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WO2004031117A1 - Nouveaux composes bioactifs a base de diphenyl ethene et leur applications therapeutiques - Google Patents

Nouveaux composes bioactifs a base de diphenyl ethene et leur applications therapeutiques Download PDF

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Publication number
WO2004031117A1
WO2004031117A1 PCT/CA2003/001497 CA0301497W WO2004031117A1 WO 2004031117 A1 WO2004031117 A1 WO 2004031117A1 CA 0301497 W CA0301497 W CA 0301497W WO 2004031117 A1 WO2004031117 A1 WO 2004031117A1
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Prior art keywords
group
propylphenyl
dimethoxy
ethenyl
unsubstituted
Prior art date
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Ceased
Application number
PCT/CA2003/001497
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English (en)
Inventor
Genhui Chen
Jianxiong Li
Wei Liu
John Webster
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Welichem Biotech Inc
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Welichem Biotech Inc
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Filing date
Publication date
Priority to JP2004540416A priority Critical patent/JP2006508930A/ja
Priority to CA002501663A priority patent/CA2501663A1/fr
Priority to EP03753179A priority patent/EP1554236A1/fr
Priority to CN038235706A priority patent/CN1688535B/zh
Priority to AU2003271470A priority patent/AU2003271470B2/en
Application filed by Welichem Biotech Inc filed Critical Welichem Biotech Inc
Publication of WO2004031117A1 publication Critical patent/WO2004031117A1/fr
Priority to US10/893,863 priority patent/US7321050B2/en
Anticipated expiration legal-status Critical
Priority to US11/865,935 priority patent/US20080255245A1/en
Priority to US11/949,529 priority patent/US7868047B2/en
Priority to US12/638,618 priority patent/US20100094041A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • C07C39/215—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring containing, e.g. diethylstilbestrol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/24—Halogenated derivatives
    • C07C39/373—Halogenated derivatives with all hydroxy groups on non-condensed rings and with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings

