JPH05509078A - Growth inhibitory factors and the Act on Measures against Cancer and Cell Proliferative Diseases - Google Patents

Abstract

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

Description

[Detailed description of the invention] Title of the invention: Growth inhibitory factors and the Act on Measures against Cancer and Cell Proliferative Diseases field of invention The present invention provides novel and highly beneficial bioflavonoid compositions 113 and methyl p-hydroxyphenyl lactate (MeHPLA) and its analogues, chemical Derivatives and chemically related compounds, phenylmethylene ketones, nitroal Kens, aurones, antitumor agents, inhibitors of proliferative cell growth, and immunosuppressants. It relates to related compounds including chalcones and the like.

Background of the invention Two types of nuclear estrogen binding sites exist in normal and malignant tissues. Ru. Type 1 sites represent classical estrogen receptors (2, τ, nuclear type ■ The site appears to result in a constant nuclear response of the sex hormones Δ4 (estrogen).

After estrogen administration, type T receptor sites bind estradiol5 and this Receptor-estrogen complexes are involved in transcriptional transcription associated with estrogen stimulation of tissue growth. • Interacts with the receptor site before the initiation of f-vent. In contrast, type ■The site has greater capacity and lower than classical estrogen receptors It binds estrogen with affinity 1 and does not appear to be translocated from the cytoplasm to the nucleus. Ru. Therefore, one novel of nuclear type ■ site is increased by estrogen administration. However, the type ■ site remains in the cytoplasm even after hormone administration. Nuclear type■location is It appears to mediate a specific nuclear response to estrogenic hormones, and uterine cells It is highly correlated with sexual hypertrophy and proliferation. Furthermore, the nuclear type ■The site is mouse Highly stimulated in malignant tissues such as breast tumors and human breast cancer. This view The results show that highly proliferative tissues have more nuclear types. This is consistent with the findings. Nuclear type ■Site stimulation has a strong correlation with uterine acid and length stimulation Since it has, the type ■ site is the mechanism by which estrogen causes uterine stimulation. It is believed to be a place associated with Buddhism. In addition, ties on the nuclear matrix The presence of the step-type site may play a role in the regulation of DNA synthesis. This suggests that

Nuclear type ■ site is a component of many, if not all, non-malignant cells. Ru. Normally, the type ■ site in non-malignant cells is methyl p-hydroxyphenylacetate. Cutate (MeHPLA or methyl 3-(4-hydroxyphenyl)-2- hydroxypropionate). Methyl p-hydroxyph Phenyl lactate (MeHPLA) is effective against normal and malignant cells and the immune system. It is an endogenous ligand for the nuclear type ■binding site in lymphoid cells of the mucosa, Through this binding action, the compound regulates cell growth and proliferation.

MeHPLA contains bioflavonoids (Qriffiths and Su+ith (1972) Biochem, J., 128:901) and/or Ciro Shin metabolism (karoum (1985) Biogenic Am1nes 2 +269). Furthermore, MeHPLA It is metabolized by malignant cells and the resulting lack of this compound in tumors is Directly associated with loss of cell growth regulation. MeHPLA binds to the type ■ site. When cancer occurs, cell growth and proliferation of non-malignant tissue is inhibited or stopped. vice versa, Malignant cells metabolize MeHPLA and therefore binding to nuclear type ■ sites is becomes insufficient and the regulation of cell growth and proliferation is lost. As a result, it was investigated All tumor cells have very high levels of unattached nuclear type ■ sites. child The same type of metabolic action is shown here by the compounds according to the invention in the immune system. It has been proposed as a possible mechanism to regulate cell proliferation effects. this These sites should be targeted by MeHPLA analogs as anti-proliferative agents.

The invention is useful for malignant or other rapidly proliferating diseases such as those in the immune system. Although it is not metabolized by some cells, it binds with high affinity to nuclear type ■ sites. The compound is disclosed. These compounds inhibit tumor cell proliferation, DNA synthesis, and lymph nodes. It is a very effective inhibitor of bulb activation. Therefore, the compounds according to the invention It is also useful as an immunosuppressant.

Nuclear type ■ Sites include various tumors and other growths such as those in the immune system Observed in sex cells. Furthermore, phenylmethylene ketones, nitroalkenes analogues or chemically related compounds such as aurones, aurones, and chalcone The compound is effective against a wide range of tumors and other rapidly proliferating cells such as activated lymphocytes. It is an effective inhibitor against These compounds are associated with various autoimmune diseases, and Immunization that suppresses cell proliferation is desirable or necessary to treat the pathological condition. It is clinically effective in measuring other pathological conditions of the system.

Consequently, especially the pancreas, cervix, liver, brain, pituitary gland and other organs and tissue sites. and other types of cancers such as leukemia, lymphoma, stromal tumors, and fibroids. Nuclear type ■ Any tumor containing site, MeHPLA, phenylmethylene keto their analogues, derivatives and chemically related compounds, such as It should respond to treatment with related compounds.

MeHPLA inhibits estrogen stimulation of normal cell growth, such as in the rat uterus. MeHPLA analogs and chemically related compounds are Measures for cervical cell hyperplasia, cervical cell hyperplasia, endometritis, and benign prostatic hyperplasia It is also beneficial. Non-proliferating, non-malignant cells are usually of the type II bound to MeHPLA. The proposed compound has minimal effects on non-malignant cell populations. It ranges from level to zero. For these reasons, MeHPLA, phenylmetal tyrene ketones, nitroalkenes, aurones, and chalcones, etc. Similar or chemically related compounds, derivatives and chemically related compounds , and its physiologically acceptable salts, may also be used to treat cancer, autoimmune diseases, and infectious diseases. As a prophylactic agent in suppressing or preventing explant-versus-host disease and abnormal proliferation of non-malignant cells. is also beneficial.

Although the exact physiological role of type ■ site is unknown, inhibition of nuclear type ■ site is Associated with intrauterine responses and conflict with estrogen. This is dexamethacin, pro diesterones, and triphenylethyl compounds such as nafoxidine and clomitzene. This applies to antagonists such as ren derivatives. Nuclear type ■ Site of estradio There is at least one endogenous inhibitor of nuclear binding, but nuclear type Specific inhibitors for this effect include those identified by some of the inventors of the present invention. Not previously confirmed. Furthermore, the inhibitor according to the present invention is directed against nuclear type ■ site. and exerts a particular effect on cytosolic or nuclear type ■ estrogen receptors. Does not interfere with estradiol binding.

These inhibitors are methyl 3-(4-hydroxyphenyl)-2-hydroxypropylene pionates, phenylmethylketones, nitroalkenes, aurones, and Derivatives and chemically related compounds such as chalcone and physiologically acceptable It has been confirmed that its salts are capable of inhibiting cell growth and growth in normal and malignant tissues. It is a powerful regulator of cell growth, proliferation, and immune function. One inhibitor is methyl p- It is known as hydroxyphenyl lagtate or MeHPLA. below , these terms are used interchangeably. Cell growth inhibition by these compounds is , the possible involvement of these compounds in the regulation of cell proliferation and DNA synthesis. the ability to interact with high affinity nuclear binding sites in certain normal and malignant cells; Involved. When MeHPLA is bound to nuclear type ■ sites, cell growth and Growth is inhibited. Endogenous 3-(4-hydroxyphenyl)-2-hydroxyp Ropionic acid has a much lower ability to inhibit cell growth. This action is based on the nuclear type ■ region. associated with its low binding affinity.

Another object of the invention is a means of cancer prevention. MeHPLA is normal for mammalian cells. Although it is a major component, it is metabolized by malignant cells, so it can be used by tumors and the immune system. phenylmethylene chloride, which is not metabolized by other rapidly proliferating cells such as Thons, nitroalkenes, aurones, and chalcones, derivatives and chemistry including physiologically relevant compounds and their physiologically acceptable salts. MeHPLA, structural analogs and chemically related Certain compounds may be used to inhibit malignant tumors and improve the immune system, including autoimmune diseases. It should also be useful in the treatment of many pathological conditions. What are these compounds? There are almost no side effects, and when taken at low doses, it can kill malignant cells. It is also supposed to suppress the proliferation of lymphocytes in the immune system.

MeHPLA is a very potent inhibitor of cell growth, so this compound and its Analogs and chemically related compounds have been used as antitumor agents. The present invention The potent antitumor and immunosuppressive effects of these compounds are disclosed.

One objective of the present invention is cancer control.

Another object of the invention is to type ■ proliferating cells containing nuclear estrogen binding sites. This is a procedure to suppress the growth of

Yet another object of the invention is a method of inhibiting the growth of estrogen-responsive tissue. .

Another object of the present invention is to treat human breast cancers containing non-binding nuclear type ■ sites. This is a treatment for other malignant tumors.

Yet another object of the present invention is to treat bisexual prostatic hypertrophy, cervical hypertrophy, and uterine cell enlargement. It is a measure for hyperplasia and endometritis.

Another object of the invention is to provide an immunosuppressant.

Summary of the invention Many anticancer drugs have immunosuppressive effects (Sledin and Steinb erg (1988) +”Inflam+++ation Ba5ic Pr 1nciplesand C11nical Correlates” (Ga lin, Goldstein, Synderman, etc.) Laben Press, new york). Many of the commonly used immunosuppressants were initially used as anticancer drugs. It was made by Immunosuppressive drugs are used clinically in the treatment of various automatic diseases. has been proven to be effective.

Another object of the present invention is to treat rheumatoid arthritis, multiple sclerosis, myasthenia gravis, and bran bed disease. , thyroiditis, grape retinitis, cyclic lupus erythema, Shogren's syndrome, autoimmune disease. It is a measure of autoimmune diseases including epidemic skin diseases and others.

Another object of the present invention is to provide a method for treating graft-versus-host disease and to prevent transplant rejection. That is.

Thus, in achieving the above objectives, according to one aspect of the present invention, Me administering HPLA, its analogues, chemical derivatives or chemically related compounds; Provided is a method for treating cancer and autoimmune diseases comprising steps that It will be done.

More specifically, the compound is selected from the group consisting of the following compounds: It will be done.

