JP4230420B2 - Vaccine precursor and vaccine - Google Patents

Description

  The present invention relates to a substrate (lipid, carbohydrate, amino acid, etc.) having a molecular weight of 10,000 or less, which basically constitutes the structure and function of an organism, and species-specific forms and functions of the organism based on the substrate. A complex precursor that produces various substances, and a vaccine precursor and vaccine composed of a polymer substance containing one or more, an antibody, a neutralizing antibody, an antitoxin, and an idioantibody The invention relates to vaccine precursors and vaccines, antibodies, neutralizing antibodies, antitoxins induced by the idioantibodies. Or antibacterial agents, antiviral agents, anticancer agents, antiprotozoan (malaria, spirochete, etc.) agents, antitoxins, non-living high molecular weight antibodies, molecular identifiers, and substances that serve as labels indicating the site of action The present invention relates to a labeling reagent having a substituent containing or a labeling substance, a heterogeneous or allogeneic tissue, an organ histocompatibility promoter or immune response promoter or immune response regulator, and a complement chain reaction promoter.

  Conventionally, the role sharing in the living body of the immune system is always excluded from the living body and recognizing the normal operation of the living body by recognizing a foreign matter that is inconvenient for the living body. For example, this immune phenomenon is related to the defense of microorganism infection, the rejection of cells derived from other individuals, the removal of mutant cells and waste tissues, and the like. It is self-evident that the presence of this antigen-antibody reaction has saved many lives by vaccines and antitoxins as preventive measures in infectious diseases. As a conventional cell destruction method that uses this immune function to extract the first-stage antigenic material used in attenuated vaccines or inactivated vaccines from microorganisms, cells infected with microorganisms or cancer cells, ultrasonic treatment is used. A method of combining freezing treatment, heat treatment and the like has been performed. In addition, the antigen-containing solution recovered by centrifugation or the like is inactivated using heat treatment, formaldehyde, paraformaldehyde or ultraviolet rays, and then an antibody titer is increased by adding an adjuvant such as A1 (OH) 3. It is coming. However, heat treatment, acid and alkali treatment, and the use of organic solvents such as alcohol, ether, acetone, and chloroform for the purification of antigenic substances can chemically modify the molecular structure (including the three-dimensional structure) of the originally intended antigen. In addition to reducing antigenicity, it does not sufficiently induce the expression of complex and purposeful immune functions that should occur in vivo, so it specifically recognizes the target in vivo macromolecular substances. The development of antibodies and vaccines that can be developed is awaited.

  In general, when an antigen receptor (antigen receptor) is present on the surface of a lymphocyte and encounters an antigen that is "non-self", it binds to the receptor (antigen recognition), and a series of elimination mechanisms work, It is also well known that it is very specific. In addition, this antigen receptor is a single protein molecule (polypeptide) produced by a gene, and it is often the case that immunological specificity and immunological memory are brought about by the diversity of the structure of this polypeptide. Are known. That is, in order to push antigen recognition smoothly and efficiently, lymphocytes make a large amount of antigen receptor and release it to bind to the partner (non-self). This form of the antigen receptor released from the cells is called an antibody. Attempts to use these antibodies artificially have been a central issue of biomedical research in this century and have produced many results. However, the diversity of the antibody is an astronomical number, and many problems still remain in the artificial manipulation of the target antibody, and a new concept and its illustration are awaited.

  In general, it is also well known that B cells are characterized by having immunoglobulin on their surface. The immunoglobulin on the surface of the B cell is not an adsorbed antibody in the blood (secretory immunoglobulin) but is a membrane immunoglobulin having a transmembrane site, and serves as a B cell receptor that recognizes foreign substances (antigens). Function. B cells activated by binding of the antigen to the B cell receptor differentiate into antibody-secreting cells (plasma cells). In this case, the antibody produced is a membrane-type immunoglobulin on the surface of the B cell. It is characterized by maintaining the same antigen specificity. The most important role of B cells in the immune system is to produce antigen-specific antibodies. It has recently been found that the diversity of antibodies capable of dealing with each of the myriad antigens is created at the genetic level. Various developments have been made on the basis of this recent biological knowledge and technology, but proposals such as antibody production methods that do not depend on the method for determining the amino acid sequence newly created from a gene are also required. ing. In other words, in the method of producing an antibody by genetic engineering, it takes time to identify an antigen and establish a production process, and the production cost is high, and it is widely used for public health purposes such as the originally intended vaccine. In some cases, the rapidity and economics are discussed as major issues.

  The immunoglobulin is composed of two heavy chains (H chain) and light chain (L chain), and in each case, the amino acid sequence on the carboxy terminal side is common to each immunoglobulin (constant region, Fc). However, the amino acid sequence on the amino terminal side varies depending on each immunoglobulin. The antigen-binding site of an immunoglobulin is composed of the variable region of the H chain and L chain, and the difference in the amino acid sequence creates differences in antigen specificity and diversity. That is, the gene part encoding the constant region of both the H chain and the L chain is fixed to one, but the gene part encoding the variable region is divided into several parts (segments). Diversity will be brought about by the combination. In other words, the part where one H chain and one L chain are paired in the antibody molecule is a segment called Fab, and as a result, there are two Fabs. A portion made of only two H chains is a segment called Fc. That is, when the antibody molecule is viewed in plan, it is Y-shaped with two Fabs and one Fc. The development of vaccines and antibodies in accordance with the structural specificity that brings about the difference in antigen specificity and its diversity has been vigorously conducted.

  The destruction of the cell membrane is triggered by the Fc part of the antibody bound to the cell. Therefore, the Fc part is also an important segment. The type and sequence of amino acids from the end of the Fab part to the half differ for each antigen, but the amino acids in the Fc part are almost the same even if the type of the corresponding antigen is different. The portion where the antibody binds to the antigen (variable region) has a different structure for each corresponding antigen, so that when the antibody is injected into an animal, a different antibody is produced corresponding to each. The variable region antigens that are distinguished by the antibodies are called idiotype antibodies, and are considered to be advanced antibodies in order to bring out the specificity of the antibodies, and various research and development are being conducted. The diversity of antibodies is a minigene system (family) consisting of 100 or more V (variable) genes, 12 D (diversity) genes, and 4 J (joining) genes. It is based on. Further, the C (constant = invariant part) gene varies depending on the function exhibited by the antibody, and is not involved in binding to the antigen. During differentiation into antibody-producing cells, one gene is selected from each minigene group and combined with each other to form a complete VDJC gene. In the case of 4,800 H chains and L chains, V, J, and C minigenes are involved, and about 400 combinations can be made. The antigen-binding site forming the H-L chain pair can have 4,800 × 400, that is, 1.92 million variations. In addition, since several DNAs are inserted into the binding sites of the V and D or D and J fractions by special enzymes during gene rearrangement, the diversity of antibody molecules is further increased astronomically. While eliciting an antigen-antibody reaction corresponding to species diversity is a goal, there is a need for a simple derivation or production method, as well as specific examples thereof.

  In general, proteins that act as antigens include proteins from other animals and individuals, bacterial toxins, viral proteins, lipoproteins and glycoproteins from the cell membranes of other animals and individuals, bacterial membranes and blood types Polysaccharides such as substances, lipopolysaccharides, and lipids such as bacterial cell walls. It is also known that an artificially synthesized chemical substance can be made to be an antigenic determinant if it is bound to a carrier to produce antibodies against it. Diazotized aromatic amino groups (dinitrophenyl DNP, trinitronephenyl TNP, dinitrochlorobenzene DNCB, etc.) are often used in research as artificial antigens. That is, since chemical substances and drugs are small molecules, if they are bound to a protein (carrier) or the like, an antibody having the chemical substance as an epitope is produced. In this way, although it does not have the ability to produce antibodies by itself, it is said that a low-molecular substance such as a chemical substance that can bind to an antibody once it is made is called a hapten, but a proposal for a substance that becomes a new hapten Is also expected.

  Various methods have been devised and implemented in the past to prevent or prevent infections, and there are many problems that still benefit greatly but still need to be improved. For example, influenza, which is one of viral infections, is associated with the onset of primary proliferation itself in the respiratory tract, which is the first infection site. There are also measles, mumps, chickenpox, etc. that develop when the virus enters the blood and spreads throughout the body after airway infection. In addition, there are things such as hepatitis and Japanese encephalitis that enter the blood, arrive at the target organ, proliferate there, and cause illness. Can be blocked. Recently, threats from various microbial infections such as HIV, hepatitis virus and Ebola virus exist. As a means for preventing such viral infection, inoculation with a virus antigen having no pathogenicity or attenuated to give immunity to the virus has been carried out to prevent infection. As the method, an inactivated vaccine prepared by killing a virus and a live vaccine using an attenuated virus are used, and it is well known that it is effective. Japanese encephalitis, hepatitis, and polio are considered to be effective even with inactivated vaccines, and it is generally known that live vaccines have excellent effects on viruses. Live vaccines are currently used for measles, rubella, mumps, chickenpox and polio. Antigens that are difficult to obtain and difficult to handle, such as hepatitis B, are safely mass-produced by recombinant DNA vaccines that incorporate the antigen gene into the DNA of the fungus and allow the fungus to produce the antigen. Antibodies against viruses have also been studied energetically. In addition, vector vaccines that incorporate the genes of antigens of other viruses into a safe virus and have immunity at the same time, and idiotypes that use anti-idiotype antibodies as vaccines utilizing the fact that anti-idiotype antibodies have the same structure as antigens New types of vaccines such as vaccines are also expected.

  Pseudomonas aeruginosa (staphylococcus, pneumococci, Pseudomonas aeruginosa, Escherichia coli, etc.) is said to be treated by phagocytosis / bactericidal action by neutrophils or immunolysis by activated complement. Bacteria contain substances that resist phagocytosis, such as the pneumococcal capsule, streptococcal M protein, and staphylococcal mucopeptides, such as Escherichia coli O-157, Shigella and Vibrio cholerae. There are also dangerous bacteria with exotoxins. Toxins produced by these bacteria (tetanus, diphtheria exotoxin, etc.) can be neutralized by binding antibodies thereto, and antibodies belonging to IgG are also main immunoglobulins. In addition, bacteria such as tuberculosis, sputum, Salmonella, and Listeria are resistant to bactericidal action and cannot be treated with short-lived neutrophils, so activation of macrophage phagocytosis and bactericidal action is a necessary condition, and they react with antigens. Macrophage activating factor is one of the lymphokines produced by T cells. In addition, the immunolysis phenomenon works effectively against gram-negative bacteria, and is considered to be an important mechanism especially for the defense against Neisseria (meningococcus / gonococci). In this mechanism, complement is also activated by secondary pathways by bacterial surface substances, but activation of the classical pathway by antibodies bound to bacteria (particularly IgM.IgG) is considered to be effective. New vaccines and antibodies corresponding to these types of bacteria are awaited. Further, for example, hepatitis B virus S antigen is used for hepatitis B vaccine, and serum from a S antigen positive person (HB virus carrier) is used as a raw material. However, this method has limited raw materials, and such sera can be a source of infection, which is dangerous to handle. As a means for solving this problem, by introducing the gene of S antigen into DNA of bacteria such as Escherichia coli and yeast by gene recombination technique, these introduced bacteria will produce S antigen. . If this introduced bacterium is cultured in a large amount, a large amount of S antigen can be obtained. That is, it is an example of the development application of a DNA recombinant vaccine. Moreover, if the base sequence of the gene DNA of an antigen is clarified, it is technically possible to chemically synthesize an antigen peptide based on the base sequence, and synthetic peptide vaccines are also produced by this method. However, if a synthetic peptide as described above is used as an antigen, it is said that it is necessary to add some adjuvant because it is weak in immunogenicity by itself. Proposal of a method that can easily approximate such a protein structure, sugar chain structure, and the like with an original target antibody and its specific possibility are expected.

  By incorporating the gene of an idioantigen of another virus of interest into a virus that has already been confirmed to be safe, the former virus can be made to express the antigen of the latter virus. When the virus whose former safety has been confirmed is used as a vaccine, immunity against the latter virus can be induced simultaneously. Although such a vaccine is a kind of vector vaccine, a vaccine in which an influenza HA antigen is made to be produced by vaccinia virus has already been put into practical use as an antigen gene of another virus incorporated without using an idioantigen. . However, even if it is a safe virus stock, it is not a method that can be used for all viruses. In some cases, it is difficult to supply vaccines in terms of time, economy, and technology, and it is expected to solve these problems.

  Complement complements the pathogen directly or indirectly and acts to kill or phagocytose macrophages. Complement can act directly on bacteria and is also activated by mannose binding proteins. Furthermore, the antibodies produced as a result of the infection can also activate complement. Complements activated in this way kill bacteria or induce macrophages, neutrophils and other phagocytic cells of the immune system. In bacteria that cause pneumonia and pharyngitis, the capsule, a membrane made of long sugar chains (polysaccharides), prevents complement from acting directly on the bacteria. This mannose-binding protein changes its shape when bound to bacteria, activates complement, and further promotes phagocytic cell activation. However, even though the protein structure is the same, it is known that the functional expression differs depending on the binding of sugar chains, but each glycoprotein with specific action is created and manufactured by genetic engineering. It is difficult to do with the conventional technology, and it is difficult to do with the diversity of organisms. Such species-specific glycoproteins are easily taken out, and production of specific vaccines, antibodies, antitoxins, neutralizing antibodies, etc., and specific examples of the effectiveness thereof are awaited.

  In addition, it has been pointed out that abnormalities in metabolic systems exist in tumorigenic cells, and that there is a possibility that abnormalities in the synthesis of cell membrane materials, particularly sugar chains, are likely to occur. This abnormality is considered to occur when the sugar chain cannot be synthesized over the entire length and can only be made partway, and when a completely different sugar chain is produced. Such a sugar chain becomes a tumor-associated antigen, and since the molecule is short in the former, it is likely to be covered with a substance that covers the cell surface and is not effective. Furthermore, there are substances such as sialomucin, hyaluronic acid, and chondroitin sulfate that cover the surface of the tumor cells, and it is pointed out that the tumor-related antigens may be covered so that immunity does not work. Yes. Attempts have been made to improve immune dysfunction due to such sugar chain abnormalities, to smoothly treat tumor cells in vivo, and to deal with prevention and treatment of malignant tumors. A proposal of a method for increasing the expression efficiency of tumor-associated antigens is expected.

  One infectious disease that has recently become a global problem is HIV. Recently, it is considered difficult to suppress HIV by a treatment that works only in one stage. Generally, an HIV virion (Virion, a virus particle itself) is roughly spherical and has a diameter of 100 nm. The outer membrane made of bilayer lipid molecules (called the envelope or envelope) is similar to the membrane around human cells and has the same evolutionary origin. The spike is made of four glycoproteins called gp120 outside the outer coat (gp stands for glycoprotein). These coat proteins play an important role when HIV binds to and enters target cells. A tricks protein layer called p17 exists just under the outer coat. Capsids are made of another protein called p24. This double-stranded RNA consists of about 9200 base pairs and is completely contained in the core of the virus. The coat glycoprotein gp120 binds strongly to CD4. Therefore, antibodies that recognize gp120 and gp41 in the outer coat of HIV bind to these and simultaneously bind to MHC molecules on the surface of healthy cells, thereby impairing immune function. gp120 and gp41 have amino acid sequences very similar to MHC molecules. Various drugs have been developed and studied based on such biological characteristics, but this is not sufficient. Although the existence of many carriers is particularly estimated, development of a vaccine that is effective in preventive medicine, such as an antibody of a special glycoprotein possessed by HIV, is required.

  In addition, the history of human beings and illnesses will not be traced, and the battle with pathogenic microorganisms such as bacteria and viruses is still vigorous, but it is still important to be solved medically. It is a serious problem. Pathogenic microorganisms and viruses such as Staphylococcus aureus, streptococci, Escherichia coli, acid-fast bacilli, and fungi are always alive in human living space and are widely known as causative bacteria for various infectious diseases. Many drugs have been developed and applied for the prevention and treatment of pathogenic microorganisms and viral infections, and many results have been achieved. However, while the development of remarkable antibacterial substances in recent years, in order to cope with mass infections and infectious diseases that occur on a large scale, development of effective vaccines for hygiene prevention is required.

  On the other hand, the scientific knowledge that it is important for the expression of various functions of organisms expressed by the multidimensional structure of the substance in the aforementioned biology and the functional diversity expressed by the multidimensional structure of the substance are considered to be the specificity of the cell species. Despite the proposed logical validity of idiotype vaccines and antibodies using the original structural diversity, it is not satisfactory. It has been awaited that the simple and specific production method and effective effects in the embodiments are exemplified. This is one of the important issues that have long been awaited as a cutting-edge technology not only in interdisciplinary aspects such as biology, chemistry, and medicine, but also in practical medicine that saves lives.

