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WO1996040620A1 - Retinoides de chalcone et leurs procedes d'utilisation - Google Patents

Retinoides de chalcone et leurs procedes d'utilisation Download PDF

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Publication number
WO1996040620A1
WO1996040620A1 PCT/US1996/011018 US9611018W WO9640620A1 WO 1996040620 A1 WO1996040620 A1 WO 1996040620A1 US 9611018 W US9611018 W US 9611018W WO 9640620 A1 WO9640620 A1 WO 9640620A1
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WIPO (PCT)
Prior art keywords
cancer
compound
chalcone
cells
retinoids
Prior art date
Application number
PCT/US1996/011018
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English (en)
Inventor
Rui Han
Zong-Ru Guo
Original Assignee
Institute Of Materia Medica
Mcinnis, Patricia, A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute Of Materia Medica, Mcinnis, Patricia, A. filed Critical Institute Of Materia Medica
Priority to EP96922607A priority Critical patent/EP0832060A1/fr
Priority to NZ311995A priority patent/NZ311995A/xx
Priority to JP9502320A priority patent/JPH11511121A/ja
Priority to IL12234196A priority patent/IL122341A0/xx
Priority to AU63423/96A priority patent/AU702423B2/en
Publication of WO1996040620A1 publication Critical patent/WO1996040620A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated

Definitions

  • the present invention relates to novel retinoids, as chalcone retinoids, and compositions thereof, which exhibit therapeutic and/or biological activity on cancer or precancer cells, as well as to methods of using same.
  • Retinoids play an important role in the development and differentiation of epidermal cells, as well as in reversing precancerous lesions.
  • Clinical trials have been conducted using N- (4-carboxyphenyl) retinamide in the treatment of some precancerous lesions, oral leukoplakia, vulval leukoplakia, atypical dysplasia of the cervix and the gastric mucosa, and the like (Han et al. , in vivo 4,:153-160 (1990)) .
  • Other retinoids, such as isoretinoin and etretinate are in current use as prescription drugs for the treatment of acne and psoriasis (Gander et al. , U.S. Patent No. 4,126,693) .
  • retinoids have a significant level of toxicity, and treatment using known retinoid agents suffers from problems due to the level of toxicity and side effects which accompany administration of known retinoid compounds. Accordingly, there exists a need to provide novel compounds having retinoid activity but which have less toxicity and/or side effects.
  • Smith et al. J. Clin . Oncol . _J_ (5) :839-864 (1992), reviews the use of retinoids in cancer therapy with most of the emphasis on anti-tumor effects in patients with acute promyelocytic leukemia (APL) .
  • Smith et al. reports that the natural retinoid, all-trans-retinoic acid (RA) ,
  • AML acute myeloid leukemia
  • neuroblastoma neuroblastoma
  • teratqcarcino a neuroblastoma
  • melanoma teratqcarcino a
  • rat rhabdomyosarcoma rat rhabdomyosarcoma cells
  • Clinical toxicities associated with the use of RA in dermatologic studies are listed in Table 6 of the Smith et al . reference with disclosure in the text that retinoids are recognized as powerful teratogens.
  • 1,127,170 is specifically directed to retinic acid N- (carboxy) -phenylamindes and 7, 8-dehydro-retinic acid N- (carboxy) -phenylamides, and discloses that, while the retinic compounds are predominantly directed toward preventing cancer, they may be used for therapeutic treatment of tumors of the bladder, the mammary gland, the skin and the mucous membranes.
  • a number of references disclose retinoids being used in cancer prophylaxis and as inducers of cell differentiation. For instance, Newton et al. , Cancer Res . 4.0:3413-3425 (1980) discloses a long list of esters, amines and amides of retinoic acid and their activity in cancer prophylaxis.
  • Preuss-Ueberschar et al. Drug Res . 3_4:1305-1313 (1984) discloses that benzopyrones, which include coumarin, are not teratogenic.
  • the pharmacology of coumarir.-related compounds is reviewed by Egan et al . which indicates that coumarin-related compounds are known to inhibit the carcinogenicity of carcinogens and that coumarin has been tested for treatment of melanoma.
  • Another object of the present invention is to provide novel retinoids, as chalcone retinoids, which have anti-neoplastic activity in vi tro .
  • a further object of the present invention is to provide novel retinoids, as chalcone retinoids, which have anti-neoplastic activity in vivo .
  • a still further object of the present invention is to provide novel retinoid compounds and compositions, using methods of the present invention, which compounds and/or compositions are useful for research and/or pharmaceutical applications in mammals, particularly humans.
  • retinoid compounds and compositions synergistically combine the cell differentiation activity of retinoids with the mitotic inhibitor activity of chalcones.
  • retinoids are also useful as chemotherapeutic agents in vitro, in si tu and/or in vivo.
  • Yet another object of the present invention is to provide synthetic methods for obtaining retinoid compounds and/or compositions according to formula (I) as descriptively enabled herein.
  • the invention is also directed to a method for treating a subject having a precancer or a cancer- related pathology by administering at least one retinoid compound and/or composition comprising or consisting essentially of a chalcone retinoid, optionally further comprising or consisting essentially of at least one anti-cancer pharmaceutical and/or immunomodulator.
  • the present invention provides a new and biologically active group of retinoids which display cancer chemoprevention activity.
  • retinoids which display cancer chemoprevention activity.
  • These derivatives include, but are not limited to, compounds according to the following formula (I) as chalcone retinoids.
  • the chalcone retinoids in accordance with the present invention have the following formula (I) :
  • R ! OH or C ⁇ -C 5 alkoxy
  • R 2 OH, carboxy, C,-C 6 alkyl ester, or NHCOR 3 where R 3 is methyl, ethyl, propyl or butyl
  • X NH or C 2 -C 4 alkenyl
  • Z NH or 0.
  • R 2 is preferably selected from the group consisting of OH, COOC 2 H 5 C00C 3 H 7 , COOCH 3 , COOH, NHCOCH j , NHCOCH 2 CH 3 .
  • the following compounds (I-A) - (I-S) shown in Table 1 are non-limiting examples of compounds according to formula (I) , and such compounds in any combination are provided as compounds or compositions according to the present invention:
  • Such retinoids of the present invention are unexpectedly discovered to have anti-cancer activity, thus providing suitable compounds and compositions for treatment of cancer-related pathologies, optionally with additional pharmaceutically active ingredients, such as antiviral, chemotherapeutic agents and/or immuno-stimulating compounds, or antiviral antibodies or fragments thereof, in vi tro, in si tu, and/or in vivo.
  • additional pharmaceutically active ingredients such as antiviral, chemotherapeutic agents and/or immuno-stimulating compounds, or antiviral antibodies or fragments thereof, in vi tro, in si tu, and/or in vivo.
  • Cancer-related pathologies in the context of the present invention include, but are not limited to, tumors and pathologies involving tumorigenesis, leukemias, lymphomas, melanomas, sarcomas, virus-related cancers, and any other known cancers.
  • anti-cancer activity is intended to mean the ability to induce at least one of (1) inhibition of growth or mitosis of transformed, mutated, preneoplastic or neoplastic cells; (2) promotion of apoptosis; and/or (3) angiogenesis inhibition.