Here, R8 is composed of an alkyl group containing carbon of Hll-6 and an aryl group. R1 and R.

is selected from the group consisting of H, OH and OCH, and R4 is H or from the group consisting of alkyl groups containing 1-6 carbons. Book A preferred compound that can be used to practice the invention is methyl 3-(4- hydroxyphenyl)-2-hydroxypropionate, n-propyl 3-(4 -Hydroxyphenyl)-2-hydroxypropione-, 3-(4-hydro xyphenyl)-2-propenoic acid, 4-(4-hydroxyphenyl)-2-buta non, 1-(4-hydroxyphenyl)-3-pentanone, methyl (4-hydro xyphenoxy)acetate, and methyl 3-(3,4-dihydroxyphenylphenyl) )-2-propenoate.

Another aspect of the invention is from the group consisting of compounds represented by the following structural formula: cancer treatment consisting of the step of administering a therapeutically effective amount of a selected compound. and pathological conditions of the immune system such as autoimmune diseases and graft-versus-host disease. Provide a method to take action.

R1 and R4 are selected from the group consisting of H and OH, and R3 and R, are selected from the group consisting of H, O H, OCH, amino, alkylamino and alkyl groups containing 1-6 carbons, selected from the group consisting of acyloxy, and halogens, and R5 is H2 Consists of groups consisting of OH, OCH, acyloxy and halogens. , R/, and R'3 are H, OH, OCH, amino, cyano, 1-6 carbon atoms Alkylamino groups containing atoms, acyloxy, halogens and a-azido and Aziridine derivatives, 3,4-hydroxyphenylmethylene, p- and droxife substituted with nylmethylene and other preferably acyloxy or halogen substituents selected from the group consisting of a phenyl group, R'II R'4t R', , RIll and RJl are H, OH, OCH, , amino, cyano and 1-6 Alkylamino groups containing carbon atoms, acyloxy, halogens and a-azido and aziridine derivatives and halogen-substituted derivatives. be done. chalcone R'' and R' are substituted to form an aziridine ring system , a three-element ring structure consisting of RR8, R'o carbon and nitrogen atoms is formed. . Preferred compounds used to practice this invention are phenylmethylene keto You can choose from alkenes, nitroalkenes, aurones and chalcones. Ru.

The most preferred phenylmethylene ketones for carrying out the present invention are: include.

Here, R1 and R4 are )-I, OH, acyloxy or halogen, and R8 and R8 are OH, OCH, amino, alkyl of 1-6 carbon atoms, or alkyl The amino group, R/, and R'1 are H, CH.

or p-hydroxy, 3,4-dihydroxy, acyloxy and halogen nuclei It is phenylmethylene with a substituent, and R/ is H, OH, OCH, and 1- It is an alkyl group containing 6 carbon atoms.

Most preferably, phenylmethylene can be used to practice the present invention. Ketones are selected from the group consisting of compounds with the following structural formula: Ru.

v-1 Bi-I MV-17 The most preferable orones for carrying out the present invention are the most preferable for carrying out the following tank water invention. Preferred nitroalkenes include compounds represented by the structural formula below.

where R,, R, and R5 are H, OH, OCH, amino, 1-6 carbon atoms are alkyl or alkylamino groups, acyloxy and halogens, and R 6 is Hl or an alkyl group of 1-6 carbon atoms.

The most preferred nitroalkenes for carrying out the present invention are represented by the following structural formula: Contains compounds that

Margin below It is a composition shown by the formula.

R, -R9 and R'□-R/, are H, OH, OCH, amino, 1-6 carbons An alkyl or alkylamino group of atoms.

The most preferred aurones useful in carrying out the present invention are MV-19 and MV-20. and MV-21 Te.

MV-19MV-20 The most preferred chalcones for carrying out the present invention are compounds represented by the following structural formula: It is a thing.

Here, R, -R,, R', -R', and R', and R'3 are H,01(.

OCH, amino, cyano, alkyl or alkylamino of 1-6 carbon atoms , acyloxy and halogens, a-azido and aziridine derivatives. .

Margin below The most preferred chalcones useful in practicing the present invention are represented by the following structural formulas: It is a composition.

2'-Hydroxychalcone 2',4',4-trihydroxychalcone 4-hydro Roxychalcone 4-47-hydroxychalcone MV-35MV-46 Another aspect of the invention provides a biologically inhibitory amount of MeHPLA, analogs thereof. , chemical derivatives, or phenylmethylene ketones, nitroalkenes, etc. Chemically related compounds, their analogs, or chalcones in growing cells. The step of administering the cell to the type ■ proliferating cells containing nuclear estrogen binding sites associated with inhibiting the growth of

Yet another aspect of the invention is to treat estrogens such as the uterus, mammary glands, uterine tumors, and mammary gland tumors. inhibition of proliferative growth of gene-responsive tissues. One special aspect is the The beta composition has been used to treat human breast cancer cells. These compositions are based on human milk. Inhibits the growth of cancer cells.

Yet another aspect of the invention is the provision of immunosuppressants. in one aspect , these compositions include MeHPLA, phenylmethylene ketones, nitroalke Chalcones, aurones, and chalcones, and their physiologically acceptable Groups composed of analogs, derivatives, and chemically related compounds such as salts. selected from the group.

Another special aspect of the invention is that MeHPLA, its analogs, and phenylmethylene Physiologically with renketones, nitroalkenes, aurones, and chalcones. therapeutically effective chemically related compounds, including acceptable salts thereof; It is a treatment method for bisexual prostatic hyperplasia that consists of the steps of administering only a certain amount.

Another special aspect of the invention is that a therapeutically effective amount of MeHPLA , their analogs, derivatives, and phenylmethylene ketones, nitroalkenes, Administration of aurones, chalcone species, and physiologically acceptable salts thereof. Composed of tep, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, diabetes. , grape retinitis, cyclic lupus erythema, Shogren's syndrome, autoimmune skin disease This is a method for the treatment of autoimmune diseases, including cancer.

Margin below Another aspect of the invention is that a therapeutically effective amount of rheumatoid arthritis comprising the step of administering a compound consisting of a compound that Ch, multiple sclerosis, myasthenia gravis, diabetes, grapevine retinitis, cyclic lupus erythema For the treatment of autoimmune diseases, including Shogren's syndrome, autoimmune skin diseases, etc. This is the best way to do it.

Here, R1 is composed of H, an alkyl group containing 1-6 carbons, and an aryl group. selected from the group, R1 and R8 are composed of H, OH, and Of:H, R4 is selected from the group consisting of H or an alkyl group containing 1-6 carbons. selected from the group created. can be used for carrying out the invention A preferred compound is methyl 3-(4-hydroxyphenyl)-2-hydroxy Propionate, n-propyl 3-(4-hydroxyphenyl)-2-hydroxy Cypropionate, n-butyl 3-(4-hydroxyphenyl)-2-hydroxy Cypropionate, 3-(4-hydroxyphenyl)-2-propenoic acid, 4-( 4-hydroxyphenyl)-2-butanone, 1(4-hydroxyphenyl)-3 -pentanone, methyl (4-hydroxyphenoxy) acetate, and methyl 3-(3,4-dihydroxyphenyl)-2-propenoate, and the following structure: It can be selected from the group consisting of compounds represented by the formula.

Margin below Here, R1 and R4 are selected from the group consisting of H and OH, R,, R, and R1 are H, OH, OCH, amino, alkylamino, and 1-6 carbon atoms. From the group consisting of alkyl groups, acyloxy, and halogens and R1 is composed of H, OH, OCH, acyloxy, and halogens. R', and R' are selected from the group H, CH,.

OH, OCH, 3,4-dihydroxyphenylmethylene, p-hydroxyphenylene nylmethylene, and preferably substituted with acyloxy or halogen substituents selected from the group consisting of other phenyl groups, R'It　R',! R' 1g R'l and R'.

is composed of H, OH, CH, and OCH acyloxy and halogen-substituted derivatives. selected from the group. Preferred embodiments that can be used to carry out the invention Preferred compounds include phenylmethylene ketones, nitroalkenes, aurones, and and chalcones.

Another aspect of the invention is phenylmethylene ketones, nitroalkenes, orones. , and chalcones, and their derivatives, chemically related compounds, and Composed of analogs of 'MeHPLA, including physiologically acceptable salts thereof. The purpose is to provide an antitumor agent.

Another aspect of the invention is phenylmethylene ketones, nitroalkenes, orones. , and chalcones, and their derivatives, chemically related compounds, and Immunization composed of analogs of MeHPLA, including physiologically acceptable salts thereof. This is to provide an anti-epidemic agent.

Another aspect of the invention relates to cancer, autoimmune diseases, graft-versus-host disease and non-malignant diseases. The present invention provides a preventive agent for suppressing or preventing cell growth. These preventive agents are MeHPLA mentioned above, phenylmethylene ketones, nitroalkenes, and Chalcones and chalcone derivatives and chemically related compounds , and physiologically acceptable salts thereof, etc. be done.

Still further objects, features, and advantages of the present invention are presented for disclosure. It will be clear from the following description of preferred embodiments of the steps.

Brief description of the drawing Figure 1 shows MV-3, M for [“H]estradiol binding to the nuclear type ■ site. Competition between V-12 and MV-88 is shown.

Figure 2 shows an analysis of nuclear type ■ location in axillary muscle lymph node nuclei.

Figure 3 shows MV-3, MV-12 and MV against MCF-7 human breast cancer cell proliferation. -88 influence.

Figure 4 shows the effect of the compounds of the invention on mouse mammary tumors in vivo. Ru.

Figure 5 shows the effects of MV-19°MV-20 and MV-20 on mouse mammary tumor growth in vivo. and MV-21.

Figure 6 shows the effect of cyclodextrin cap on mouse mammary tumor growth in vivo. It shows the influence of cellular MV-88.

Figure 7 shows inhibition of the development of autoimmune grapevine retinitis.

Detailed description of specific examples Definition "Methyl 3-(4-hydroxyphenyl)-2-hydroxypropionate" is Also known as methyl p-hydroxyphenyl lactate or MeHPLA ing. The term rMeHPLAJ binds to nuclear type ■ sites and does Its analogues, chemical derivatives, and chemically related compounds that inhibit cell proliferation by It is meant to include certain compounds.

The term "chemically related compounds" refers to compounds that are structurally related to MeHPLA. and p-rimalic acid, p-hydroxyphenylbutylene, disclosed herein. thanone, (4-hydroxyphenoxy)acetate and arylpropenal Dehyde, arylarylethynyl ketones, arylbutenaldehyde, alkaline Kylarylpropenyl ketones and derivatives of arylpropenyl ketones and similar meanings.