On the other hand, biological components such as substrates (lipids, carbohydrates, amino acids, etc.) that basically constitute the structure and functions of organisms, peptides, proteins, enzymes, nucleic acids, and genes (DNA, tRNA) that are biologically synthesized from substrates. , MRNA, rRNA), and other organisms are species-specific by the multi-dimensional structure (conformation) of cell membranes, intracellular organelles, and intracellular and extracellular substrates, which are the basic components of biological components. It is well known that multidimensional structures are important for the expression of physiological functions and the recognition of substances, as well as the recognition and reception of substances (Albert, Bray, Lewis, Raff, Roberts and Watson, The Molecular Biology of the Cell, Garland Publishing Inc, 3 <Reference 1>). It is known that the substances whose functions are expressed by these multidimensional structures are different in the state of molecular charge distribution and molecular charge density not only in the species difference and normal state but also in the pathological state <Reference 1>. In addition, viruses, which are living organisms that do not have cell membranes, are composed of peptide chains and proteins formed by combining a large number of inanimate amino acids, and are composed of 2D, 3D, 4D structures (helix structures; helices (helixes) ) Has 3.6 amino acid residues per helix revolution, creating a space that can be occupied by a side chain in a 3.6-helix, and all possible hydrogen bonds can be formed). It is also an important known fact that the functions of the α domain, β domain, α / β domain, exon, and intron are expressed by their multidimensional structure. In homologous proteins, the core portion in the structure is conserved, but the helix loop region is altered. What kind of conformation is taken depends not on the amino acid sequence, but on the number of amino acids contained in the helix loop and the type of secondary structure in which the loop is connected, that is, α-α, β-β, α It is also known that it often depends on which of -β and β-α is taken. These multidimensional structures are important for the mechanism of physiological functions based on the recognition of the 2D and 3D structures of each substance applicable to various genes and antibodies based on recent molecular biology knowledge. It is a known scientific fact that there is <Document 1>. With the elucidation of such detailed functions of living organisms at the substance level, it is becoming increasingly popular to artificially create substances that respond specifically to each substance. As a result of this integration, elucidation of the functions of species-specific organisms with diversity and the development of treatments based on them are awaited.
International Publication Number WO96 / 07403 By Albert, Bray, Lewis, Raff, Roberts and Watson, The Molecular Biology of the Cell, Garland Publishing Inc, 3rd edition

  Based on the biological facts mentioned above, the non-functionality of polymer materials with their respective characteristics is suppressed or inhibited by the multidimensional structure of complex polymer materials that form living organisms and non-living organisms. By making the basic structural substance as close to the functional expression as possible while inducing sex, vaccine precursors, vaccines, antibodies (including idioantibodies), neutralizing antibodies, antitoxins, or their idiodes with high selectivity and specificity Antibacterial agents, antiviral agents, neutralizing antibodies, antitoxins produced using antibodies, anticancer agents using them, antiprotozoal (malaria, spirochete, etc.) agents, molecular identification agents, antibodies as labeling reagents, anti-idio antibodies and tissues Development of organ histocompatibility promoters, immune response promoters, immune response regulators, complement chain reaction promoters, and the like has been desired.

  The object of the present invention is to solve the above-mentioned problems, and can be produced by a simple method, and is close to the origin that brings about variety of species without limiting selectivity and specificity, or easily identifies the target substance to be recognized. Vaccine precursors, vaccines, antibodies (including idioantibodies), neutralizing antibodies, antitoxins, or antibacterial agents, antiviral agents, neutralizing antibodies, antitoxins, anticancer agents, antiprotozoa produced by the idioantibodies (Malaria, spirochete, etc.) Agents, molecular identification agents, labeling reagents, anti-idio antibodies and tissues, organ histocompatibility promoters, immune response promoters, immune response regulators, complement chain reaction promoters There is.

  In order to achieve the above object, the present inventors have conducted extensive research, and as a result, have clarified cells as antibacterial agents, antifungal agents, antiviral agents, bactericidal disinfectants, and anticancer agents that have antigenic substance inducers described later. Utilizing the action of granulating and dispersing, or antigen-antibody reaction inhibitory action, reducing action, free radical scavenging action, desulfurization action, depolymerization action, copolymerization action with antigenic substance inducers for non-living macromolecules, Using the surface activity improving action, microphase transition action, phase transition action, etc., it is possible to produce the vaccine precursors, vaccines, antibodies (including idioantibodies), neutralizing antibodies, and antitoxins shown above, and It is also possible to produce a labeling reagent having a substituent or a labeling substance containing a substance that serves as a label indicating an action site, and it is also possible to create an antibody of a non-living polymer substance. Rus, anticancer, antiprotozoal (malaria, spirochete, etc.), molecular identification agent, labeling reagent, histocompatibility promoter, immune response promoter or immune response regulator, complement chain reaction promoter, etc. The present invention has been completed by finding that it has an effective effect according to the purpose.

In order to achieve the above object, the invention described in the claims comprises contacting an antigen substance-inducing agent capable of producing a vaccine precursor, a vaccine, an antibody, a neutralizing antibody, an antitoxin, and an idio antibody with a cancer cell. A vaccine precursor and a vaccine containing an induced antigen as an active ingredient .

  As the basic principle of the present invention, the quantum thermodynamic decomposition and fragmentation action of the antigen substance inducer is used to kill bacteria, viruses, cancer cells, protozoa (malaria, spirochetes), etc. The purpose is to make the living body acquire the antibody recognizing ability by using the structural material. In addition, we create antibodies that use the quantum of the action of antigenic substance inducers and molecular mechanisms, such as the production of attenuated vaccines, inactivated vaccines, neutralizing antibodies, antitoxins, artificial antibodies, etc. It is trying to express. This antigenic substance inducer has already been published internationally under the international publication number WO96 / 07403, including its production method, etc., in terms of its molecular expression function inhibitor.

  The antigen substance inducer according to the present invention comprises a compound represented by each of the following general formulas as an active ingredient.

（ただし、式中（ｉ）Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６はそれぞれ独立に水素原子；ハロゲン原子；Ｃ１〜Ｃ６アルキル基；アミジノ基；Ｃ３〜Ｃ８シクロアルキル基；Ｃ１〜Ｃ６アルコキシＣ１〜Ｃ６アルキル基；アリール基；アリル基；ベンゼン、ナフタレン及びアントラセン環から成る群より選ばれる芳香族環に１若しくは２以上のＣ１〜Ｃ６アルキル基が結合したアラルキル基；Ｃ１〜Ｃ６アルキレン基；ベンゾイル基；シンナミル基；シンナモイル基；又はフロイル基であり、（ｉｉ）Ａは水素原子又は

であり、（ただし、Ｒ７はＣ１〜Ｃ６アルキル基；スルフィド基；又はフォスフェイト基であり、Ｒ８及びＲ９はそれぞれ独立に水素原子；ハロゲン原子；直鎖状若しくは分岐状Ｃ１〜Ｃ６アルキル基；アリール基；アリル基；ベンゼン、ナフタレン及びアントラセン環から成る群より選ばれる芳香族環に１若しくは２以上のＣ１〜Ｃ６アルキル基が結合したアラルキル基；Ｃ１〜Ｃ６アルキレン基；ベンゾイル基；シンナミル基；シンナモイル基；又はフロイル基である）（ｉｉｉ）Ｒ１、Ｒ２、Ｒ３及びＲ４のいずれか並びに／又はＲ５及びＲ６のいずれかは置換若しくは非置換シクロペンチル基；置換若しくは非置換シクロヘキシル基；又は置換若しくは非置換ナフチル基であってもよく、（ｉｖ）Ｒ５及びＲ６は他の縮合多環式炭化水素化合物又はヘテロ環系化合物と結合して環を形成していてもよく、（ｖ）Ｒ３、Ｒ４、Ｒ５及びＲ６は、ハロゲン原子、シアノ基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、Ｃ１〜Ｃ６アルキル基、Ｃ１〜Ｃ６アルコキシ基、Ｃ１〜Ｃ７アルコキシカルボニル基、アリール基、Ｃ３〜Ｃ６シクロアルキル基、Ｃ１〜Ｃ６アシルアミノ基、Ｃ１〜Ｃ６アシルオキシ基、Ｃ２〜Ｃ６アルケニル基、Ｃ１〜Ｃ６トリハロゲノアルキル基、Ｃ１〜Ｃ６アルキルアミノ基及びジＣ１〜Ｃ６アルキルアミノ基から成る群より選ばれる１つ以上の置換基により置換されていてもよく、（ｖｉ）Ｒ２及びＲ５は、ハロゲン原子、Ｃ１〜Ｃ６アルキル基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、保護されていてもよいＣ１〜Ｃ６アルキルアミノ基、保護されていてもよいＣ１〜Ｃ６アミノアルキル基、保護されていてもよいＣ１〜Ｃ６アルキルアミノＣ１〜Ｃ６アルキル基、保護されていてもよいＣ１〜Ｃ６ヒドロキシアルキル基及びＣ３〜Ｃ６シクロアルキルアミノ基から成る群より選ばれる１つ以上の置換基で置換されていてもよく、（ｖｉｉ）Ｒ３、Ｒ４、Ｒ５及びＲ６がアルキル基の場合には、該アルキル基の末端がＣ３〜Ｃ８シクロアルキル基によって置換されていてもよい）で示される。 A in formula 1 according to claim 1 is

(Wherein, (i) R1, R2, R3, R4, R5 and R6 are each independently a hydrogen atom; a halogen atom; a C1-C6 alkyl group; an amidino group; a C3-C8 cycloalkyl group; a C1-C6 alkoxy C1. -C6 alkyl group; aryl group; allyl group; aralkyl group in which one or two or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of benzene, naphthalene and anthracene ring; C1-C6 alkylene group; benzoyl A group; a cinnamyl group; a cinnamoyl group; or a furoyl group, and (ii) A is a hydrogen atom or

Wherein R7 is a C1-C6 alkyl group; a sulfide group; or a phosphate group, and R8 and R9 are each independently a hydrogen atom; a halogen atom; a linear or branched C1-C6 alkyl group; an aryl An aralkyl group in which one or two or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of a benzene, naphthalene and anthracene ring; a C1-C6 alkylene group; a benzoyl group; a cinnamyl group; A group; or a furoyl group) (iii) any of R1, R2, R3 and R4 and / or any of R5 and R6 is a substituted or unsubstituted cyclopentyl group; a substituted or unsubstituted cyclohexyl group; or a substituted or unsubstituted It may be a naphthyl group, (iv) R5 and R6 are other condensed polycyclic carbonizations And (v) R3, R4, R5 and R6 may be a halogen atom, a cyano group, an optionally protected carboxyl group or a protected group. An optionally protected hydroxyl group, an optionally protected amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C7 alkoxycarbonyl group, an aryl group, a C3-C6 cycloalkyl group, a C1-C6 acylamino group, Substituted by one or more substituents selected from the group consisting of C1-C6 acyloxy groups, C2-C6 alkenyl groups, C1-C6 trihalogenoalkyl groups, C1-C6 alkylamino groups and di-C1-C6 alkylamino groups. (Vi) R2 and R5 may be a halogen atom, a C1-C6 alkyl group, an optionally protected carboxy group; Group, optionally protected hydroxyl group, optionally protected amino group, optionally protected C1-C6 alkylamino group, optionally protected C1-C6 aminoalkyl group, protected Optionally substituted with one or more substituents selected from the group consisting of a C1-C6 alkylamino C1-C6 alkyl group, an optionally protected C1-C6 hydroxyalkyl group and a C3-C6 cycloalkylamino group. Or (vii) when R3, R4, R5 and R6 are alkyl groups, the terminal of the alkyl group may be substituted with a C3-C8 cycloalkyl group).

  In general formula 1, a, the aryl group in (i), (ii) and (v) is a phenyl, tolyl, xylyl or naphthyl group, and the substituted cyclopentyl group in (iii) is a cyclopentylamino group or cyclopentylcarbyl group. The substituted cyclohexyl group is a cyclohexylamino group, a cyclohexylaldehyde group or a cyclohexylacetic acid group, the substituted naphthyl group is a naphthylamino group or a naphthylaminosulfonic acid group, and the condensed polycyclic group in (iv) The hydrocarbon compounds are pentalene, indene, naphthalene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, phenanthene, anthracene, pentacene, hexacene, dibenzophenanthrene, 1H- Black is a penta cyclooctene or benzocyclooctene, the heterocyclic compound is furan, thiophene, pyrrole, .gamma.-pyran, .gamma.-thiopyran, pyridine, thiazole, imidazole pyrimidine, it may be an indole or quinoline.

（ただし、式中（ｉ）Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ１０及びＲ１１はそれぞれ独立ノ 水素原子；ハロゲン原子；Ｃ１〜Ｃ６アルキル基；アミジノ基；Ｃ３〜Ｃ８シクロアルキル基；Ｃ１〜Ｃ６アルコキシＣ１〜Ｃ６アルキル基；アリール基；アリル基；ベンゼン、ナフタレン及びアントラセン環から成る群より選ばれる芳香族環に１若しくは２以上のＣ１〜Ｃ６アルキル基が結合したアラルキル基；Ｃ１〜Ｃ６アルキレン基；ベンゾイル基；シンナミル基；シンナモイル基；又はフロイル基であり、（ｉｉ）Ａは水素原子又は

であり、（ただし、Ｒ７はＣ１〜Ｃ６アルキル基；スルフィド基；又はフォスフェイト基であり、Ｒ８及びＲ９はそれぞれ独立に水素原子；ハロゲン原子；直鎖状若しくは分岐状Ｃ１〜Ｃ６アルキル基；アリール基；アリル基；ベンゼン、ナフタレン及びアントラセン環から成る群より選ばれる芳香族環に１若しくは２以上のＣ１〜Ｃ６アルキル基が結合したアラルキル基；Ｃ１〜Ｃ６アルキレン基；ベンゾイル基；シンナミル基；シンナモイル基；又はフロイル基である）（ｉｉｉ）Ｒ１、Ｒ２、Ｒ３及びＲ４のいずれか並びに／又はＲ５、Ｒ６、Ｒ１０及びＲ１１のいずれかは置換若しくは非置換シクロペンチル基；置換若しくは非置換シクロヘキシル基；又は置換若しくは非置換ナフチル基であってもよく、（ｉｖ）Ｒ５、Ｒ６、Ｒ１０及びＲ１１は他の縮合多環式炭化水素化合物又はヘテロ環系化合物と結合して環を形成していてもよく、（ｖ）Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ１０及びＲ１１は、ハロゲン原子、シアノ基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、Ｃ１〜Ｃ６アルキル基、Ｃ１〜Ｃ６アルコキシ基、Ｃ１〜Ｃ７アルコキシカルボニル基、アリール基、Ｃ３〜Ｃ６シクロアルキル基、Ｃ１〜Ｃ６アシルアミノ基、Ｃ１〜Ｃ６アシルオキシ基、Ｃ２〜Ｃ６アルケニル基、Ｃ１〜Ｃ６トリハロゲノアルキル基、Ｃ１〜Ｃ６アルキルアミノ基及びジＣ１〜Ｃ６アルキルアミノ基から成る群より選ばれる１つ以上の置換基により置換されていてもよく、（ｖｉ）Ｒ２及びＲ５は、ハロゲン原子、Ｃ１〜Ｃ６アルキル基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、保護されていてもよいＣ１〜Ｃ６アルキルアミノ基、保護されていてもよいＣ１〜Ｃ６アミノアルキル基、保護されていてもよいＣ１〜Ｃ６アルキルアミノＣ１〜Ｃ６アルキル基、保護されていてもよいＣ１〜Ｃ６ヒドロキシアルキル基及びＣ３〜Ｃ６シクロアルキルアミノ基から成る群より選ばれる１つ以上の置換基で置換されていてもよく、（ｖｉｉ）Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ１０及びＲ１１がアルキル基の場合には、該アルキル基の末端がＣ３〜Ｃ８シクロアルキル基によって置換されていてもよい）で示される。 B of the general formula 1 according to claim 3 is

(In the formula, (i) R1, R2, R3, R4, R5, R6, R10 and R11 are each independently an independent hydrogen atom; halogen atom; C1-C6 alkyl group; amidino group; C3-C8 cycloalkyl group; C1. -C6 alkoxy C1-C6 alkyl group; aryl group; allyl group; aralkyl group in which one or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of benzene, naphthalene and anthracene ring; C1-C6 An alkylene group; a benzoyl group; a cinnamyl group; a cinnamoyl group; or a furoyl group, and (ii) A is a hydrogen atom or

Wherein R7 is a C1-C6 alkyl group; a sulfide group; or a phosphate group, and R8 and R9 are each independently a hydrogen atom; a halogen atom; a linear or branched C1-C6 alkyl group; an aryl An aralkyl group in which one or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of a benzene, naphthalene and anthracene ring; a C1-C6 alkylene group; a benzoyl group; a cinnamyl group; A group; or a furoyl group) (iii) any of R1, R2, R3 and R4 and / or any of R5, R6, R10 and R11 is a substituted or unsubstituted cyclopentyl group; a substituted or unsubstituted cyclohexyl group; or It may be a substituted or unsubstituted naphthyl group, and (iv) R5, R6, R1 And R11 may be bonded to other condensed polycyclic hydrocarbon compounds or heterocyclic compounds to form a ring. (V) R3, R4, R5, R6, R10 and R11 are each a halogen atom, cyano Group, optionally protected carboxyl group, optionally protected hydroxyl group, optionally protected amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C7 alkoxycarbonyl group, aryl group , C3-C6 cycloalkyl group, C1-C6 acylamino group, C1-C6 acyloxy group, C2-C6 alkenyl group, C1-C6 trihalogenoalkyl group, C1-C6 alkylamino group and di-C1-C6 alkylamino group Optionally substituted by one or more substituents selected from the group, (vi) R2 and R5 are each a halogen atom, C ~ C6 alkyl group, optionally protected carboxyl group, optionally protected hydroxyl group, optionally protected amino group, optionally protected C1 to C6 alkylamino group, protected Selected from the group consisting of a good C1-C6 aminoalkyl group, an optionally protected C1-C6 alkylamino C1-C6 alkyl group, an optionally protected C1-C6 hydroxyalkyl group and a C3-C6 cycloalkylamino group (Vii) when R 3, R 4, R 5, R 6, R 10 and R 11 are alkyl groups, the end of the alkyl group is replaced by a C 3 -C 8 cycloalkyl group. Which may be substituted).