  • inhibition or stimulation is between 10 and 100 percent inhibition and 10 and 1000 percent stimulation, relative to a suitable control, such as, but not limited to the same cell or animal under the same conditions, except for the presence or administration of one or more retinoids according to the present invention.
  • the present invention also provides synthetic methods for obtaining retinoid compounds according to formula (I) , which would be clear to one of ordinary skill in the art, based on the teaching and guidance presented herein, in combination with what is known in the related fields of art.
  • components of completely synthesized chalcone compounds and/or retinoyl compounds can be provided as starting materials, and the appropriate side groups can be added, modified or used in suitable, known chemical reaction steps to provide retinoid compounds according to formula (I) .
  • a solution of a specific molar amount (e.g., 2.5 mmole) of a chalcone derivative is provided in a suitable amount (e.g., 20 ml) of an anhydrous organic solvent (e.g., anhydrous tetrahydrofuran (THF) ) , and a slight excess (e.g., 2.75 mmole) of a secondary or tertiary alkyl substituted amine (e.g., triethylamine) is added.
  • anhydrous organic solvent e.g., anhydrous tetrahydrofuran (THF)
  • THF anhydrous tetrahydrofuran
  • an excess molar amount (e.g., 2.75 mmole) of an alkyl halo formate (e.g., ethyl chloroformate) is added dropwise and stirred at room temperature for 0.2-3.0 hours (e.g., 1 hr.) .
  • Petroleum ether is then added and the separated solid filtered.
  • the filtrate is then concentrated in vacuo to dryness.
  • a suitable amount of anhydrous organic solvent e.g., 20 ml of anhydrous acetonitrile
  • an alkyl substituted phenol e.g., 2.5 mmole of acetaminophenol
  • the mixture is then warmed to a clear solution and a suitable amount (e.g., 0.25 g) of the secondary or tertiary alkyl substituted amine (e.g., triethylamine) and another suitable amount (e.g., 20 mg) of a disubstituted alkyl amino pyridine (e.g., 4-dimethylaminopyridine) is added while stirring.
  • a suitable amount e.g. 0.25 g
  • the secondary or tertiary alkyl substituted amine e.g., triethylamine
  • a disubstituted alkyl amino pyridine e.g., 4-dimethylaminopyridine
  • the mixture is heated to 40-60 ° C (e.g., 50°C) for 0.5-3 hours (e.g., 1 hr.) to concentrate the mixture to half its original volume by solvent removal. Crystals formed from the concentration of the mixture are collected, washed, and recrystall
  • vi tro assays for determining whether a given compound and/or composition has anti ⁇ neoplastic activity. Such methods are well known in the art and provide the means for one of ordinary skill in the art to determine, using routine experimentation, whether a given retinoid of the present invention has a specific anti-cancer activity for a given cancer-related pathology. The following are examples of methods which can be used to screen chalcone retinoids according to formula (I) for determining at least one pharmaceutical utility; without undue experimentation, based on the teaching and guidance presented herein.
  • Non-limiting examples of anti-neoplastic in vi tro activity include but are not limited to, activity (1) against phosphorylation of phospholipids promoted by tetradecanoylphorbol-13-acetate in HeLa cells as a screening test for anti-tumor promoting effect; (see, e.g., Shibata,
  • Non-limiting examples of anti-neoplastic in vivo activity include, but are not limited to, activity in (1) inhibition of tumorigenesis in mouse skin tumors (see, e.g., Shibata, Stem Cells 12:44-52 (1994)) ; (2) inhibition of animal carcinogenesis model systems (see, e.g., Kennedy, Prev. Med.
  • predictive statistics and artificial intelligence can be used to provide computer programs which integrate matrix data to calculate patterns of activity, structural motifs, and a cell's expression of molecular targets to predict a given compound's mechanism of action to combine screening assay data and structure based drug design and testing, einstein et al. , Stem Cells 12:12-22 (1994), the contents of which reference is entirely incorporated herein by reference.
  • compositions comprising chalcone retinoid compounds of the present invention, include all compositions wherein at least one pharmaceutical compound or composition is contained in an amount effective to achieve its intended purpose.
  • pharmaceutical compositions containing at least one pharmaceutical compound or composition may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • Pharmaceutical compositions of the present invention can also include anti-neoplasties and/or immunomodulators.
  • a pharmaceutical compound or composition of the present invention may further comprise or consist essentially of at least one member selected from a single chain ribosome inhibitory protein (acting to block expression of a cancer related protein in a cancer related receptor cell or tissue) ; a cytokine; or a growth factor.
  • Cytokines that are produced by lymphocytes are termed lymphokines, whereas peptides produced by monocytes or macrophages are given the term monokines .
  • the terms cytokines, lymphokines, and interleukins may be used interchangeably to designate those peptide molecules that modulate host responses to foreign antigens or host injury by regulating the growth, mobility and differentiation of leukocytes and other cells .
  • Cytokines used according to the present invention are those suitable for use as additional active ingredients of compositions of the present invention.
  • a cytotoxic or a chemotherapeutic agent may be further included in a pharmaceutical composition of the present invention, optionally further comprising a delivery vector that preferentially binds to, or facilitates association of the pharmaceutical/diagnostic compound or composition with pathologic cells as target cells involved in cancer.
  • the targets for this type of therapy can also be growth factor receptors, differentiation antigens, or other less characterized cell surface antigens specifically associated with cancer or precancer cells.
  • Pharmaceutical compositions can also include suitable solutions for administration by injection or orally, and contain from about 0.001 to 99 percent, preferably from about 20 to 75 percent of active component.
  • Pharmaceutical compositions for oral administration include tablets and capsules. Compositions which can be administered rectally include suppositories.
  • Non- sprayable forms can be semi-solid or solid forms comprising a carrier conducive to topical application and having a dynamic viscosity preferably greater than that of water.
