WO1991017749A1 - Inhibiteurs de croissance cellulaire et procedes servant a traiter le cancer et des maladies a proliferation cellulaire - Google Patents

Inhibiteurs de croissance cellulaire et procedes servant a traiter le cancer et des maladies a proliferation cellulaire Download PDF

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Publication number
WO1991017749A1
WO1991017749A1 PCT/US1991/003130 US9103130W WO9117749A1 WO 1991017749 A1 WO1991017749 A1 WO 1991017749A1 US 9103130 W US9103130 W US 9103130W WO 9117749 A1 WO9117749 A1 WO 9117749A1
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group
acyloxy
och3
alkyl
halogens
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PCT/US1991/003130
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English (en)
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Barry Markaverich
Rebecca Gregory
Rajender Singh Varma
Manju Varma
James Clark
John C. Waldrep
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Baylor College Of Medicine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to the use of new and useful bioflavonoid compounds and related compounds which include methyl p-hydroxyphenyllactate (MeHPLA), its analogs, chemical derivatives and chemically related compounds, phenylmethylene ketones, nitroalkenes, aurones, and chalcones as antitumor agents, inhibitors of proliferative cell growth and immunosuppressive agents.
  • MeHPLA methyl p-hydroxyphenyllactate
  • Type I sites represent the classical estrogen receptor and nuclear Type II sites appear to mediate a specific nuclear response to estrogenic hormones.
  • Type I receptor sites bind estradiol and this receptor-estrogen complex interacts with nuclear acceptor sites before the initiation of the transcriptional events that are associated with estrogen stimulation of tissue growth.
  • Type II sites bind estrogen with a higher capacity and a lower affinity than the classical estrogen receptor and do not appear to be translocated from the cytoplasm to the nucleus.
  • Type II sites remain in the cytoplasm after hormone administration.
  • Nuclear Type ⁇ sites appear to mediate a specific nuclear response to estrogenic hormones and are highly correlated with uterine cellular hypertrophy and hyperplasia. Additionally, nuclear Type II sites are highly stimulated in malignant tissues such as mouse mammary tumors and human breast cancer. This observation is consistent with the findings that highly proliferative tissue has an increased number of nuclear Type II sites. Because the stimulation of nuclear Type II sites is closely correlated with the stimulation of uterine growth, it has been postulated that the Type II sites are the location for the mechanisms by which estrogens cause uterotropic stimulation. Furthermore, the presence of Type II sites on the nuclear matrix suggests a potential role in the regulation of DNA synthesis. Nuclear Type II sites are constituents of many, if not all, non-malignant cells.
  • MeHPLA methyl p- hydroxyphenyllactate
  • Methyl p-hydroxyphenyllactate is an endogenous ligand for nuclear type II binding sites in normal and malignant cells, as well as in lymphocyte cells of the immune system, and this compound regulates cell growth and proliferation through this binding interaction.
  • MeHPLA may be derived endogenously from bioflavonoid (Griffiths and Smith (1972) Biochem, J., 128:901) and/or tyrosine metabolism (Karoum (1985) Biogenic Amines 2:269).
  • MeHPLA is metabolized by malignant cells, and the resulting deficiency of this compound in tumors is directly correlated with the loss of cell growth regulation.
  • MeHPLA binds to Type II sites, cell growth and proliferation of non-malignant tissues are slowed down or stopped.
  • malignant cells metabolize MeHPLA and, thus, there is insufficient binding to the nuclear Type II sites and the regulation of cell growth and proliferation is lost. Consequently, all tumor cell populations examined have very high levels of unbound nuclear Type II sites.
  • This same metabolic activity is herein proposed as the probable mechanism wherein the compounds of the present invention regulate the cell proliferative activity in the immune system. These sites should represent targets for the analogs of MeHPLA as anti-proliferative agents.
  • This invention discloses compounds which are not metabolized by malignant or other rapidly proliferating cells such as those of the immune system but which bind to nuclear Type JT sites with high affinity. These compounds are very effective inhibitors of tumor cell proliferation, DNA synthesis and lymphocyte activation. Therefore, the compounds of the present invention are also useful as immunosuppressive agents. Nuclear Type ⁇ sites have been observed in a variety of tumor and other proliferating cells such as those of the immune system.
  • analogs and chemically related compounds such as phenylmethylene ketones, nitroalkenes, aurones, and chalcones are effective inhibitors of a broad spectrum of tumors and other rapidly proliferating cells such as activated lymphocytes.
  • any tumor which contains nuclear Type LI sites should respond to treatment with MeHPLA, its analogs, such as phenylmethylene ketones, nitroalkenes, aurones, and chalcones, derivatives and chemically related compounds, including cancers of the pancreas, cervix, liver, brain, pituitary, prostate and other organ or tissue sites, as well as other cancers, such as leukemias, lymphomas, stromal myomas and leiomyomas, among others.
  • MeHPLA MeHPLA
  • its analogs such as phenylmethylene ketones, nitroalkenes, aurones, and chalcones, derivatives and chemically related compounds, including cancers of the pancreas, cervix, liver, brain, pituitary, prostate and other organ or tissue sites, as well as other cancers, such as leukemias, lymphomas, stromal myomas and leiomyomas, among others.
  • MeHPLA also blocks estrogen stimulation of normal cell growth such as that in the rat uterus (Table I)
  • analogs and chemically related compounds of MeHPLA are also useful for the treatment of uterine hyperplasia, cervical hyperplasia, endometriosis and benign prostatic hypertrophy. Because non-proliferating non-malignant cells normally have their Type II sites bound with MeHPLA, the effects of the proposed compounds on non-malignant cell populations will be minimal to non-existent.
  • MeHPLA its analogs and chemically related compounds, such as phenylmethylene ketones, nitroalkenes, aurones, and chalcones, derivatives and chemically related compounds and physiologically acceptable salts thereof are also useful as prophylactic agents in the inhibition and prevention of cancer, autoimmune disease, graft vs. host disease and abnormal proliferation of non- malignant cells.
  • Type II sites The precise physiological role of Type II sites is unknown, but inhibition of the nuclear Type JT sites is associated with antagonism of uterotropic responses to estrogen. This is true for steroid antagonists such as dexamethas ne, progesterone and triphenylethylene derivatives such as nafoxidine and clomiphene. While there is at least one endogenous inhibitor of estradiol binding to nuclear Type II sites, no specific inhibitors for the nuclear Type II sites had been identified previous to those identified by some of the inventors of the present invention. Furthermore, the inhibitors of the present invention are specific to nuclear Type II sites and do not interfere with estradiol binding to cytoplasmic or nuclear Type I estrogen receptors.
  • the inhibitors are identified as methyl 3-(4- hydroxyphenyl)-2- hydroxypropionate, its analogs, derivatives and chemically related compounds, such as phenylmethylene ketones, nitroalkenes, aurones, and chalcones, and physiologically acceptable salts thereof and are potent regulators of cell growth and proliferation in normal and malignant tissues, as well as in the regulation of immune function.
  • One inhibitor is also known as methyl p-hydroxyphenyllactate or MeHPLA. These terms may be used interchangeably.
  • Cell growth inhibition by these compounds resides in their ability to interact with the high-affinity nuclear binding sites in normal and malignant cells which may be involved in the regulation of cellular proliferation and DNA synthesis.