These chemically related compounds include the above compounds and their esters, Cis and trans isomers of ethers and ketones with S in place of O atom Or it contains a derivative containing N. More specifically, these structurally related analogs and derivatives in which Ro is methyl, ethyl, n-propyl, n-butyl, Represents isopropyl, tert-butyl or aryl group, R1 and R are H, OH, or OCR, represents a group, and R is H or an alkyl group of 1-6 carbon atoms. Contains compounds that show. Each of these compounds structurally related to MeHPLA Certain analogs of the class have biological activity as defined herein (Tables ■ and ■) and is therefore an effective inhibitor of cell proliferation, tumor cell growth, and It has been shown to play a role similar to MeHPLA as an immunosuppressant. good Preferably analogs and chemically related compounds useful in carrying out the invention. The substances include phenylmethylene ketones, nitroalkenes, aurones, and chalco Contains such things as Most preferably, these analogs have the structural formula: selected from the group consisting of compounds that

Here, R1 is composed of H, an alkyl group containing 1-6 carbons, and an aryl group. R3 and R1 are selected from the group consisting of H, OH1 and OCH, and R4 is H or an alkyl group containing 1-6 carbons. 0 selected from the group consisting of A preferred compound that can be used is methyl 3-(4-hydroxyl)-2-hydroxypropylene. onate, n-propyl 3-(4-hydroxyphenyl)-2-hydroxypro pionate, n-butyl 3-(4-hydroxyphenyl)-2-hydroxypro pionate, 3-(4-hydroxyphenyl)-2-propenoic acid, 4-(4-hydroxyphenyl)-2-propenoic acid, Droxyphenyl)-2-butanone, 1-(4-hydroxyphenyl)-3-pe tantanone, methyl (4-hydroxyphenoxy) acetate, and methyl 3- Group consisting of (3,4-dihydroxyphenyl)-2-propenoate You can choose from.

Another aspect of the invention provides compounds selected from the group consisting of the following structural formulas: Cancer and autoimmunity consists of administering only therapeutically effective doses. Treat pathological conditions of the immune system, including sexually transmitted diseases and graft-versus-host disease. provide a method for

Margin below Here, R1 and R4 are selected from the group consisting of H and OH, and R8 and R4 are selected from the group consisting of H and OH. and R, are H, OH, OCH, amino, alkylamino, and 1-6 carbon atoms. Selected from the group consisting of alkyl groups, acyloxy, and halogens, including and R.

is selected from the group consisting of H, OH, OCH, acyloxy and halogens. R'1 and R'3 are H,CH,,OH,OCH,,3,4-dihydroxy phenylmethylene, p-hydroxyphenylmethylene, and preferably acylo Groups composed of other substituted phenyl groups substituted with xy or halogen substituents R'IT　R'4f　RZf　R'□ and R' are H2O H, OCH, amino, cyano, alkylamino group of 1-6 carbon atoms, acylo oxy, halogens, and a-azido and aziridine derivatives, acyloxy, and halogen-substituted derivatives. carrying out the invention Preferred compounds that can be used to It can be selected from alkenes and chalcones.

Margin below The most preferred phenylmethylketones for practicing this invention include: nothing.

R1 and R4 are H, OH, alkoxy or halogens, and R3 and R, is OH, OCH amino, ■ -6 carbon atom alkyl or alkylamino group or halogens, and R'1 and R' are H, CH, or p- Hydroxy, 3,4-dihydroxy, acyloxy, and halogen ring substituted is phenylmethylene, and R' is H, OH, OCH, and 1-6 carbon atoms. It is an alkyl group from an atom.

Most preferably, phenylmethylene can be used to practice the present invention. Ketones are selected from the group consisting of the following structural formulas.

Y-1 M'v-I MV-17 Among the nitroalkenes most preferably used to carry out the present invention are the following: There is something like that.

The aurones most preferably used to carry out the present invention are as follows. There is.

Stone-19MV-20 Margin below The most preferable chalcone for carrying out the present invention is a composition represented by the following structural formula. is included.

7-hydroxychalcone 2',4',4-trihydroxychalcone 4-hydro Xychalcone 4-4'-dihydroxychalcone MV-35MV-46 V-47 The term "individual" is used to include animals and humans.

The term "biological inhibition" or inhibition of the growth of proliferating cells refers to , is used to mean partial or total inhibition, and is also used to imply partial or total inhibition of cells. It is also used to mean a decrease in the rate of proliferation or growth. Compounds according to the invention Doses that have biologically suppressive effects on malignant tumor cell growth in tissue culture and in animals growth of the uterus (see Figures 14 and 15), or Markaveric h etc. Cancer Research 43: 3208-3211 (1 Effect of test compound on tumor growth in animals as described in 983) or by other methods known to those skilled in the art. Can be done. These methods are described in the United States Patent Application, which is incorporated herein in its entirety. 11h219.680.

“Immunosuppressive” or “immune suppressive” or “immune system suppression” The term is used to include partial or total immunosuppression. ``This term includes changes that normalize abnormal J immune function.'' It is used in The dose having an immunosuppressive effect of the present invention is defined by Gery et al. (19 86) Invest, Ophthalmol, Vis, Sci, 27:12 Established rat models of experimental autoimmune grape retinitis as described in 96 or by evaluating the effect of the test compound on the can be determined by other methods.

``The term prophylactic agent J refers to the partial or total suppression of a disease or the spread of a disease. It is also used to mean drugs that can be used for prophylaxis or prophylaxis. It also includes drugs used for the prevention of disease or for preventive measures against disease. It is used to mean.

Administration of compounds useful in the methods of the invention may be topical, parenteral, oral, intranasal, intravenous, intramuscular. This can be done intradermally, subcutaneously, or by other appropriate means. Amount administered the age, weight, type of concurrent measures, if any, and the malignant tumor. Based on the nature of the tumor or pathological immune condition. Effective compounds useful in the methods of the invention is available in capsules, tablets, aqueous solutions, suspensions, or elixirs for oral administration. Administered in the form of a silage or a bland solution such as a solution, suspension or emulsion. can be given. saline or any inert solution such as phosphate-buffered saline Any substrate which is also preferably used or which is used in the method according to the invention is Possesses suitable solubility properties.

The compounds according to the invention can also be placed in biologically effective carriers. this biology A pharmaceutically effective carrier is one with which the compounds according to the invention can coexist and which are compatible with the amount to be administered. Contains any solvent that is not toxic to the individual.

Most preferably, the compounds according to the invention are administered as encapsulated compounds. Ru. Many of the compounds useful in the practice of this invention have low solubility in water; , another aspect of the invention is a cyclodextrin encapsulated within a ribosome, Or silastic implant ) consists of a drug delivery system for compounds according to the invention. However However, the compounds according to the invention can be prepared by other methods and by methods known to those skilled in the art. It can also be encapsulated with other compounds.

The term "anti-tumor agent" refers to a drug that reduces cell growth or that is administered to tumor cells in an effective amount. This includes drugs that suppress the growth of tumor cells when administered. used for.

One specific embodiment of the invention is MeHPLA, its analogs, chemical derivatives. , or an anti-tumor agent comprising chemically related compositions. MeHPLAs A specific example of an analogue is a derivative of a compound represented by the following structural formula.

Here, R1 is composed of H, an alkyl group containing 1-6 carbons, and an aryl group. selected from the group, R1 and R1 are the group consisting of H2OH and OCH, R4 is a group consisting of an alkyl group containing R21-6 carbons; selected from the group. Preferred compounds that can be used in the practice of this invention are methane 3-(4-hydroxyphenyl)-2-hydroxybrobionate, n-propylene Lopyl 3-(4-hydroxyphenyl)-2-hydroxypropionate, n- Butyl 3-(4-hydroxyphenyl)-2-hydroxypropionate, 3- (4-hydroxyphenyl)-2-propenoic acid, 4-(4-hydroxyphenyl) )-2-butanone, 1-(4-hydroxyphenyl)-3-pentanone, methyl (4-hydroxyphenoxy)acetate, and methyl 3-(3,4-dihydro) (roxyphenyl)-2-propionate Can be done.

One specific example of this type of compound is R1 is CH, R is H, R is OH, This is the case where R4 is H. This has been isolated and characterized, and the present invention It is a naturally occurring endogenous compound that has been identified as identical to that of its analogues Other examples of R groups include ethyl, n-propyl, n-butyl, isopropyl, tar replaced with t-butyl or aryl group, R8 and/or R5 are H, Replaced with OH, or OCH, group, R, is H or 1-6 carbon alkyl Contains compounds that replace kill groups. These esters are D and L exists in the form

Another group of compounds includes derivative compounds having the formula:

Examples of these compounds are p-fumaric acid, 3-(4-hydroxyphenyl)-2-propylene Lopenic acid and its esters.

These substances exist as cis and trans isomers.

In the case of fumaric acid, R1 and R1 are hydrogen and R1 is OH.

Other esters include R1 being methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl or aryl, R3 and/or R, H, OH or OCR, groups.

Another analogue is caffeic acid, 3-(3,4-dihydroxyphenyl)-2 -propenoic acid, in which case R1 is Hl and R1 and R, are both OH. Ru.

Margin below Other compounds with anti-tumor activity include 1- (4-hydroxyphenyl)-3-butanone derivative.

Here, R1 is composed of H, an alkyl group containing 1 to 6 carbons, and an aryl group. R3 and R.

is selected from the group consisting of H, OH and OCH, and R, is H or selected from the group consisting of alkyl groups containing 1-6 carbons; present invention A preferred compound that can be used for the implementation of is methyl 3-(4-hydro xyphenyl)-2-hydroxypropionate, n-propyl 3-(4-hydro roxyphenyl)-2-hydroxypropionate *8, n-butyl 3-(4- hydroxyphenyl)-2-hydroxypropionate, 3-(4-hydroxy phenyl)-2-propenoic acid, 4-(4-hydroxyphenyl)-2-butanone , 1-(4-hydroxyphenyl)-3-pentanone, methyl(4-hydroxy phenoxy)acetate, and methyl 3-(3゜4-dihydroxyphenyl )-2-propionate.

Ketone derivatives have methyl, ethyl, n-propyl, n-butyl, iso at the R1 position. propyl, tert-butyl, or aryl group, and in the R and R1 positions H, OH1 or 0CR1, and most preferably Hl and 0CR1 in the R1 position. This includes compounds having OH at the R, position.