  In general formula 1, b, the aryl group in (i), (ii) and (v) is a phenyl, tolyl, xylyl or naphthyl group, and the substituted cyclopentyl group in (iii) is a cyclopentylamino group or cyclopentylcarbyl group. The substituted cyclohexyl group is a cyclohexylamino group, a cyclohexylaldehyde group or a cyclohexylacetic acid group, the substituted naphthyl group is a naphthylamino group or a naphthylaminosulfonic acid group, and the condensed polycyclic group in (iv) The hydrocarbon compounds are pentalene, indene, naphthalene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, phenanthene, anthracene, pentacene, hexacene, dibenzophenanthrene, 1H- Black is a penta cyclooctene or benzocyclooctene, the heterocyclic compound is furan, thiophene, pyrrole, .gamma.-pyran, .gamma.-thiopyran, pyridine, thiazole, imidazole pyrimidine, it may be an indole or quinoline.

（ただし、式中（ｉ）Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６はそれぞれ独立に水素原子；ハロゲン原子；Ｃ１〜Ｃ６アルキル基；アミジノ基；Ｃ３〜Ｃ８シクロアルキル基；Ｃ１〜Ｃ６アルコキシＣ１〜Ｃ６アルキル基；アリール基；アリル基；ベンゼン、ナフタレン及びアントラセン環から成る群より選ばれる芳香族環に１若しくは２以上のＣ１〜Ｃ６アルキル基が結合したアラルキル基；Ｃ１〜Ｃ６アルキレン基（ただし、Ｒ１、Ｒ２が一緒になってＣ１アルキレン基を形成する場合を除く）；ベンゾイル基；シンナミル基；シンナモイル基；又はフロイル基であり、（ｉｉ）Ｒ１、Ｒ２、Ｒ３及びＲ４のいずれか並びに／又はＲ５及びＲ６のいずれかは置換若しくは非置換シクロペンチル基；置換若しくは非置換シクロヘキシル基；又は置換若しくは非置換ナフチル基であってもよく、（ｉｉｉ）Ｒ５及びＲ６は他の縮合多環式炭化水素化合物又はヘテロ環系化合物と結合して環を形成していてもよく、（ｉｖ）Ｒ３、Ｒ４、Ｒ５及びＲ６は、ハロゲン原子、シアノ基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、Ｃ１〜Ｃ６アルキル基、Ｃ１〜Ｃ６アルコキシ基、Ｃ１〜Ｃ７アルコキシカルボニル基、アリール基、Ｃ３〜Ｃ６シクロアルキル基、Ｃ１〜Ｃ６アシルアミノ基、Ｃ１〜Ｃ６アシルオキシ基、Ｃ２〜Ｃ６アルケニル基、Ｃ１〜Ｃ６トリハロゲノアルキル基、Ｃ１〜Ｃ６アルキルアミノ基及びジＣ１〜Ｃ６アルキルアミノ基から成る群より選ばれる１つ以上の置換基により置換されていてもよく、（ｖ）Ｒ２及びＲ５は、ハロゲン原子、Ｃ１〜Ｃ６アルキル基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、保護されていてもよいＣ１〜Ｃ６アルキルアミノ基、保護されていてもよいＣ１〜Ｃ６アミノアルキル基、保護されていてもよいＣ１〜Ｃ６アルキルアミノＣ１〜Ｃ６アルキル基、保護されていてもよいＣ１〜Ｃ６ヒドロキシアルキル基及びＣ３〜Ｃ６シクロアルキルアミノ基から成る群より選ばれる１つ以上の置換基で置換されていてもよく、（ｖｉ）Ｒ３、Ｒ４、Ｒ５及びＲ６がアルキル基の場合には、該アルキル基の末端がＣ３〜Ｃ８シクロアルキル基によって置換されていてもよい）で示される。 The general formula 2 according to claim 5 is

(Wherein, (i) R1, R2, R3, R4, R5 and R6 are each independently a hydrogen atom; a halogen atom; a C1-C6 alkyl group; an amidino group; a C3-C8 cycloalkyl group; a C1-C6 alkoxy C1. -C6 alkyl group; aryl group; allyl group; aralkyl group in which one or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of benzene, naphthalene and anthracene ring; C1-C6 alkylene group (provided that , R1, R2 together to form a C1 alkylene group) ; a benzoyl group; a cinnamyl group; a cinnamoyl group; or a furoyl group, and (ii) any of R1, R2, R3 and R4 and / or Or any of R5 and R6 is a substituted or unsubstituted cyclopentyl group; a substituted or unsubstituted cyclohexyl group; Or (iii) R5 and R6 may be bonded to other condensed polycyclic hydrocarbon compounds or heterocyclic compounds to form a ring; and (iv) R3, R4, R5 and R6 are each a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected hydroxyl group, an optionally protected amino group, a C1-C6 alkyl group, a C1- C6 alkoxy group, C1-C7 alkoxycarbonyl group, aryl group, C3-C6 cycloalkyl group, C1-C6 acylamino group, C1-C6 acyloxy group, C2-C6 alkenyl group, C1-C6 trihalogenoalkyl group, C1-C6 It may be substituted with one or more substituents selected from the group consisting of alkylamino groups and di-C1-C6 alkylamino groups. , (V) R2 and R5 are a halogen atom, a C1-C6 alkyl group, a carboxyl group that may be protected, a hydroxyl group that may be protected, an amino group that may be protected, or a protected group Good C1-C6 alkylamino group, optionally protected C1-C6 aminoalkyl group, optionally protected C1-C6 alkylamino C1-C6 alkyl group, optionally protected C1-C6 hydroxyalkyl group And optionally substituted with one or more substituents selected from the group consisting of C3 to C6 cycloalkylamino groups, (vi) when R3, R4, R5 and R6 are alkyl groups, The terminal may be substituted with a C3-C8 cycloalkyl group).

  In General Formula 2, the aryl group in (i) and (iv) is a phenyl, tolyl, xylyl, or naphthyl group, and the substituted cyclopentyl group in (ii) is a cyclopentylamino group or a cyclopentylcarbinol group, The substituted cyclohexyl group is a cyclohexylamino group, a cyclohexylaldehyde group or a cyclohexylacetic acid group, the substituted naphthyl group is a naphthylamino group or a naphthylaminosulfonic acid group, and the condensed polycyclic hydrocarbon compound in (iii) is pentalene , Indene, naphthalene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, phenanthene, anthracene, pentacene, hexacene, dibenzophenanthrene, 1H-cyclopent A cyclooctene or benzocyclooctene, the heterocyclic compound is furan, thiophene, pyrrole, .gamma.-pyran, .gamma.-thiopyran, pyridine, thiazole, imidazole pyrimidine, it may be an indole or quinoline.

（ただし、式中（ｉ）Ｒ３及びＲ４はそれぞれ独立に水素原子；ハロゲン原子；Ｃ１〜Ｃ６アルキル基；アミジノ基；Ｃ３〜Ｃ８シクロアルキル基；Ｃ１〜Ｃ６アルコキシＣ１〜Ｃ６アルキル基；アリール基；アリル基；ベンゼン、ナフタレン及びアントラセン環から成る群より選ばれる芳香族環に１若しくは２以上のＣ１〜Ｃ６アルキル基が結合したアラルキル基；Ｃ１〜Ｃ６アルキレン基；ベンゾイル基；シンナミル基；シンナモイル基；又はフロイル基であり、（ｉｉ）Ｒ３及びＲ４のいずれかは置換若しくは非置換シクロペンチル基；置換若しくは非置換シクロヘキシル基；又は置換若しくは非置換ナフチル基であってもよく、（ｉｉｉ）Ｒ５及びＲ６は他の縮合多環式炭化水素化合物又はヘテロ環系化合物と結合して環を形成し、（ｉｖ）Ｒ３、Ｒ４、Ｒ５及びＲ６は、ハロゲン原子、シアノ基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、Ｃ１〜Ｃ６アルキル基、Ｃ１〜Ｃ６アルコキシ基、Ｃ１〜Ｃ７アルコキシカルボニル基、アリール基、Ｃ３〜Ｃ６シクロアルキル基、Ｃ１〜Ｃ６アシルアミノ基、Ｃ１〜Ｃ６アシルオキシ基、Ｃ２〜Ｃ６アルケニル基、Ｃ１〜Ｃ６トリハロゲノアルキル基、Ｃ１〜Ｃ６アルキルアミノ基及びジＣ１〜Ｃ６アルキルアミノ基から成る群より選ばれる１つ以上の置換基により置換されていてもよく、（ｖ）Ｒ５は、ハロゲン原子、Ｃ１〜Ｃ６アルキル基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、保護されていてもよいＣ１〜Ｃ６アルキルアミノ基、保護されていてもよいＣ１〜Ｃ６アミノアルキル基、保護されていてもよいＣ１〜Ｃ６アルキルアミノＣ１〜Ｃ６アルキル基、保護されていてもよいＣ１〜Ｃ６ヒドロキシアルキル基及びＣ３〜Ｃ６シクロアルキルアミノ基から成る群より選ばれる１つ以上の置換基で置換されていてもよく、（ｖｉ）Ｒ３及びＲ４がアルキル基の場合には、該アルキル基の末端がＣ３〜Ｃ８シクロアルキル基によって置換されていてもよい）で示される。 A in the general formula 3 according to claim 7 is

(Wherein, (i) R3 and R4 are each independently a hydrogen atom; a halogen atom; a C1-C6 alkyl group; an amidino group; a C3-C8 cycloalkyl group; a C1-C6 alkoxy C1-C6 alkyl group; an aryl group; An aralkyl group in which one or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of a benzene, naphthalene and anthracene ring; a C1-C6 alkylene group; a benzoyl group; a cinnamyl group; a cinnamoyl group; Or (ii) any of R3 and R4 may be a substituted or unsubstituted cyclopentyl group; a substituted or unsubstituted cyclohexyl group; or a substituted or unsubstituted naphthyl group, and (iii) R5 and R6 are combined with other condensed polycyclic hydrocarbon compound or heterocyclic compound to form a ring, iv) R3, R4, R5 and R6 are each a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected hydroxyl group, an optionally protected amino group, a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C7 alkoxycarbonyl group, aryl group, C3-C6 cycloalkyl group, C1-C6 acylamino group, C1-C6 acyloxy group, C2-C6 alkenyl group, C1-C6 trihalogenoalkyl group, C1 May be substituted with one or more substituents selected from the group consisting of a -C6 alkylamino group and a di-C1-C6 alkylamino group, and (v) R5 is a halogen atom, a C1-C6 alkyl group, protected. Carboxyl group which may be protected, hydroxyl group which may be protected, amino group which may be protected C1-C6 alkylamino group which may be protected, C1-C6 aminoalkyl group which may be protected, C1-C6 alkylamino C1-C6 alkyl group which may be protected, C1 which may be protected May be substituted with one or more substituents selected from the group consisting of a -C6 hydroxyalkyl group and a C3-C6 cycloalkylamino group; (vi) when R3 and R4 are alkyl groups, the alkyl group Is optionally substituted with a C3-C8 cycloalkyl group.

  In general formula 3, a, the aryl group in (i) and (iv) is a phenyl, tolyl, xylyl, or naphthyl group, and the substituted cyclopentyl group in (ii) is a cyclopentylamino group or a cyclopentylcarbinol group. The substituted cyclohexyl group is a cyclohexylamino group, a cyclohexylaldehyde group or a cyclohexylacetic acid group, the substituted naphthyl group is a naphthylamino group or a naphthylaminosulfonic acid group, and the condensed polycyclic hydrocarbon compound in (iii) above Are pentalene, indene, naphthalene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, phenanthene, anthracene, pentacene, hexacene, dibenzophenanthrene, 1H-cyclo A printer cyclooctene or benzocyclooctene, the heterocyclic compound is furan, thiophene, pyrrole, .gamma.-pyran, .gamma.-thiopyran, pyridine, thiazole, imidazole pyrimidine, it may be an indole or quinoline.

（ただし、式中（ｉ）Ｒ３、Ｒ４、Ｒ５及びＲ６はそれぞれ独立に水素原子；ハロゲン原子；Ｃ１〜Ｃ６アルキル基；アミジノ基；Ｃ３〜Ｃ８シクロアルキル基；Ｃ１〜Ｃ６アルコキシＣ１〜Ｃ６アルキル基；アリール基；アリル基；ベンゼン、ナフタレン及びアントラセン環から成る群より選ばれる芳香族環に１若しくは２以上のＣ１〜Ｃ６アルキル基が結合したアラルキル基；Ｃ１〜Ｃ６アルキレン基；ベンゾイル基；シンナミル基；シンナモイル基；又はフロイル基であり、（ｉｉ）Ｒ３及びＲ４のいずれか並びに／又はＲ５及びＲ６のいずれかは置換若しくは非置換シクロペンチル基；置換若しくは非置換シクロヘキシル基；又は置換若しくは非置換ナフチル基であってもよく、（ｉｉｉ）Ｒ５及びＲ６は他の縮合多環式炭化水素化合物又はヘテロ環系化合物と結合して環を形成していてもよく、（ｉｖ）Ｒ３、Ｒ４、Ｒ５及びＲ６は、ハロゲン原子、シアノ基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、Ｃ１〜Ｃ６アルキル基、Ｃ１〜Ｃ６アルコキシ基、Ｃ１〜Ｃ７アルコキシカルボニル基、アリール基、Ｃ３〜Ｃ６シクロアルキル基、Ｃ１〜Ｃ６アシルアミノ基、Ｃ１〜Ｃ６アシルオキシ基、Ｃ２〜Ｃ６アルケニル基、Ｃ１〜Ｃ６トリハロゲノアルキル基、Ｃ１〜Ｃ６アルキルアミノ基及びジＣ１〜Ｃ６アルキルアミノ基から成る群より選ばれる１つ以上の置換基により置換されていてもよく、（ｖ）Ｒ５は、ハロゲン原子、Ｃ１〜Ｃ６アルキル基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、保護されていてもよいＣ１〜Ｃ６アルキルアミノ基、保護されていてもよいＣ１〜Ｃ６アミノアルキル基、保護されていてもよいＣ１〜Ｃ６アルキルアミノＣ１〜Ｃ６アルキル基、保護されていてもよいＣ１〜Ｃ６ヒドロキシアルキル基及びＣ３〜Ｃ６シクロアルキルアミノ基から成る群より選ばれる１つ以上の置換基で置換されていてもよく、（ｖｉ）Ｒ３、Ｒ４、Ｒ５及びＲ６がアルキル基の場合には、該アルキル基の末端がＣ３〜Ｃ８シクロアルキル基によって置換されていてもよい）で示される。 B in the general formula 3 according to claim 9 is

(Wherein, (i) R3, R4, R5 and R6 are each independently a hydrogen atom; a halogen atom; a C1-C6 alkyl group; an amidino group; a C3-C8 cycloalkyl group; a C1-C6 alkoxy C1-C6 alkyl group. Aryl group; allyl group; aralkyl group in which one or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of benzene, naphthalene and anthracene ring; C1-C6 alkylene group; benzoyl group; cinnamyl group A cinnamoyl group; or a furoyl group, and (ii) either R3 and R4 and / or any of R5 and R6 is a substituted or unsubstituted cyclopentyl group; a substituted or unsubstituted cyclohexyl group; or a substituted or unsubstituted naphthyl group (Iii) R5 and R6 may be other condensed polycyclic hydrocarbonation Or (iv) R3, R4, R5 and R6 may be a halogen atom, a cyano group, an optionally protected carboxyl group or a protected group. Hydroxyl group, amino group which may be protected, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C7 alkoxycarbonyl group, aryl group, C3-C6 cycloalkyl group, C1-C6 acylamino group, C1 -C6 acyloxy group, C2-C6 alkenyl group, C1-C6 trihalogenoalkyl group, C1-C6 alkylamino group and one or more substituents selected from the group consisting of di-C1-C6 alkylamino groups (V) R5 is a halogen atom, a C1-C6 alkyl group, an optionally protected carboxyl group, a protected group. An optionally protected hydroxyl group, an optionally protected amino group, an optionally protected C1 to C6 alkylamino group, an optionally protected C1 to C6 aminoalkyl group, an optionally protected C1 to C1 A C6 alkylamino C1 to C6 alkyl group, an optionally protected C1 to C6 hydroxyalkyl group and a C3 to C6 cycloalkylamino group may be substituted with one or more substituents selected from the group ( vi) when R3, R4, R5 and R6 are alkyl groups, the terminal of the alkyl group may be substituted by a C3-C8 cycloalkyl group).

