conventional methods and herpes simplex DNA (virus load analysis) using PCR Respectively. As a result of experiments carried out according to the above procedure, the gallium maltolate and related compounds of the present invention have been shown to be effective in treating herpes simplex infection, including recurrent wounds and more severe systemic diseases. As expected, the use of gallium and acyclovir or gancyclovir together is more effective than either one, and the synergistic action of gallium and the dinucleoside analogue is also known as MacSynergy II It has been proved by several computational data analysis techniques including methods by computer programs.
[141] Example 9
[142] Clinical Evaluation of Gall Maltolate for the Treatment of Herpes Varicella-Zoster (VZV) Infection and Recurrence
[143] Clinical evaluation of gallate maltolate efficacy in treating Varicella-Zoster (VZV) infections of HIV-negative individuals with no indication of any type of immune dysfunction. Patients infected with VZV were treated once a day with gelatin capsules containing gallium maltolate. The population of patients was divided into subgroups infected with recurrent VZV (shingles) and acute acute VZV (varicella). These different subgroups were randomly divided into two nearly equal groups with approximately equal four subgroups administered with 0 (placebo), 250, 500, or 750 mg gallium maltolate per day for about 6 months . Group 1 of each subgroup received acyclovir 800 mg 5 times daily with gallate maltolate. Group 2 of each subgroup received cyanoboryl chloride 500 mg twice daily with gallium maltolate. During the study period, patients were observed, including a partial recurrence of latent VZV infection or a medical observation of the medical symptoms of an acute VZV infection, including the in situ hybridization of VZV DNA dermatosis. For the group infected with acute VZV, sera samples were obtained from the patients on days 1-5, and analysis of VZV particles (virus load analysis) using VZV particles and PCR was performed by a conventional method. As a result of the experiments carried out according to the above procedure, the gallium maltolate and related compounds of the present invention have been shown to be effective in treating VZV infections, including recurrent wounds and more serious systemic diseases. As expected, the use of gallium and acyclovir or gancyclovir together is more effective than either one, and the synergistic action of gallium and the dinucleoside analogue is also known as MacSynergy II It has been proved by several computational data analysis techniques including methods by computer programs.
[144] Example 10
[145] Clinical evaluation of Gall maltolate for the treatment of Epstein-Barr virus (EBV) infection
[146] Clinical evaluation of the efficacy of gallate maltolate in treating EBV infection of HIV negative individuals with no evidence of any type of immune dysfunction other than EBV mononucleosis. (2000), " Regression of Epstein-Barr virus-associated lymphoproliferative disorders in patients with acquired immunodeficiency syndrome during therapy with foscarnet, " Ann. Hematol. 79 (4): 214-6] were used for the evaluation. Patients infected with EBV were treated with gelatin capsules once a day with gallium maltolate. The population of patients was divided into subgroups infected with recurrent VZV (shingles) and acute acute VZV (varicella). These different subgroups were randomly divided into two nearly equal groups with approximately equal four subgroups administered with 0 (placebo), 250, 500, or 750 mg gallium maltolate per day for about 6 months . Group 1 of each subgroup received cyanoboryl 500 mg twice daily with gallium maltolate. Group 2 received 5500 mg of Foscarnet and IV infusion over a period of 1.5-2 hours with gallium maltolate twice a day. During the study period, patients were screened for histopathologic examination of hematologic smears to evaluate the level of characteristic cell lymphocytes, with splitting of EBV infection. Serum samples were obtained from patients on days 1, 3, 7, 10, 14, 17, 21, 24 and 28 for acute VZV infected groups and EBV DNA by conventional methods and PCR Virus load analysis). As a result of the experiments carried out according to the above procedure, the gallium maltolate and related compounds of the present invention have been shown to be effective in treating EBV infection, including recurrent wounds and more serious systemic diseases. As expected, the use of gallium and acyclovir or gancyclovir together is more effective than either one, and the synergistic action of gallium and the dinucleoside analogue is also known as MacSynergy II It has been proved by several computational data analysis techniques including methods by computer programs.
