JPH06501449A - Use of trinitrobenzenes or carminic acid in the treatment of cancer or viral diseases - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Trinitrobenzenes or carminic acid in the treatment of cancer or viral diseases The present invention broadly relates to the use of trinitrates that exhibit anticancer or antiviral activity at specific low concentrations. compounds based on lobenzene and/or carminic acid (or its derivatives) Concerning compounds and therapeutic preparations.

Conventional cancer treatments typically include surgery, radiation therapy, chemotherapy, or some other of these. Includes a combination of several. These treatments often prolong a patient's life or While sometimes effective in curing cancer, it has well-known and serious side effects. It is something. More recently, alternative attempts for the treatment of certain cancers have been developed. coming.

One such technology, “immunotherapy,” is a method that uses the innate ability of a patient's immune system to fight cancer. It is planned to increase capacity.

Despite significant improvements in diagnostic and therapeutic techniques over the past decade, patients, especially Overall survival rates for patients with solid tumors treated with these traditional methods have improved little. It has not been. And although alternative technologies such as "immunotherapy" are promising, These greatly improved treatments can only help a limited number of patients. flaws, still exhibit toxic side effects, and/or are complex to implement. and expensive.

In the field of antiviral drugs, many antiviral drugs are known, but they are not effective for treatment. vines with patent or limited efficacy characterized by high dosages. In HIV treatment, Although AZT is the only drug with significant effects found to date, treatment results is uncertain and drugs are expensive.

The present invention utilizes readily available trinitrobenzene compounds and or) by the use of low doses of carminic acid (either alone or in combination). approach these issues. Now, quite surprisingly, such compounds is anticancer or antiviral when administered at low concentrations, regardless of patient weight. It was found to be effective as a disinfectant. Therefore, the poisons associated with prior art The gender and cost issues do not apply.

Therefore, in one aspect, the present invention provides For use in the treatment or prevention of tumors (neapla+m) or viral infections. Dissolved in an aqueous medium at a concentration of 10-3 to 10-110-l5/A' for or distributed, general formula (In the formula, X is OH, NO2, halogen, sulfonic acid group (sull.

group), carboxyl group, 0CI (3 or substituted or unsubstituted Expressions that are not: (In the formula, A is hydrogen or an unpaired electron of a nitrogen atom, Y is hydrogen or an organic group , Z is an organic group, or Y and Z are a nitrogen-containing heterocycle together with adjacent nitrogen atoms. selected from among the hydrazyl groups represented by When it is a hydrazyl group substituted or unsubstituted, NO, one of the groups one of which may be replaced with a sulfonic acid group) provide the agent. The sulfonic acid group is preferably a sulfonic acid group, optionally a sulfonic acid group. Sodium sulfonate or potassium sulfonate (SO3Na or 503K ), the carboxyl group is preferably a carboxylic acid group, optionally a carboxyl group. Sodium carboxylate or potassium carboxylate.

In another aspect, the invention provides a method for treating tumors in humans and non-human animals. for use in the treatment or prevention of viral infections; Gen, sulfonic acid group, carboxyl group, OCH3 or substituted or substituted Formula that is not: (wherein A is hydrogen or an unpaired electron of a nitrogen atom, Y is hydrogen or an organic group, Z is an organic group, or Y and Z together with the adjacent nitrogen atom selected from among the hydrazyl groups represented by (forming a hydrogen-containing heterocycle); and X is replaced by H substituted or unsubstituted as described above. one or more compounds of (b) providing a formulation comprising a quinone such as carminic acid or a derivative thereof; .

A further aspect of the invention is that the compound as defined above contains about 10-3 to 10''zol e/j! pharmaceutical or veterinary products dissolved or dispersed in an aqueous medium at a concentration of It is a drug.

Significantly, carminic acid is used alone at low molar concentrations according to the present invention. It was found that it exhibits antiviral effects when used. Therefore, the importance of the present invention One aspect is the production of medicines for the prevention or treatment of viral diseases such as AIDS. The use of carminic acid and its derivatives in Such derivatives are: General formula (wherein R is C00II (i.e. carminic acid) or other organic How to do it! Inorganic functional groups such as IH, SO2 [K, H or Na], and C-glycosides can be any sugar). Anthraquinone optionally It may be zoquinone (monocyclic) or naphthakifun (bicyclic).