  • An additional object of the present invention is a means for the prevention of cancer. Since MeHPLA is a normal constituent of mammalian cells, but metabolized by malignant cells, MeHPLA, structural analogs and chemically related compounds as described herein, including, but not limited to phenylmethylene ketones, nitroalkenes, aurones, and chalcones, derivatives and chemically related compounds and physiologically acceptable salts thereof, which are not metabolized by tumors or other rapidly proliferating cells such as those of the immune system should be useful in the prevention of malignancy and in the treatment of many pathological conditions of the immune system, including, but not limited to autoimmune diseases. These compounds possess little if any side effects, and if taken in a low level maintenance dose should inhibit the proliferation of malignant cells, as well as lymphocytes of the immune system.
  • MeHPLA is such a potent inhibitor of cell growth
  • this compound as well as its analogs and chemically related compounds were used as potential antitumor agents.
  • the present invention discloses the potent antitumor and immunosuppressive activity of these compounds.
  • An object of the present invention is a treatment for cancer.
  • An additional object of the present invention is a procedure to inhibit the growth of proliferating cells which include a Type LI nuclear estrogen binding site.
  • a further object of the present invention is a method for inhibiting the growth of estrogen responsive tissues.
  • An additional object of the present invention is the treatment of human breast cancer, and other malignancies which contain unbound nuclear Type II sites.
  • Another object of the present invention is the treatment of benign prostatic hyperplasia, cervical hyperplasia, uterine hyperplasia and endometriosis.
  • An additional object of the present invention is to provide an immunosuppressive agent.
  • Immunosuppressive drugs possess immunosuppressive- activity (Seldin and Steinberg (1988) In: “Inflammation Basic Principles and Clinical Correlates", (Galin, Goldstein, Snyderman, eds.) Raven Press, Ltd., New York). Many of the commonly used immunosuppressive agents were originally designed as anti- cancer drugs. Immunosuppressive drugs have proven to be therapeutically effective in treating a variety of autoimmune diseases.
  • An additional object of this invention is the treatment of autoimmune diseases, including, but not limited to, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitis, thyroiditis, uveoretinitis, systemic lupus erythematosus, Sjorgen's syndrome, autoimmune skin diseases, and others.
  • autoimmune diseases including, but not limited to, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitis, thyroiditis, uveoretinitis, systemic lupus erythematosus, Sjorgen's syndrome, autoimmune skin diseases, and others.
  • An additional object of the present invention is to provide a treatment for graft vs. host disease and to prevent transplant rejections.
  • a method of treating cancer and autoimmune disease comprising the step of administering a therapeutic dose of MeHPLA, its analogs, chemical derivatives or chemically related compounds. More specifically the compound is selected from the group consisting of the formula:
  • Ri is selected from the group consisting of H, alkyl groups containing 1 to 6 carbons, and aryl groups; R2 and R3 are selected from the group consisting of H, OH and OCH3 and R 4 is selected from the group consisting of H, or alkyl group containing 1 to 6 carbons.
  • Preferred compounds which may be used to practice the present invention may be selected from the group consisting of methyl 3-(4-hydroxyphenyl)-2-hydroxypropionate, n-propyl 3-(4- hydroxyphenyl)-2-hydroxypropionate, n-butyl 3-(4-hydroxyphenyl)-2- hydroxypropionate, 3-(4-hydroxyphenyl)-2-propenoic acid, 4-(4-hydroxyphenyl)- 2-butanone, l-(4-hydroxyphenyl)-3-pentanone, methyl (4- hydroxyphenoxy)acetate, and methyl 3-(3,4-dihydroxyphenyl)-2-propenoate.
  • Another aspect of the invention provides a method of treating cancer and pathological conditions of the immune system, including, but not limited to, autoimmune diseases and graft vs. host disease, comprising administering a therapeutic dose of a compound selected from the group consisting of the formulas:
  • Ri and R4 are selected from the group consisting of H and OH;
  • R2 and R3 are selected from the group consisting of H, OH, OCH3, amino, alkylamino and alkyl groups containing 1 to 6 carbons, acyloxy, and halogens;
  • R5 is selected from the group consisting of H, OH, OCH3, acyloxy and halogens;
  • R' ⁇ and R'2 are selected from the group consisting of H, OH, OCH3, amino, cyano, alkylamino groups of 1 to 6 carbon atoms, acyloxy, halogens and a-azido and aziridine derivatives, 3,4-dihydroxyphenylmethylene, p-hydroxyphenylmethylene and other substituted phenyl groups preferably with acyloxy or halogen substituents;
  • R'3, R'4, R'5, R" ⁇ and R"2 are selected from the group consisting of H, OH, OCH3, amino, cyan
  • chalcone R" ⁇ and R"2 When the chalcone R" ⁇ and R"2 is substituted to form an aziridine ring system, a three membered ring structure comprising the R" ⁇ and R"2 carbons and a nitrogen atom is formed.
  • Preferred compounds which may be used to practice the present invention may be selected from phenylmethylene ketones, nitroalkenes, aurones and chalcones. Phenylmethylene ketones most preferred for practicing the present invention include
  • Ri, and R4 are H; OH, acyloxy or halogens, R2 and R3 are OH, OCH3, amino, alkyl or alkylamino groups of 1 to 6 carbon atoms or halogens, R'p and R'2 are H, CH3, or phenylmethylene having p-hydroxy, 3,4-dihydroxy, acyloxy and halogen ring subtituents and R * 3 is H, OH, CH3 ,OC ⁇ b, and alkyl groups from 1-6 carbon atoms.
  • phenylmethylene ketones which may be used to practice the present invention are selected from the group consisting of
  • Nitroalkenes most preferred for practicing the present invention include
  • Ri, R2 and R3 are H, OH, OCH 3 , amino, alkyl or alkylamino groups of 1 to 6 carbon atoms, acyloxy and halogens, and Re is H, or alkyl group of 1 to 6 carbon atoms.
  • nitroalkenes most preferably used to practice the present invention are:
  • aurones most preferable for practicing the present invention are:
  • R1-R4 and R'I-R'S are H, OH, OCH3, amino, alkyl or alkylamino groups of 1 to 6 carbon atoms.
  • the most preferable aurones useful in practicing the present invention are MV-19, MV-20 and MV-21.
  • chalcones most preferable for practicing the present invention are:
  • R 1 -R5, R' l -R's, R" ⁇ and R' 2 are H, OH, OCH 3 , amino,cyano, alkyl or alkylamino groups of 1 to 6 carbon atoms, acyloxy and halogens and a- azido and aziridine derivatives.
  • chalcones useful in practicing the present invention are:
  • Another aspect of the invention involves the inhibition of the growth of proliferating cells which include a Type II nuclear estrogen binding site by the step of administering a biological inhibiting dose of MeHPLA, its analogs, chemical derivatives or chemically related compounds such as phenylmethylene ketones, nitroalkenes, analogs and chalcones to the proliferating cells.
  • An additional aspect of the present invention is the inhibition of the proliferative growth of estrogen responsive tissues such as uterus, mammary gland, uterine tumors and mammary tumors.
  • the above- mentioned compounds have been used for the treatment of human breast cancer cells.
  • the compounds inhibit the growth of human breast cancer cells.