[147] Example 11
[148] Clinical evaluation of gall maltolate for the treatment of co-infection with HIV and hepatitis B
[149] The gallium compounds of the present invention which are orally administrable, highly Tf-linked and well distributed are expected to have synergistic effects with existing HAART therapies. By synergy, a more successful reconstitution of the immune system is likely in terms of recovery of a higher proportion of infected patients and a longer specific immune response to HIV and other intracellular microorganisms. In doing so, the compounds of the present invention also potentiate or potentiate the possibility of using biological, humoral, hormonal agents to stimulate a specific immune response against HIV or another intracellular pathogen.
[150] Recent additions to the combination therapy of adding nucleoside analogs to interferon-alpha (alpha-interferon) in the treatment of hepatitis B and hepatitis C have led to the combined use of gallium Indicating another significant advantage of the compound. The compounds of the present invention are effective against a combination of viruses because they are effective against any intracellular pathogen that destroys the iron metabolism of the host cell and produces DNA during the life cycle.
[151] Hepatitis B and hepatitis C therapies are traditionally based only on interferon, and it is generally known that nucleoside analogs have been added as a combination antimicrobial therapy; People infected with HIV are often infected with one or both, and once their immune system has been impaired, the effect of interferon administration is lost even if it is not adversely affected. Thus, the present invention provides a synergistic combination with nucleoside analogues, which can control hepatitis B in HIV patients without interferon and synergistically combine with anti-HIV therapy to enhance specific immunity to hepatitis virus , Thereby potentiating the addition of interferon-alpha to anti-hepatitis therapy after a significant improvement in the immune function measured by CD4 + levels or other methods is observed.
[152] Clinical evaluation of gallate maltolate efficacy in treating co-infection of hepatitis B in HIV-1 patients. In addition to the methods used to evaluate HIV disease in Example 5, Yao et al. (1997), " Treatment of Chronic Hepatitis B: New Antiviral Therapies, " Curr. Gastroenterol. Rep. 1 (1): 20-26); The methods used in the clinical studies described in Hoofnagle et al. (1997), "New therapies for chronic hepatitis B," supra, were used for the evaluation.
[153] Patients were treated once a day with gelatin capsules containing gallium maltolate. A population of patients infected with hepatitis B and HIV, first, based on the number of CD4 + (350 / mm ³ or more and 350 / mm ³ or less) 2 were divided each into two subgroups. These subgroups were randomly divided into two groups at random and divided into four subgroups each receiving 0 (placebo), 250, 500, or 750 mg gallium maltolate per day for about 6 months, Made almost equal subgroups of dogs. All subgroups received the same non gallium antiretroviral therapy as described in Example 5 (HAART treatment). Since the combination of interferon therapy with nucleoside analogs for hepatitis is relatively recent, interferon plus gallium has been compared with interferon plus gallium plus nucleoside analogs. Specifically, interferon-alpha (a-interferon) was used. The most common nucleoside analogs for hepatitis B are lamivudine, and newer alternatives include palmyclovir, robucavir, and adefovir dipivoxil.