Without being bound to one definite mechanism, the compounds shown above are free radicals. initiate and propagate a mechanism of action that selectively attacks abnormal cell structures Active species fche! ni:al　5peci! It functions by producing l. I believe that. Cancer Research (Canes: Rzea+ch) 36 (1978), 1745-1750, Bacha et al. , in conjunction with the known biological effects of quinone-containing anticancer drugs, the possible free radical Cal mechanism is described. These drugs contain superoxide (sup ++ o engineering 1 de) or oxygen-dependent free radicals such as hydroxyl radicals It is hypothesized that it can generate cal.

In the present invention, said compounds are linked to free radicals such as superoxide. Redox-recycling (+edox-+cycling) that occurs continuously It seems to act as a catalyst for the mechanism. free radicals, or The byproducts selectively attack cancer cells or viruses.

Preferred formulations of the invention include trinitrobenzene derivatives (picrylic chloride or or diphenylpicrylhydrazine (DPPH), etc.), which have a glycoside moiety. anthraquinone (such as carminic acid or its derivatives), or one or more Contains a mixture of several trinitrobenzene derivatives and anthraquinone glycosides. Ru. Carminic acid is used in the laboratory for nucleic acid staining and is an interesting In particular, its effect on DNA is is inhibited by radical scavengers (Loin et al. Bioor aaic Chez (Bioor aaic Chez) 8 (1979), 17-24). Furthermore, such formulations contain 10-3 in an aqueous medium. From 10-110-l5/j! active ingredients dissolved or suspended in concentrations ranging from It contains drugs that can be administered orally or parenterally. Carminic acid is particularly effective against Useful for virus treatment.

For a more complete understanding of the invention and its advantages, it may be read in conjunction with the accompanying drawings. Reference should be made to the detailed description below. In the attached drawing, Figure 1 shows NMRI mice transplanted with MAC16 colon cancer cells using the technique of the present invention. Therefore, the average life expectancy after treatment with various therapeutically effective concentrations of picryl chloride This is a graph of the lifespan (days).

Figure 2 shows diphenylpicryl of GM 892 cell line according to the technique of the present invention. Hydrazyl (D P P Z) and diphenylpicrylhydrazine (D P PH) is a dose response graph.

By the way, looking at various aspects unique to the present invention, we find that the free radical mechanism Compounds capable of initiating and transmitting rhythms range from about 10-3 to IQ''' aule/Il. may be dissolved or dispersed in an aqueous medium at a therapeutically effective concentration. Such a compound substances catalyze free radical chain reactions, thereby causing abnormal cell produces active chemical species that selectively attack. One such group of compounds is: General formula: Phoxyl group, OCH3, or substituted or unsubstituted hydrazyl (selected from the group). For example, if X is hydroxyl If it is a radical, the compound is picric acid. If X is chlorine, pickle loride is formed. The sulfonic acid group is preferably a sulfonic acid group, optionally a sulfonic acid group. With sodium sulfonate or potassium sulfonate (SO3N! or 503K) and the carboxyl group is preferably a carboxylic acid group, optionally a sodium carboxylic acid group. potassium carboxylate. Halogen is CI, Br or F.

Preferably, the hydrazyl group or derivative has the following general formula: (wherein A is hydrogen or is one unpaired electron of a nitrogen atom, Y is hydrogen or an organic group, Z is an organic group, or Y and Z together with adjacent nitrogen atoms form a nitrogen-containing heterocycle (for example, is a radical of a carbazyl group)); with the proviso that X is substituted as described above or When it is an unsubstituted hydrazyl group, one of the NO2 groups is a sulfonic acid group. May be replaced. For example, if A is hydrogen and Y and Z are phenyl groups, The entire compound is diphenylpicrylhydrazine ('DPPH). A If is an unpaired electron and Y and Z are phenyl groups, then diphenylpicrylhydrazide (D P P Z) radical is formed. A is hydrogen, and Y and 2 are a pair If it is a phenyl group, carbazylpicrylamine (CPZ) is formed and Thus, a nitrogen-containing heterocycle is formed.

One particularly desirable water-soluble derivative has the following structural formula of a hydrazyl-derived group: (wherein Y and Z are phenyl groups and potassium is optionally hydrogen or sodium have).

Another particularly preferred water-soluble derivative is diphenyl dinitrosulfonate. -Phenylhydrazyl (DD-nylhydrazine and 2-chloro-3,5-dinitoko In dilute alcohol or dioxane with potassium salt of benzene sulfonic acid interaction and subsequent oxidation of hydrazine with lead dioxide. be synthesized. Additional details regarding the synthesis of the DOSH radical are included here for reference. M, Ni, Ikrina, etc. are included (!11. A, 1 +ina N Investigation by ali in the field of the chemise Tory of Free Radicals of the Hydrazine Series No.