  • An additional aspect of the present invention is the provision of an immunosuppressive agent.
  • these compounds are selected from the group consisting of MeHPLA, its analogs, derivatives and chemically related compounds including, but not limited to, phenylmethylene ketones, nitroalkenes, aurones, and chalcones, and physiologically acceptable salts thereof.
  • Another specific aspect of the present invention is a method for treating benign prostatic hyperplasia comprising the step of administering a therapeutic dose of MeHPLA, its analogs, derivatives and chemically related compounds including, but not limited to, phenylmethylene ketones, nitroalkenes, aurones, and chalcones, and physiologically acceptable salts thereof.
  • Another specific aspect of the present invention is a method for treating autoimmune diseases, including, but not limited to, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitis, thyroiditis, uveoretinitis, systemic lupus erythematosus, Sjogren's syndrome, autoimmune skin diseases, and others comprising the step of administering a therapeutic dose of MeHPLA, its analogs, derivatives and chemically related compounds including, but not limited to, phenylmethylene ketones, nitroalkenes, aurones, and chalcones, and physiologically acceptable salts thereof.
  • Another specific aspect of the present invention is a method for treating autoimmune diseases, including, but not limited to, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitis, thyroiditis, uveoretinitis, systemic lupus erythematosus, Sjogren's syndrome, autoimmune skin diseases, and others comprising the step of administering a therapeutic dose of a compound selected from the group consisting of
  • Ri is selected from the group consisting of H, alkyl groups containing 1 to 6 carbons, and aryl groups; R2 and R3 are selected from the group consisting of H, OH and OCH 3 and R 4 is selected from the group consisting of H, or alkyl group containing 1 to 6 carbons.
  • Preferred compounds which may be used to practice the present invention may be selected from the group consisting of methyl 3-(4-hydroxyphenyl)-2-hydroxypropionate, n-propyl 3-(4r hydroxyphenyl)-2-hydroxypropionate, n-butyl 3-(4-hydroxyphenyl)-2- hydroxypropionate, 3-(4-hydroxyphenyl)-2-propenoic acid, 4-(4-hydroxyphenyl)- 2-butanone, l-(4-hydroxyphenyl)-3-pentanone, methyl (4- hydroxyphenoxy)acetate, and methyl 3-(3,4-dihydroxyphenyl)-2-propenoate. and
  • Ri and R4 are selected from the group consisting of H and OH;
  • R2, R3 and Re are selected from the group consisting of H, OH, OCH3, amino, alkylamino and alkyl groups containing 1 to 6 carbons, acyloxy, and halogens;
  • R5 is selected from the group consisting of H, OH, OCH3, acyloxy and halogens;
  • R' ⁇ and R'2 are selected from the group consisting of H, CH 3 , OH, OCH3, 3,4- dihydroxyphenylmethylene, p-hydroxyphenylmethylene and other substituted phenyl groups preferably with acyloxy or halogen substituents;
  • R'3, R' 4 , R'5, R" ⁇ and R !
  • Preferred compounds which may be used to practice the present invention may be selected from phenylmethylene ketones, nitroalkenes, aurones and chalcones.
  • Another aspect of the present invention is the provision of an antitumor agent which comprises analogs of MeHPLA, including, but not limited to, phenylmethylene ketones, nitroalkenes, aurones, and chalcones, derivatives and chemically related compounds and physiologically acceptable salts thereof.
  • an immunosuppressive agent which comprises analogs of MeHPLA, including, but not limited to, phenylmethylene ketones, nitroalkenes, aurones, and chalcones, derivatives and chemically related compounds and physiologically acceptable salts thereof.
  • prophylactic agents to inhibit and prevent cancer, autoimmune disease, graft versus host disease and non- malignant cell growth.
  • These prophylactic agents include the above-mentioned MeHPLA, its analogs, including but not limited to, phenylmethylene ketones, nitroalkenes, aurones, and chalcones, chemical derivatives or chemically related compounds and pharmaceutically acceptable salts thereof.
  • Figure 1 represents the competition of MV-3, MV-12 and MV-88 for
  • Figure 2 represents the analysis of nuclear type II binding sites in popliteal Lymph node nuclei.
  • Figure 3 represents the effects of MV-3, MV-12, and MV-88 on MCF-7 human breast cancer cell proliferation.
  • Figure 4 represents the effects of the compounds of the present invention on Mouse Mammary tumor growth in vivo.
  • Figure 5 represents the effects of MV-19, MV-20 and MV-21 on mouse mammary tumor growth in vivo.
  • Figure 6 demonstrates the effects of cyclodextrin encapsulated MV-88 on mouse mammary tumor growth in vivo.
  • Figure 7 demonstrates the inhibition of the development of autoimmune uveoretinitis.
  • MeHPLA methyl p-hydroxyphenyllactate
  • chemically related compounds refers to the derivatives and analogs of p-coumaric acid, p-hydroxyphenylbutanone, (4- hydroxyphenoxy)acetate and the arylpropenaldehydes, alkyl arylethenyl ketones, aryl arylethenyl ketones, aryl butenaldehydes, alkyl arylpropenyl ketones and arylpropenyl ketones which are structurally related to MeHPLA and disclosed herein.
  • chemically related compounds include the cis and trans isomers of said compounds and their esters, ethers, ketones and derivatives containing S or N in place of O atoms.
  • these structurally related analogs and derivatives include compounds where Ri represents the methyl, ethyl, n-propyl, n- butyl, isopropyl, tert-butyl or aryl group and R2 and R3 represent H, OH or OCH3 groups and R4 is H or an alkyl group of 1 to 6 carbons.
  • R2 and R3 represent H, OH or OCH3 groups and R4 is H or an alkyl group of 1 to 6 carbons.
  • Specific analogs of each class of these structurally related compounds to MeHPLA have been demonstrated to possess biological activity (Tables I and II) as defined herein and therefore mimic MeHPLA as an effective inhibitor of cell proliferation, tumor cell growth and as immunosuppressive agents.
  • analogs and chemically related compounds effective in practicing the present invention include, but are not limited to, phenylmethylene ketones, nitroalkenes, aurones, and chalcones. Most preferably, these analogs are selected from the group consisting of the general formulas:
  • Ri is selected from the group consisting of H, alkyl groups containing 1 to 6 carbons, and aryl groups; R2and R3 are selected from the group consisting of H, OH and OCH3 and R4 is selected from the group consisting of H, or alkyl group containing 1 to 6 carbons.
  • Preferred compounds which may be used to practice the present invention may be selected from the group consisting of methyl 3-(4-hydroxyphenyl)-2-hydroxypropionate, n-propyl 3-(4- hydroxyphenyl)-2-hydroxypropionate, n-butyl 3-(4-hydroxyphenyl)-2- hydroxypropionate, 3-(4-hydroxyphenyl)-2-propenoic acid, 4-(4-hydroxyphenyl 2-butanone, l-(4-hydroxyphenyl)-3-pentanone, methyl (4- hydroxyphenoxy)acetate, and methyl 3-(3,4-dihydroxyphenyl)-2-propenoate.