Furthermore, as shown in the structural formula, the number of CH, groups between the aromatic and keto groups can be changed. A special example of a compound is 1-(4-hydroxyphenyl). phenyl)-3-pentanone and 1-(4-hydroxyphenyl)-3-butano It is.

These compounds have been shown to bind to type ■ sites and exhibit antitumor and antitumor activity in clinical assays. and has antiproliferative activity.

Another group of compounds that exhibit antiproliferative effects in the rat uterus is shown by the structural formula: Ru.

These compounds are analogs linked to ethers of (4-hydroxyphenoxy)acetic acid. For example, methyl (4-hydroxyphenoxy) acetate. these In all of the compounds, R1 is an alkyl carbon chain of H, C, -C, or an aryl group, R, and R, include analogs of H, OH or OCH. This fenoki Further variations of the compound include, for example, R1 is H or C, -C, Alkyl carbon chain or aryl group, R3 and R8 are H, OH, or O CR, is a compound represented by the following structure.

Compounds of the following structural formula are also useful.

R, is C, -C, alkyl chain or aryl group, R3 and R, are H, OH1 Or OCR.

Margin below Another group of compounds that exhibit antiproliferative activity can be represented by the general structural formula below. Wear.

Here, R1 is H, an alkyl group containing 1 to 6 carbon atoms, and substituted or unsubstituted It is from the group consisting of aryl groups, and R3 and R1 are H, OH1 or and OCH.

Margin below Preferred compounds of this group that can be used in the practice of this invention have the following structures: It is a compound represented by the formula.

r-Hydroxychalcone γ,4',4-trihydroxychalcone 4-hydroxy Sichalcone 4-47-sihydroxychalcone MV-35MV-46 V-47 The most preferred compounds of this group for practicing the invention are 3-(4-hydro xyphenyl)-1-phenyl-2-propen-1-one, and 4-(4-hyphenyl)-1-phenyl-2-propen-1-one; (Droxyphenyl)-3-buten-2-one, their analogues and chemical derivatives and chemically related compounds, and pharmaceutically acceptable salts thereof. be.

Other embodiments of the invention include clinically effective amounts of MeHPLA, analogs thereof, the step of administering a chemical derivative or chemically related compound. This includes methods to treat cancer caused by cancer. This compound is one of the antitumor compounds mentioned above. It may be either.

In addition to being used for the treatment of cancer, these anticancer drugs are of type Also useful as an inhibitor of cell proliferation and growth in cells containing estrogen binding sites It's a benefit.

These compounds bind to nuclear estrogen binding sites and regulate cell growth. do. Specific proliferating cells sensitive to the binding of these compounds include the uterus, mammary glands, and offspring. Contains estrogen-responsive tissues such as breast tumors and breast cancer. The compound mentioned above The drug inhibits the ability of human breast cancer cells to proliferate, thereby making it possible to effectively treat the disease. provide medical treatment. Benign prostatic hyperplasia is also a proliferative condition that the compounds mentioned above can beneficially treat. This is another example of tissue disease.

Margin below Another group of compounds that exhibit tumor antiproliferative and immunosuppressive effects include the following common It can be shown by a structural formula.

Here, R8 is H, an alkyl group containing 1 to 6 carbons, and substituted or unsubstituted. It is from the group consisting of aryl groups, and R3 and R1 are H, OH and and OCH. What can be used to carry out the present invention? Preferred compounds of this group that can be made are the following compounds.

? -Hydroxychalcone 2',4',4-trihydroxychalcone 4-hydro Xychalcone 4-4'-dihydroxychalcone MV-35MV (6 The most preferred compounds for practicing this invention are 2'-hydroxychalcone, 2' , 4', 4-trihydroxychalcone, 4-hydroxychalcone, 4-4'-di Hydroxychalcone, MV-35.

MV-46 and MV-47, analogs, chemical derivatives and chemically related compounds compounds, and pharmacologically acceptable salts thereof.

Another embodiment of the invention includes a clinically effective amount of MeHPLA, phenylmethylene Ketones, nitroalkenes, aurones and their analogues, including chasicons , or their derivatives or chemically related compounds. This transformation The compound may be any of the antitumor or immunosuppressive compounds mentioned above.

Example 1 [“H]Estradiol Binding Assay Various Rat Tissues Nuclear Type] [”H] has an endogenous ligand that blocks estradiol binding. However, this compound inhibits [°H]estradiol binding to estrogen receptors. Do not interfere with it. Uterine tissue from rats implanted with estradiol is It was cut out from an animal. This uterine nucleus was previously described by Markevich, B., M. et al. J, Biol.

Chew, 258: 11663-11671 (1983), and the present invention It was prepared according to the method disclosed in the specification as a reference example. The uterine nucleus is est Prepared by ovariectomy from adult rats implanted with rogen. washed Nuclear pellets were diluted to a concentration of 10 mg/d equivalent to fresh uterus. At this concentration , the influence of endogenous inhibitory factors was at the lowest level, but nuclear type Binding to strradiol was at the highest level.

Aliquots of these nuclei and various concentrations of the compound according to the invention were mixed at a temperature of 4°C for 1 [”H]estradiol and its containing 2uM diethylstilbestrol The cells were incubated for approximately 60 minutes in the presence of 40 mM estradiol without [°H].

Under these conditions, nuclear type ■ sites can be quantitatively measured without interference from type 1 sites. determined. This nuclear pellet was added to 1 ml of lomM Tris-1, 5mM ED. Resuspended in TA, centrifuged, ethanol extracted, and counted. This conclusion Bound [“H]estradiol compared to buffer control 45, or 0% inhibition if 100% is combined. Expressed as a percentage of inhibition equivalent to OOOcpm.

Figure 1 shows that when the concentration of these compounds is 10 nM or higher, [”H]estradiol Representative data showing that nuclear type ■ reacts with site is shown. Shown in Figure 1 The results shown are the average of three sets of determinants + standard for four replicate experiments for each sample. Shows semi-error.

Binding assays are high in mouse mammary tumor and human mammary cancer samples versus non-malignant tissue This shows that it has a level of unbound nuclear type ■ site. Normal mammary glands Contains significantly higher levels of overall inhibitory factor activity compared to murine mammary tumors.

Human breast cancer contains low levels of suppressive factors. Therefore, this evidence is malignant Tumor tissue has high levels of unbound nuclear type ■ sites and suppressor activity is absent. It shows that you are adding up. This deficiency in suppressor activity may contribute to these tumor types. Unattached nuclear type observed in the tissue group ■ High level of site, proliferation, and cell growth and the reason for the rapid rate of DNA synthesis.

Two endogenous inhibitors in normal tissues such as rat uterus and normal mouse mammary glands The existence of factors (a and f) has previously been clarified (this book U.S. Patent Application Nct 079,199) incorporated by reference in the specification , a high correlation between the f-peak component and the increase in the number of unbound nuclear types and binding sites was also found in La. It has been shown in rats, mice and human mammary tumors.

The data shown in Figure 1 is for aircraft such as A V-3, MV-12, and MV-88. As in the case of MeHPLA, this compound has a very high binding affinity (Kd-1- 1-1On shows that it binds to the nuclear type ■ site. Table I shows Similar inhibition curves were obtained for all compounds. Ki for the binding interaction is It was judged.

This Ki suppresses [“H]estradiol binding to the nuclear type ■ binding site by 50%. This is the concentration of the drug used. Data for all compounds shown on the table are binding affinities. It shows a high correlation between the cell growth inhibitory effect and the cell growth inhibitory effect.

Margin below Table ■ Nuclear type ■ Binding site, MCF-7 human breast cancer cell growth in vitro, and the effect of MV-compounds on mouse mammary tumor growth in vivo. Phenylmethylene ketones MV-434,00 inert not tested MV-30,061,00+++ MV-170, 5001, 60 not tested MV-180, 8001, 00 not tested Nitroalkenes AV-Nl 710.0 1,40 Untested MV-N3 0.220 0.8 0 Untested aurones MV-1910,0800 negative A V-202,8001,90+ AV-210,080,78+++ Chalcone-cyclodextrin complex AV-88CD Untested 3.00 +++ aKi is for nuclear type ■ site [“H]Concentration of compound required to inhibit estradiol binding by 50% (aM ) (see Figure 5). bKi inhibits MCF-7 human breast cancer cell proliferation by 50% This is the concentration (lag/d) of the compound required to achieve this (see Figure 5).

0 This compound inhibited the growth of well-differentiated murine mammary sarcomas in vivo (See Figure 7-9).

Nuclear type ■ Test whether the binding site is also present in tissues of the immune system In order to do this, the popliteal muscle ganglia nucleus was created, and the nucleus type ■ binding site analysis was [”H] Estradiol exchange was performed. Popliteal lymph nodes were removed from adult female mice. removed, separated from extraneous tissue, weighed, and added to TE buffer y-(10mM It was homogenized in Tris; 1.5mM EDTA, pH 7.4). child The homogenate was centrifuged at 800xg for 20 minutes to obtain a nuclear pellet. this Resuspend the nuclear pellet and centrifuge in TE buffer (800 x g x 7 min) Wash three times by separating and finally the washed nuclear sample has a final volume of 30 mg tissue wet weight equivalent/d (8,6m), and type Estradiol exchange (Markaverich et al., Endocri Assayed by Nology 109: 62-69 (1981)) It was. Briefly, this operation converts an aliquot (250d) of the nuclear suspension into [”H] Presence (total binding) or absence (non-specific) of estradiol (4-4OnM) The step consisted of incubation for 60 minutes at a temperature of 4°C under conditions of ing. After incubation, the nuclei were resuspended and centrifuged four times in TE buffer. Wash repeatedly and finally wash the washed nuclear pellet with 1-ethanol (100%). ) was extracted. Transfer this ethanolic extract to a vial and perform liquid scintillation. ・The radioactivity was measured by counting method. A special connection is a total connection within the system. This was investigated by taking out the non-special bonds (NS) for the The result is phosphorus Expressed in picomole of [”H]nisradiol bound to 1 gram wet weight of node tissue. 1 picomole was expressed as 70265 cpm. Figure 2 shows the popliteus muscle lymph node. Nuclear type■ Indicates the presence of estrogen binding sites. This in the popliteal lymph node Type ■ Binding sites are similar to those observed in other tissues such as the rat uterus. It has a similar binding affinity (Kd>2OnM) to that of other non-estrogens. were present in numbers similar to those measured in non-malignant tissues. popliteal lymph nodes Contains almost exclusively lymphoma cells, and these cells are therefore MeHP Inhibited by LA-related analogs and derivatives through binding to nuclear type ■ sites be done.