Vllll(1+vc++igation lp The Field O! T he Chemist+70f F+er Radicals 01 The H7d+azirIe Se+i++ No, Vllll)% Journal obsi Ei Haimi (2hv+bal Ob+cheiKbiziij, 32 volumes, 1G . +2.3952-3957, December 1962.

The above trinitrobenzene derivatives, such as diphenylvicrylhydrazine, Within the range of about 10 to 15 molar concentrations (i.e., "therapeutically effective concentrations") When administered to the host (bOVr) in a substantially pure aqueous solution/suspension diluted to It has been shown to be effective when FIG. 1 shows picrylic chloride according to the teachings of the present invention. MAC16 colon after treatment with subcutaneous injections of various therapeutically effective concentrations. It is a graph of the average survival period (days) of NMRI mice transplanted with cancer cells. Figure 1 As shown in Figure 2, untreated control animals survived for less than 10 days on average. Ta. However, animals treated with various specific concentrations of picryl chloride showed significant The survival rate was shown. Best results have been obtained at 10-12 molar concentrations, with animals given for 5 days ( (one injection per day) when injected subcutaneously. At this concentration, the treatment The majority of animals tested remained tumor-free for 60 days.

Figure 2 shows diphenylpicrylhydrazyl (D P P Z) in GM892 cell line. and dose-response graphs for diphenylpicrylhydrazine (DPPH). It's rough. The figure shows a Coulter counter used to count the number of cells. The average of 3-6 different experiments is shown. As seen in Figure 2, both drugs have approximately 10- 3 to B-15 in substantially pure aqueous solutions/suspensions diluted within the molar range. provides significant in-vitro antitumor effects against this cell line when given .

Pronounced therapeutic results can be obtained in aqueous media at the aforementioned concentrations, singly or in combination. using a pharmaceutical or veterinary composition based on the above compound dissolved or suspended in I can do it. For example, carminic acid alone (or its derivatives) is particularly It is useful as a rinsing agent. Carminic acid has the following formula: C- attached to the side chain of polyhydroxyanthraquinone as defined by It has a glycoside (C6H1105).

In combination form, one preferred composition includes one or more trinitro a benzene derivative and an anthraquinone with a glycoside moiety, optionally carminic acid. It is a mixture. For example, one such composition is picrylic chloride (also is a mixture of picrylsulfonate) and carminic acid. means a restriction However, the preferred ratio of picryl chloride to carminic acid is 1:1 to 1:2, but the concentration of active ingredient is about 10' to -15 molar. Therapeutically effective concentrations are between. For therapeutic use of pharmaceutical compositions in solution or suspension The effective amount is 2.0-5.0 ml, and this amount is clearly dependent on the host animal's body weight. Virtually irrelevant.

If desired, more than one trinitrobenzene can be conveniently incorporated into the mixture. Wear. For example, when using picric acid and DPPH, these trinitrobenes Zhenzenes are responsible for generating free radicals and free radical chain reaction mechanisms. and can work cooperatively. Quinones, if used, can provide OH free radicals. It can be a source of supply. In one embodiment, a predetermined amount of Phosphoric acid, DPPH and carminic acid were added to approximately 10-3 to 15 molar concentrations. Mix into a substantially pure aqueous fi/suspension at a dilution range such as DPPH is the most The dilution rate is highest, followed by carminic acid, then picric acid.

Although not meant to be limiting, pharmaceutical or veterinary compositions must first be prepared under sterile conditions. Dissolve the hydrazine derivative in double-distilled deionized water in a clean glass container. The vine is made by Then add carminic acid to the solution and mix. match. Next add the picric acid and mix the solution thoroughly. Then serial dilution By doing so, the desired molar concentration can be obtained. Instead, there are three The ingredients are mixed together before being dissolved in a carrier.

According to another feature of the invention, the effect of the free radical chain reaction mechanism is or by the administration of any other transition metal, especially copper. For details, please refer to Although not listed, the anticancer agents mentioned above can be administered subcutaneously, intravenously or as tolerated. It is also contemplated that carriers or excipients can be used to administer the host. Ru. Also, double-distilled deionized water is the preferred solution/suspension liquid, but Methyl sulfoxide/aqueous solution, peanut oil, olive oil, vegetable oil or corn oil. Other diluents may be effective as well. Furthermore, due to free radical mechanisms, Another effective catalyst is the long-chain free calcium typically found in lipids. It is a (low concentration) polyunsaturated fatty acid that is a bonic acid.