  • Another aspect of the invention provides a method of treating cancer and pathological conditions of the immune system, including, but not limited to, autoimmune diseases and graft vs. host disease, comprising administering a therapeutic dose of a compound selected from the group consisting of the formulas:
  • Ri and R 4 are selected from the group consisting of H and OH;
  • R2 and R3 are selected from the group consisting of H, OH, OCH3, amino, alkylamino and alkyl groups containing 1 to 6 carbons, acyloxy, and halogens;
  • R5 is selected from the group consisting of H, OH, OCH 3 , acyloxy and halogens;
  • R' ⁇ and R'2 are selected from the group consisting of H, CH3, OH, OCH3, 3,4- dihydroxyphenylmethylene, p-hydroxyphenylmethylene and other substituted phenyl groups preferably with acyloxy or halogen substituents;
  • R'3, R'4, R'5, R" ⁇ and R' 2 are selected from the group consisting of H, OH, OCH 3 , amino, cyano, alkylamino groups of 1 to 6 carbon atoms, acyloxy, halogens and a-azido and aziridine derivatives
  • Ri, and R4 are H; OH, acyloxy or halogens, R2 and R3 are OH, OCH3, amino, alkyl or alkylamino groups of 1 to 6 carbon atoms or halogens, R' and R'2 are H, CH3, or phenylmethylene having p-hydroxy, 3,4-dihydroxy, acyloxy and halogen ring subtituents and R' 3 is H, OH, CH 3 ,OCH 3 and alkyl groups from 1-6 carbon atoms.
  • phenylmethylene ketones which may be used to practice the present invention are selected from the group consisting of
  • nitroalkenes most preferably used to practice the present invention are:
  • aurones most preferable for practicing the present invention are:
  • chalcones most preferable for practicing the present invention are:
  • the term "individual” is meant to include animals and humans.
  • biologically inhibiting or “inhibition” of the growth of proliferating cells is meant to include partial or total growth inhibition and also is meant to include decreases in the rate of proliferation or growth of the cells.
  • the biologically inhibitory dose of the compounds of the present invention may be determined by assessing the effects of the test compound on malignant cell growth in tissue culture (see Figure 3), uterine growth in the animal (see Figures 14 and 15) or tumor growth in the animal as previously described by Markaverich et al., Cancer Research 43:3208-3211 (1983), or any other method known to those of ordinary skill in the art. These methods have also been fully described in U.S. Patent Application No. 219,680 which is incorporated herein by reference as if it appeared in full.
  • immunosuppresive or “immunosuppressing” or “suppression of the immune system” is meant to include partial or total immune suppression and is also meant to include changes in immune function such that "abnormal" immune functions become more normalized.
  • the immunosuppressive dose of the compounds of the present invention may be determined by assessing the effects of the test compound in the established rat model of experimental autoimmune uveoretinitis as described by Gery et al., (1986) Invest. Ophthalmol. Vis. Sci. 27: 1296, or any other method known to those of ordinary skill in the art.
  • prophylactic agent is meant to include agents which may be used for partial or total inhibition or prevention of disease and the spread of disease and also is meant to include agents which may be used as a precaution against disease and for preventive treatment of disease.
  • Administration of the compounds useful in the method of the present invention may be by topical, parenteral, oral, intranasal, intravenous, intramuscular, subcutaneous, or any other suitable means.
  • the dosage administered is dependent upon the age, weight, kind of concurrent treatment, if any, and nature of the malignancy or the pathological immune condition.
  • the effective compound useful in the method of the present invention may be employed in such forms as capsules, tablets, liquid solutions, suspensions, or elixirs, for oral administration, or sterile liquid forms such as solutions, suspensions or emulsions.
  • Any inert carrier is preferably used, such as saline, or phosphate-buffered saline, or any such carrier in which the compounds used in the method of the present invention have suitable solubility properties.
  • the compounds of the present invention may be administered in a biologically effective carrier.
  • the biologically effective carriers may include any solvent with which the compounds of the present invention are compatible and which are non-toxic to the individuals treated at the amounts administered.
  • the compounds of the present invention are administered as an encapsulated composition. Due to the low aqueous solubility of many of the compounds effective in carrying out the present invention, another aspect of the present invention comprises the drug delivery system of the compounds of the present invention encapsulated in cyclodextrin, liposomes or as silastic implants. However, the compounds of the present invention may be encapsulated by other methods and with other compounds by methods known to those skilled in the art.
  • agent is meant to include agents which decrease cell growth, or inhibit the proliferation of tumor cells when administered to said tumor cells in an effective dose.
  • One specific embodiment of this invention is an antitumor agent including MeHPLA, its analogs, chemical derivatives or chemically related compounds.
  • MeHPLA analogs are derivatives of the general formula
  • Ri is selected from the group consisting of H, alkyl groups containing 1 to 6 carbons, and aryl groups; R2and R3 are selected from the group consisting of H, OH and OCH3 and R4 is selected from the group consisting of H, or alkyl group containing 1 to 6 carbons.
  • Preferred compounds which may be used to practice the present invention may be selected from the group consisting of methyl 3-(4-hydroxyphenyl)-2-hydroxypropionate, n-propyl 3-(4- hydroxyphenyl)-2-hydroxypropionate, n-butyl 3-(4-hydroxyphenyl)-2- hydroxypropionate, 3-(4-hydroxyphenyl)-2-propenoic acid, 4-(4-hydroxyphenyl 2-butanone, l-(4-hydroxyphenyl)-3-pentanone, methyl (4- hydroxyphenoxy)acetate, and methyl 3-(3,4-dihydroxyphenyl)-2-propenoate.
  • Ri is CH 3
  • R2 is H
  • R3 is OH
  • R4 is H.
  • This is a naturally occurring endogenous compound which was isolated and characterized and identified as the present invention.
  • Other examples of analogs include the compounds in which the R group has been replaced by an ethyl, n-propyl, n-butyl, isopropyl, tert-butyl or aryl group; R2 and/or R3 have been replaced with an H, OH or OCH3 group and R4 is H or an alkyl group of 1 to 6 carbons.
  • R2 and/or R3 have been replaced with an H, OH or OCH3 group
  • R4 is H or an alkyl group of 1 to 6 carbons.
  • Each of these esters can exist in the D and L form.
  • Another group of derivative compounds includes those with the formula:
  • Examples of these compounds are p-coumaric acid, 3-(4-hydroxyphenyl> 2-propenoic acid, and its esters. These substances exist as cis and trans isomers.
  • Ri and R 2 are hydrogen and R3 is OH.
  • Additional esters include compounds wherein Ri is methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl or aryl and R2 and/or R3 is a H, OH or OCH3 group.
  • Additional analogs include caffeic acid, 3-(3,4-dihydroxyphenyl)-2-propenoic acid, wherein Ri is H and R2 and R3 are both OH.
  • Other compounds with antitumor activity are the derivatives of l-(4- hydroxyphenyl)-3-butanone, such as compounds with the formula:
  • Rl is selected from the group consisting of H, alkyl groups containing 1 to 6 carbons, and aryl groups;
  • R2 and R3 are selected from the group consisting of H, OH and OCH3 and
  • R4 is selected from the group consisting of H, or alkyl group containing 1 to 6 carbons.