  • sprayable aerosol preparations where the active ingredient is preferably in combination with a solid or liquid inert carrier material.
  • the aerosol preparations can contain solvents, buffers, surfactants, perfumes, and/or antioxidants in addition to the retinoid compounds or compositions of the present invention.
  • compositions of the present invention may be administered by any means that achieve its intended purpose, for example, to treat or prevent a cancer or precancerous condition.
  • protection as in “protection from a cancerous or precancerous condition”, as used herein, encompasses “prevention,” “suppression” or “treatment.”
  • prevention involves administration of a pharmaceutical composition prior to the induction of the disease.
  • “Suppression” involves administration of the composition prior to the clinical appearance of the disease. “Treatment” involves administration of the protective composition after the appearance of the disease. It will be understood that in human and veterinary medicine, it is not always possible to distinguish between “preventing” and “suppressing” since the ultimate inductive event or events may be unknown, latent, or not ascertained in the patient until well after the occurrence of the event or events. Therefore, it is common to use the term ' “prophylaxis” as distinct from “treatment” to encompass both “preventing” and “suppressing” as defined herein.
  • the term “protection, " as used herein, is meant to include “prophylaxis.” See, e.g., Berkow et al, eds.
  • At least one retinoid compound or composition of the present invention may be administered by any means that achieves the intended purpose, using a pharmaceutical composition as previously described.
  • administration may be by various parenteral routes such as subcutaneous, intravenous, intradermal, intramuscular, intraperitoneal, intranasal, intracranial, transdermal, or buccal routes.
  • Parenteral administration can also be by bolus injection or by gradual perfusion over time.
  • administration may be by the oral route.
  • An additional mode of using of a pharmaceutical compound or composition of the present invention is by topical application.
  • a pharmaceutical compound or composition of the present invention may be incorporated into topically applied vehicles such as salves or ointments.
  • a typical regimen for treatment or prophylaxis includes administration of an effective amount over a period of one or several days, up to and including between one week and about six months.
  • the dosage of a pharmaceutical compound or composition of the present invention administered in vivo will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the pharmaceutical effect desired.
  • the ranges of effective doses provided herein are not intended to be limiting and represent preferred dose ranges. However, the most preferred dosage will be tailored to the individual subject, as is understood and determinable by one skilled in the relevant arts.
  • the total dose required for each treatment may be administered by multiple doses or in a single dose.
  • the pharmaceutical compound or composition may be administered alone or in conjunction with other pharmaceuticals directed to the pathology, or directed to other symptoms of the pathology.
  • Effective amounts of a pharmaceutical compound or composition of the present invention are from about 0.001 ⁇ g to about 100 mg/kg body weight, preferably about 5 mg/kg to 100 mg/kg body weight, most preferably about 20 mg/kg to 50 mg/kg body weight administered at intervals of 4-72 hours, for a period of 2 days to 5 years.
  • the compounds and/or compositions of the present invention are to be administered to preferably mammalian recipients, most preferably humans. Having now generally described the invention, the same will be more readily understood through reference to the following example which is provided by way of illustration, and is not intended to be limiting of the present invention.
  • Example 1 A Chalcone Retinoid Compound (I-N) According to Formula I
  • the purified retinoyl compound-chalcone derivative was crystallized from dilute alcohol, with a yield of 0.4 g (51.3%), and the following characteristics: mp:306-- 308°C, and MS (m/z) 513 (M + ) , 498, 377(100%) , 349, 319.
  • Example 8 A Chalcone Retinoid Compound (I-S) According to Formula I
  • Human promyelocytic leukemia HL-60 cells were cultured in RPMI-1640 medium supplemented by 10% heat- inactivated calf serum and 100 U/ml of penicillin plus 100 ⁇ g/ml of streptomycin. The flasks containing cells and medium were incubated in an incubator with 5% C0 2 at 37°C. Log phase cells were seeded into the medium at a concentration of 1.2xl0 5 to 1.4xl0 5 cells per ml and cultured in flasks containing 5 ml of medium. Each group consisted of three flasks. Different concentrations of chalcone-retinoids were added.
  • NBT reducing activity For a determination of NBT reducing activity, a . portion of the chalcone-retinoid-treated cells was removed at intervals following treatment and centrifuged. After centrifugation, 0.5 ml of 0.1% NBT (containing 100 ng TPA) was added to each tube. The contents of the test tubes were then incubated for 1 hour at 37°C. Cell smears were prepared from the cell sediment and stained using the Wrigh -Giemsa technique. For each smear prepared, 200 cells were isolated for examination under a light microscope with an oil immersion lens. Cells stained with blue-black granules were considered NBT-positive cells. The 50% differentiation or effective concentration (ED 50 or EC 50 ) is shown in terms of molar (M) concentration of the coumarin-retinoid tested.
  • M molar
  • a cell smear was prepared at intervals following treatment of cells for each chalcone-retinoid concentration group using the Wright- Giemsa stain technique. Stained cells were counted and classified under a light microscope with an oil immersion lens. After treatment with coumarin-retinoids, the morphological development of HL-60 cells proceeded toward mature granulocytes. This development was manifested by decreased cell volume; a lower nuclei to cytoplasm ratio; smaller or missing nuclei; concentration of chromatin; and the appearance of a certain proportion of intermediate and late granuloblasts (progranulocytes) , elongated rod granulocytes, and granulocytes with branched nuclei.
  • progranulocytes intermediate and late granuloblasts