Trinitrobenzene derivatives useful in the present invention are preferably picric acid, picric acid, Kryl chloride, vicryl sulfonate, diphenylpicrylhydrazine and and diphenylpicrylhydrazyl, but other trinitrobenzene compounds It should be taken into account that phosphorus is also a suitable catalyst for free radical mechanisms. It is. Such compounds are included in the general formula above.

In the general formula, when A is a hydrogen atom and Y is a phenyl group, Z is, for example, Can be any aromatic group shown in Appendix ■ or an aliphatic group shown in Appendix H . Alternatively, Y and Z may be any of the aromatic compounds shown in Appendix 111.

Another group of "phenyl" derivatives is derived from the compounds listed in Appendix 1v1; The group of "Zyl" derivatives is defined by the formula shown in Appendix V. does not mean limited However, a preferred hydrazine derivative is diphenylvicrylhydrazine (DP P H) and diphenylvicrylhydrazyl (DPPZ), phenylpic Rylhydrazine (PPH), carbazylpicrylamine (CPZ) and 2-su Its derivatives such as rufophenyl, 2-sulfophenyl, picrylhydrazine, etc. be.

In the foregoing description, novel anticancer and antiviral treatments are emphasized. However, trinitrobenzene and carminic acid derivatives according to the present invention It should be considered that active chemical species also have demonstrable antifungal and antibacterial effects. It is possible. The use of such low-dose treatments may also help treat genetic and autoimmune diseases. It is being researched in relation to medical treatment.

In a trial study of the present invention, advanced cervical cancer Ice+vical Cas+e +’, a 64-year-old woman was treated with diphenylφ dinitrosulfonate phenylhydra. treated with Jill (DDSH). On histological examination, the patient showed mild abdominal pain, anemia and and vaginal bleeding. On gynecological examination, a large mass) is found protruding from the birth canal. It was located and extended to the side wall of the pelvis.

The patient was diagnosed with stage 3 cervical cancer (squamous cell carcinoma), which was later diagnosed as abdominal cancer. Confirmed at exploratory surgery where a widespread metastatic mass was similarly found. . After a routine check-up, the patient is given a solution of IQ'Molar in double-distilled deionized water. A single 2.0 ml subcutaneous injection of DDSH was administered. No other treatment was given. I couldn't get used to it. Recent laboratory tests show that the patient does not have cancer, but rather a metastatic mass. There was no trace of it remaining.

In another pilot study, 16 patients were diagnosed with metastatic pheochromocytoma of the liver and jawbone. The same <10' molar concentration of DDSH was administered by subcutaneous injection to a female male. inspect first when the patient had extremely high blood pressure], H/160, abnormal heart rate and jaw He had widespread pain in the area. The first subcutaneous injection was administered in April 1990; Subsequent injections were made in November 2019. Recent tests show that the patient's blood pressure is normal. The pain in his wide jawbone has subsided and his general health is considered good.

Ongoing pilot studies show that carminic acid, when dissolved at low concentrations in aqueous media, It has a clear antiviral effect. In one pilot study, standard EL A 37-year-old man was diagnosed as HIV positive through the ISA test. first 1 On examination in November 1990, the patient had thrush in the mouth and left facial dysfunction including the left orbital area. very severe herpes zoster, hard bilateral cervical lining It had a segment and a swollen liver and pancreas. The patient was then given double distillation Carminic acid was dissolved at a 10-6 molar concentration in deionized water and administered by subcutaneous injection. did. For 5 days, patients received a single 2.0 ml injection per day. 5 days later , similar 5-day course (1 injection per day for 5 days) was repeated. After the fourth course (20 injections), the patient had a good general condition. In this state, the anemia and oral thrush are no longer present, and the cervical lymph nodes and herpes zoster have cleared. The infection had healed. The pancreas and liver were normal and the patient had gained weight . Importantly, the patient's white blood cell count (WBC) ranged from 2.0 GO cells/mm” to 12 ．． 400 cells/■”, and hemoglobin (Hb) correspondingly increased to 11..8 g/d1 to 1.4.7 g/di.

These diagnostic results are meaningful and suggest that therapeutically effective concentrations as described above may be achieved. This suggests that carminic acid may stimulate the immune system. have side chain sugars Other quinones (and derivatives thereof) may also be used according to the techniques herein. It is believed that it can exhibit antiviral activity when administered. in this way , an important aspect of the present invention is the use of pharmaceuticals for the prevention or treatment of viral diseases such as AIDS. In the preparation of medicines is the use of carminic acid and its derivatives. That's it The eel derivative has the following general formula.