[154] In each subgroup, four subgroups of the first group of each subgroup (greater than 350 / mm ³ and 350 / mm ³ ) received an additional 10 million IU interferon injections with gallium maltolate once daily. This is twice the dose used for the non-HIV infected individual of Example 6, due to the immunological effects of HIV disease. In each subgroup, four of the second group received lamodyne 150 mg twice daily with gallate maltolate. Patients should also be aware of liver disease, including medical examination of hepatic function tests and medical symptoms of hepatitis B infection during the study period, as well as careful attention to the possibility that the drug itself may cause liver disease and elevate liver function tests received. Such liver function tests were performed on week 1, week 2 and every two weeks thereafter. Also, liver biopsy samples obtained from the patients at 0, 30, 90, and 180 days were analyzed by biopsy and immunochromatography, and liver histopathology using in situ hybridization for appropriate antigens and nucleic acids Study. Blood analysis was performed by conventional methods on appropriate antigens including the hepatitis B surface antigen (HbsAg) and the " e " antigen (HbeAg) every first week, second week and every two weeks thereafter. In the case of successful treatment, patients with chronic hepatitis B can be converted from a cloned state (HBeAg positive) to a non-cloned state (HBeAg negative), and some patients may be cured by a complete loss of HbsAg , And the likelihood of HIV disease cure is expected to decrease. Lamovudine has been shown to be effective against HIV, but newer nucleoside analogues used in hepatitis B are likely to be effective against HIV. Appropriate doses of nucleosides that can replace lamodin are as follows: palciclovir 500 mg twice daily; Robucavir 400 mg once a day; Adefovir dipivoxil (adefovir) 120 mg Once a day. The dose of adefovir is 4 times the dose proven to be effective against hepatitis B and the higher of the two doses (60 mg and 120 mg per day) evaluated only for HIV disease.
[155] Experiments conducted in accordance with the literature procedure show that the gallium maltolate and related compounds of the present invention are effective in combination with interferon and interferon plus nucleoside analogs and are capable of synergizing with both in the treatment of hepatitis B infection Respectively. Also, MacSynergy II According to the computer program, nucleoside analogs used in the treatment of hepatitis, like gallium, synergized with HAART therapy in influencing HIV infection. Elevated levels of CD4 + cells are associated with an increased rate of hepatitis improvement in patients with low CD4 + subpopulations, where the low CD4 + group is less responsive overall as expected, but in the low CD4 + subpopulation group experiencing a surge in CD4 + levels, (A less proportional increase in CD4 + is observed). Patients in the low CD4 + group who do not undergo a significant increase in CD4 + levels do not undergo acceleration of hepatitis dissection, although the response to treatment is minimal.
[156] Example 12
[157] Clinical evaluation of gall maltolate for prevention of CMV disease in HIV patients
[158] Although CMV retinitis is a common complication of HIV disease, CMV has been shown to cause other diseases in immunocompromised individuals, including interstitial pneumonia and acute malignant CMV hepatitis. While nucleoside analogs effective against HIV are known to be effective against other retroviruses, different nucleoside analogs are commonly used and more effective for members of the human herpesvirus line, including the eight members mentioned above, and antiretroviral Nucleoside analogs different from sex nucleosides are commonly used to treat herpes viruses.
[159] Because of the mechanism of action of the gallium compounds of the present invention, specifically cross-organismal efficacy, and synergistic action with each other antiviral therapy, the treatment of multiple infections is enriched in various ways. For example, people with HIV and CMV who are receiving conventional HAART may not respond to interferon because the immune system is damaged. Conventional HAART therapies plus liver cycloplegia are not a combination therapy for CMV disease, although they have resistance to HAART despite the cumulative side effects of hepcyclovir and antiretroviral nucleoside analogs on host cells. Adding gallium compounds of the present invention to HAART plus gancyclovir therapy synergistically enhances HAART and synergistically reinforces acyclovir therapy for CMV. In addition, enhanced HAART (EHAART) can be used to reconstitute some specific immune functions for both HIV and CMV, to make it possible to add interferon or leukotrienes to therapy and to reconstitute specific immune responses, Lt; RTI ID = 0.0 > CMV < / RTI >