Example 2 Suppression of cell proliferation in vitro A, MCF-7 Human Breast Cancer Cell Proliferation Assay Assay for Tumor Growth Reactivity To do so, the MCF-7 human breast cancer cell line in tissue culture was used. person skilled in the art This is due to the effects of hormones and drugs on the growth and proliferation of human cancer cells. MC, which will prove to be an excellent model system for blocking F-7 cells have both type I and nuclear type II estrogen receptor sites. It responds to estrogen hormones in a proliferative manner. Furthermore, it MC, which is suppressed by well-known antiestrogens such as tamoxifen. F-7 cells were placed in a 30-hole veterinary dish at a ratio of 5xto' cells/dish; Dulbecco's modified model, which included fetal calf formation, stripped with charcoal at approximately 10% The cells were cultured for about 48 hours in a Glucose culture medium. During this time, the cells become plastic The cells adhered to the dish and grew exponentially at such a rate that the cells doubled in about 24 hours.

The cells were left attached to the dish for approximately 48 hours, and the culture medium was changed ( These cells were allowed to grow exponentially for approximately 6 days. Zero mouth point Then, these cells were exposed to the compound to be tested, e.g. methyl p-hydroxyphene. Nil lactate ethanol is treated in an amount ranging from 0.1-10ug/d within 10ul. was managed. The culture medium was changed on approximately day 2 and day 4. When the culture medium is changed, Control and test solutions were also added again. On the 6th day, cells were removed and hemosa It is counted with a cytometer, and the DNA content per push is determined by Bourdon-App. (Burton, K.).

Biochem, J. 62: 315-323.1956), the results are Number of cells or DNA components (ug/dish) per day 6 days after treatment (Sh). The results are shown in FIG.

Effect of compounds MV-3, MV-12 and MV-88 on MCF-7 cell proliferation Hibiki was evaluated. MCF-7 cells were grown at 10 cells at a ratio of 2X10' cells/well. in Dulbecco's Modified Eagles Medium (DMEM) containing % fetal calf serum. I was let in. After 24 hours, these cells were lysed in 10 ul ethanol. Treated at concentrations ranging from 02-105n/+12. The control is similar to 1 treated with ethanol. Cell numbers were determined 48 hours after treatment.6 Figure 3 As shown, MV-3, MV-12, and MV-88 also suppressed the proliferation of breast cancer cells. Y-79 retinoblastoma, ME-180 human uterus Proliferation of cervical cancer cells and human melanoma cells was also inhibited (data not shown). ), similar results obtained from inhibition curves for all compounds shown in Table ■ 1 was investigated for cell inhibition using the data of . The Ki for suppression is small. It is defined as the concentration of drug (μg/d) required to inhibit cell proliferation by 50%. Ru.

Table ■ Human melanoma (HSO294 cells) and Inhibition of cell proliferation of breast cancer (MCF-7 cells) melanoma cell aMCF- 7 cells 8MV-390,90,9 MV-465,05,O MV-470,96,O MV-723,03,O MV-881,51,0 8 The numerical value indicates Ki for inhibition, and Ki is for controlling cell proliferation (not yet This is the concentration (μg/d) required to inhibit 50% compared to treated cells).

The effects of inhibition are reversible. It takes about 24 hours for the cells to recover and the f-peak It took 7-24 days to re-grow a complete monolayer after removal of the inhibitor.

B. Melanoma Similar experiments were performed using human melanoma cells, MV-39°MV-46, MV- 47, MV-72 and MV-88 inhibited the proliferation of these cells at relatively low concentrations (Table ■) was suppressed. Therefore, chalcones (MV-72 and MV-88), and So(7) Schiff/(MV-46°MV-47) and Azide(MV- 35”) derivative also inhibited the proliferation of malignant tumor cells.

Tumor cells metabolize or inactivate the f-peak suppressor, leading to tumor cell proliferation. The growth is thought to be very rapid. This means that methyl p-hydroxy Phenyl lactate was found to be bound to normal tissue types. This is also supported by the fact that it is not observed in malignant tumor tissue. cell Proliferation is regulated by ligands that bind to nuclear type ■ sites. Number of unbound sites determines the rate of proliferation. In tumor cells, the number of unbound type ■ sites increased, but Therefore, its growth is normally inhibited by the amount of endogenous inhibitory factors present within the cell. It is not done. Thus, tumor cell proliferation is replaced by normal cell proliferation (e.g., unattached). Synthesis type] is rapidly accelerated compared to cells with few or no sites) It is. These rapidly proliferating cells can be treated with the inhibitors described in this invention. By administering only the effective amount, it is possible to return to normal state or stimulate cell proliferation. can be reduced. Evaluation of effects on human melanoma cells (H5O294 cells) The experimental procedures used were similar to those described above for MCF-7 cells.

Example 3 Inhibition of mammary tumor growth in vivo Implantable mouse mammary glands to assess effects on tumor growth in vivo A tumor model system was used.

This tumor model and its use for assays as an anti-tumor agent are published by Makev. Cancer Res, 43: 3208 (1983) by Erich et al. and is incorporated herein by reference.

Briefly, female mice with transplanted mammary tumors with the same genetic composition are They were divided into experimental groups as described below. ! The size of the tumor is 0.5X0. When the animals are about 5 (length x) (day O), they are completely silastic (silastic) capsules (control) or test compound at 25 It was treated with silastic capsules containing 1 g of I. m The size of the tumor is the size of the finger after treatment. monitored at specified times. These implants receive 450 doses of the compound daily. ng was administered continuously. Figure 4 shows MV-3, MV-12 and MV-88. shows that the growth of these tumors was inhibited compared to controls. similar The binding affinity (Table I) and antitumor activity of MV-19, MV-20 and MV-21 were A high correlation was observed between sex (FIG. 19).

Example 4 Uterine zone assay The rat uterus is highly responsive to estrogen; this hormone Cell hypertrophy, proliferation, and DNA synthesis begin within 24 hours after a single injection . Nuclear type ■ Estodiol stimulation of the site is a prerequisite for such a reaction to occur It is. This assay uses a saline-ethanol vehicle, nisradiol-17f and involves injecting the compound to be tested into immature female rats. Ru.

Control rats received saline-ethanol vehicle and estradiol- Only 17f was injected. The rats were sacrificed 24 hours later, and the dry weight of their uteruses was and wet weight was determined.

These wet and dry weight measurements provide a precisely defined biochemical component of estrogenic action. point and is a direct indicator of changes in cell proliferation and DNA synthesis. Ru. The results of such experiments with various compounds are shown in Table m.

Margin below Table ■ Uterine growth and nuclear type ■ MeHPLA analogues and site binding inhibition Effects of related compoundsgj & 3Episode 4-. ．． eJ″0Xy7X)ht90,O o, 83-(4-hydroxyphenyl)-2-hydroxypropene, o, o So,.

Methyl 3-(3,4-dihydroxy phenyl)-2-propionate 7°・0 1.0 methyl 3-(4-hydro Roxy-3- methoxyphenyl) -2-propenoate 56.0 6.0 foot uterine area a Ability of the compound (10 μg) to block estradiol stimulation in C. aureus Judgment.

Pentanuclear type ■ Concentration of compound that inhibits the binding site by 50% (nMX10'').

Additional measurements in vivo using a uterine zone assay inhibit cell proliferation. The utility of these compounds is demonstrated. Apart from hydroxyphenylrough acid, p- Small doses of hydroxyphenyllactate can cause a decrease in offspring in immature rats. Estradiol stimulation of cephalic growth is blocked (see Figure 14 and Table ■). but However, a certain partial antagonism phenomenon occurs at high doses of hydroxyphenyllafic acid. Can be seen. Hydroxyphenylluff acid is methyl p-hydroxyphenyllactate It is known that it binds to nuclear type sites with 1/20th the affinity compared to This is not surprising, since

The results so far are based on nuclear type ■ Ratio of bound and unbound sites plays an important role in the regulation of cell growth and is the main bond in normal cells. The inhibitor is methyl p-hydroxyphenyl lactate (Markaverich et al., 1988).

These data indicate that tumor cells inactivate methyl p-hydroxyphenyl lagtate. It shows that it has the ability to Similar or chemically related compounds may be synthesized to avoid such inactivation. It was. Therefore, compounds with various side rings and various substituents on the aromatic ring Administration resulted in suppression of uterine growth.

1-(4-hydroxyphenyl), a compound containing a C-terminal methyl group -3-Butanone (p-hydroxyphenylbutanone) has a C-C bond in the methyl group. Since it is related to estradiol, it is not affected by estradiol. This compound is cheaper and therefore better efficacy as an inhibitor in culture and in vivo. Demonstrate results. Furthermore, using 1-(4-hydroxyphenyl)-3-butanone Previous experiments showed that it binds with high affinity to nuclear type ■ sites and is injected into immature rats. When administered, it blocks estradiol stimulation of uterine growth. Therefore, 1-(4 -hydroxyphenyl)-3-butanone is an effective inhibitor of cell growth and It is a regulator of cell proliferation.

Many of the compounds according to the invention, especially phenylmethylketones, nitroalkenes, and chalcones are dissolved in aqueous solutions commonly used as injection bases. Very low quality. This insolubility has implications for drug administration and clinical use potential. Submit a big problem. their formulation to improve drug solubility and administration methods. The compounds can also be encapsulated to facilitate administration. Drugs useful in the present invention As a drug delivery system, for example, incorporation into liposomes or cyclodextrin encapsulation, etc.

Example 5 Improvements in methods of administering compounds according to the invention Cyclodextrins metabolize hydrophilic compounds and improve absorption in the gastrointestinal tract ( Szerji, (1982) “Cyclodextrins and The ir Inclusion Complexes'', Akademiai K iado, Budapest.