  • Preferred compounds which may be used to practice the present invention may be selected from the group consisting of methyl 3-(4-hydroxyphenyl)-2-hydroxypropionate, n-propyl 3-(4- hydroxyphenyl)-2-hydroxypropionate**, n-butyl 3-(4-hydroxyphenyl)-2- hydroxypropionate, 3-(4-hydroxyphenyl)-2-propenoic acid, 4-(4-hydroxyphenyl> 2-butanone, l-(4-hydroxyphenyl)-3-pentanone, methyl (4- hydroxyphenoxy)acetate, and methyl 3-(3,4-dihydroxyphenyl)-2-propenoate.
  • Ketone derivatives include compounds with a methyl, ethyl, n-propyl, n- butyl, isopropyl, tert-butyl or aryl group at the Ri position, H, OH or OCH3 group at the R2 and R3 positions; and most preferably H at the R2 position and OH at the R3 position.
  • the number of CH2 groups between the aromatic entity and the keto group can be varied.
  • Specific examples of compounds are l-(4-hydroxyphenyl)-3-pentanone and l-(4-hydroxyphenyl)-3- butanone. These compounds have been shown to bind to Type II sites and to have antitumor and anti-proliferative activity in the uterotropic assay.
  • Another group of compounds which show anti-proliferative activity in the rat uterus is described by the formula:
  • These compounds are ether-linked analogs of (4-hydroxyphenoxy)acetic acid, for example, methyl (4-hydroxyphenoxy)acetate. All of these compounds bind to the Type II binding sites.
  • These ether-linked compounds include analogs wherein Ri is H, a Ci to C alkyl carbon chain or an aryl group, R2 and R3 are H, OH or OCH3.
  • An additional variation on the phenoxy compounds include the ether compounds, for example, 2-(4-hydroxyphenoxy) ethyl methyl ether, wherein R l can be H or any Ci to C ⁇ alkyl carbon chain or an aryl group, R2 and R3 are H, OH or OCH 3 in the formula:
  • Ri is a Ci to C ⁇ alkyl chain or an aryl group
  • R2and R3 are H, OH or OCH 3 .
  • Another group of compounds which show tumor anti-prolif erative action is described by the general formulas:
  • Ri is from the group consisting of H, alkyl groups containing 1 to 6 carbons, and substituted or unsubstituted aryl groups; and R2and R3 are selected from the group consisting of H, OH and OCH3.
  • Preferred compounds of this group which may be used to practice the present invention are:
  • Most preferred compounds of this group for practicing the present invention are 3-(4-hydroxyphenyl)-l-phenyl-2-propen-l-one and 4-(4- hydroxyphenyl)-3-buten-2-one, analogs, chemical derivatives and chemically related compounds and pharmaceutically acceptable salts thereof.
  • Another embodiment of the present invention includes a method for treating cancer comprising the step of administering a therapeutic dose of MeHPLA, its analogs, chemical derivatives or chemically related compounds.
  • This compound can be any of the above-described antitumor compounds.
  • these antitumor agents are also useful as inhibitors of cell growth and proliferation in those cells which include a Type II nuclear estrogen binding site.
  • These compounds bind to Type II nuclear estrogen binding sites and regulate cell growth.
  • Specific proliferating cells which are sensitive to the binding of these compounds include estrogen responsive tissues such as uterus, mammary gland, uterine tumors and mammary tumors.
  • the above-described compounds inhibit the proliferative capacity of human breast cancer cells and thus provide an effective therapy for this disease.
  • Benign prostatic hyperplasia is another example of a proliferative tissue disease in which the above-described compounds can successfully be used in the treatment.
  • Ri is from the group consisting of H, alkyl groups containing 1 to 6 carbons, and substituted or unsubstituted aryl groups; and R2and R3 are selected from the group consisting of H, OH and OCH3.
  • Preferred compounds of this group which may be used to practice the present invention are:
  • Most preferred compounds of this group for practicing the present invention are 2'-hydroxychalcone, 2',4',4,-trihydroxychalcone, 4-hydroxychalcone, 4-4- dihydroxychalcone, MV-35, MV-46, and MV-47, analogs, chemical derivatives and chemically related compounds and pharmaceutically acceptable salts thereof.
  • Another embodiment of the present invention includes a method for treating autoimmune diseases comprising the step of administering a therapeutic dose of MeHPLA, its analogs, including, but not limited to, phenylmethylene ketones, nitroalkenes, aurones, and chalcones, chemical derivatives or chemically related compounds.
  • This compound can be any of the above-described antitumor or immunosuppressive compounds.
  • Nuclear Type ⁇ sites bound maximum quantities of [ ⁇ Hjestradiol. Aliquots of these nuclei and various concentrations of the compounds of the present invention were incubated at about 4°C for approximately 60 min in the presence of 40 mM of pH] estradiol with and without 12 uM diethylstilbestrol. Under these conditions, nuclear Type II sites were quantitatively measured without interference from Type I sites. The nuclear pellets were resuspended in 1 ml of 10 mM Tris-1.5 mM EDTA and centrifuged, ethanol extracted, and counted.
  • Ki is the concentration (mM) of the compound required to inhibit [ H]estradiol binding to Nuclear Type II sites by 50% (see Figure 5).
  • ''Ki is the concentration (mg ml) required to inhibit MCF-7 human breast cancer cell proliferation by 50% (see Figure 5).
  • c This compound inhibited the growth of well differentiated mouse mammary adenocarcinomas in vivo (see Figures 7-9).
  • popliteal lymph node nuclei were prepared and analysis of Nuclear Type L ⁇ binding sites were performed by [SHjestradiol exchange. Popliteal lymph nodes were removed from mature female mice, dissected from extraneous tissue, weighed and homogenized in TE buffer (10 mM Tris; 1.5 mM EDTA, pH 7.4). The homogenate was centrifuged at 800 x g for 20 minutes to obtain the nuclear pellet.
  • the nuclear pellet was washed three times by resuspension and centrifugation in TE buffer (800 x g x 7 minutes), and the final washed nuclear preparation was diluted to a final volume of 30 mg tissue wet weight equivalents/ml (8.6 ml) and assayed for Type LI binding sites by ⁇ H] estradiol exchange (Markaverich et al, Endocrinology 109: 62-69 (1981)).
  • Results were expressed as picomoles of [ 3 H] estradiol bound per gram wet weight of lymph node tissue and 1 pmole represented 70265 cpm.
  • Figure 2 demonstrates the presence of nuclear type LI estrogen binding sites in the popliteal lymph nodes. These type II binding sites in popliteal lymph nodes possessed an equivalent binding affinity (Kd»20nM) to those sites observed in other tissues such as the rat uterus, and were present in equivalent numbers as compared to those measured in other non- estrogenized, non-malignant tissues. Popliteal lymph nodes contain almost exclusively lymphocyte cells and these cells should therefore be inhibited by MeHPLA related analoges and derivatives through binding interactions with nuclear type LI sites.
  • the MCF-7 human breast cancer cell line in tissue culture was used.
  • the MCF-7 cells have both Type I and nuclear Type II estrogen receptor sites and respond in a proliferative fashion to estrogenic hormones. Furthermore, they are inhibited by well-known anti- estrogens such as Tamoxifen.
  • the MCF-7 cells were plated at 5 x l cells/dish in 30 mm petri dishes and grown in Dulbecco's Modified Eagles Medium containing about 10% charcoal stripped fetal bovine serum for approximately 48 hours.
  • the cells attached to the plastic dishes and then underwent exponential growth with a cell-doubling time of approximately 24 hours.