[160] In this example, the prevention of CMV disease rather than its treatment will be studied. Since interferons require periodic injections, they are only chemopreventive by antiviral agents rather than immunostimulants such as interferon. Foscarnet is an antiviral agent that is used only for injection, but is studied for comparison with oral antiviral agents.
[161] Clinical evaluation of gallate maltolate efficacy in preventing CMV disease in HIV patients. In addition to the method used to evaluate HIV disease in Example 5, Esophageal ulcer caused by cytomegalovirus (HIV) was used in the treatment of acquired immunodeficiency syndrome, South Med. J. 93 (8): 818-20) Some of the methods were used for the evaluation.
[162] Patients were treated once a day with gelatin capsules containing gallium maltolate. CMV (almost universal positive serum or culture positive patients) and a population of patients infected with HIV with a CD4 + first reference number (350 / mm ³ or more and 350 / mm ³ or less) 2 were divided each into two subgroups. These subgroups were randomly divided into two groups at random and divided into four subgroups each receiving 0 (placebo), 250, 500, or 750 mg gallium maltolate per day for about 6 months, Made almost equal subgroups of dogs. All subgroups received the same non gallium antiretroviral therapy as described in Example 5 (HAART treatment). The nucleoside analogs commonly used in CMV are hepcyclovir, foscavir when the gancyclovir is ineffective, and combinations thereof to treat CMV retinitis and other diseases. In order to avoid the reverse reaction, you must slowly inject the Foscarnet. In each sub-group, each sub-group (350 / mm ³ or more and 350 / mm ³ or less), the 5500 mg foscarnet over 1.5-2 hours with four lower group of the first group is additionally administered gallium maltol rate, IV injection twice a day. In each subgroup, four groups of the second group received 1000 mg of cyclosporine liver with gallium maltolate four times a day. In addition, patients were correctly observed for HIV disease as described in Example 5. During the study period, they also received medical observations of CMV disease, including testing and testing for medical symptoms such as CMV retinitis. Any mucosal disease or skin disease was studied by in situ hybridization to CMV DNA. Blood and urine for histopathological, immunological and histological evaluation by routine methods at 0, 30, 60, 90, 120, 150, 180 days, and every 30 days thereafter to track patients over one year Samples and pulmonary bronchoalveolar lavage samples were taken on a regular and extensive medical examination. Blood and urine analysis was performed by conventional methods including PCR for CMV DNA on appropriate antigen and CMV DNA every week 1, week 2 and every two weeks thereafter.
[163] Experiments carried out according to literature procedures show that the gallium maltolate and related compounds of the present invention are effective in combination with foscarnet or ganciclovir and synergistic with both in the prevention of CMV disease. Also, MacSynergy II According to the computer program, nucleoside analogs used in the treatment of CMV synergized with HAART treatment in the impact on HIV infection as well as gallium. Elevated levels of CD4 + cells are associated with a decreased rate of CMV disease in patients with low CD4 + levels who have undergone elevated CD4 + levels for treatment, although the lower population of low CD4 + This is a phenomenon observed at a lower level in the high CD4 + group. Patients with low CD4 + levels that do not undergo a significant increase in CD4 + levels are most likely to develop CMV disease. It is also possible to prevent CMV disease using only oral supplementation, with gallium plus hepcyclovir being more suitable and showing better results than placebo plus hepcyclovir.
[164] Example 13
[165] Clinical evaluation of gallium maltolate for prevention of EBV or KSV neoplasm in HIV patients