  In general formula 3, b, the aryl group in (i) and (iv) is a phenyl, tolyl, xylyl, or naphthyl group, and the substituted cyclopentyl group in (ii) is a cyclopentylamino group or a cyclopentylcarbinol group. The substituted cyclohexyl group is a cyclohexylamino group, a cyclohexylaldehyde group or a cyclohexylacetic acid group, the substituted naphthyl group is a naphthylamino group or a naphthylaminosulfonic acid group, and the condensed polycyclic hydrocarbon compound in (iii) above Are pentalene, indene, naphthalene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, phenanthene, anthracene, pentacene, hexacene, dibenzophenanthrene, 1H-cyclo A printer cyclooctene or benzocyclooctene, the heterocyclic compound is furan, thiophene, pyrrole, .gamma.-pyran, .gamma.-thiopyran, pyridine, thiazole, imidazole pyrimidine, it may be an indole or quinoline.

  The mechanism of action and logical disclosure of the aspect of each antigen substance inducer as a molecular expression function inhibitor have already been published in International Publication No. WO96 / 07403. The present invention shows that the treatment with each antigenic substance inducer can produce a superselective recognition action as described below. In addition, the present invention has demonstrated the possibility of producing neutralizing antibodies specific for toxins by processing toxins and the like produced by living organisms in vitro such as test tubes and recognizing the treatment liquid in the organism. It is. These vaccine precursors, vaccines, antibodies, neutralizing antibodies, antitoxins, and idioantibodies are present on the surface of viruses, bacteria, and cells using the quantum thermodynamic properties of the antigenic substance inducer of the present invention. The so-called adhesive substance and the function of stopping the function of a substance involved in signal transmission, the destruction of the envelope of viruses, bacteria, protozoa, and cell membranes, and the inactivation action are utilized. Therefore, the antigen substance inducer of the present invention is used in the same manner as organic solvents such as formalin and paraformaldehyde that have been used for inactivation and attenuation in the production process of conventional vaccines, etc. It can be inactivated or attenuated in a form close to the basic structure of adhesive substances such as protozoa, bacteria, and cancer cells, signal transmission substances, and toxins. In addition, the degree of attenuation, inactivation, destruction, or death can be adjusted by amount or concentration.

  Furthermore, it is self-evident that a detailed academic study is started based on the present invention, such as whether it is a humoral antibody present in blood or a membrane antibody immobilized on a specific cell membrane. In other words, antibodies produced by the production method of the present invention bring about selectivity based on the self-recognition of living organisms and include basic and fundamental facts that promote future research and development. It is. For example, if a specific molecule is isolated from complex polymer substances, it can be purified and concentrated from mRNA using techniques such as genetic engineering and cell fusion using cDNA. Not limited to the example, it is easy to guess many possibilities and usefulness. In addition, the ability to process toxins produced by living organisms in vitro such as test tubes, recognize the treatment solution in the organism, and create neutralizing antibodies specific for the toxins is a risk of secondary infection. It can also be reduced.

  Prion, virus, rickettcher, bacteria, bacterial toxin, cancer cell, various diseases and pathological tissue organs (especially intractable disease) due to unknown causes, etc. single vaccine, complex vaccine (consisting of multiple cells), It can be easily analogized that a cross vaccine or the like can be prepared according to the purpose. In other words, because it does not break the basic construction characteristics of biological species, it can produce multiple antibodies or recognize multiple antigens corresponding to the biochemical composition of species that are embryologically similar It is also possible to create antibodies (variety of antibody recognition).

  In addition, activation of the autoimmune system (preventive as well as low (non-lethal) amount) pathogenic bacteria, cancer, etc., when administered in vivo, the building elements (granules) such as dead cells are transferred to the host It is also conceivable that the immune system is stimulated, new antibodies are produced in vivo, and the vicious circulatory system in vivo such as subsequent proliferation and infiltration is blocked in a positive feedback manner. That is, amplification of an inactivated vaccine in vivo, and this method can also be applied as a preventive treatment for diseases. It is obvious that non-living substances can be applied as a kind of antibody catalyst.

  In addition, each extract extracted in the present invention can be further detoxified with heat, an organic solvent such as aldehyde, ultraviolet rays, etc., which have been conventionally used, depending on the purpose required.

  A vaccine precursor, vaccine, antibody, neutralizing antibody and antitoxin produced using the antigen substance inducer according to claims 1 to 11, an idioanti antibody, a vaccine produced using this idio antibody, an antibody, A halogen atom, a cyano group, an optionally protected carboxyl group at either or both ends of each structural terminal (mainly an amino group and a carboxyl group) such as a sum antibody and an antitoxin, and a labeling reagent and a histocompatibility promoter, Hydroxyl group which may be protected, amino group which may be protected, alkyl group, alkoxy group, alkoxycarbonyl group, aryl group, cycloalkyl group, acylamino group, acyloxy group, lower alkenyl group, trihalogeno-lower alkyl group Lower alkylamino group or di-lower alkylamino group, di-lower alkyl In one or more substituents selected from an amino-lower alkyl group or a cyclic amino lower alkyl group may be substituted.

  Unless otherwise specified in this specification, a halogen atom is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; and an alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n -A C1-10 alkyl group such as butyl, isobutyl, sec-butyl, tort-butyl, benzyl, hexyl, or octyl; a lower alkyl group is, for example, a C1-5 alkyl group among the above alkyl groups An alkoxy group, for example, -O-alkyl group (the alkyl group represents the above-mentioned C1-10 alkyl group); a lower alkylamino group, for example, methylamino, ethylamino, propylamino, etc. C1-5, an alkylamino group such as: a di-lower alkylamino group is, for example, dimethyl A di C1-5 alkylamino group such as ruamino; a lower alkenyl group is, for example, a C2-5 alkenyl group such as vinyl, allyl, 1-propenyl or 1-ptenyl; a cycloalkyl group is cyclo A C2-6 cycloalkyl group such as propyl, cyclobutyl, cyclopentyl or cyclohexyl; an aryl group such as phenyl or naphthyl; an alkoxycarbonyl group such as a —COO-alkyl group (an alkyl group is The above-mentioned C1-10 alkyl group is a hydroxy lower alkyl group, for example, a hydroxy-C1-5 alkyl group such as hydroxymethyl, hydroxyethyl or hydroxypropyl; an amino lower alkyl group is For example, aminomethyl, aminoethyl Or an amino-C1-5 alkyl group such as aminopropyl; a lower alkylamino lower alkyl group is, for example, a C1-5 alkylamino-C1- such as methylaminomethyl, ethylaminomethyl or ethylaminoethyl. A 5-alkyl group; a di-lower alkylamino lower alkyl group, for example, a di-C1-5 alkylamino-C1-5 alkyl group such as dimethylaminomethyl or diethylaminomethyl; a cyclic amino group, for example, piperazinyl , A 4- to 10-membered cyclic amino group such as morpholinyl or 1,4-diazabicyclo (3,2,1) octyl; and the cyclic amino lower alkyl group includes, for example, 1-piperazinylmethyl, 1-pyrrolidinylmethyl, 1-azetidinylmethyl or 1-morpholinylmethyl, etc. An acylamino group is a C1-4 acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, etc .; an acyloxy group is For example, a C1-4 acyloxy group such as formyloxy, acetyloxy, propionyloxy or butyryloxy; a trihalogeno-lower alkyl group is, for example, a trihalogeno-C 1-5 alkyl such as trichloromethyl or trifluoromethyl. A heterocyclic group means a 5- or 6-membered ring containing one or more atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, or a condensed ring thereof such as furyl, pyrrolyl, thienyl, oxazolyl Imidazolyl, thiazolyl, 1-pyrrole Groups such as dinyl, benzofuryl, benzothiazolyl, pyridyl, quinolyl, pyrimidinyl or morpholinyl are meant respectively.

  Examples of the carboxyl-protecting group include a pharmaceutically acceptable carboxyl-protecting group such as an ester-forming group that is easily eliminated in vivo.

  Examples of the protecting group for the amino group, amino lower alkyl group, lower alkylamino group, and lower alkylamino lower alkyl group include pharmaceutically acceptable amino protecting groups that are easily eliminated in vivo.

  Furthermore, examples of the protecting group for the hydroxyl group and the hydroxy lower alkyl group include a pharmaceutically acceptable hydroxyl protecting group that is easily eliminated in vivo.

  In order to induce each target organ or tissue and to efficiently induce each target effect, for example, combined use of a pharmaceutically acceptable carrier and the like can be mentioned.

  Examples of the pharmaceutically acceptable carrier include polyoxyalkylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyvinyl pyrrolidone, hydrocarbon, paraffin, alcohol, polyhydric alcohol, alcohol ester, polyhydric alcohol ester, fatty acid or fatty acid. Biologically acceptable carriers such as those mixed with metal salts, artificially prepared liposomes, etc., or evenly dispersed or dispersed.

  Further, vaccine precursors and vaccines according to the present invention, antibodies (including idioantibodies), neutralizing antibodies, vaccines produced using antitoxins or produced idioantibodies, antibodies, neutralizing antibodies, antitoxins, etc. When used in combination with an acceptable carrier, it can be used in various forms depending on the form of treatment known in the art, such as suspensions and liquids. Furthermore, you may add a solubilizing agent, an isotonic agent, a pH adjuster, a deodorant, an antiseptic | preservative, or a flavoring agent.

  As a method for extracting an antigenic substance from cells or cancer cells infected with microorganisms, for example, it is possible to take out by washing with physiological saline or dissolving and washing with Triton detergent. It is also possible to combine ultrasonic treatment and freezing treatment as a conventionally used cell destruction method. After inactivating the antigen-containing solution collected by centrifugation or the like using heat treatment, formaldehyde, or ultraviolet rays, an antibody titer can be increased by adding an adjuvant such as A1 (OH) 3.

  For the inactivation of the vaccine, typical basic steps already used (document [Provost, PJ et al., Proc. Soc. Exp. Biol. Med. 160, 213 (1979); Provost, PJ Etc., J. Med. Virol. 19, 23 (1986)]), each target extract is subjected to heat, pH change, irradiation, treatment with an organic solvent such as formalin or paraformaldehyde. And can be used in an untreated state.

  It is also possible to increase immunogenicity by embedding a small granule substance whose structure is known chemically into an antibody made according to the present invention to form an ICOM (immunostimulating complex).

  As a method for extracting an antigenic substance from cells or cancer cells infected with microorganisms, for example, it is possible to take out by washing with physiological saline or dissolving and washing with Triton detergent. It is also possible to combine ultrasonic treatment and freezing treatment as a conventionally used cell destruction method.

It is also possible to produce a vaccine by adding a stabilizer having the composition shown in Table 1 below after inactivating the antigen-containing solution collected by centrifugation or the like alone or after heat treatment, formaldehyde, or ultraviolet rays. is there.

  In addition, after washing the precipitate of the culture solution in which each of the cells and bacteria have been killed, the target extract is subjected to heat, pH change, irradiation, treatment with an organic solvent such as formalin or paraformaldehyde. Can be supplemented or additionally deactivated. When treated with formaldehyde, a suspension concentration of 0.001-0.05 (v / v)% is desirable, and when inactivated with ultraviolet light, 356 nm ultraviolet light is applied at 5.0 × 10 1 J / m 2. A range of −5.4 × 10 4 J / m 2 is desirable. However, it is desirable not to use unless necessary. The temperature when using formaldehyde or ultraviolet rays is desirably kept at 4 ° C. or lower. In any case, as the amount of heat, formaldehyde or ultraviolet irradiation increased, the antibody titer and specificity changed significantly. For example, the immunoglobulin obtained with an agar gel was reduced to 1/100 or more. In the present invention, the adsorption and clustering of antigen particles have already been expressed even alone, and more usefulness has already been provided, but the antibody titer can be increased by adding a surfactant (Twin 80). Can do.

  In addition, the deactivated extract substance can be adsorbed on aluminum hydroxide or precipitated together with aluminum hydroxide to increase the effect as an adjuvant and carrier. For example, direct precipitation of the deactivated extract into aluminum hydroxide is performed by first adding potassium aluminum sulfate to the oxixol-treated or formalin deactivated bulk solution, and finally adding the precipitate to sodium hydroxide. Generate by. The supernatant can be removed from the suspension to remove formaldehyde and residual salts, which can be replaced with saline.

  Further, after washing the precipitate of the culture solution in which each of the cells and bacteria was killed in the same manner as in the conventional vaccine or antigen harvest solution, each target extract was organically extracted. For example, a mixture of chloroform and an antifoaming agent such as isoamyl alcohol is added and extracted, and a DEAE spherodex gel is placed in a column with 0.1 N hydrochloric acid and 20 mmol phosphoric acid at pH 7.5. A column was prepared by passing a buffer solution, a 2 g / l sodium chloride solution containing 2% formalin, and a 1 M sodium chloride solution. For column equilibration and chromatography, a pH 7.5 phosphate buffer (20 mM phosphate, 0.1% Tween 80) is run to completely equilibrate the pH and osmotic concentration, The sample was passed so that the osmotic concentration did not exceed 280 milliosmoles, and pH 7.5 phosphate buffer (20 mmol phosphoric acid, 0.5 molar sodium chloride, 0.1% twin 80) was flowed at a flow rate of 45 cm / hour. It was washed away. By this operation, the antigenic substance was eluted and purified. The antibody fraction obtained from the gel filtration column is concentrated under conditions similar to the above-described concentration operation. Adjust the final volume after rinsing to 2.5 liters. A purified collection can be obtained by filtering the concentrated antibody fraction through a Durapore 0.2 micron membrane.

  As an additional gel filtration method, the final step of gel filtration chromatography can be carried out following anion exchange chromatography. For example, a column K215 / 100 manufactured by Pharmacia is used which is packed with 26.5 liters of Sepharose 6BCL. The column system, piping, detector, etc. are sterilized by flowing a solution containing 2% formalin and 2% sodium chloride at a flow rate of 1.7 liters / hour, and a phosphate buffer (pH 7.5) ( 20 mM phosphoric acid, 0.1% Tween 80) is allowed to flow for 48 hours at a flow rate of 2.7 liters / hour to rinse and equilibrate the column. Concentrated antigenic substance is added to the column by gravity, and filtered with pH 7.5 phosphate buffer (20 mM phosphate, 0.1% Twin 80) at a flow rate of 2.7 liters / hour. A purified recovered product can be obtained.

  In addition to chloroform, extraction can be performed using a halogenated lower alkane such as methylene chloride or tetrachloroethane as a solvent. The anion exchange matrix used in the extraction operation by ion exchange chromatography is not limited, but includes the following. That is, DEAE cellulose, DEAE agarose, DEAE biogel, DEAE dextran, DEAE Sephadex, DEAE Sepharose, aminohexyl sepharose, exteola cellulose, TEAE cellulose, QAE cellulose, mono-Q, or benzoylated diethylaminoethyl cellulose.

  Vaccine precursors and vaccines used in the present invention, antibodies, neutralizing antibodies and antitoxins, idioantibodies, vaccines produced using these idioantibodies, antibodies, neutralizing antibodies and antitoxins can be used for the above purposes even when administered alone. In addition, it can be used in the form of an acid addition salt, an emulsifier, an ester, or a polymerization agent as long as the potency, selectivity, or specificity is not significantly changed. For example, acid addition salts include pharmaceutically acceptable non-toxic salts such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and other inorganic acids, and acetic acid, citric acid, tartaric acid, lactic acid, succinic acid. And organic acids such as fumaric acid, maleic acid and metasulfonic acid.

  In the present invention, a vaccine precursor, vaccine, antibody, neutralizing antibody, antitoxin, idioantibody produced using an antigen substance inducer, vaccine, antibody, neutralizing antibody and antitoxin produced using the idioantibody Antibacterial antibodies, antiviral antibodies, anticancer antibodies, antiprotozoal (malarial, spirochete, etc.) antibodies as antibacterial agents, antiviral agents, anticancer agents, antiprotozoal (malaria, spirochete, etc.) agents, immune response promoters or immune response control agents When used, it can be administered alone or in combination with a pharmaceutically acceptable carrier. In addition, a local anesthetic such as xylocaine can be added in the case of inducing pain as in administration forms, for example, subcutaneous injection. However, it is not necessary to limit to the method shown in the present invention. The composition is determined by the administration route, the administration schedule, and the like.

  Vaccine precursors, vaccines, antibodies, neutralizing antibodies, antitoxins, idioantibodies produced using the antigen substance inducer of the present invention, vaccines produced using the idioantibodies, antibodies, neutralizing antibodies and antitoxins, anti Antibacterial, antiviral, anticancer, antiprotozoal (malarial, spirochete, etc.) agent, immune response promoter or immune response control agent for bacterial antibody, antiviral antibody, anticancer antibody, antiprotozoal (malarial, spirochete, etc.) antibody When used as the above pharmaceuticals, it is mixed with pharmacologically acceptable ingredients such as pharmacologically acceptable additives (for example, carriers, excipients, diluents, etc.) as appropriate, and powders, granules, tablets, capsules, injections The pharmaceutical composition can be administered orally or parenterally.