Hungary). Biochemicals such as quercetin (closely related to MV-88) Olavonoids have recently been administered in this manner (Yan et al., (1) 988) Zhongcaoyoa, 19: 492), 2-hydroxy Propyl f-cyclodextrin and poly f-cyclodextrin (?-cyclodextrin) It has been demonstrated in animals that the soluble form of lodextrin (lodextrin) is not cytotoxic. (Pitha and Pitha (1985) J, Pharm, S ci. 19:492), and - has also been demonstrated to some extent in humans ( Pitha, J. (1984) Third International, Syn+po s, On C1athrate Compounds, Tokyo.

p, 69), these compounds contain MY-88 related enones and chalcones. Improved efficacy and certainty in administration. Cyclodextrin is a water-soluble alkali Pitha and Pitha (19 2-hydroxydextrin was obtained as described by (85). This drug is Roxycyclodextrin is added to an aqueous solution of water or saline in excess (with 2x filtration). (e.g. 200 mg for 100 mg 2-hydroxydextrin) I got it. The drug was added to a solution of cyclodextrin in methanol. . This suspension is then stirred at room temperature and excess unsolubilized drug is removed (Pitha and Pitha (1985) J, Pharm, Sci, 19: 492) was removed by centrifugation and ultrafiltration using procedures as described in . Siku Quantification of drugs encapsulated within lodextrin samples is performed using high performance liquid chromatography. performed by Laffey (HPLC). Briefly, this step involves drying Weigh the cyclodextrin-drug mixture and add the known amount of the sample ( The procedure consists of dissolving 1mg/m12) in ethanol. This procedure MV-88 can be quantified by HPLC if the drug is a cyclodextrin. extracted from. A known amount of MV-88 standard to perform HPLC analysis. Standard (1-20ug) or fixed amount (5-50ul) of cyclodextrin - Inject the KV-88 sample onto a Waters uBondapak C18 column. , eluted using water:methanol (30:70) at a flow rate of 1 d per minute. Ta. Sample detected at 268nM relative to known MV-88 standard. encapsulated within cyclodextrin by examining the area of le peaks. The concentration of MV-88 could be quantified. MV-88 Standard and Sample Preparation Injection The peak area is measured by measuring the peak height (C2) and measuring the peak area at half the height. The determination was made by multiplying the peak by Ill(an) (area: C11lt). this method A standard curve was constructed (MV-8811 degrees vs. On268m constant value), and the sample UchinoMV-88 (7) 11 degrees (OD268 measurement value) was determined from the slope of the standard curve. Ta. Typical value is approximately 1 mg per 12 mg of cyclodextrin MY-88 complex. Met.

The present invention in inhibiting tumor growth when encapsulated in cyclodextrins encapsulated in cyclodextrin to test the efficacy of compounds by MV-88 was dissolved in a saline vehicle and injected subcutaneously into mice bearing mammary tumors. It was administered by injection. MV-88 is not soluble under aqueous conditions. Shika Shinakara, M Y-88 cylindrical; FO dextrin (MD-88CD: Table ■) depends on the dosage. It inhibited mammary gland tumors in mice in a dependent manner (Figure 6).

Administered by injection using other vehicles such as dimethyl sulfoxide saline MV-88 is effective in suppressing the growth of this tumor. It was less effective compared to when administered after encapsulation. But long were administered in a continuous manner by means of a silastic implant (Figure 4). MV-88 significantly inhibited tumor growth.

A series containing 25 mg of the test compound was administered to mice with metastatic mammary tumors. Embedded with a Rustic Capsule.

Controls were implanted with empty capsules and filled with tumor size (length x width). The results were determined at 0, 3.6 and 14 days after injection. These capsules give per day released 450 ng of test compound (10-151 g/kg body weight). g). Comparing treated individuals and control individuals, the size on body weight was No significant changes were observed during the entire period of the experiment. Figure 4 shows the silastic i MV-3, MV-12 and MV-88 installed in the Treatment of murine mammary tumors resulted in complete suppression of mammary tumor growth in vivo. However, cilaste containing MV-19 and MV-20 Treatment of mice with metastatic mammary tumors using mic capsules The Silastic effectively releases MV-19 and MV-20 from the capsule. Therefore, no significant change in growth inhibition was observed compared to the control group. It did not fit. Therefore, these compounds have limited solubility in aqueous injection vehicles. It was administered using a reinforcing cyclodextrin encapsulation procedure. This structure Binding affinity and binding activity studies were conducted in the case of MV-19, MV-20 and MV-21. We demonstrated that there is a robust structure/activity relationship between the observed tumor growth inhibition. M Y-19 and MV-20 do not bind with high affinity to the nuclear type ■ site and are inhibited by mammary tumor growth. was not suppressed. However, MV-21 binds with relatively high affinity. It was found that treatment with MV-21 significantly inhibited tumor growth. (Figure 5) Administration Altered methods and dosages may result in complete suppression of tumor growth .

Example 6 Immunosuppressive effect Many anticancer drugs have immunosuppressive effects (Seldin and Steinb erg (1988), “Inflammation Ba5ic Pr1n ciplesand C11nical Correlates”, (Gali n, J, I, Goldstein.

M. Snyderman, Ro, eds,) Raven Press, Ltd., New York). Immunosuppressants are used to treat various autoimmune diseases. It has been found to be clinically effective. In the United States, all blindness 10-15% are caused directly or indirectly by the grape retinal tract or grape retinitis. be awakened. Unless clinical intervention is initiated for grape retinitis, recovery is not possible. This can lead to permanent damage to the retina, leading to decreased retinal function and/or blindness. Probably. At present, corticosteroid administration is the most effective treatment for grapevine retinitis. This is a very effective method. However, the use of corticosteroids is limited by intraocular pressure. It is accompanied by side effects such as agitation and cataract formation. Interleukin-2 receptor expression and Cyclosporin-A (csA), which inhibits the growth of T-lymphoma through interaction Immunosuppressants that have been used so far, including produce bad side effects.

Tests for the immunosuppressive effects of compounds according to the invention, such as MV-3, have been conducted using experimental autoimmune therapy. was performed using an established rat model of epidemic grape retinitis (Gery et al. 1986) Invest, Opthamol.

Vi, s, Scj,, t03: 1559), writing style is 100 = 20c) A 7-year-old female Luis U. Lido gave birth to a calf at amino acid position 52 of the human calf. 3. Corresponds to ~538 4Finter photoreceptor retinoid binding protein ( [BP). This sequence called #89G is an amino It has the acid sequence LTSHRTATAAEEEFAFL. These rats are 2. Omg/d X, Complete Freund's Adjuva Containing Tuberculous H37Ra by single foot injection of 50 mg IRBP #896 emulsified in immunized with These rats were simultaneously treated with 10xi09 by intraperitoneal injection. Heat-killed B. pertussis bacteria were also given. control measures Individuals that did not receive significant bacterial anterior grape retina 9 or 100 days after immunization. inflammation and posterior grape retinitis occurred. The animals that were the subjects of the experiment were 0.3 or On day 7 and 7, long MV-3 was injected intraperitoneally. Strong immunosuppression of MV-3 The production version is shown in the experiment in Figure 7. Figures 7a and 7b are interphotoreceptors. Lewis Lat with Retinoid Binding Protein (IRBP) Peptide #896 On the 9th day after immunization, 1lateral and 10% panuveitis It shows that 0% is induced. In contrast, rats treated with MV-3 (Fig. 70) disease was completely prevented. These results are self-evident at normal starting points. The dynamic immune response is suppressed, and a mild disease develops and develops after the 6th day. We show that this leverage phenomenon occurs after active levels of MV-3 decrease.

Furthermore, the typical inflammatory response at the footprint immunization site in rats treated with MV-3 was also suppressed. It was controlled. These results suggest that MV-J and its related compounds also have anti-inflammatory properties. This suggests that there is a Mv-3 and the glutinous compound according to the invention are Rheumatoid arthritis, Tahatsu sclerosis, severe asthenia, diabetes, thyroid, hypertrophy, Including N-ring erythema syndrome, cicogen syndrome, autoimmune disease, and sexual skin diseases. Provide effective ways to treat and/or prevent other autoimmune diseases. It will be done. Additionally, MV-3 and related compounds may be used to combat graft-versus-host disease and transplantation. It provides an effective means to prevent rejection.

Those skilled in the art will understand that the present invention performs the tasks as set forth above, as well as its objects and advantages, as well as their be readily understood to be suitable for achieving essentially related purposes and benefits. There will be. The compounds, methods, and procedures described herein are currently They are representative of preferred embodiments and are provided by way of example only. , are not introduced to limit the scope of the invention. departing from the spirit of the invention. Without exception, modifications and other uses as defined in the claims appended hereto. Those skilled in the art will also easily come up with the following.

In addition, a person skilled in the art can carry out the above tasks and achieve the above objectives and benefits, as well as those essential thereto. be easily understood as being suitable to achieve relevant objectives and benefits; The compounds, methods, procedures and techniques described herein are currently preferred. This is a representative example of a new implementation example, and is introduced as a specific example. It is not introduced to limit the scope of the invention. Deviate from the spirit of the invention However, modifications and other uses as defined in the claims appended hereto are also contemplated. Entrepreneurs will easily come up with one.

Margin below FIGURE 1 10' 102 103 10' + os [competitive factor] nM FIGURE 2 [3H] Estradio-# (nM) FIGURE 3 FICIIRE 4 B heat FIGURE 5 FIGURE 6 MV-88CD inhibition of mammary tumor growth o　o,s　s,o　to,.