[166] In the case of CMV ulceration of the esophagus without any anti-CMV treatment, the combination of the immune response in HIV patients with splitting and the combination of antiretroviral therapy is observed. To overcome the pathology caused by members of the herpes virus lineage Illustrating the importance of the immune response (Monkemuller et al. (2000) supra). The addition of the gallium compounds of the present invention to the treatment of patients with AIDS and opportunistic viral infections will result in a higher rate of cleavage. The enhancement of the combined anti-retroviral therapy is due to the better reconstitution of the immune system for a greater number of patients and the direct activation of CMV disease. Since CMV retinitis is a major cause of blindness in AIDS patients, adding the gallium compounds of the present invention to the antiretroviral and anti-CMV therapies to be administered orally (gallium maltolate is administered topically to the eye or gallium maltolate preparation is introduced May be injected) is promising to help more AIDS patients maintain their vision for longer.
[167] Both EBV and KSV cause neoplasms, both with lymphoma and KSV (HHV-7) with HHV-7, possibly in cooperation with HHV-6 associated with the pathogenesis of Kaposi's sarcoma. Most humans have all these viruses. None of the patients will be able to study HIV populations without determining whether they are seropositive or cultured for these pathogens. Preferably, HIV patients who are both seropositive or culture-positive in both EBV and KSV can be found. In order to prevent opportunistic neoplasia caused by herpes virus by the combination antiviral treatment by applying the method of Example 12 under the guidance of Schneider et al. (2000) mentioned above, the gallium compound of the present invention Obtain a protocol to evaluate the contribution.
[168] By using a protocol similar to that of Example 12 but targeting a group of HIV-infected patients that are both seropositive or culture positive for both EBV and KSV and using a specific assay such as PCR and serum detection for EBV and KSV viruses instead, The role of gallium as a combination drug in the prevention of neoplasia caused by members of the herpes virus family in HIV disease can be assessed. The subpopulations were divided according to the number of CD4 as in Example 12. Group 1 of each subgroup was treated with interferon-alpha in addition to Foscarnet. Group 2 of each subgroup was treated with the same doses of foscarnet and interferon-alpha as the first group in addition to liver ciclovir. The dose of foscarnet and interferon-alpha was according to Example 12, and the dose of gall maltolate for each of the four subgroups is the same. Thus, within each subpopulation, gallium plus fog carnets plus conventional HAART were compared to gallium plus phoscarnets plus conventional HAART plus hepcyclovir. All oral treatments are preferable, but the likelihood of success is low. The dose level of interferon-alpha used is the dose used to treat Kaposi's sarcoma (20 million IU / day by injection), and some patients may require adjustment for tolerance. As in Example 12, the study should be more than one year and sufficient to be able to produce a traceable and statistically significant outcome of the patient population.
[169] As a result of experiments carried out according to the literature procedure, the gallium maltolate and related compounds of the present invention are effective in combination with foscarnet, interferon, and gancyclovir, and are effective in preventing both herpesvirus neoplasia It was shown to be synergistic. MacSynergy II The computer program has synergized with the HAART treatment in influencing HIV infection, as well as the nucleoside analogs used for preventive therapy and interferon-alpha galactomannan. The lower population of low CD4 + was less responsive overall as expected, but for patients with low CD4 + levels experiencing an elevated CD4 + level for treatment, the elevation in CD4 + cells is associated with a decreased rate of neoplasia, This is a phenomenon that is observed to a lesser extent in the high CD4 + group. Patients in the low CD4 + group who do not experience a significant increase in CD4 + levels are most likely to develop neoplasia. The prevention of opportunistic herpes virus-associated neoplasms was best achieved with gallocytosine, foscarnet, gancyclovir, and interferon in high CD4 + groups. Thus, antiviral therapy maintains high levels of CD4 +, thereby enabling subsequent prevention strategies and enabling oral antiviral combination therapy after diagnosis of HIV infection to be used at earliest times.