  Vaccine precursors, vaccines, antibodies, neutralizing antibodies, antitoxins, idioantibodies produced using the antigen substance inducer of the present invention, vaccines produced using the idioantibodies, antibodies, neutralizing antibodies and antitoxins, anti Antibacterial, antiviral, anticancer, antiprotozoal (malarial, spirochete, etc.) agent, immune response promoter or immune response control agent for bacterial antibody, antiviral antibody, anticancer antibody, antiprotozoal (malarial, spirochete, etc.) antibody For oral administration, it is used in the form of tablets, capsules, powders, granules, liquids, etc., and for parenteral administration, it is used in the form of a liquid sterilized state. When used in the form as described above, a solid or liquid non-toxic carrier may be included in the composition.

  As an example of the solid carrier, a capsule of gelatin type is usually used. In addition, the active ingredient is tableted, granulated or powder-packed with or without an adjuvant. Excipients used in these cases include: water: gelatin: sugars such as lactose and glucose: starch such as corn, wheat, rice, corn starch: fatty acids such as stearic acid: calcium stearate, magnesium stearate, etc. Fatty base: talc: vegetable oil: alcohol such as stearyl alcohol, benzyl alcohol: gum: polyalkylene glycol.

  These capsules, tablets, granules and powders generally contain 0.1-80% by weight, preferably 0.1-60% by weight, of the active ingredient. The liquid carriers are generally water, saline, dextrose. Alternatively, similar sugar solutions, glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are preferred as the liquid carrier.

  When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, it is used as a sterile solution to which other solutes such as saline or glucose are added in order to make the solution isotonic. Suitable solvents for injection include sterilized water, lidocaine hydrochloride solution (intramuscular injection), physiological saline, glucose, intravenous injection liquid, electrolyte solution (for intravenous injection) and the like. In the case of these injection solutions, it is preferable to contain 0.01 to 20% by weight, preferably 0.05 to 5% by weight of the active ingredient.

  In the case of a solution for oral administration, a suspension or syrup containing 0.01 to 20% by weight of the active ingredient is preferable. In this case, water-based excipients such as fragrances, syrups and pharmaceutical micelles are used as carriers.

  The chemical substance used in the present invention is not particularly limited, but it is not specifically stated as a substance that is easy to synthesize because it is the simplest in organic chemistry and is considered to be biologically relevant. As a specific example of the antigen substance inducer, 4,4-dimethyl-6-methylene-2-cyclohexen-1-one (a of the general formula 3) which is an infinitely simple and low molecular substance In which R3, R4, R5, and R6 are hydrogen atoms (hereinafter referred to as Yoshixol and Yoshixol), and their effectiveness is demonstrated.

  Murine leukemia cell L-1210 (obtained from Cancer Research Institute) in 2 ml of medium containing fetal calf serum (Dainippon Pharmaceutical) (Minimum EssentialMedium, Gibco; glutamine, Dainippon Pharmaceutical) 30 When cultured in a 5% CO2 incubator at 37 degrees Celsius for 1 × 10 6 cells, 2 mol of Yoshixol 4 microliter dissolved in ethanol was added to induce cell death. As a result, the viability of the cells was determined based on the state of methylene blue uptake. As a result, the number of viable cells in 2 hours after the addition of Yoshixol was 5 × 10 4, and most cells died after 20 hours, and after 30 hours. There were no living cells. It was confirmed again that the cells in the culture medium had been killed. Then, the culture liquid containing the dead cells was centrifuged at 1000 rpm for 5 minutes for 1 minute, and the supernatant was removed by suction. Then, 0.9 cc of physiological saline was added to the precipitated components and stirred, followed by centrifugation at 1000 rpm for 5 minutes, and this operation was repeated twice. Then, 0.9 cc of physiological saline was added to the remaining washed precipitate and stirred, and then filtered through a Millipore filter of cellulose acetate having a diameter of 0.45 micrometers. This filtrate was inoculated intraperitoneally at 0.2 cc per CDF1 male mouse (Charles River). The mouse leukemia cell L-1210 (1 × 10 6 / ml) already cultivated on the 31st day after the inoculation of the broth with 0.3 cc of the control group and a mouse that has not been pre-inoculated with the above-mentioned broth Each of the treated immunized mice was administered intraperitoneally, and the difference in the date of death due to leukemia was observed. As a result, as shown in FIG. 1, all mice in the control group died 8 days after cell transplantation. On the other hand, in the mice treated with the filtrate, death cases appeared from 12 days after cell transplantation, and the longest survival cases were extended to 14 days. This result shows that prolongation of mouse survival in leukemia can be induced by promoting antibody formation in mice using substances remaining after cells are destroyed with yoshixol as an antigen.

  Morphological changes that occur after treatment of mouse leukemia cells with yoshixol were examined with a scanning electron microscope (JSM-6000F, manufactured by JEOL Ltd.). In the untreated group, the cultured cells showed irregular structures such as a round donut shape, a spongy structure, and a protrusion structure with a hole in the center, such as the tip of a pig's nose. (Figure 2a). In contrast, in the treatment group in which Yoshixol 10 microliter was added to the culture solution, the cultured cells had many cells that were destroyed to various extents, and neither cell adhesion nor aggregation was observed. It was almost as close as possible to the morphological image (Fig. 2b). Particulate matter of this fragmented cell composition (10-100 nanometers), mainly proteoglycan, acts as an antigen and easily receives phagocytosis action of macrophages, lymphocytes, etc. It is shown that these particulate substances are incorporated into a typical immune surveillance mechanism.

  In the evaluation of the survival time of the above mice, pathological examination at the level of light microscope at the time when each mouse died was performed. Mouse heart, liver, kidney, lung, spleen, and small intestine pieces were fixed with a buffered 10% formaldehyde solution, embedded in paraffin, sectioned, HE-stained, and observed. In the untreated group, leukemia cells infiltrated in each organ remarkably. In the liver, histological features such as portal vein dilatation and vascular wall destruction were observed. In the lungs, alveoli were destroyed, and neovascular nodules from the blood vessels. Was remarkable. It was also characteristic that ascites was bloody at the time of dissection. On the other hand, in the sensitized treated group, the general histology was similar to that in the untreated group, but the degree of each characteristic finding was mild. Regardless of the findings at the time of death, the qualitative differences were generally similar except that the ascites was not bloody. This result suggests that at least the vaccine treatment of the present invention is related to the biological mechanism (blood vessel wall destruction, etc.) that prevents the expression of bloody ascites caused by transplanted leukemia cells. Is.

  Murine leukemia cell L-1210 (obtained from Cancer Research Institute) in 2 milliliters of medium containing fetal calf serum (Dainippon Pharmaceutical) (Minimum EssentialMedium, Gibco; glutamine, Dainippon Pharmaceutical) 30 After culturing in a 5% CO2 incubator at 37 degrees Celsius for 1 × 10 6 cells, 2 mol of Yoshixol 4 microliter dissolved in ethanol was added to induce cell death. It was confirmed again that the cells in the culture medium had been killed. Then, the culture liquid containing the dead cells was centrifuged at 1000 rpm for 5 minutes for 1 minute, and the supernatant was removed by suction. Then, 0.9 cc of physiological saline was added to the precipitated components and stirred, followed by centrifugation at 1000 rpm for 5 minutes, and this operation was repeated twice. Then, 0.9 cc of physiological saline was added to the remaining washed precipitate and stirred, and then filtered through a Millipore filter of cellulose acetate having a diameter of 0.45 micrometers. 1 cc of this solution was administered intravenously per pupae. One month after the administration, the sputum was anesthetized with Nembutal and then sacrificed for blood removal. The blood was immediately centrifuged to remove blood cell components and secure serum. Whether or not an antibody (immunoglobulin) against mouse leukemia cells was produced in this sputum serum was examined with a sputum serum antibody (Jackson ImmunoResearch Lab, PA, USA) against sheep serum by an agar gel diffusion method. As a result, it was confirmed that a new immunoglobulin band was formed as shown in FIG.

  The control serum shown in this example was prepared as follows. In Japanese white cocoons born from the same parent of the same type and the same type used in this example, 2 mol of Yoshixol dissolved in ethanol was mixed with 5 ml of each culture solution or liquid medium at a rate of 10 microliters per body weight. The solution was passed through a Millipore filter made of cellulose acetate having a diameter of 0.45 micrometers and then slowly administered over about 3 minutes from the ear vein of the sputum. No abnormality was observed for one month immediately after administration. One month after the administration, the sputum was anesthetized with Nembutal and then sacrificed for blood removal. The blood was immediately centrifuged to remove blood cell components and to secure serum, which was used as control sputum serum.

  In addition, the immunoelectrophoresis used in this example was performed according to the following procedure. However, the present invention is not limited by this examination method. First, 1 g of agar agar (Wako Pure Chemical Industries, Ltd.) was heated and dissolved in 100 ml of 0.03M veronal buffer to prepare a 1% agar sol. Veronal buffer (pH 8.6) was prepared from 5,5-diethyl barbituric acid (Wako Pure Chemical), sodium 5,5-diethyl barbiturate (Wako Pure Chemical), and sodium nitride (Wako Pure Chemical). The operating procedure is as follows: First, agar sol was poured onto a glass plate (10 x 10 cm) degreased with ethanol, hardened, and then the graph paper was drawn with the origin position and groove layout of the serum, and the agar plate was placed. Then, a hole for the sample was made and an agar plate was made by cutting the groove for the antibody. Next, 4 ul of a test serum sample added with bromophenol blue (Wako Pure Chemical Industries) was set in the sample hole. Then, the agar plate is set in the electrophoresis tank, and subjected to immunoelectrophoresis according to the Ouchterloy method for about 18 hours at a constant current of 2-3 mA / cm using an electrophoresis apparatus (power supply ATT0-Power Station 1000 VC). And remove the agar from the groove that was previously marked for the antibody. A 58 mg / ml sheep anti-rabbit serum (Jackson ImmunoResearch Lab, PA, USA) was added to the groove and allowed to react overnight at room temperature while preventing drying in a wet box. Thereafter, the sample is immersed in physiological saline for a day, and further immersed in distilled water for a day to remove adhesion of impurities. In order to clarify the observation evaluation, the sample was stained with CBB staining solution (Wako Pure Chemical Industries) for 40 minutes, then washed with distilled water, and after video recording, digital signal processing was performed for image analysis and rendering. The determination was made using the position of the sinking line, the sharpness, the radius of curvature, and symmetry as indices. Generally, when there are many newly produced antibodies (sample sera), the position of the sedimentation line is inclined toward the antibody side in the groove and the sharpness is blurred. When the amount of newly produced antibody is small, the position is close to the axis of the hole containing the sample, and the sharpness on the sample side is poor. Furthermore, in the case of a low molecule, it is inclined toward the antibody in the groove, and the radius of curvature increases. On the contrary, in the case of a polymer, the radius of curvature is close to the sample side. It is known that the sedimentation line is symmetric in the case of uniformity and asymmetric in the case of non-uniformity.

  Mouse melanoma cells (B16 strain, purchased from RIKEN Cell Bank) 2 milliliter culture medium containing fetal bovine serum (Dainippon Pharmaceutical Co., Ltd.) (Minimum Essential Medium, Gibco; Glutamine, Dainippon Pharmaceutical Co., Ltd.) ) For 30 hours at 37 degrees Celsius in a 5% CO2 incubator to give 2 × 10 5 cells, 2 mol of Yoshixol 4 microliter dissolved in ethanol was added to induce cell death. Subsequently, the culture solution containing dead cells was centrifuged at 1000 rpm for 5 minutes for 1 minute, and the supernatant was removed by suction. Then, 0.9 cc of physiological saline was added to the precipitated components and stirred, followed by centrifugation at 1000 rpm for 5 minutes, and this operation was repeated twice. Then, 0.9 cc of physiological saline was added to the remaining washed precipitate and stirred, and then filtered through a Millipore filter of cellulose acetate having a diameter of 0.45 micrometers. This filtrate was inoculated intraperitoneally at 0.2 cc per C57BL 6 week old female mouse (Japan SCL). On the 30th day after the inoculation of the lysate, 0.3 cc of the mouse melanoma cells (2 × 10 5) already cultured were treated with the mice that had not previously been inoculated with the above-mentioned lysate, which was the control group. The immunized mice were inoculated into a foot pad and observed for the degree of local proliferation of melanoma cells B16 and the degree of metastasis to the lung. As a result, as shown in FIG. 4, the mice in the control group had an average weight increase of 120 mg from the knee joint to the distal limb 45 days after the cell transplantation, whereas the mice treated with the rosin solution had the cell transplantation. After 45 days, the average was 11 milligrams. Furthermore, when the metastasis state to the lung was measured pathologically, the average was 122 or more in the control group, while the average was 10 or less in the treatment group. This result shows that proliferation and metastasis of melanoma in mice can be prevented by promoting the antibody formation in mice by using as an antigen a substance remaining after cells are destroyed with yoshixol in advance.

  Morphological changes that occur after treatment of mouse melanoma cells B16 with yoshixol were examined with a scanning type (JEOL Ltd., JSM-6000F) electron microscope in the same manner as in the case of leukemia cells. In the untreated group, the cultured cells were orderly grown like Ishigaki, some cells showed a bifission image, and intracellular organelles were also observed normally. It was filled with extracellular matrix without intercellular connections or blanks (see FIG. 5a). On the other hand, in the treatment group in which Yoshixol 4 microliters was added to the culture solution, the cultured cells showed various irregular forms, and there were many cells in which cell membranes and intracellular organelles were destroyed to various degrees. Intercellular connections were also irregularly separated, and the extracellular matrix was irregularly dispersed from the cells as dots of various sizes (see FIG. 5b). The cultured cells in the treatment group have many cells that have been destroyed to various extents, and there is no adhesion or aggregation between cells, which is almost as close as possible to the morphological image called natural death or apoptosis (Fig. 5c). Particulate matter of this fragmented cell composition (10-100 nanometers), mainly proteoglycan, acts as an antigen and easily receives phagocytosis action of macrophages, lymphocytes, etc. It is morphologically shown that antibodies capable of recognizing melanoma cell B16 in vivo are produced as a result of incorporating these particulate substances into a typical immune surveillance mechanism and molecular recognition.

  Mouse melanoma cell B16 (purchased from Riken Cell Bank) in 2 milliliters of medium containing fetal calf serum (Dainippon Pharmaceutical Co., Ltd.) (Minimum Essential Medium, Gibco; glutamine, Dainippon Pharmaceutical Co., Ltd.) 30 When 2 × 10 5 cells were cultured in a 5% CO 2 incubator at 37 ° C. for 2 hours, 2 mol of Yoshixol 4 microliter dissolved in ethanol was added to induce cell death. It was confirmed again that the cells in the culture medium had been killed. Then, the culture liquid containing the dead cells was centrifuged at 1000 rpm for 5 minutes for 1 minute, and the supernatant was removed by suction. Then, 0.9 cc of physiological saline was added to the precipitated components and stirred, followed by centrifugation at 1000 rpm for 5 minutes, and this operation was repeated twice. Then, 0.9 cc of physiological saline was added to the remaining washed precipitate and stirred, and then filtered through a Millipore filter of cellulose acetate having a diameter of 0.45 micrometers. 1 cc of this solution was administered intravenously per pupae. One month after the administration, the sputum was anesthetized with Nembutal and then sacrificed for blood removal. The blood was immediately centrifuged to remove blood cell components and secure serum. Whether or not an antibody (immunoglobulin) against mouse melanoma cells was produced in this sputum serum was examined with a sputum serum antibody (Jackson ImmunoResearchLab, PA, USA) against sheep serum by an agar gel diffusion method. As a result, it was confirmed that a new immunoglobulin band was formed as shown in FIG.

  Methicillin-resistant Staphylococcus aureus (MRSA) was collected and cultured from human sepsis patients and examined using a strain (proprietary strain SCK84) that causes strong circulatory shock in mammals (mouse, rat, rabbit, dog). A brain heart infusion agar medium (manufactured by Nissui Pharmaceutical) was used as the medium. The number of bacteria was zero after culturing at 37 ° C. for 24 hours at a concentration of 7.6 × 10 8 using 2 mol of yoshixol dissolved in ethanol (10 microliters per milliliter of culture). . Although 0.1 ml of the liquid medium in which the number of bacteria became zero was uniformly spread on a petri dish-shaped heart infusion agar medium (manufactured by Eiken Chemical Co., Ltd.) and cultured at 37 ° C. for 48 hours None of the colonies developed. The above-mentioned culture solution containing 5 cc of the dead bacteria component was centrifuged at 1000 rpm for 1 minute for 5 minutes, and 2.5 cc of the supernatant component was removed by suction. Then, 2.5 cc of physiological saline was added to the remaining 2.5 cc and stirred, and then centrifuged at 1000 rpm for 5 minutes. This operation was repeated twice, and the washed final solution was passed through a cellulose acetate Millipore filter having a 0.45 micrometer diameter. As a result, a test solution of about 3 cc was obtained. This test solution was administered intravenously at 1.5 cc per rabbit. One month after the administration, the sputum was anesthetized with Nembutal and then sacrificed for blood removal. The blood was immediately centrifuged to remove blood cell components and secure serum. Whether or not an antibody against MRSA (immunoglobulin) was produced in this sputum serum was examined with a sputum serum antibody (Jackson ImmunoResearch Lab, PA, USA) against sheep serum by an agar gel diffusion method. As a result, it was confirmed that a new immunoglobulin band was formed as shown in FIG. This result shows that an effective antibody can be produced against MRSA, which is a gram-positive bacterium that has acquired resistance to other antibiotics.