(wherein R is C00I ((carminic acid) or other organic or NHSSo [It is an inorganic functional group such as K, H or Na, and what kind of C-glycoside is it? may be a sugar). Anthraquinone is optionally benzoquinone (monocyclic) or or natsutaquinone (bicyclic).

Although the invention has been described in part with reference to various preferred embodiments, A trader may make various changes, substitutions, omissions and alterations without departing from this. There will be.

Concentration logarithm CM] Dose-response log concentration for DPPH/DPPZj in GM892 cell line [ M] TABLE I TABLE In (d) [-C=C-C)12-C=C-1nTABLE III (a) (b) TABLE Engineering I TABLE The "carbasil" derivative group is defined by the following formula.

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Claims (15)

[Claims] 1. Dissolved in an aqueous medium at a concentration ranging from 10-3 to 10-15 mole/l or Dispersed, general formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, X is OH, NH2, halogen, sulfonic acid group, carboxyl group, OCH 3 or a substituted or unsubstituted formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A is hydrogen or an unpaired electron of a nitrogen atom, Y is hydrogen or an organic group, and Z is The organic group or Y and Z together with adjacent nitrogen atoms form a nitrogen-containing heterocycle is selected from the hydrazyl group represented by When it is a substituted or unsubstituted hydrazyl group, NO2 group (one of which may be substituted with a sulfonic acid group) Treatment of tumors or viral infections in humans and non-human animals consisting of or preparations for use in prophylaxis. 2. (a) General formula: X-p (wherein, P is trinitrophenyl and X is OH, NH2, halogen, sulfone acid group, carboxyl group, OCH3 or substituted or unsubstituted No formulas: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A is hydrogen or an unpaired electron of a nitrogen atom, Y is hydrogen or an organic group, and Z is The organic group or Y and Z together with adjacent nitrogen atoms form a nitrogen-containing heterocycle is selected from the hydrazyl group represented by When it is a substituted or unsubstituted hydrazyl group, NO2 group (one of which may be substituted with a sulfonic acid group) or a plurality of compounds; and (b) a quinone, optionally an anthraquine having a glycoside moiety. in humans and non-human animals, comprising non-carminic acid, preferably carminic acid. Preparations for use in the treatment or prevention of tumors or viral infections. 3. The sulfonic acid group is a sulfonic acid group, optionally sodium sulfonate or sulfonate. 3. The formulation according to claim 1 or 2, which is potassium phonate. 4. The carboxyl group is a carboxylic acid group, optionally a sodium or carboxylic acid group. The preparation according to claim 1 or 2, which is potassium rubonate. 5. 3. The formulation according to claim 1 or 2, wherein the halogen is Cl, Br or F. 6. Picric acid, picryl chloride, picryl sulfonate or diphenyl lupicrylhydrazine or any two or more of them The formulation according to any one of claims 1 to 5, comprising: 7. In unit dosage form, each unit optionally contains 2.0 to 5.0 ml of solution or The formulation according to any one of claims 1 to 6, consisting of a dispersion. 8. The radical or compound according to claim 1 contains 10-3 to 10-15 mole/ A pharmaceutical or veterinary product dissolved or dispersed in an aqueous medium at a concentration in the range of l. agent. 9. In unit dosage form, each unit optionally contains 2.0 to 5.0 ml of solution or 9. The formulation according to claim 8, wherein is a dispersion. 10. Claim 8 or 9 consisting of an anthraquinone glycoside, optionally also carminic acid. The formulation described. 11. The radical or compound of the formulation according to claim 1 optionally comprises anthraquinonic acid. Used with glycosides such as carminic acid to prevent cancer or viral diseases or is for use in the preparation of therapeutic medicaments. 12. The concentration of said radical or compound is from 10-3 to 10-15 mole/l 12. The use according to claim 11 in an aqueous medium. 13.Dissolved in an aqueous medium at a concentration ranging from 10-3 to 10-15 mole/l Viral susceptibility in humans consisting of anthraquinone glycosides, optionally carminic acid Preparations for use in the treatment of infections. 14. Anthraquinone glycosides in the preparation of medicaments for the prevention or treatment of viral infections body, optionally uses of carminic acid. 15. 15. The use according to claim 14, wherein the medicament is for preventing or treating HIV infection.