权利要求:
Claims (25)
[1" claim-type="Currently amended] Treating a therapeutically effective amount of gallium with a neutral 3: 1 (hydroxypyrone: gallium) complex, wherein the hydroxypyrone is unsubstituted or substituted with one to three C ₁ -C ₆ alkyl substituents which may be the same or different. Wherein said therapeutically effective amount refers to an amount of prokaryotic prokaryotic, DNA virus, or retroviral in a subject that is sufficient to provide a plasma gallium concentration sufficient to prevent or treat infection, A method of treating or preventing an infection.
[2" claim-type="Currently amended] 2. The method of claim 1, wherein the complex is administered orally.
[3" claim-type="Currently amended] 3. The method of claim 2, wherein the complex is administered in an amount of about 10 to 2500 mg per day.
[4" claim-type="Currently amended] The method of claim 1, wherein the hydroxypyrone is selected from the group consisting of 3-hydroxy-4-pyrone, 3-hydroxy-2-methyl- -6-methyl-4-pyrone. ≪ / RTI >
[5" claim-type="Currently amended] 5. The method of claim 4, wherein the hydroxypyrone is selected from the group consisting of 3-hydroxy-2-methyl-4-pyrone and 3-hydroxy-2-ethyl-4-pyrone.
[6" claim-type="Currently amended] 6. The method of claim 5, wherein the hydroxypyrone is 3-hydroxy-2-methyl-4-pyrone.
[7" claim-type="Currently amended] 2. The method of claim 1, wherein the pharmaceutical composition further comprises an additional active agent.
[8" claim-type="Currently amended] 8. The method according to claim 7, wherein the infection is caused by a virus, and the further active agent is a nucleoside analogue having activity against an infectious virus.
[9" claim-type="Currently amended] 8. The method according to claim 7, wherein the infection is by intramedullary prokaryotes and the further active agent is a bacterial antibiotic.
[10" claim-type="Currently amended] 9. The method of claim 8, wherein the infection is by retrovirus, and wherein the composition further comprises a protease inhibitor.
[11" claim-type="Currently amended] The method according to claim 1, wherein the infection is caused by a prokaryotic or viral infection associated with AIDS in an HIV infected individual.
[12" claim-type="Currently amended] 3. The method of claim 1, wherein the infection is retrovirus and HIV infection.
[13" claim-type="Currently amended] 13. The method of claim 12, wherein the pharmaceutical composition further comprises at least one additional active agent selected from the group consisting of nucleoside analogs, protease inhibitors and non-nucleoside reverse transcriptase inhibitors.
[14" claim-type="Currently amended] 14. The method of claim 13, wherein the further active agent comprises at least one agent selected from the group consisting of nucleoside analogs and non-nucleoside reverse transcriptase inhibitors.
[15" claim-type="Currently amended] 15. The method of claim 14, wherein the at least one nucleoside analog is selected from the group consisting of AZT, ddI, and ddC.
[16" claim-type="Currently amended] 15. The method of claim 14, wherein the composition further comprises a protease inhibitor.
[17" claim-type="Currently amended] 17. The method of claim 16, further comprising administering a biomolecule that stimulates the immune system.
[18" claim-type="Currently amended] 2. The method of claim 1 wherein the infection is a human herpesvirus infection.
[19" claim-type="Currently amended] 19. The method of claim 18, wherein the pharmaceutical composition further comprises one or more nucleoside analogs effective against a member of the herpes virus family.
[20" claim-type="Currently amended] 20. The method of claim 19, wherein the at least one nucleoside analog effective against a member of the herpes virus family is selected from the group consisting of acyclovir, gancyclovir, and foscarnet. .
[21" claim-type="Currently amended] 21. The method of claim 20, further comprising administering a biomolecule that stimulates the immune system.
[22" claim-type="Currently amended] The method of claim 1, wherein the infection is a hepatitis B infection.
[23" claim-type="Currently amended] 2. The method of claim 1 wherein the pharmaceutical composition is administered locally and the carrier is suitable for local drug administration.
[24" claim-type="Currently amended] 3. The method of claim 1, wherein the pharmaceutical composition is administered locally in the eye, and wherein the carrier is suitable for topically administering the drug to the eye.
[25" claim-type="Currently amended] Treating a therapeutically effective amount of gallium with a neutral 3: 1 (hydroxypyrone: gallium) complex, wherein the hydroxypyrone is unsubstituted or substituted with one to three C ₁ -C ₆ alkyl substituents which may be the same or different. Wherein said therapeutically effective amount is an amount sufficient to provide a plasma gallium concentration sufficient to prevent or treat infection or co-infection, wherein said prokaryotic organism , A DNA virus, or a retrovirus.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US9879023B2|2018-01-30|Therapeutic compounds