  In order to examine the effect on fungi, examination was performed using Candida Albicans. The medium used was Sabouraud medium, 5 milliliters, and the number of ringworm bacteria was (5.2 × 10 6 CFU / milliliter). Using a concentration of 2 moles of yoshixol dissolved in ethanol (10 microliters per milliliter of culture medium), the CFU became zero after 1 hour in the treatment group at 37 ° C under the condition of 10 8 bacteria and 3 hours. It was zero later. Although 0.1 ml of the liquid medium in which the number of bacteria became zero was uniformly spread on a petri dish-shaped heart infusion agar medium (manufactured by Eiken Chemical Co., Ltd.) and cultured at 37 ° C. for 48 hours None of the colonies developed. The above-mentioned culture solution containing 5 cc of the dead bacteria component was centrifuged at 1000 rpm for 1 minute for 5 minutes, and 2.5 cc of the supernatant component was removed by suction. Then, 2.5 cc of physiological saline was added to the remaining 2.5 cc and stirred, and then centrifuged at 1000 rpm for 5 minutes. This operation was repeated twice, and the washed final solution was passed through a cellulose acetate Millipore filter having a 0.45 micrometer diameter. As a result, a test solution of about 3 cc was obtained. This test solution was administered intravenously at 1.5 cc per rabbit. One month after the administration, the sputum was anesthetized with Nembutal and then sacrificed for blood removal. The blood was immediately centrifuged to remove blood cell components and secure serum. Whether or not an antibody (immunoglobulin) against white bacteria was produced in this sputum serum was examined with a sputum serum antibody (Jackson ImmunoResearch Lab, PA, USA) against sheep serum by an agar gel diffusion method. As a result, it was confirmed that a new immunoglobulin band was formed as shown in FIG. This result shows that an effective antibody against white bacteria can also be produced by a composite material after white bacteria are killed by Yoshikisol.

  It examined using Pseudomonas aeruginosa. The medium used was a heart infusion agar medium (Nissui Pharmaceutical Co., Ltd.). Using a concentration of 2 mol of yoshixol dissolved in ethanol (10 microliters per milliliter of culture medium), the CFU was reduced to zero after 1 hour in the treatment group at 37 ° C. at 1 × 10 8 bacteria. It was zero after 3 hours. Although 0.1 ml of the liquid medium in which the number of bacteria became zero was uniformly spread on a petri dish-shaped heart infusion agar medium (manufactured by Eiken Chemical Co., Ltd.) and cultured at 37 ° C. for 48 hours None of the colonies developed. The above-mentioned culture solution containing 5 cc of the dead bacteria component was centrifuged at 1000 rpm for 1 minute for 5 minutes, and 2.5 cc of the supernatant component was removed by suction. Then, 2.5 cc of physiological saline was added to the remaining 2.5 cc and stirred, and then centrifuged at 1000 rpm for 5 minutes. This operation was repeated twice, and the washed final solution was passed through a cellulose acetate Millipore filter having a 0.45 micrometer diameter. As a result, a test solution of about 3 cc was obtained. This test solution was administered intravenously at 1.5 cc per rabbit. One month after the administration, the sputum was anesthetized with Nembutal and then sacrificed for blood removal. The blood was immediately centrifuged to remove blood cell components and secure serum. Whether or not an antibody (immunoglobulin) against Pseudomonas aeruginosa was produced in this sputum serum was examined with a sputum serum antibody (Jackson ImmunoResearch Lab, PA, USA) against sheep serum by an agar gel diffusion method. As a result, it was confirmed that a new immunoglobulin band was formed as shown in FIG. This result shows that an effective antibody against Pseudomonas aeruginosa can also be produced by a composite substance after killing Pseudomonas aeruginosa with Yoshixol.

  A mycobacterial rapid acid bacterium, which is an acid-fast bacterium, was used for examination. The medium used was a heart infusion agar medium (Nissui Pharmaceutical Co., Ltd.). Using a concentration of 2 mol of yoshixol dissolved in ethanol (10 microliters per milliliter of culture solution), the CFU was reduced to zero after 1 hour in the group treated with 37 × 10 5 bacteria at 37 ° C. It was zero even after 3 hours. Although 0.1 ml of the liquid medium in which the number of bacteria became zero was uniformly sprayed on a petri dish-shaped heart infusion agar medium (manufactured by Eiken Chemical Co., Ltd.) and cultured at 37 ° C. for 72 hours. None of the colonies developed. The above-mentioned culture solution containing 5 cc of the dead bacteria component was centrifuged at 1000 rpm for 1 minute for 5 minutes, and 2.5 cc of the supernatant component was removed by suction. Then, 2.5 cc of physiological saline was added to the remaining 2.5 cc and stirred, and then centrifuged at 1000 rpm for 5 minutes. This operation was repeated twice, and the washed final solution was passed through a cellulose acetate Millipore filter having a 0.45 micrometer diameter. As a result, a test solution of about 3 cc was obtained. This test solution was administered intravenously at 1.5 cc per rabbit. One month after the administration, the sputum was anesthetized with Nembutal and then sacrificed for blood removal. The blood was immediately centrifuged to remove blood cell components and secure serum. Whether or not antibodies (immunoglobulin) against atypical mycobacteria were produced in this sputum serum was examined with a sputum serum antibody (Jackson ImmunoResearch Lab, PA, USA) against sheep serum by the agar gel diffusion method. As a result, it was confirmed that a new immunoglobulin band was formed as shown in FIG. This result shows that an effective antibody against atypical mycobacteria can also be produced by a complex substance after atypical mycobacteria have been killed by yoshixol.

  The effect of Yoshixol on such bacteria showed interesting findings even in its killing form. In MRSA, each microbial colony is separated individually, and the surface structure of each bacterium is a scanning electron microscope image showing the appearance of a small granule of about 10-50 nanometers exploding from inside the cell (FIG. 11a). To those that show concentric discrete states like fireworks in the end. Such a finding was also observed in a transmission electron microscope image. In observation of E. coli with a scanning electron microscope, the surface was composed of a large number of particles having a size of about 10-50 nanometers, and the smoothness of the surface was not recognized, and swelling swelling appeared (FIG. 11b). Of course, in this case as well, the adhesion aggregate of the cells disappeared, and the final structure was finely divided. The same changes were observed in acid-fast bacteria (FIG. 11c) and fresh bacteria (FIG. 11d). Moreover, it was observed that Pseudomonas aeruginosa was bulged like a balloon, and eventually ruptured to make the bacterial structure finer (FIG. 11e). This result shows that Yoshikisol has antibacterial and bactericidal effects, but its killing mechanism is different from that of conventional antibacterial fungicides such as degeneration, necrosis, and coagulation, which prevents bacterial conjugation. However, according to the molecular composition involved in the morphogenesis of each bacterial species, it is characterized by causing finer formation of bacterial cell components while showing the form of eruption structure, explosion structure, and ballooning structure. . Such morphological findings indicate that each cell is converted to a species-specific macromolecular substance and becomes a species-specific antigen.

  In addition, when the final destruction structure of each bacterium was observed with an electron microscope, it showed a morphological change similar to that of peptidoglycan. In the case of Staphylococcus aureus (FIG. 12a) and Pseudomonas aeruginosa (FIG. 12b), transmission electron micrographs that are considered to be close to the respective final forms caused by treatment with yoshixol are shown. This finding indicates that these peptide glucans act as effective species-specific antigens by separating the peptide glucans constituting each bacterial membrane by treatment with yoshixol.

  Chondroitin sulfate (Taiyo Suisan) 5 mg, actin (Sigma) 1 mg, human fibrinogen (Diagnostica Stago, France) 0.5 mg, insulin (Novo, Copenhagen) 1.6 mg 10 microliters of Yoshixol was added to a turbid liquid mixed with 1 milliliter of saline, and the filtrate through a millipore filter of cellulose acetate having a diameter of 0.45 micrometers was administered into the vein of the sputum. One month after the administration, the sputum was anesthetized with Nembutal and then sacrificed for blood removal. The blood was immediately centrifuged to remove blood cell components and secure serum. Whether or not an antibody (immunoglobulin) against a complex component of chondroitin sulfate, actin, human fibrinogen, and insulin has been produced in this sputum serum, a serum antibody of the sputum against sheep serum (Jackson ImmunoResearch Lab, PA, USA) ). As a result, it was confirmed that a new immunoglobulin band was formed as shown in FIG. This result shows that if chondroitin or protein complex is treated with yoshixol in advance, an effective antibody can be produced against chondroitin or protein that does not become an antigen. This result also shows that antigenic substance inducers such as yoshixol have an action as a hapten.

  Although the embodiment of the present invention has been described above, the present invention is not limited to the embodiment described above, and it is needless to say that modifications can be appropriately made within the scope of the gist of the present invention.

  The effect and action of the present invention have been described using yoshixol, which is one of the molecular expression function inhibitors internationally disclosed in International Publication No. WO96 / 07403, which is a specific example. The present invention is not limited by the embodiment shown in FIG.

<Summary of action, unique action mechanism and its significance>
The present invention outlines a wide range of specific actions and effects such as recognition, function expression, and information transmission at the molecular level, and antigen and antibody reactions. The illustration is far from the description scope of the present application, so the following two are shown as references for scientifically known matters. <Reference 2> Bern and Levy, Physiology, Sanders Publishing Inc. <Reference 3> Roy, Raff, Roberts and Watson, The Molecular Biology of the Cell, Grammar Publishing Inc. :

  The immune system is roughly divided into the following two. In the first humoral antibody response, the antibody produced circulates in the blood and specifically binds to the foreign antigen that caused the induction. When an antibody binds to an antigen, it becomes easier for phagocytes to prey on the antigen, and a protein system called complement in the blood is activated thereby to help destroy the antigen. The second cell-mediated immune response is a reaction that produces special cells that react with foreign antigens on the surface of the host cell. When the antigen is an infectious virus or the like, the cell deals with the antigen by killing the host cell or inducing production of another cell such as a phagocytic cell that destroys the antigen. In addition, T cells (T cells) are involved in cellular immunity, and B cells (B cells) also basically produce antibodies. B cells create antibody molecules with different antigen binding sites for each clone. First, the cells bind the antibody molecules to the cell membrane and act as cell surface receptors for the antigen. When an antigen binds thereto, the B cell is activated and proliferated, and a large amount of a soluble antibody having the same antigen-binding site is synthesized and released into the blood.

  Due to the fact that the three-dimensional structure of a protein molecule such as an antibody is determined solely by the amino acid sequence, a denatured (unfolded) antibody molecule regenerates into a form that can bind to the antigen without the antigen. When antigen binds to this cell surface receptor, the cells are activated, proliferate and mature. Thus, the foreign antigen is preliminarily provided with a receptor having antigen specificity complementary thereto, and can selectively stimulate cells in a responsive state. This is the reason why antigen specificity appears in the immune response and is the root of the immune surveillance system. It is also believed that all proteins and most macromolecules including polysaccharides can be antigens.

  The part that binds to the antigen-binding site of the antibody molecule or lymphocyte receptor on the surface of the antigen is called an antigen determinant. Molecules that specifically bind to antibodies and lymphocyte receptors but cannot elicit an immune response are called haptens. A hapten becomes an antigen when bound to an appropriate polymer carrier, and a hapten often used in immunization experiments is dinitrophenol (DNP), which is usually bound to a protein as an antigen. It was shown by the present invention that Yoshixol shown in the examples of the present invention is also a substance that becomes a hapten.

  There are two types of antibodies, membrane-bound, that is, those that act as cell surface receptors specific to antigens, and those that exist as water-soluble secreted forms. IgM and IgD are antibodies on the surface of resting B cells. It is said to occupy a major part of.

  The binding between the antigen and the antibody is reversible like the binding between the substrate and the enzyme. This bond is the sum of many relatively weak non-covalent bonds, including hydrophobic bonds, hydrogen bonds, van der Waals forces, and ionic interactions. These weak forces are said to work effectively when the antigen molecule is sufficiently close to the antibody so that its atomic arrangement fits into a complementary cavity on the antibody surface (understood as a key-keyhole relationship). However, it has been shown that the present invention is also valid from the quantum thermodynamic logic of molecules. In addition, antiserum raised against an antigen is a mixture of various antibodies that react with various antigenic determinants in the antigen, so it is common to create a crosslink with the antigen. If the valency is appropriate and the combination is capable of forming large aggregates, the size of the antigen-antibody complex is determined by the relative molar concentration of antigen and antibody. Even from the chemical characteristics of Yoshixol used in the examples of the present invention, the vaccine and antibody production methods of the present invention are appropriate.

  The fact that the idiotype of the antibody molecule forms the basis of the immune network is the result of immunochemistry to date. In addition to protecting the body from infection, antibodies themselves play an important role in regulating the immune response. That is, when an antibody is secreted to a certain antigen and binds to the antigen, the receptor on the B cell cannot bind to the antigen and thus is not stimulated. As a result, the immune response is terminated. This is simple feedback suppression. In addition, antibodies form part of the immune network and play an even more complex role in immune regulation. It is also an acquired defense mechanism that is necessary for living organisms to survive, and based on this network system, species specificity and diversity are preserved. It is also the significance of the present invention to utilize this evolutionary diversity.

  In addition, the antibody itself has antigenicity. Therefore, the C.I. Production of antibodies that recognize part of both V regions as antigenic determinants can occur. L. This is called an idiotype when the antigen binding site becomes such an antigenic determinant in the V region of the H chain. Since different antigen binding sites can each be several idiotypes, the millions of antigen binding sites an animal has can be millions of idiotypes. Since there are very few individual idiotypes in the body, the animals are not immune-tolerant to their antibody idiotypes, and can respond easily to both T and B cells.

  For example, an animal immunized with antigen A is thought to produce a large amount of anti-A antibody first and then produce antibodies against the anti-A antibody idiotype. This is followed by sequential chain reaction, followed by antibodies against anti-idiotype antibodies. The existence of this type of immune network response has been demonstrated for cases where the majority of antibodies produced in the initial response when given an antigen exhibit the same idiotype. In such a simple immune response, the production of an antibody that specifically recognizes the idiotype and the activation of T cells occur, and as a result, the activation of lymphocytes having the idiotype as a receptor is inhibited. It is promoted.

  It means that an individual makes antibodies against any of their own idiotypes. Probably there will be at least as many idiotypes as there are types of antigen binding sites, so conversely, a standard antigen binding site must recognize at least one idiotype in its own immune system. Become. Thus, the antigen binding site of the immune system potentially forms a complex network of all idiotype-anti-idiotype interactions. Also, since T · B cells appear to share at least some idiotype, both lymphocytes are likely involved in this type of network. Thus, it has recently been proposed that it is appropriate to think of the immune response as an echoic perturbation of the immune system network (a decaying vibration-like one) rather than the individual response of lymphocytes in response to an antigen. ing. This is consistent with the basic idea of the present invention.

  The central component of the proteolytic chain reaction in such an immune response is the complement component C3, which is a reaction in which activation due to the degradation is the center of the complement activation reaction series. However, polysaccharides on the cell surface of certain microorganisms protect these membrane-bound C3b-like molecules and protect them from denaturation and destruction. It is also known that the chain reaction of the complement system produces small protein fragments with biological activity by the degradation of various protein components. This complement chain reaction is thought to be strictly designed and regulated to attack only the immediate membrane. Such deactivation of the activating component occurs in at least two ways. First, when there is a special inhibitory protein in the blood and it is activated by proteolysis, it binds to or cleaves a specific component and acts to terminate the chain reaction. For example, the inhibitory protein binds to the activation component of the C1 complex and prevents further action promotion. There are other inhibitory proteins in the blood that cleave and inactivate C3b. Without these inhibitors, it is quite possible that serum C3 should be completely consumed by the action of the positive feedback created by the second pathway. Second, the active component in the chain reaction has an unstable component, which plays an important role in regulation. Such an unstable component is immediately deactivated unless it is bonded to an appropriate component in a chain reaction or a nearby membrane, and is particularly remarkable in C4 and C3b. Both components, when generated upon cleavage, undergo a series of rapid conformational changes and become short-lived active forms. This active form has a hydrophobic region and a highly reactive glutamate side chain, which is created by mechanical cleavage of a special thioester bond in the protein. As a result, this glutamic acid forms a covalent bond with a protein or polysaccharide in the immediate membrane. Since the half-life of this active form is very short (less than 0.1 milliseconds), C4 and C3b can only bind to the membrane in the immediate vicinity where the complement components necessary for activation are bound. Therefore, it is thought that complement attack is limited to the membrane on the surface of the microorganism and does not extend to nearby normal host cells. In addition, cleavage of the thioester bond between the protein side chains results in a very reactive carbonyl group that causes a covalent bond with another polymer, forming an ester bond or an amide bond. However, since the reaction ability of the protein disappears with a half-life of about 60 microseconds, the reaction partner is limited to a membrane in the immediate vicinity where the peptide bond is cleaved and activated. Such biochemical knowledge can understand the effects shown in the examples of the present invention without contradiction even from the chemical characteristics of Yoshixol used in the examples of the present invention.