  • the plated cells were allowed to attach for approximately 48 hours and the medium was replaced ("day zero").
  • the cells were allowed to grow exponentially for about 6 days.
  • the cells were treated with doses ranging from 0.1- 10 ug/ml of the compound of interest, for example, methyl p- hydroxyphenyllactate, in 10 ul of ethanol.
  • the medium was changed at about 2 and 4 days.
  • the control and test solutions were also re-added when the medium was changed.
  • the cells were harvested, counted on a hemocytometer and DNA content per dish was determined by the Burton assay (Burton, K., Biochem. J. 62:315-323, 1956). Results are expressed as cells/dish or DNA content (ug dish) at 6 days following treatment. The results are shown in Figure 3.
  • MCF-7 cells were plated at 2 x 10 ⁇ cells/well in Dulbecco's Modified Eagles Medium (DMEM) containing 10% fetal calf serum.
  • DMEM Dulbecco's Modified Eagles Medium
  • the cells were treated with concentrations of MV-3, MV-12 or MV-88 at concentrations ranging from l( ⁇ to 10 ⁇ ng/ml dissolved in 10 ul ethanol. Controls were treated with an equivalent volume of ethanol. The cell number was determined 48 hrs following treatment. As demonstrated in Figure 3, MV-3, MV-12, and MV-88 also inhibited the proliferation of MCF-7 human breast cancer cells. The proliferation of Y-79 retinoblastoma cells, ME- 180 human cervical cancer cells and human melanoma cells was also inhibited (data not shown). Utilizing similar data derived from inhibition curves for all of the compounds shown in Table ⁇ , the Ki's for cell inhibition was determined.
  • the Ki for inhibition is defined as the concentration of drug ( ⁇ g/ml) required to inhibit cell proliferation by 50%.
  • Table IT INHIBITION OF HUMAN MELANOMA (HS0294 CELLS) AND BREAST CANCER (MCF-7 CELLS) CELL PROLIFERATION BY CHALCONES AND THEIR DERIVATIVES.
  • Ki for inhibition where Ki is the concentration ( ⁇ g/ml) required to inhibit cell proliferation by 50% (see Figure 5) relative to control (untreated cells).
  • tumor cell proliferation is very rapid because the tumor cell metabolizes or inactivates the J- peak inhibitor. This is supported by the observation that methyl p-hydroxyphenyllactate is found bound to Type II sites in normal tissues but is not found in malignant tissue.
  • Cell proliferation is regulated by ligand binding to nuclear Type LI sites. The number of unbound sites determines the rate of proliferation. Since tumor cells have an increased number of unbound nuclear Type LI sites and thus, their growth is not inhibited by the amount of endogenous inhibitor normally present in the cells. Therefore, tumor cell proliferation is dramatically accelerated as compared to the rate of normal cell proliferation (i.e., cells with fewer or no unbound nuclear Type II sites).
  • a transplantable mouse mammary tumor model system was utilized. This tumor model and its use as an assay for anti-tumor drugs has been previously described by Markaverich et al. Cancer Res. 43:3208 (1983) and is incorporated herein by reference. Briefly, syngeneic female mice bearing transplanted mammary tumors were divided into experimental groups as indicated. When the tumors were approximately 0.5 x 0.5 cm in size (length x width) (day 0), the animals were treated with blank silastic capsules (controls), or silastic capsules containing 25 mg of the test compound. Tumor size (length x width) was monitored at the indicated times following treatment. These implants continuously released 450 ng of the compound daily.
  • Figure 4 demonstrates that MV-3, MV-12 and MV-88 inhibited the growth of these tumors as compared to controls. Similarly, an excellent correlation was observed between binding affinity (Table I) and the anti-tumor activity of MV-19, MV-20 and MV-21 ( Figure 19).
  • the rat uterus is extremely sensitive to estrogen, and this hormone stimulates uterine cellular hypertrophy, hyperplasia and DNA synthesis within 24 hours following a single injection. Estradiol stimulation of nuclear Type II sites is a prerequisite for these responses.
  • This assay includes injecting immature female rats with saline-ethanol vehicle, estradiol-17i and the test compound of interest. Control rats were injected only with saline-ethanol vehicle and estradiol-17j. The rats were sacrificed 24 hours later and the uterine wet and dry weights were determined. The wet and dry weight measurements are well defined biochemical end points of estrogen action and are a direct index of changes in cell proliferation and DNA synthesis. The results of these experiments with various compounds are shown in Table LLL
  • l-(4-hydroxyphenyl)-3-butanone which includes a C-terminal methyl group is not subject to the esterase cleavage since the methyl group is attached by a C-C bond.
  • This compound is more stable and thus a better inhibitor in culture and in vivo.
  • experiments with l-(4-hydroxyphenyl)-3-butanone demonstrated that it binds to the nuclear Type LI sites with a high affinity and blocks estradiol stimulation of uterine growth when injected into immature rats.
  • l-(4- hydroxyphenyl)-3-butanone is an effective inhibitor of tumor growth and regulator of cell proliferation.
  • the compounds of the present invention particularly phenylmethylene ketones, nitroalkenes, aurones, and chalcones, have very low solubility in aqueous solutions such as those commonly used as injection vehicles. This insolubility causes major problems with drug delivery and potential use clinically.
  • the compounds may be encapsulated to improve their delivery.
  • the types of drug delivery systems useful in the present invention are incorporation into liposomes and encapsulation in cyclodextrins.
  • Cyclodextrins solubilize hydrophobic compounds and improve gastrointestinal absorption (Szejtli, (1982) In: “Cyclodextrins and Their Inclusion Complexes", Akadmiai Kiado, Budapest, Hungary).
  • Bioflavonoids such as quercetin (closely related to MV-88) have recently been administered by this method (Yan, et al (1988) Zhongcaoyoa, 19:492).
  • the lack of cytotoxicity of 2- hydroxypropyl J-cyclodextrin and poly J-cyclodextrin (a soluble form of ?- cyclodextrin) has been demonstrated in animals (Pitha and Pitha (1985) J. Pharm. Sci.
  • Cyclodextrin was condensed with propylene oxide in aqueous alkali to give 2- hydroxycyclodextrin as described in Pitha and Pitha (1985). The drug was added in excess (2 fold excess, i.e., 200 mg drug to 100 mg 2-hydroxycyclodextrin) to a solution of 2-hydroxycyclodextrin dissolved in water or saline.
  • HPLC high performance liquid chromatography
  • MV-88 encapsulated in cyclodextrin was dissolved in saline vehicle and administered by subcutaneous injection to mammary tumor bearing mice.
  • MV-88 is insoluble under aqueous conditions.
  • MV-88 cyclodextrin (MV-88 CD; Table I) inhibited mouse mammary tumor growth in a dose-dependent fashion ( Figure 6).
  • MV-88 when administered by injection in other vehicles such as dimethylsulfoxide saline, MV- 88 was not as effective at inhibiting the growth of this tumor as when administered after cyclodextrin encapsulation.
  • MV- 88 when administered in a continuous fashion by silastic implant ( Figure 4), significantly inhibited tumor growth.
  • mice bearing transplantable mammary tumors were implanted with silastic capsules containing 25 mg of the test compound. Controls were implanted with blank capsules and tumor size (length x width) was determined at the 0, 3, 6 and 14 days following implantation. The capsules releases approximately 450 ng of test compound per day (about 10-15 mg/Kg of body weight). No significant effects on the body weights of the treated animals relative to controls were observed throughout the experimental period.