MY-88 injection (MG) - Copy and translation of amendment) Submission (Article 184-8 of the Patent Law)

Claims (1)

[Claims] 1. A method of treating cancer comprising the step of administering a clinically effective amount of a compound selected from the group of compounds represented by the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Numbers There are formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and ▲ Numbers There are formulas, chemical formulas, tables, etc.▼Here, R1 and R4 are groups composed of H and OH. R■, R■ and R■ are selected from the group consisting of H, OH, OCH2, amino, alkylamino and alkyl groups containing 1-6 carbons, acyloxy, and halogens; R■ is H, OH, OCH2, acyloxy, and halogens, and R'1 and R'2 are H, OH, OCH2, amino, cyano, alkyl or alkyl containing 1-6 carbons. lyamino group, acyloxy, halogens, a-azido and aziridine derivatives, 3,4-dihydroxyphenylmethylene, p-hydroxyphenylmethylene and and other phenyl groups preferably substituted with acyloxy or halogen substituents. R'2, R'4, R', R''1 and R' '2 are H, OH, OCH2, amino, cyano, alkyl of 1-6 carbon atoms, or selected from the group consisting of alkylamino groups, acyloxy, halogens, a-azido, aziridine, acyloxy and halogen-substituted derivatives. 2. Claims in which the compound is selected from the group consisting of the following structural formulas: The method described in box 1. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Here, R1 and R4 are H, OH, acyloxy, or halogens, and R2 and R3 are OH, OCH2, amino , alkyl or alkylamino of 1-6 carbon atoms R'1 and R'2 are H, CH2, or phenylmethylene having p-hydroxy, 3,4-dihydroxy, acyloxy, and halogen nuclear substituents, and R'3 is H , OH, CH2 and alkyl groups from 1-6 carbon atoms. 3. The method according to claim 1, wherein the compound is a compound represented by the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1 and R4 are selected from the group consisting of H and OH, and R2 and R3 are selected from the group consisting of H, OH, OCH2, amino, alkylamino, and 1-6 carbons. Contains Al selected from the group consisting of kill groups, R'1 and R'2 are H, CH2, OH, OCH2, 3,4-dihydroxyphenylmethylene, p-hydroxyphenyl selected from the group consisting of nylmethylene, and other substituted phenyl groups. 4. Claim 1, wherein the compound is a compound represented by the following structural formula: Law. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1 and R4 are selected from the group consisting of H and OH, and R2, R3 and R'3 are selected from the group consisting of H, OH, OCH2, amino, alkylamino and 1- selected from the group consisting of alkyl groups containing 6 carbons, and R'1 and R'2 are H, CH2, OH, OCH2,3,4-dihydroxyphenylmethylene, p-hydroxyphenylmethylene, and other Groups composed of substituted phenyl groups selected from the group. 5. The method of claim 1, wherein the compound is represented by the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1, R3 and R■ are H, OH, OCH2, amino, 1-6 carbon atoms Child alkyl or alkylamino groups, acyloxy and halogens, and R is H or an alkyl group of 1-6 carbon atoms. 6. The method of claim 1, wherein the compound is represented by the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1-R4 and R'1-R'4 are H, OH, OCH2, amino, alkyl of 1 to 6 carbon atoms, or alkylamino group. 7. The method of claim 1, wherein the compound is represented by the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ R1-R4, R'1-R'4, R''1 and R'' are H, OH, OCH2, amino, cyano, alkyl of 1-6 carbon atoms, or alkylamino group, acylo xy, halogens, a-azido, arizidine and halogen-substituted derivatives. 8. Type pronuclear est consisting of the step of administering a compound selected from the group consisting of compounds represented by the following structural formula in an amount that has a biologically suppressive effect. A method of inhibiting the growth of proliferating cells containing rogogen binding sites. ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Numbers There are formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and ▲ Numbers There are formulas, chemical formulas, tables, etc.▼Here, R1 and R4 are selected from the group consisting of H and OH, and R2, R3 and R4 are H, OH, OCH2, amino, amino, etc. selected from the group consisting of alkylamino and alkyl groups containing 1-6 carbons, acyloxy and halogens, R2 is selected from the group consisting of H, OH, OCH2, acyloxy and halogens, R'1 and R'2 are H, CH2,OH, OCH2,3,4-dihydroxyphenylmethylene, p-hydro selected from the group consisting of phenyl groups substituted with xyphenylmethylene, and other preferably acyloxy or halogen substituents, R′2, R′4, R′3, R′′1 and R′′2 is a group consisting of H, OH, OCH2, amino, cyano, alkyl or alkylamino groups of 1 to 6 carbon atoms, acyloxy, halogens, a-azido, alizidine, acyloxy and halogen-substituted derivatives. selected from the loop. 9. 9. The method of claim 8, wherein the compound is selected from the group consisting of compounds represented by the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and ▲There are mathematical formulas, chemical formulas, tables, etc.▼10. 10. The method of claim 9, wherein the compound is selected from the group consisting of compounds having the following structural formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Here, R1 and R4 are selected from the group consisting of H and OH, and R2, R3 and R' are H, OH, selected from the group consisting of OCH2, amino, alkylamino, and alkyl groups containing 1-6 carbons, and R'1 and R'2 are H, CH2, OH, OCH2,3,4-dihydroxyphenyl Methylene, p-H selected from the group consisting of droxyphenylmethylene and other substituted phenyl groups. 11. 10. The method of claim 9, wherein the compound has the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1 and R4 are selected from the group consisting of H and OH, and R2 and R3 are selected from the group consisting of H, OH, OCH2, amino, alkylamino, and 1-6 carbons. Including a and R'1 and R'2 are selected from the group consisting of H, CH2, OH, OCH2,3,4-dihydroxyphenylmethylene, p-hydroxy phenylmethylene and other substituted phenyl groups. selected from the group that is displayed. 12. 9. The method of claim 8, wherein the compound has the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1 and R4 are H, OH, acyloxy, or halogen; R2 and R3 are OH, OCH2, amino, alkyl or alkylamino groups of 1-6 carbon atoms, or halogen. and R'1 and R'2 are H, CH2 or p-hydroxy Phenyl with cy, 3,4-dihydroxy, acyloxy and halogen nuclear substituents lumethylene, R'2 is H, OH, CH2, OCH2 and 1-6 carbon atoms It is an alkyl group from a child. 13. 9. The method of claim 8, wherein the compound has the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1, R2 and R3 are H, OH, OCH2, amino, and 1-6 carbon atoms. alkyl or alkylamino groups, acyloxy, and halogens; R4 is H or an alkyl group having 1-6 carbon atoms; 14. 9. The method of claim 8, wherein the compound has the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1-R4 and R'1-R'4 are H, OH, OCH2, amino, alkyl of 1 to 6 carbon atoms, or alkylamino group. 15. 9. The method of claim 8, wherein the compound has the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1-R4 and R'1-R', R''1 and R'' are H, OH, OCH2, amino, cyano, 1-6 carbon atoms. Alkyl or alkylami acyloxy, halogens, a-azido, arizidine, acyloxy, and halogen-substituted derivatives. 15. 9. The method of claim 8, wherein said proliferating cells are estrogen-responsive tissues selected from the group consisting of uterus, mammary glands, uterine tumors, and mammary tumors. 16. 16. The method of claim 15, wherein said estrogen-responsive tissue is human breast cancer cells. 17. Compounds selected from the group consisting of compounds represented by the following structural formulas Treatment for benign prostatic hypertrophy consists of administering a clinically effective amount of How to put it. ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Numbers There are formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and ▲ Numbers There are formulas, chemical formulas, tables, etc.▼Here, R1 and R4 are groups composed of H and OH. R2, R3 and R4 are H, OH, OCH2, amino, alkyl and R is selected from the group consisting of H, OH, OCH2, acyloxy, and halogens; R'1 and R'2 are H, CH2, OH, OCH2,3,4-dihydroxyphenylmethylene, p-hydro xyphenylmethylene and other phenyl groups preferably substituted with acyloxy or halogen substituents, R', R'4, R', R'1 and R'2 are H, OH, OCH2, amino, cyano, Alkyl or alkyl of 1-6 carbon atoms halogen, a-azido, arizidine, acylokidi, and halogen-substituted derivatives. 18. The compound is selected from the group consisting of compounds represented by the following structural formula. 18. The method of claim 17. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Here, R1 and R4 are H, OH, acyloxy or halogens, R2 and R3 are OH, OCH2, amino, 1- an alkyl or alkylamino group of 6 carbon atoms, or halogens, R'1 and R'2 are H, CH2, or p-hydroxy Phyloxy, 3,4-dihydroxy, acyloxy, and phenols with halogen nuclear substituents Nylmethylene and R'2 is H, OH, CH2, OCH2 and an alkyl group having 1-6 carbon atoms. 19. 18. The method of claim 17, wherein the compound is a compound represented by the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1 and R4 are selected from the group consisting of H and OH, and R and R2 are selected from the group consisting of H, OH, OCH2, amino, alkylamino, and 1-6 carbon atoms. Including a and R'1 and R'3 are selected from the group consisting of H,OH, OCH2,3,4-dihydroxyphenylmethylene, p-hydroxyphenylmethylene and other substituted phenyl groups. selected from. 20. 18. The method of claim 17, wherein the compound is a compound represented by the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1 and R4 are selected from the group consisting of H and OH, and R2, R3 and and R' are selected from the group consisting of H, OH, OCH2, amino, alkylamino and alkyl groups containing 1-6 carbons, and R'1 and R'2 are H, CH2, OH, OCH2, 3,4-dihydroxyphenylmethylene, p-hypermethylene selected from the group consisting of droxyphenylmethylene and other substituted phenyl groups. 21. The method according to claim 17, wherein the compound is a compound represented by the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1, R■ and R■ are H, OH, OCH2, amino, 1-6 carbon atoms child alkyl or alkylamino group, R■ is H or 1-6 carbon atom Child alkyl group. 22. The method according to claim 17, wherein the compound is a compound represented by the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1-R4 and R'1-R' are H, OH, OCH2, amino, 1-6 carbon. It is a subatomic alkyl or alkylamino group. 