---

US10654827B2|2020-05-19|Therapeutic compounds

---

US10426780B2|2019-10-01|Antiviral therapy

---

Fradin et al.1991|Oral cyclosporine for severe chronic idiopathic urticaria and angioedema

---

ES2279407T3|2007-08-16|Antineoplasic combinations.

---

DK173585B1|2001-04-02|Use of alpha-lipoic acid for the manufacture of a drug for the control of diseases caused by retroviruses

---

US8962652B2|2015-02-24|Derivatives of purine or deazapurine useful for the treatment of | viral infections

---

US20180104270A1|2018-04-19|Compositions and methods for treating disease states associated with activated t cells and/or b cells

---

JP2019163303A|2019-09-26|Modulators of toll-like receptors for the treatment of hiv

---

AT401470B|1996-09-25|Pharmaceutical use of 17-ketosteroids

---

Izzedine et al.2005|Antiviral drug-induced nephrotoxicity

---

US6143738A|2000-11-07|Therapeutic uses for an aminosterol compound

---

Hattori et al.1989|Preliminary evidence for inhibitory effect of glycyrrhizin on HIV replication in patients with AIDS

---

AU2006315512B2|2012-11-01|Administration of an mTOR inhibitor to treat patients with cancer

---

ES2274378T3|2007-05-16|Binding the ep4 receiver and use against neuropathic pain, colon cancer, hiv and migraine.

---

JP2888453B2|1999-05-10|Pharmaceutical composition for treating or preventing Pneumocystis carinii pneumonia

---

US20090227608A1|2009-09-10|Use of c-src inhibitors alone or in combination with sti571 for the treatment of leukaemia

---

JP2008019278A|2008-01-31|Nordihydroguaiaretic acid derivative for use in treatment of tumor

---

US20050239748A1|2005-10-27|Pharmaceutical salts of 3-O-| betulinic acid

---

US6930093B2|2005-08-16|Use of ribofuranose derivatives against inflammatory bowel diseases

---

US6350784B1|2002-02-26|Antimicrobial prevention and treatment of human immunedeficiency virus and other infectious diseases

---

US20050220895A1|2005-10-06|Use of gallium to treat inflammatory arthritis

---

EA030967B1|2018-10-31|SODIUM |-7,9-DIOXO-10-|CARBAMOYL)-2,3,4,5,7,9,13,13a-OCTAHYDRO-2,5-METHANOPYRIDO[1',2':4,5]PYRAZINO[2,1-b][1,3]OXAZEPIN-8-OLATE

---

PT2477987T|2018-03-13|Modulators of toll-like receptors

---

DE60202278T2|2005-12-15|Activation of natural killer cells by adenosine a3 receptor agonists

同族专利:

---

公开号 | 公开日

---

JP2003510362A|2003-03-18|

---

DE60032915D1|2007-02-22|

---

EP1218011B1|2007-01-10|

---

CA2386325A1|2001-04-12|

---

ES2280259T3|2007-09-16|

---

AU1197601A|2001-05-10|

---

US20060222628A1|2006-10-05|

---

EP1218011A1|2002-07-03|

---

AU775459B2|2004-08-05|

---

MXPA02003463A|2004-09-10|

---

CA2386325C|2010-08-03|

---

US20030083308A1|2003-05-01|

---

WO2001024799A1|2001-04-12|

---

DE60032915T2|2007-10-25|

---

EP1218011A4|2004-08-18|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
1999-10-04|Priority to US15746099P

---

1999-10-04|Priority to US60/157,460

---

2000-10-04|Application filed by 로렌스 리차드 베른스타인

---

2000-10-04|Priority to PCT/US2000/028174

---

2002-06-01|Publication of KR20020041451A

优先权:

---

申请号 | 申请日 | 专利标题

---

US15746099P| true| 1999-10-04|1999-10-04|

---

US60/157,460|1999-10-04|

---

PCT/US2000/028174|WO2001024799A1|1999-10-04|2000-10-04|Gallium complexes of 3-hydroxy-4-pyrones to treat infection by intracellular prokaryotes, dna viruses and retroviruses|