  Antigen idiotype antibodies that undergo complement proteolytic chain reactions not only bind to anti-X antibodies in solution, but also bind to B cells that have the same antibody on their surface as receptors for antigen X. When an anti-idiotype antibody binds to a receptor on the B cell surface, the ability of B cells to recognize and respond to antigen X is inhibited. It has also been pointed out that an idiotype common to B cell and T cell receptors may be encoded by a gene fragment that defines the V region of an immunoglobulin heavy chain. However, the T cell receptor is a completely new class of immunoglobulin, possibly produced by a gene group encoding a constant region different from that of an antibody molecule and a gene fragment encoding the VH region of a normal antibody. . It has also been pointed out that B cells and T cells that react with the same antigen express an idiotype (antigenic determinant in the antigen binding site of an antibody) similar to cell surface receptors. The creation of an idiotype antibody using yoshixol or the like used in the examples of the present invention can easily create the required antibody based on evolutionary diversity without genetic engineering. The significance of showing sex is great.

  When cytotoxic T cells encounter vertebrate cells infected with heterologous cells or viruses, they are activated for several days to become effector cells that specifically bind to the cells that triggered the activation. And kill this. Helper T cells are essential for the production of antibodies in response to antigens, but there are some antigens that can activate B cells without the help of T cells. Such T cell-independent antigens are usually large polymers with repeated structures of identical antigenic determinants. When regulatory T lymphocytes recognize target cells, there is also a method based on an idiotype-anti-idiotype interaction. In an antibody response where most of the produced antibodies are of the same idiotype, two types of helper T cells are found. The first is to recognize foreign antigens on the surface of B cells, and the second is the idiotype of membrane-bound antibody molecules that act as receptors on the surface of B cells. In any case, the production of an idiotype antibody using yoshixol or the like used in the examples of the present invention has a great significance that has shown a new possibility of contributing to scientific investigation of details of further immune networks.

  The following points should be noted, although there are some repeated points. That is, an idiotype vaccine is also being developed as a notable type of vaccine. The idea is that an antibody molecule has a molecular structure that is unique to that antibody that meshes with an antigenic determinant, and that can be immunized to an animal to make an antibody against that part. is there. This antibody is called an anti-idiotype antibody. That is, the anti-idiotype antibody and the antigen-binding portion (idiotype) of the original antibody should mesh well. This indicates that the antigenic determinant and the anti-idiotype antibody have a common structure. That is, an anti-idiotype antibody can be used instead of an antigen. This description does not exclude the appropriate combination of the conventionally used methods such as inactivation and attenuation. Since this anti-idiotype antibody is an antibody molecule, it is safe to handle, and the species specificity of each organism can be determined and induced specifically in a complex manner. In other words, in the DNA recombination method, the peptide part may be the same, but the sugar chain part may be different. There are features such as being able to.

  One of the immunological monitoring mechanisms is an antigen that causes an immune response against tumor cells, which is called a tumor-associated antigen. These tumor-related antigens are present at one stage of ontogeny, and then disappeared antigens (α-fetoprotein, etc.) that reappeared by tumorigenesis, and antigens of tissues other than the tumor-producing tissue Appearances, allogeneic antigens that do not exist in themselves, expressed by tumorigenesis, antigens derived from tumor viruses, antigens expressed as a result of oncogene activation, sugars of cell membrane substances due to metabolic abnormalities associated with tumorigenesis In the case of B cell-type tumors, there are idiotypes of surface immunoglobulin, etc., which have changed chains and become new antigens. Among these, tumor-specific antigens that are not present in any normal cells but are expressed only in tumor cells are called tumor-specific antigens. However, only a few have been confirmed so far, and intensive studies have been conducted at the gene level. ing. The present invention utilizes the anticancer activity disclosed in the molecular expression function inhibitor published internationally under International Publication No. WO96 / 07403 as the specificity of the tumor cell, and the tumor cell functions and Depending on the form, it is utilized that it is destroyed as much as possible to a fine structure and expresses cell death similar to apoptosis. Utilizing a complex substance that is infinitely finely divided into fine particles as an antigen can induce antibodies specific to the original tumor cells in a complex manner. Further, a specific antibody with higher accuracy can be prepared using this idio antibody as an antigen.

  Attempts have also been made to treat tumors using anti-tumor immunity. A substance that is thought to enhance a biological response to a tumor is called a BRM (biological response modifier). Bacteria-derived substances, basidiomycete-derived substances, antibiotics, cytokines (interleukin 2, interferon, TNF, etc.) are used for these, and various studies have been made. In addition, the antigenic substance inducer described in the present invention is used for a living tissue obtained by a method such as excision, excision, excision, biopsy, etc. by open surgery or endoscope, using a tissue culture method or the like. It can also be used for an idioantibody produced by this method or an antibody prepared using this idiobody as an antigen. In other words, it is possible to investigate various problems such as tissue specificity and cancer specificity of the patient himself and to bring out an antitumor effect that addresses various variations of individual individuals and developmental lesions. For this possibility, use syngeneic animals as laboratory animals, kill tumor cells that have developed in one animal in an appropriate manner, and inject it into another healthy animal. If a living tumor is planted in an untreated animal, the tumor will engraft and grow and cause the animal to die. However, it has been observed that in pretreated animals, tumors do not survive and are rejected. This is very similar to avoiding infection by vaccination, but no specific and reproducible way to properly kill the cells has been proposed. . The basic logic in the present invention is one that is inextricably linked to the molecular expression function inhibitor internationally disclosed in International Publication No. WO96 / 07403, which has been shown to stop or prevent functions that are appropriate in terms of molecular biology. Yes, the biomedical logic is disclosed together with specific examples (anticancer, anticancer action, etc.). The present invention can provide a vaccine having a high degree of selectivity and specificity, an idio antibody, and an antibody using an idio antibody as an antigen, and can prevent infection by systematically manipulating a specific activated immune response. As well as being treated, it can be expected from the past. Vaccine precursor and vaccine produced using the antigen substance inducer of the present invention, antibody, neutralizing antibody or antitoxin, idioantibody produced using the antigen substance inducer, vaccine produced using the idio antibody Antibodies, neutralizing antibodies, antitoxins and the like are useful and long-awaited.

  In addition, vaccine precursors and vaccines produced using the antigen substance-inducing agent of the present invention, antibodies, neutralizing antibodies and antitoxins, idioantibodies, vaccines produced using the idioantibodies produced thereby, antibodies, neutralization Antibodies, antitoxins, and the like can selectively or specifically control molecular recognition of each receptor.

  The basic significance of the present invention is that various forms expressed by a multidimensional structure created by a macromolecular substance constituting a living organism or a non-living organism are used in conventional organic solvents, heat, ultraviolet rays, ultrasonic waves, etc. Instead of obtaining antigenic material by destructive extraction, it inhibits biological functions expressed by the multidimensional structure possessed by macromolecular substances and changes their functions in a quantum thermodynamic manner. This is the first point with a specific example that it is possible to obtain an antigenic substance in a state close to that and to produce antibodies that retain substance recognition for a variety of substances in vivo. Moreover, the significance of showing a specific method as a means for solving the unknown points of the biological signal transmission system and information processing system, such as the transmission, reception and decoding of biological immunity monitoring signals that are complex and diverse, is medically significant. Of course, it can be said that industrial significance is also great.

  In addition, for organisms, suppression and inhibition of functions expressed by multi-dimensional structures with species specificity of cell membranes, which are evolutionarily determined by each species and constructed for coexistence with the outside world The significance of showing in the present invention that this can be achieved is great, and the significance of scientific history showing that the mechanism can be understood by molecular orbital theory is great. In addition, its practical significance is as shown in this specification. Furthermore, the social significance of the present invention is not only the effect, but also the treatment and prevention of diseases of unknown cause, and the effective utilization of substances with complex and diverse structures is promoted efficiently. It can be done. For example, the effectiveness against viruses, which are pathogenic pathogenic microorganisms composed of polymer structures, and especially HIV infection, which is currently a global problem, is well-known in scientific knowledge and books on molecular biology. It can be sufficiently predicted from the embodiment of the invention. In addition, it is possible not only to predict the interaction of medicines, the occurrence of side effects with concomitant drugs, the early prediction of the emergence of resistant bacteria in consideration of the ecosystem and the preventive measures in advance, but also the origin of science history Since the present invention incorporates the basis of the regression logic, the significance of the present invention was described.

  The basic principle of the present invention will be summarized. However, it is needless to say that the present invention is not limited by the description summary. That is, the above-mentioned virus, rickettcher, and protozoa are obtained by utilizing the action of destructing and subdividing the components of cell structure into non-functional macromolecules by destructing and subdividing the biological structure of yoshixol shown in the examples of the present invention. It is intended to kill bacteria, cancer cells, etc., and to use the subdivided structural substances as antigens to acquire the ability of antibodies to recognize antibodies, and to produce and use antitoxins and vaccines. In addition, it is intended to create neutralizing antibodies and antibodies using the action, quantum, and molecular mechanism that can change the stereospecificity of molecules of molecular expression function inhibitors thermodynamically It is. This is also inferred from the effect of Yoshixol, which is one of the following molecular expression function inhibitors. The effects are as follows: 1) Cells (whether prokaryotic or eukaryotic) can be broken into fine granules of 10-400 nanometers. 2) The morphology of fine broken granules depends on the cell type. 3) Peptidoglycan and proteoglycan are similar to the structure of peptidoglycan and proteoglycan from the morphological image, and 4) Peptidoglycan and proteoglycan are important for maintaining the shape of cell membrane structure. 5) Peptidoglycan and proteoglycan play important roles in cytokines and surface antibodies, as well as receptor function expression, structure formation, and signal transduction (high affinity receptors, etc.). 6) Peptidoglycan and proteoglycan are extracellular substrates such as chondroitin, fibrin and collagen. 7) It is possible to induce apoptosis with Yoshixol, and 8) When the action period on the cell cycle is examined with a flow cytometer after treatment with Yoshixol, the G0 / G1-early S stage of the cell cycle is examined. 9) It affects the synthesis period of RNA-Protein and the active period of phosphorylation and methylation of G-protein. 9) As the action of yoshixol, electron density and electron orbital (quantum theory) Changes the multi-dimensional structure of complex proteins such as enzymes (eg, lipase, HIV protease, funeseal transferase, etc.) and G-proteins known as signal mediators. It is to suppress and regulate the function expression.

  From the above, Yoshixol refines the structure and stops functioning in a form that preserves the morphological components and functions that bring about the diversity of cells depending on DNA. Therefore, a substance structure depending on the specificity of each cell (heat, chemical treatment) can be obtained. An animal that has been administered with such a finely divided composite polymer substance as an antigen self-forms an antibody against the administered composite polymer substance, and the produced antibody is a cell that is the source of the composite polymer substance. Is properly and accurately recognized, and the cells different from the invading self are treated as foreign substances. That is, selective activation of self-defense by antigen-antibody reaction and construction of a new immune surveillance system. In order to understand and use cell growth, division, mass transport, and cell-to-cell signal transduction, the state of dynamic activity (chemical Reaction, physical reaction, interaction thereof, etc.), that is, vaccine precursors, vaccines, antibodies, neutralizing antibodies and antitoxin or idioantibodies and their anti-antibodies and their anti-antibodies disclosed in the present invention, which are complex substances in the state of function expression. It shows that vaccines, antibodies, neutralizing antibodies, antitoxins and the like induced by idioantibodies can be provided.

  That is, treatment with yoshixol can acquire the molecular recognition action that brings out this superselectivity or specificity. These antibodies produced based on the present invention bring about selectivity in diversity based on the self-recognition of organisms. In addition, by isolating specific molecules from complex polymer materials and using appropriate vectors, it is easy to purify and concentrate using mRNA-based genetic engineering and cell fusion techniques. Shows that it is possible. Further, Yoshixol used in the present invention has a low molecular weight and retains the function as a hapten, and also includes prions, viruses, rickettchers, bacteria, bacterial toxins, cancer cells, pathological tissue organs of various diseases (especially intractable diseases), etc. In addition to the direct effects of these diseases, it is inevitable that the in vivo immune surveillance system that appears concomitantly when the direct effects are obtained may be activated to increase the synergistic therapeutic effect. That is, activation of the autoimmune system (preventive as well as small (non-lethal doses) pathogenic bacteria, cancer, etc., when administered in vivo, these dead cells and other building elements (granules) Naturally, there is a possibility of blocking the vicious circulatory system in the living body by positive feedback, such as stimulation, production of antibodies, and subsequent proliferation and invasion.

  Furthermore, the toxins produced by organisms, etc. are processed in a test tube, the treatment solution is recognized in the organism, and neutralizing antibodies specific for toxins can be created, and test antibodies are systematically designed and manufactured. Needless to say. In addition, it is possible to create antibodies such as artificial composite polymer substances in vivo, isolate and isolate the generated antibodies, and selectively recognize artificial composite polymer substances. It is obvious that it can be applied to applications such as production of antibodies or molecular recognition agents (for example, antibody catalysts) that are industrially required. It is also possible to control the production of antibody molecules against a substance in a colloidal state (a state where one kind of substance is suspended and not precipitated in another substance).

  In addition, from the sedimentation line by immunoelectrophoresis as shown in the embodiment of the present invention, a protein sequence analysis method using an existing western blotting method or a protein sequencer, or a measuring instrument such as a liquid chromatogram or a mass spectrometer can be used. It goes without saying that the composition and structural analysis of the target antibody substance can be made more by using them.

FIG. 1 shows an example of a vaccine precursor, vaccine, antibody, neutralizing antibody and antitoxin produced using the antigenic substance inducer according to the present invention, an idioantibody and an anti-idioantibody induced by this idioantibody. It is the graph which evaluated the survival rate of leukemia L1210. FIG. 2a is an electron micrograph of mouse leukemia L1210 before using the antigen substance inducer according to the present invention. FIG. 2b is an electron micrograph showing the killed form of mouse leukemia L1210 after using an antigen substance inducer. It can be seen that a fine granular structure containing membrane components such as proteoglycan has appeared. FIG. 3 shows an example of a vaccine precursor, vaccine, antibody, neutralizing antibody and antitoxin produced using the antigen substance-inducing agent according to the present invention, an idio antibody and an anti-idio antibody induced by this idio antibody. It is a figure of the immunoelectrophoresis which shows that the novel antibody production with respect to leukemia L1210 has occurred in the serum of sputum. FIG. 4a shows an example of a vaccine precursor, vaccine, antibody, neutralizing antibody and antitoxin produced using the antigen substance-inducing agent of the present invention, an idio antibody, and an anti-idio antibody induced by this idio antibody. It is the graph which evaluated the transplant limb weight change of melanoma B16. FIG. 4b is a graph evaluating the number of lung metastases of mouse melanoma B16 of the same example as FIG. 4a. FIG. 5 shows a morphological change of mouse melanoma B16 cells observed using the antigen substance inducer according to the present invention, and FIG. FIG. 5b is a phase contrast microscope image after the treatment. FIG. 5c shows a scanning electron microscope image. FIG. 6 shows an example of a vaccine precursor, vaccine, antibody, neutralizing antibody and antitoxin produced using the antigenic substance inducer according to the present invention, an idioantibody and an anti-idioantibody antibody induced by this idioantibody. It is an immunoelectrophoresis figure which shows that the novel antibody production with respect to melanoma B16 has occurred in the serum of sputum. FIG. 7 shows vaccine precursors, vaccines, antibodies, neutralizing antibodies and antitoxins produced using the antigenic substance-inducing agent according to the present invention, idioantibodies, and mesitylin as an example of anti-idioantibodies induced by these idioantibodies. It is an immunoelectrophoresis figure which shows that the novel antibody production with respect to resistant Staphylococcus aureus occurs in the serum of sputum. FIG. 8 shows a white background of an example of a vaccine precursor, vaccine, antibody, neutralizing antibody and antitoxin produced using the antigen substance inducer according to the present invention, an idio antibody and an anti-idio antibody induced by this idio antibody. It is a figure of the immunoelectrophoresis which shows that the novel antibody production with respect to a fresh microbe has occurred in the serum of a sputum. FIG. 9 shows an example of a vaccine precursor, vaccine, antibody, neutralizing antibody and antitoxin produced using the antigen substance inducer according to the present invention, an idioantibody, and an anti-idioantibody induced by this idioantibody. It is a figure of the immunoelectrophoresis which shows that the novel antibody production with Pseudomonas aeruginosa has arisen in the serum of sputum. FIG. 10 shows vaccine precursors, vaccines, antibodies, neutralizing antibodies and antitoxins produced using the antigen substance inducer according to the present invention, an idioantibody and an anti-idioantibody induced by this idioantibody. It is a figure of the immunoelectrophoresis which shows that the novel antibody production with respect to acid-bacteria occurs in the serum of sputum. FIG. 11a is an electron micrograph showing the killed form of methicillin-resistant Staphylococcus aureus after using the antigen substance inducer according to the present invention. FIG. 11b is an electron micrograph showing the killed form of E. coli. FIG. 11c is an electron micrograph showing the killed form of white bacteria. FIG. 11d is an electron micrograph showing the killed form of Pseudomonas aeruginosa. FIG. 11e is an electron micrograph showing the killed form of mycobacteria. It can be seen that a fine granular structure containing the membrane components of each bacterium appears. FIG. 12a is a transmission electron micrograph showing the killed form of methicillin-resistant Staphylococcus aureus after using the antigen substance inducer according to the present invention. FIG. 12b is a transmission electron micrograph showing the killed form of E. coli. It can be seen that the structure is composed of membrane components such as proteoglycan. FIG. 13 shows vaccine precursors, vaccines, antibodies, neutralizing antibodies and antitoxins produced using the antigenic substance inducer according to the present invention, idioantibodies and chondroitin of one embodiment of anti-idioantibodies induced by these iodioantibodies. It is an immunoelectrophoresis figure which shows that the novel antibody production with respect to the composite solution of a sulfuric acid, fibrinogen, actin, and insulin has arisen in the serum of sputum. .