  • Figure 4 demonstrates that treatment of mouse mammary tumors with MV-3, MV-12, and MV-88 in silastic implants caused a complete inhibition of the growth of the mammary tumor in vivo.
  • Immunosuppressive drugs have proven to be therapeutically effective in treating a variety of autoimmune diseases. In the United States, 10-15% of all blindness is caused directly or indirectly by inflammation of the uveal tract or uveitis. Unless therapeutic intervention in uveoretinitis is initiated, irreversible damage can occur resulting in reduced retinal function and/or blindness. The administration of corticosteroids is currently the most effective treatment for uveoretinitis.
  • Immunosuppressive drugs used heretofore including cyclosporin-A (csA) which blocks the proliferation of T-lymphocytes by interference with the Interleukin-2 receptor expression produce adverse side effects such as hepatotoxicity and nephrotoxicity.
  • csA cyclosporin-A
  • the compounds of the present invention such as MV-3 were tested for immunosuppressive activity using the established rat model of experimental autoimmune uveoretinitis (Gery et al. (1986) Invest. Opthalmol. Vis. Sci. 103: 1559).
  • Female Lewis rats weighing 100-200 grams were immunized with Interphotoreceptor Retinoid Binding Protein (LRBP) peptide corresponding to amino acid positions 523-538 of the bovine and human molecules.
  • LRBP Interphotoreceptor Retinoid Binding Protein
  • This sequence designated #896 has the amino acid sequence LTSHRTATAAEEFAFL.
  • the rats were immunized by a single foot pad injection of 50 micrograms of LRBP #896 emulsified in complete Freund's adjuvant containing 2.0 mg/ml M.
  • tuberculosis H37Ra (Difco).
  • the rats simultaneously received 10x10 ⁇ heat-killed B. pertussis organisms by intraperitoneal injection. 100% of the control, untreated animals developed severe, bilateral anterior uveitis and posterior uveoretinitis by day 9 or day 10 following immunization.
  • Experimental animals were given intraperitoneal injections of 10 mg of MV-3 on Days 0, 3 and 7.
  • MV-3 and related compounds also have anti-inflammatory properties.
  • MV-3 as well as other compounds of the present invention provide a useful method for treating and/or preventing other autoimmune diseases, including, but not limited to, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitis, thyroiditis, systemic lupus erythematosus, Sjorgen's syndrome, autoimmune skin diseases, and others.
  • MV-3 and related compounds provide a useful treatment for graft vs host disease and prevention of transplant rejections.

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Abstract

On décrit des composés nouveaux et utiles comprenant le p-hydroxyphényllactate méthylique, ses analogues, ses dérivés chimiques, des composés chimiques et des composés chimiquement connexes, ainsi que leur utilisation en tant qu'agents antitumoraux et immunosuppresseurs, en tant qu'inhibiteurs de la croissance de cellules prolifératives et en tant qu'agents prophylactiques servant à inhiber et prévenir le cancer et la croissance de cellules bénignes.
PCT/US1991/003130 1990-05-17 1991-05-06 Inhibiteurs de croissance cellulaire et procedes servant a traiter le cancer et des maladies a proliferation cellulaire WO1991017749A1 (fr)

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011757A1 (fr) * 1991-12-10 1993-06-24 Orion-Yhtymä Oy Compositions de medicaments pour usage parenteral
US5393785A (en) * 1988-10-31 1995-02-28 Endorecherche, Inc. Therapeutic antiestrogens
US5395842A (en) * 1988-10-31 1995-03-07 Endorecherche Inc. Anti-estrogenic compounds and compositions
WO1996019209A1 (fr) * 1994-12-20 1996-06-27 Indena S.P.A. Chalcones et leurs esters a activite antiproliferative dans les tumeurs de l'uterus, de l'ovaire et du sein
US5686465A (en) * 1988-10-31 1997-11-11 Endorecherche Inc. Sex steroid activity inhibitors
WO1998058913A1 (fr) * 1997-06-19 1998-12-30 Indena S.P.A. Chalcones possedant une activite antiproliferante
US6060503A (en) * 1991-12-02 2000-05-09 Endorecherche, Inc. Benzopyran-containing compounds and method for their use
WO2001017988A1 (fr) * 1999-09-03 2001-03-15 Indena S.P.A. Nouvelles chalcones
WO2001017984A1 (fr) * 1999-09-03 2001-03-15 Indena S.P.A. Coumarine à base de chalcone
US6423740B1 (en) 1997-06-19 2002-07-23 Indena S.P.A. Chalcones having antiproliferative activity
WO2005063774A1 (fr) * 2003-12-22 2005-07-14 Johns Hopkins University Analogues d'aryle d'acide boronique
GB2425061A (en) * 2005-04-06 2006-10-18 Engelhard Lyon Aurone compounds having melanogenesis/depigmenting activity
WO2006136429A1 (fr) * 2005-06-24 2006-12-28 Dsm Ip Assets B.V. Composés pour le traitement du syndrome x et/ou de diabetes mellitus de type 2 non auto-immun
WO2008040208A1 (fr) * 2006-09-07 2008-04-10 Fudan University (2z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2h)-one utilisé pour la fabrication de médicaments destinés au traitement de cancers
WO2010110646A1 (fr) * 2009-03-27 2010-09-30 Biotropics Malaysia Berhad Aurones en tant qu'inhibiteurs sélectifs de pde et leur utilisation dans des affections et troubles neurologiques
WO2010110647A1 (fr) * 2009-03-27 2010-09-30 Biotropics Malaysia Berhad Aurones en tant que modulateurs de récepteur d'oestrogène et leur utilisation dans des maladies dépendantes des hormones sexuelles
CN103467320A (zh) * 2013-08-15 2013-12-25 沈阳药科大学 2,5-双取代环戊酮类衍生物及其应用
WO2014022660A1 (fr) * 2012-08-03 2014-02-06 Georgia State University Research Foundation, Inc. Analogues de curcumine et procédés de fabrication et d'utilisation de ceux-ci
FR3007970A1 (fr) * 2013-07-02 2015-01-09 Oreal Utilisation de derives de l'acide 4-hydroxyphenoxy-acetique en tant qu'agents apaisants
WO2017103637A1 (fr) 2015-12-18 2017-06-22 Blirt S.A. Composés de diphénylpropane et leur activité cytotoxique
CN107253915A (zh) * 2010-08-20 2017-10-17 有联生技股份有限公司 1，5‑二苯基‑戊‑1，4‑二烯‑3‑酮化合物
CN111655665A (zh) * 2017-12-27 2020-09-11 蒙得维的亚巴斯德研究所 硝基烯烃非甾体抗炎药(na-nsaids)及治疗炎症相关病症的方法