23. The method according to claim 17, wherein the compound is a compound represented by the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ R1-R4, R'1-R'4, R''1 and R''2 are H, OH, OCH2, amino, cyano, alkyl of 1-6 carbon atoms or alkylamino group, acylo oxy, halogens, a-azido, azilidene, acyloxy, and halogen-substituted derivatives. 24. Compounds selected from the group consisting of compounds represented by the following structural formulas A method of administering a substance in a clinically effective amount. ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Numbers There are formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and ▲ Numbers There are formulas, chemical formulas, tables, etc.▼Here, R1 and R4 are groups composed of H and OH. R2, R3 and R4 are H, OH, OCH2, amino, alkyl selected from the group consisting of alkyl groups containing 1-6 carbons, acyloxy, and halogens, where R is H, OH, OCH2, acyloxy, and halogens, R'1 and R'2 are selected from the group consisting of H, CH2, OH, OCH2,3,4-dihydroxyphenylmethylene, p-hydroxyphenylmethylene and preferably acyloxy or halogen substituents. Other phenyl groups substituted with mino group, acyloxy, halogen, a-azido, arizidine, acyloxy, and and halogen-substituted derivatives. 25. Compounds selected from the group consisting of compounds represented by the following structural formulas A method for inhibiting the growth of proliferating cells, which comprises the step of administering a biologically inhibiting amount of a substance. ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Numbers There are formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and ▲ Numbers There are formulas, chemical formulas, tables, etc.▼Here, R1 and R4 are groups composed of H and OH. R2, R3 and R4 are H, OH, OCH2, amino, alkyl selected from the group consisting of ruamino and alkyl groups containing 1-6 carbons, acyloxy and halogens, where R is H, OH, OCH2, acyloxy and halogens. R'1 and R'2 are selected from the group consisting of H, CH2, OH, OCH2,3,4-dihydroxyphenylmethylene, p-hydroxyphenylmethylene, phenylmethylene and other phenyl groups preferably substituted with acyloxy or halogen substituents, R'3, R'4, R', R''1 and R''2 are H, OH, OCH2, amino, cyano, 1 -6 carbon atom alkyl or alkylamino acyloxy, halogen, a-azido, arizidine, acyloxy, and halogen-substituted derivatives. 26. Compounds selected from the group consisting of compounds represented by the following structural formulas Treatment of autoimmune diseases consists of administering drugs in clinically effective doses. How to put it. ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Numbers There are formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and ▲ Numbers There are formulas, chemical formulas, tables, etc.▼Here, R1 and R4 are groups composed of H and OH. R3, R2 and R■ are selected from the group consisting of H, OH, OCH2, amino, alkyl selected from the group consisting of ruamino and alkyl groups containing 1-6 carbons, acyloxy and halogens, where R is H, OH, OCH2, acyloxy and halogens. R'1 and R'2 are selected from the group consisting of H, CH2, OH, OCH2,3,4-dihydroxyphenylmethylene, p-hydroxyphenylmethylene, phenylmethylene and other phenyl groups preferably substituted with acyloxy or halogen substituents, R'3, R'4, R', R''1 and R''2 are H, OH, OCH2, amino, cyano, 1 -6 carbon atom alkyl or alkylamino acyloxy, halogen, a-azido, arizidine, acyloxy, and gelup consisting of halogen-substituted derivatives. 27. The compound is selected from the group consisting of compounds represented by the following structural formula. 27. The method of claim 26. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Here, R1 and R4 are H, OH, acyloxy, or halogens, and R and R are OH, OCH2, amino, 1- Alkyl or alkyla of 6 carbon atoms R'1 and R'2 are H, CH2, or p-hydroxy, 3,4-dihydroxy, acyloxy, and halogen core substituents. and R' is H, OH, CH2, OCH2 and an alkyl group from 1-6 carbon atoms. 28. The method according to claim 26, wherein the compound is a compound represented by the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1 and R4 are H, OH, acyloxy, or halogens, and like R2, and R3 are OH, OCH2, amino, alkyl or alkyl of 1-6 carbon atoms. ruamino group or halogens, and R'1 and R'3 are H, CH2 or are p-hydroxy, 3,4-dihydroxy, acyloxy and halogen nuclear substituents, and R'2 is H, OH, CH2, OCH2 and 1-6 carbon atoms. These are the alkyl groups. 29. The method according to claim 26, wherein the compound is a compound represented by the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1 and R4 are H, OH, acyloxy, or halogens, and R2 and and R3 is OH, OCH2, amino, alkyl of 1-6 carbon atoms, or alkyl. Kylamino group or halogen, R'1 and R'2 are H, CH2 and p-hydroxy, 3,4-dihydroxy, acyloxy and halogen nuclear substituents, and R' is H, OH, CH2, OCH2 and an alkyl group from 1 to 6 carbon atoms. 30. 27. The method of claim 26, wherein the compound has the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1, R2 and R■ are H, OH, OCH2, amino, 1-6 carbon atoms. is a child alkyl or alkylamino group, and R is H or 1-6 carbon atom Child alkyl group. 31. 27. The method of claim 26, wherein the compound has the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1-R4 and R'1-R' are H, OH, OCH2, amino, alkyl of 1 to 6 carbon atoms, or alkylamino group. 32. The compound is selected from the group consisting of compounds represented by the following structural formula. 27. The method of claim 26. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R1-R4, R'1-R' and R''2 are H, OH, OCH2, amino, cyano, alkyl of 1-6 carbon atoms, or alkylamino. base, a Siloxy, halogens, a-azide, aziridine, acyloxy, and halogen It is a substituted derivative. 33. If the disease is rheumatoid arthritis, multiple sclerosis, myasthenia gravis, diabetes, thyroid hypertrophy, grape retinitis, cyclic lupus erythematosus, Sjorgins syndrome, or 33. The method of any of claims 26-32, selected from the group consisting of dynamic immune skin diseases, and graft-versus-host diseases, and organ and tissue transplant rejection. 34.2-(hydroxybenzylidene)-5-methyl-cyclopentanone (MV-1), 2,6-bis(4-hydroxybenzylidene)-4-methyl-cyclo Hexanone (MV-17), 2,6-bis(3,4-dihydroxybenzylide) )-4-methylcyclohexane (MV-18), 4-hydroxy-∫-methyl-∫-nitrostyrene (MV-N1), 3,4-dihydroxy-∫-methyl-∫-nitrostyrene (MV-N3) , auron (MV-19), 4'-hydroxy auron (MV-20), 3,4'-dihydroxy auron (MV-21), 2'-hydroxychalcone (MV-22), 2',4', 4-trihydroxycal (RV-40), 4-hydroxychalcone (MV-88), a-azido-2'-hydroxychalcone (MV-35), 3,4-dihydroxy-4'-cyanochalcone (MV-46) and The method comprises the step of administering a clinically effective amount of a compound selected from gelup consisting of '-cyanochalcone (MV-47). A method to treat cancer. 35.2-(hydroxybenzylidene)-5-methyl-cyclopentanone (MV-1), 2,6-bis(4-hydroxybenzylidene)-4-methyl-cyclo Hexanone (MV-17), 2,6-bis(3,4-dihydroxybenzylide) )-4-methylcyclohexane (MV-18), 4-hydroxy-∫-methyl-∫-nitrostyrene (MV-N1), 3,4-dihydroxy-∫-methyl-∫-nitrostyrene (MV-N3) , auron (MV-19), 4'-hydroxy auron (MV-20), 3,4'-dihydroxy auron (MV-21), 2'-hydroxychalcone (MV-22), 2',4', 4-trihydroxycal (RV-40), 4-hydroxychalcone (MV-88), a-azido-2'-hydroxychalcone (MV-35), 3,4-dihydroxy-4'-cyanochalcone (MV-46) and a step of administering a biologically suppressive amount of a compound selected from the group consisting of '-cyanochalcone (MV-47). Inhibits the growth of proliferating cells containing type II nuclear estrogen binding sites, which are composed of How to control. 36.2-(Hydroxybenzylidene)-5-methyl-cyclopentanone (MV-1), 2,6-bis(4-hydroxybenzylidene)-4-methyl-cyclo Hexanone (MV-17), 2,6-bis(3,4-dihydroxybenzylide) )-4-methylcyclohexane (MV-18), 4-hydroxy-∫-methyl-∫-nitrostyrene (MV-N1), 3,4-dihydroxy-∫-methyl-∫-nitrostyrene (MV-N3) , auron (MV-19), 4'-hydroxy auron (MV-20), 3,4'-dihydroxy auron (MV-21), 2'-hydroxychalcone (NV-22), 2',4', 4-trihydroxycal (RV-40), 4-hydroxychalcone (MV-88), a-azido-2'-hydroxychalcone (MV-35), 3,4-dihydroxy-4'-cyanochalcone (MV-46) and A method for treating benign prostatic hypertrophy, comprising administering a clinically effective amount of a compound selected from the group consisting of '-cyanochalcone (MV-47). 37.2-(Hydroxybenzylidene)-5-methyl-cyclopentanone (MV-1), 2,6-bis(4-hydroxybenzylidene)-4-methyl-cyclo Hexanone (MV-17), 2,6-bis(3,4-dihydroxybenzylide) )-4-methylcyclohexane (MV-18), 4-hydroxy-∫-methyl-∫-nitrostyrene (MV-N1), 3,4-dihydroxy-∫-methyl-∫-nitrostyrene (MV-N3) , auron (MV-19), 4'-hydroxy auron (MV-20), 3,4'-dihydroxy auron (MV-21), 2'-hydroxychalcone (MV-22), 2',4', 4-trihydroxycal (RV-40), 4-hydroxychalcone (MV-88), a-azido-2'-hydroxychalcone (MV-35), 3,4-dihydroxy-4'-cyanochalcone (MV-46) and A method of administering a compound selected from the group consisting of '-cyanochalcone (MV-47) in a biologically suppressive amount A method for inhibiting the growth of proliferating cells, which consists of 38.2-(Hydroxybenzylidene)-5-methyl-cyclopentanone (MV-1), 2,6-bis(4-hydroxybenzylidene)-4-methyl-cyclo Hexanone (MV-17), 2,6-bis(3,4-dihydroxybenzylide) )-4-methyl cyclohexane (MV-18), 4-hydroxy-∫-methy Ru-∫-nitrostyrene (MV-1), 3,4-dihydroxy-∫-methyl-∫-nitrostyrene (MV-N3), Auron (MV-19), 4'-Hydroxy Auron (MV-20), 3,4'-dihydroxyauron (MV-21), 2'-hydroxychalcone (MV-22), 2',4',4-trihydroxychalcone (RW-40), 4-hydroxychalcone (MV-88), a-azido-2'-hydroxychalcone (MV-35), 3,4-dihydroxy-4'-cyano chalcone (MV-46) and The method comprises the step of administering a clinically effective amount of a compound selected from gelup consisting of '-cyanochalcone (MV-47). A method for treating autoimmune diseases. 39. Methyl p-hydroxyphenyllactate, methyl p-hydroxyphenylacetate Chemical derivation of methyl p-hydroxyphenyllactate, an analogue of lulactate compounds selected from the group consisting of chemically related compounds A self-administered method comprising the step of administering a compound to proliferating cells in a biologically suppressive amount. Methods for treating dynamic immune diseases. 40. The compound is selected from the group consisting of compounds represented by the following structural formula. 39. The method of claim 39. ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Numbers There are formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemistry There are formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼Here, R1 is H, an alkyl group containing 1-6 carbons, and an ali R2 and R3 are selected from the group consisting of H, OH, OCH2, and R4 is M and an alkyl group of 1-6 carbons. selected from the group consisting of