Claims (10)

A in general formula 1

(Wherein, (i) R1, R2, R3, R4, R5 and R6 are each independently a hydrogen atom; a halogen atom; a C1-C6 alkyl group; an amidino group; a C3-C8 cycloalkyl group; a C1-C6 alkoxy C1. -C6 alkyl group; aryl group; allyl group; aralkyl group in which one or two or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of benzene, naphthalene and anthracene ring; C1-C6 alkylene group; benzoyl A group; a cinnamyl group; a cinnamoyl group; or a furoyl group, and (ii) A is a hydrogen atom or

Wherein R7 is a C1-C6 alkyl group; a sulfide group; or a phosphate group, and R8 and R9 are each independently a hydrogen atom; a halogen atom; a linear or branched C1-C6 alkyl group; an aryl. An aralkyl group in which one or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of a benzene, naphthalene and anthracene ring; a C1-C6 alkylene group; a benzoyl group; a cinnamyl group; A group; or a furoyl group) (iii) any of R1, R2, R3 and R4 and / or any of R5 and R6 is a substituted or unsubstituted cyclopentyl group; a substituted or unsubstituted cyclohexyl group; or a substituted or unsubstituted It may be a naphthyl group, (iv) R5 and R6 are other condensed polycyclic carbonizations And (v) R3, R4, R5 and R6 may be a halogen atom, a cyano group, an optionally protected carboxyl group or a protected group. An optionally protected hydroxyl group, an optionally protected amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C7 alkoxycarbonyl group, an aryl group, a C3-C6 cycloalkyl group, a C1-C6 acylamino group, Substituted by one or more substituents selected from the group consisting of C1-C6 acyloxy groups, C2-C6 alkenyl groups, C1-C6 trihalogenoalkyl groups, C1-C6 alkylamino groups and di-C1-C6 alkylamino groups. (Vi) R2 and R5 may be a halogen atom, a C1-C6 alkyl group, an optionally protected carboxylic acid; Group, optionally protected hydroxyl group, optionally protected amino group, optionally protected C1-C6 alkylamino group, optionally protected C1-C6 aminoalkyl group, protected Optionally substituted with one or more substituents selected from the group consisting of a C1-C6 alkylamino C1-C6 alkyl group, an optionally protected C1-C6 hydroxyalkyl group and a C3-C6 cycloalkylamino group. And (vii) when R3, R4, R5 and R6 are alkyl groups, the end of the alkyl group may be substituted with a C3-C8 cycloalkyl group). A vaccine precursor and vaccine containing, as an active ingredient, an antigen derived by bringing an antigenic substance inducer into contact with cancer cells . In the antigen substance inducer, the aryl group in (i) (ii) and (v) is a phenyl, tolyl, xylyl or naphthyl group, and the substituted cyclopentyl group in (iii) is a cyclopentylamino group or a cyclopentylcarbyl group. The substituted cyclohexyl group is a cyclohexylamino group, a cyclohexylaldehyde group or a cyclohexylacetic acid group, the substituted naphthyl group is a naphthylamino group or a naphthylaminosulfonic acid group, and the condensed polycyclic group in (iv) hydrocarbon compounds pentalene, indene, naphthalene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, Fenantoen, anthracene, pentacene, hexacene, dibenzo phenanthrene, 1H- Black is a penta cyclooctene or benzocyclooctene, the heterocyclic compound is furan, thiophene, pyrrole, .gamma.-pyran, .gamma.-thiopyran, pyridine, thiazole, vaccine of claim 1 is imidazole pyrimidine, indole or quinoline Precursors and vaccines . B in the general formula 1

(Wherein, (i) R1, R2, R3, R4, R5, R6, R10 and R11 are each independently a hydrogen atom; a halogen atom; a C1-C6 alkyl group; an amidino group; a C3-C8 cycloalkyl group; C1 -C6 alkoxy C1-C6 alkyl group; aryl group; allyl group; an aralkyl group in which one or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of benzene, naphthalene and anthracene ring; C1-C6 An alkylene group; a benzoyl group; a cinnamyl group; a cinnamoyl group; or a furoyl group, and (ii) A is a hydrogen atom or

Wherein R7 is a C1-C6 alkyl group; a sulfide group; or a phosphate group, and R8 and R9 are each independently a hydrogen atom; a halogen atom; a linear or branched C1-C6 alkyl group; an aryl. An aralkyl group in which one or two or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of a benzene, naphthalene and anthracene ring; a C1-C6 alkylene group; a benzoyl group; a cinnamyl group; A group; or a furoyl group) (iii) any of R1, R2, R3 and R4 and / or any of R5, R6, R10 and R11 is a substituted or unsubstituted cyclopentyl group; a substituted or unsubstituted cyclohexyl group; or It may be a substituted or unsubstituted naphthyl group, and (iv) R5, R6, R1 And R11 may be bonded to other condensed polycyclic hydrocarbon compounds or heterocyclic compounds to form a ring. (V) R3, R4, R5, R6, R10 and R11 are each a halogen atom, cyano Group, optionally protected carboxyl group, optionally protected hydroxyl group, optionally protected amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C7 alkoxycarbonyl group, aryl group , C3-C6 cycloalkyl group, C1-C6 acylamino group, C1-C6 acyloxy group, C2-C6 alkenyl group, C1-C6 trihalogenoalkyl group, C1-C6 alkylamino group and di-C1-C6 alkylamino group Optionally substituted by one or more substituents selected from the group, (vi) R2 and R5 are each a halogen atom, C ~ C6 alkyl group, optionally protected carboxyl group, optionally protected hydroxyl group, optionally protected amino group, optionally protected C1 to C6 alkylamino group, protected Selected from the group consisting of a good C1-C6 aminoalkyl group, an optionally protected C1-C6 alkylamino C1-C6 alkyl group, an optionally protected C1-C6 hydroxyalkyl group and a C3-C6 cycloalkylamino group (Vii) when R 3, R 4, R 5, R 6, R 10 and R 11 are alkyl groups, the end of the alkyl group is replaced by a C 3 -C 8 cycloalkyl group. An antigen induced by contacting a cancer cell with an antigenic substance inducer comprising a compound represented by Vaccine precursor and vaccine containing as minutes . In the antigen substance inducer, the aryl group in (i) (ii) and (v) is a phenyl, tolyl, xylyl or naphthyl group, and the substituted cyclopentyl group in (iii) is a cyclopentylamino group or a cyclopentylcarbyl group. The substituted cyclohexyl group is a cyclohexylamino group, a cyclohexylaldehyde group or a cyclohexylacetic acid group, the substituted naphthyl group is a naphthylamino group or a naphthylaminosulfonic acid group, and the condensed polycyclic group in (iv) hydrocarbon compounds pentalene, indene, naphthalene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, Fenantoen, anthracene, pentacene, hexacene, dibenzo phenanthrene, 1H- Black is a penta cyclooctene or benzocyclooctene, the heterocyclic compound is furan, thiophene, pyrrole, .gamma.-pyran, .gamma.-thiopyran, pyridine, thiazole, vaccine according to claim 3 is imidazole pyrimidine, indole or quinoline Precursors and vaccines . General formula 2

(Wherein, (i) R1, R2, R3, R4, R5 and R6 are each independently a hydrogen atom; a halogen atom; a C1-C6 alkyl group; an amidino group; a C3-C8 cycloalkyl group; a C1-C6 alkoxy C1. -C6 alkyl group; aryl group; allyl group; aralkyl group in which one or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of benzene, naphthalene and anthracene ring; C1-C6 alkylene group (provided that , R1, R2 together to form a C1 alkylene group) ; a benzoyl group; a cinnamyl group; a cinnamoyl group; or a furoyl group, and (ii) any of R1, R2, R3 and R4 and / or Or any of R5 and R6 is a substituted or unsubstituted cyclopentyl group; a substituted or unsubstituted cyclohexyl group; Or (iii) R5 and R6 may be bonded to other condensed polycyclic hydrocarbon compounds or heterocyclic compounds to form a ring; and (iv) R3, R4, R5 and R6 are each a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected hydroxyl group, an optionally protected amino group, a C1-C6 alkyl group, a C1- C6 alkoxy group, C1-C7 alkoxycarbonyl group, aryl group, C3-C6 cycloalkyl group, C1-C6 acylamino group, C1-C6 acyloxy group, C2-C6 alkenyl group, C1-C6 trihalogenoalkyl group, C1-C6 It may be substituted with one or more substituents selected from the group consisting of alkylamino groups and di-C1-C6 alkylamino groups. , (V) R2 and R5 are a halogen atom, a C1-C6 alkyl group, a carboxyl group that may be protected, a hydroxyl group that may be protected, an amino group that may be protected, or a protected group Good C1-C6 alkylamino group, optionally protected C1-C6 aminoalkyl group, optionally protected C1-C6 alkylamino C1-C6 alkyl group, optionally protected C1-C6 hydroxyalkyl group And optionally substituted with one or more substituents selected from the group consisting of C3 to C6 cycloalkylamino groups, (vi) when R3, R4, R5 and R6 are alkyl groups, end contacting the antigenic substance inducer and cancer cells as an active ingredient a compound represented by may also be) optionally substituted by C3~C8 cycloalkyl group Vaccine precursor and vaccines containing antigens derived by as an active ingredient. In the antigen substance inducer, the aryl group in (i) and (iv) is a phenyl, tolyl, xylyl or naphthyl group, and the substituted cyclopentyl group in (ii) is a cyclopentylamino group or a cyclopentylcarbinol group. The substituted cyclohexyl group is a cyclohexylamino group, a cyclohexylaldehyde group or a cyclohexylacetic acid group, the substituted naphthyl group is a naphthylamino group or a naphthylaminosulfonic acid group, and the condensed polycyclic hydrocarbon compound in (iii) above There pentalene, indene, naphthalene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, Fenantoen, anthracene, pentacene, hexacene, dibenzo phenanthrene, 1H-cyclo A printer cyclooctene or benzocyclooctene, the heterocyclic compound is furan, thiophene, pyrrole, .gamma.-pyran, .gamma.-thiopyran, pyridine, thiazole, vaccine precursor according to claim 5 which is an imidazole pyrimidine, indole or quinoline Body and vaccine . A in general formula 3

(Wherein, (i) R3 and R4 are each independently a hydrogen atom; a halogen atom; a C1-C6 alkyl group; an amidino group; a C3-C8 cycloalkyl group; a C1-C6 alkoxy C1-C6 alkyl group; an aryl group; An aralkyl group in which one or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of a benzene, naphthalene and anthracene ring; a C1-C6 alkylene group; a benzoyl group; a cinnamyl group; a cinnamoyl group; Or (ii) any of R3 and R4 may be a substituted or unsubstituted cyclopentyl group; a substituted or unsubstituted cyclohexyl group; or a substituted or unsubstituted naphthyl group, and (iii) R5 and R6 are Combine with other condensed polycyclic hydrocarbon compounds or heterocyclic compounds to form a ring; iv) R3, R4, R5 and R6 are each a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected hydroxyl group, an optionally protected amino group, a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C7 alkoxycarbonyl group, aryl group, C3-C6 cycloalkyl group, C1-C6 acylamino group, C1-C6 acyloxy group, C2-C6 alkenyl group, C1-C6 trihalogenoalkyl group, C1 May be substituted with one or more substituents selected from the group consisting of a -C6 alkylamino group and a di-C1-C6 alkylamino group, and (v) R5 is a halogen atom, a C1-C6 alkyl group, protected. Carboxyl group which may be protected, hydroxyl group which may be protected, amino group which may be protected C1-C6 alkylamino group which may be protected, C1-C6 aminoalkyl group which may be protected, C1-C6 alkylamino C1-C6 alkyl group which may be protected, C1 which may be protected May be substituted with one or more substituents selected from the group consisting of a -C6 hydroxyalkyl group and a C3-C6 cycloalkylamino group; (vi) when R3 and R4 are alkyl groups, the alkyl group A vaccine precursor containing, as an active ingredient, an antigen derived by contacting a cancer cell with an antigen substance-inducing agent comprising a compound represented by (2), wherein the terminal is optionally substituted with a C3-C8 cycloalkyl group) and vaccine. In the antigen substance inducer, the aryl group in (i) and (iv) is a phenyl, tolyl, xylyl, or naphthyl group, and the substituted cyclopentyl group in (ii) is a cyclopentylamino group or a cyclopentylcarbinol group. The substituted cyclohexyl group is a cyclohexylamino group, a cyclohexylaldehyde group or a cyclohexylacetic acid group, the substituted naphthyl group is a naphthylamino group or a naphthylaminosulfonic acid group, and the condensed polycyclic hydrocarbon compound in (iii) above Is pentalene, indene, naphthalene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, phenanthene, anthracene, pentacene, hexacene, dibenzophenanthrene, 1H-cyclo The vaccine precursor according to claim 7, which is nantacyclooctene or benzocyclooctene, and the heterocyclic compound is furan, thiophene, pyrrole, γ-pyran, γ-thiopyran, pyridine, thiazole, imidazole pyrimidine, indole or quinoline. Body and vaccine. B in the general formula 3

(Wherein (i) R3, R4, R5 and R6 are each independently a hydrogen atom; a halogen atom; a C1-C6 alkyl group; an amidino group; a C3-C8 cycloalkyl group; a C1-C6 alkoxy C1-C6 alkyl group. Aryl group; allyl group; aralkyl group in which one or more C1-C6 alkyl groups are bonded to an aromatic ring selected from the group consisting of benzene, naphthalene and anthracene ring; C1-C6 alkylene group; benzoyl group; cinnamyl group A cinnamoyl group; or a furoyl group, and (ii) either R3 and R4 and / or any of R5 and R6 is a substituted or unsubstituted cyclopentyl group; a substituted or unsubstituted cyclohexyl group; or a substituted or unsubstituted naphthyl group (Iii) R5 and R6 may be other condensed polycyclic hydrocarbonation Or (iv) R3, R4, R5 and R6 may be a halogen atom, a cyano group, an optionally protected carboxyl group or a protected group. Hydroxyl group, amino group which may be protected, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C7 alkoxycarbonyl group, aryl group, C3-C6 cycloalkyl group, C1-C6 acylamino group, C1 -C6 acyloxy group, C2-C6 alkenyl group, C1-C6 trihalogenoalkyl group, C1-C6 alkylamino group and one or more substituents selected from the group consisting of di-C1-C6 alkylamino groups (V) R5 is a halogen atom, a C1-C6 alkyl group, an optionally protected carboxyl group, a protected group. An optionally protected hydroxyl group, an optionally protected amino group, an optionally protected C1 to C6 alkylamino group, an optionally protected C1 to C6 aminoalkyl group, an optionally protected C1 to C1 A C6 alkylamino C1 to C6 alkyl group, an optionally protected C1 to C6 hydroxyalkyl group and a C3 to C6 cycloalkylamino group may be substituted with one or more substituents selected from the group ( vi) When R3, R4, R5 and R6 are alkyl groups, the terminal of the alkyl group may be substituted with a C3-C8 cycloalkyl group)) A vaccine precursor and vaccine containing as an active ingredient an antigen derived from contacting cancer cells . In the antigen substance inducer, the aryl group in (i) and (iv) is a phenyl, tolyl, xylyl or naphthyl group, and the substituted cyclopentyl group in (ii) is a cyclopentylamino group or a cyclopentylcarbinol group. The substituted cyclohexyl group is a cyclohexylamino group, a cyclohexylaldehyde group or a cyclohexylacetic acid group, the substituted naphthyl group is a naphthylamino group or a naphthylaminosulfonic acid group, and the condensed polycyclic hydrocarbon compound in (iii) above There pentalene, indene, naphthalene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, Fenantoen, anthracene, pentacene, hexacene, dibenzo phenanthrene, 1H-cyclo A printer cyclooctene or benzocyclooctene, the heterocyclic compound is furan, thiophene, pyrrole, .gamma.-pyran, .gamma.-thiopyran, pyridine, thiazole, vaccine precursor according to claim 9 is imidazole pyrimidine, indole or quinoline Body and vaccine .

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