US10899727B2 (en) 2016-04-11 2021-01-26 Middle Tennessee State University Therapeutic aurones
CN114304062A (zh) * 2020-09-30 2022-04-12 北京市眼科研究所 一种自身免疫性视网膜病变动物模型的构建方法及其应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070092551A1 (en) * 2003-05-02 2007-04-26 Takara Bio Inc. Therapeutic agent

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0270690A1 (fr) * 1986-06-21 1988-06-15 Dainippon Ink And Chemicals, Inc. Medicament pour le traitement et la prophylaxie de maladies du rein et du foie

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1568633A1 (de) * 1966-12-02 1970-03-19 Bayer Ag Verfahren zur Herstellung von Cyclopentanonderivaten
JPS6242925A (ja) * 1985-08-20 1987-02-24 Kanegafuchi Chem Ind Co Ltd 酵素阻害剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0270690A1 (fr) * 1986-06-21 1988-06-15 Dainippon Ink And Chemicals, Inc. Medicament pour le traitement et la prophylaxie de maladies du rein et du foie

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
EDWARDS et al., "Chalcones, a New Class of Antimitotic Agents", J. Med. Chem., Vol. 33, pp 1948-1954 (1990, see entire reference. *
See also references of EP0528975A4 *
SMITH et al., "Mass Spectrometry of Some Substituted 2-Benzylidenecyclo Hexanones and 2, 6-Bis. Benzylidenecyclohexanones", Can. J. Chem. Vol. 51, pp 1458-1470 (1973), see entire reference. *

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US5393785A (en) * 1988-10-31 1995-02-28 Endorecherche, Inc. Therapeutic antiestrogens
US5395842A (en) * 1988-10-31 1995-03-07 Endorecherche Inc. Anti-estrogenic compounds and compositions
US5686465A (en) * 1988-10-31 1997-11-11 Endorecherche Inc. Sex steroid activity inhibitors
US5840735A (en) * 1988-10-31 1998-11-24 Endorecherche Inc. Sex steroid activity inhibitors
US6060503A (en) * 1991-12-02 2000-05-09 Endorecherche, Inc. Benzopyran-containing compounds and method for their use
US5571534A (en) * 1991-12-10 1996-11-05 Orion-Yhtyma Oy Drug formulations for parenteral use
WO1993011757A1 (fr) * 1991-12-10 1993-06-24 Orion-Yhtymä Oy Compositions de medicaments pour usage parenteral
CN1087609C (zh) * 1994-12-20 2002-07-17 因迪纳有限公司 有抗子宫、卵巢和乳腺肿瘤增生活性的查耳酮及其酯
WO1996019209A1 (fr) * 1994-12-20 1996-06-27 Indena S.P.A. Chalcones et leurs esters a activite antiproliferative dans les tumeurs de l'uterus, de l'ovaire et du sein
US5808137A (en) * 1994-12-20 1998-09-15 Indena S.P.A. Chalcones and esters thereof with antiproliferative activity in uterus, ovary and breast tumors
KR100264369B1 (ko) * 1994-12-20 2000-08-16 다리오 보나꼬르시 자궁, 난소 및 유방암에 항증식작용을 갖는 천연 및 합성 찰콘류 및 그의 에스텔과 그들을 함유한 제제
WO1998058913A1 (fr) * 1997-06-19 1998-12-30 Indena S.P.A. Chalcones possedant une activite antiproliferante
US6147082A (en) * 1997-06-19 2000-11-14 Indena Spa Chalcones having antiproliferative activity
US6423740B1 (en) 1997-06-19 2002-07-23 Indena S.P.A. Chalcones having antiproliferative activity
WO2001017988A1 (fr) * 1999-09-03 2001-03-15 Indena S.P.A. Nouvelles chalcones
WO2001017984A1 (fr) * 1999-09-03 2001-03-15 Indena S.P.A. Coumarine à base de chalcone
US6620842B2 (en) 1999-09-03 2003-09-16 Indena Spa Chalcones
US6767916B2 (en) 1999-09-03 2004-07-27 Indena S.P.A. Chalcone coumarins
WO2005063774A1 (fr) * 2003-12-22 2005-07-14 Johns Hopkins University Analogues d'aryle d'acide boronique
US7829742B2 (en) 2003-12-22 2010-11-09 Johns Hopkins University Boronic acid aryl analogs
US8304579B2 (en) 2003-12-22 2012-11-06 Johns Hopkins University Boronic acid aryl analogs
ES2301348A1 (es) * 2005-04-06 2008-06-16 Lyon Engelhard Utilizacion de al menos una aurona o un derivado de aurona o un analo go de aurona.
GB2425061B (en) * 2005-04-06 2008-06-25 Engelhard Lyon Use of aurones for their depigmenting activity or melanogenesis-inhibiting activity in cosmetic or dermatological compositions
GB2425061A (en) * 2005-04-06 2006-10-18 Engelhard Lyon Aurone compounds having melanogenesis/depigmenting activity
WO2006136429A1 (fr) * 2005-06-24 2006-12-28 Dsm Ip Assets B.V. Composés pour le traitement du syndrome x et/ou de diabetes mellitus de type 2 non auto-immun
WO2008040208A1 (fr) * 2006-09-07 2008-04-10 Fudan University (2z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2h)-one utilisé pour la fabrication de médicaments destinés au traitement de cancers
CN101511355B (zh) * 2006-09-07 2012-11-21 复旦大学 (2z)-2-(3,4-二羟基亚苄基)-1-苯并呋喃-3(2h)-酮在制备抗癌药物中的应用
WO2010110646A1 (fr) * 2009-03-27 2010-09-30 Biotropics Malaysia Berhad Aurones en tant qu'inhibiteurs sélectifs de pde et leur utilisation dans des affections et troubles neurologiques
WO2010110647A1 (fr) * 2009-03-27 2010-09-30 Biotropics Malaysia Berhad Aurones en tant que modulateurs de récepteur d'oestrogène et leur utilisation dans des maladies dépendantes des hormones sexuelles
CN107253915A (zh) * 2010-08-20 2017-10-17 有联生技股份有限公司 1，5‑二苯基‑戊‑1，4‑二烯‑3‑酮化合物
US9884825B2 (en) 2012-08-03 2018-02-06 Georgia State University Research Foundation, Inc. Curcumin analogs and methods of making and using thereof
WO2014022660A1 (fr) * 2012-08-03 2014-02-06 Georgia State University Research Foundation, Inc. Analogues de curcumine et procédés de fabrication et d'utilisation de ceux-ci
FR3007970A1 (fr) * 2013-07-02 2015-01-09 Oreal Utilisation de derives de l'acide 4-hydroxyphenoxy-acetique en tant qu'agents apaisants
CN103467320A (zh) * 2013-08-15 2013-12-25 沈阳药科大学 2,5-双取代环戊酮类衍生物及其应用
WO2017103637A1 (fr) 2015-12-18 2017-06-22 Blirt S.A. Composés de diphénylpropane et leur activité cytotoxique
US10899727B2 (en) 2016-04-11 2021-01-26 Middle Tennessee State University Therapeutic aurones
US11286245B2 (en) 2016-04-11 2022-03-29 Middle Tennessee State University Therapeutic aurones
CN111655665A (zh) * 2017-12-27 2020-09-11 蒙得维的亚巴斯德研究所 硝基烯烃非甾体抗炎药(na-nsaids)及治疗炎症相关病症的方法
CN114304062A (zh) * 2020-09-30 2022-04-12 北京市眼科研究所 一种自身免疫性视网膜病变动物模型的构建方法及其应用

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EP0528975A4 (en) 1993-09-15
CA2084208A1 (fr) 1991-11-18

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