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Nouveaux composés de rétinoïdes, tels que les rétinoïdes de chalcone, et compositions les contenant, présentant une activité thérapeutique et/ou biologique par rapport aux cellules cancéreuses ou pré-cancéreuses, ainsi que leurs méthodes d'utilisation.
PCT/US1996/011018 1995-06-07 1996-06-07 Retinoides de chalcone et leurs procedes d'utilisation WO1996040620A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP96922607A EP0832060A1 (fr) 1995-06-07 1996-06-07 Retinoides de chalcone et leurs procedes d'utilisation
NZ311995A NZ311995A (en) 1995-06-07 1996-06-07 Chalcone retinoids and methods of use of same in cancer and precancer cells
JP9502320A JPH11511121A (ja) 1995-06-07 1996-06-07 カルコンレチノイドおよびその使用方法
IL12234196A IL122341A0 (en) 1995-06-07 1996-06-07 Retinoid derivatives and their use
AU63423/96A AU702423B2 (en) 1995-06-07 1996-06-07 Chalcone retinoids and methods of use of same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US47557395A 1995-06-07 1995-06-07
US08/475,573 1995-06-07

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WO1996040620A1 true WO1996040620A1 (fr) 1996-12-19

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EP (1) EP0832060A1 (fr)
JP (1) JPH11511121A (fr)
AU (1) AU702423B2 (fr)
CA (1) CA2223948A1 (fr)
IL (1) IL122341A0 (fr)
NZ (1) NZ311995A (fr)
WO (1) WO1996040620A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8188277B2 (en) 2004-08-06 2012-05-29 Otsuka Pharmaceutical Co., Ltd. Aromatic compounds for suppressing the generation of collagen
US8236826B2 (en) 2005-12-05 2012-08-07 Otsuka Pharmaceutical Co., Ltd. Diarylether derivatives as antitumor agents
US8263599B2 (en) 2006-10-02 2012-09-11 Otsuka Pharmaceutical Co., Ltd. STAT3/5 activation inhibitor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0404039A1 (fr) * 1989-06-23 1990-12-27 Roche Diagnostics GmbH Médicaments contenant des dérivés di-tert.butylhydroxyphényliques et dérivés
WO1993023357A1 (fr) * 1992-05-21 1993-11-25 Research Corporation Technologies, Inc. Derives de stilbene utilises comme agents anticancereux
JPH06247919A (ja) * 1992-12-28 1994-09-06 Medicine Inst Chinese Acad Medical Science 安息香酸誘導体およびその用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0404039A1 (fr) * 1989-06-23 1990-12-27 Roche Diagnostics GmbH Médicaments contenant des dérivés di-tert.butylhydroxyphényliques et dérivés
WO1993023357A1 (fr) * 1992-05-21 1993-11-25 Research Corporation Technologies, Inc. Derives de stilbene utilises comme agents anticancereux
JPH06247919A (ja) * 1992-12-28 1994-09-06 Medicine Inst Chinese Acad Medical Science 安息香酸誘導体およびその用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 122, no. 13, 27 March 1995, Columbus, Ohio, US; abstract no. 151372m, KAKU S.: "Benzoates and IgE formation inhibitors containing them" page 151380; XP002015619 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8188277B2 (en) 2004-08-06 2012-05-29 Otsuka Pharmaceutical Co., Ltd. Aromatic compounds for suppressing the generation of collagen
US8236826B2 (en) 2005-12-05 2012-08-07 Otsuka Pharmaceutical Co., Ltd. Diarylether derivatives as antitumor agents
US8263599B2 (en) 2006-10-02 2012-09-11 Otsuka Pharmaceutical Co., Ltd. STAT3/5 activation inhibitor

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AU6342396A (en) 1996-12-30
CA2223948A1 (fr) 1996-12-19
NZ311995A (en) 1999-03-29
MX9709982A (es) 1998-06-28
JPH11511121A (ja) 1999-09-28
IL122341A0 (en) 1998-04-05
EP0832060A1 (fr) 1998-04-01
AU702423B2 (en) 1999-02-18

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