Definitions

  • Stilbene derivatives are well-known in the art to have a wide range of activities and are widely distributed in nature. There is a growing interest in stilbene derivatives because of a range of activities that have been observed in some of the naturally occurring as well as some of the synthetic stilbenes.
  • the invention disclosed herein relates to compounds of Formula I, pharmaceutically acceptable salts thereof, pharmaceutical composition of these compounds that have been found useful as immune- modulating agents.
  • R is selected from the group consisting of unsubstituted or substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl group, halo, or COR 9 ;
  • R 2 and R 3 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl;
  • R 9 is selected from H, unsubstituted or substituted alkyl, cycloalky
  • R 10 and R u are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl;
  • R 12 is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl.
  • the configuration of the double bond of the compound of formula I is E or Z.
  • Highly preferred compounds include the following: 4-[2-(3.5-Dihydroxy-4-/-propylphenyl)ethenyl]benzoic acid (6). 3-[2-(3.5-Dihydroxy-4-/-propylphenyl)ethenyl]benzoic acid (7). 5-[2-(4-Hydroxyphenyl)ethenyl]-2-i-propyl-l,3-benzenediol (13).
  • the invention also covers use of the compounds of general formula I as immune-modulating agents.
  • the compounds of this invention may be synthesized using general procedures disclosed in patent publication WO02/057219 with specific modifications. Examples given herein are illustrative only, and are not considered as limitations of this invention.
  • the stilbene structures of the compounds of the invention are constructed via Wittig olefination (Scheme 1) and Heck reaction (Scheme 2).
  • the corresponding 1,3-benezendiol can be obtained by a deprotection reaction.
  • R 1 is to start with a bromostilbene (Scheme 3).
  • the bromide can be converted to other functional groups by Suzuki coupling or a bromo-lithium exchange followed by reacting with an electrophile.
  • the compounds utilized in accordance with the present invention have Z orE configuration of the double bonds resulting in trans and cis isomers.
  • the scope of the present invention is intended to cover all such isomers as well as mixtures of cis and trans isomers.
  • a pharmaceutically acceptable salt may be prepared for any compounds in this invention having a functional capability of forming such salt.
  • Pharmaceutically acceptable salts may be formed with inorganic and/or organic acids and bases. Suitable acids include, for example, hydrochloric, sulfuric, nitric, benzenesulfonic, acetic, maleic, tartaric and the like, which are pharmaceutically acceptable. While pharmaceutically acceptable salts are preferred, particularly when employing the compounds of the invention as medicaments, other salts find utility, for example, in the production of these compounds, or where non-medicament-type uses are contemplated.
  • pharmaceuticals having a compound or compounds with immune-modulating activity are useful agents for the treatment of disorders such as: clinical transplants (such as organ transplant, acute transplant or heterograft or homograft (such as is employed in burn treatment)) rejection; protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes; transplantation tolerance induction; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; inflammatory bowel disease, including ulcerative colitis and Crohn's disease; lupus (systemic lupus erythematosis); graft vs.
  • clinical transplants such as organ transplant, acute transplant or heterograft or homograft (such as is employed in burn treatment)
  • protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes
  • transplantation tolerance induction
  • T-cell mediated hypersensitivity diseases including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); psoriasis; contact dermatitis (including that due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrome; Autoimmune Hyperthyroidism, such as Graves' Disease; Addison's disease (autoimmune disease of the adrenalglands); Autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome; other autoimmune diseases; glomerulonephritis, serum sickness; uticaria; allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides; acute inflammatory responses (such as acute respiratory distress syndrome and ishchemia/reperfusion injury); der
  • the present invention thus provides methods for the treatment of disorders associated with the abovementioned activities, comprising the step of administering to a subject in need thereof at least one compound of the formula I in an amount effective therefore.
  • Other therapeutic agents such as those known to the skilled in the art may be employed with the inventive compounds in the present methods.
  • such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
  • compositions include any solid (tablets, pills, capsules, granules, powder, suppositories etc.) or liquid (solutions, suspensions or emulsions) in a suitable composition for oral, topical, parenteral or rectal administration.
  • These formulations may contain the pure compound or be in combination with a carrier or some other pharmaceutically active compound.
  • These compositions may need to be sterile when administered parenterally.
  • topical use it will be preferred to use in the form of creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I (For purposes of this application, topical application shall include mouth washes and gargles.)
  • Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
  • inflammation may be effectively treated by the administration of from about 0.01 to about 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material that may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • This material was prepared from l-(3,5-dimethoxy-4-z * -propylphenyl)-2-(3,5-dimethoxyphenyl)ethene and BBr3 by the same procedure as described in example 11.
  • This material was prepared from diethyl (3,5-dimethoxy-4-z ' -propylbenzyl)phosphonate and 3- fluorobenzaldehyde in the same way as described in example 21.
  • Example 23 l-(3,5-Dimethoxy-4-z-propylphenyl)-2-(4-fluorophenyl)ethene (29). This material was prepared from diethyl (3,5-dimethoxy-4-z ' -propylbenzyl)phosphonate and 4- fluorobenzaldehyde in the same procedure as described in example 21.
  • Example 25 l-(2,4-Difluorophenyl)-2-(3,5-dimethoxy-4-z ' -propylphenyl)ethene (31) (3,5-Dimethoxy-4- -propylphenyl)ethane.
  • methyltriphenylphosphonium bromide 6.89g, 19.3mmol
  • THF lOOmL
  • BuLi 7.7ml, 2.5M in hexane, 19.3mmol
  • Example 30 5-[2-(3-Fluorophenyl)ethenyl]-2- z-propylphenyl-l,3-diol (38).
  • This material was prepared from l-(3,5-dimethoxy-4-/-propylphenyl)-2-(4-fluorophenyl)ethene 29 and pyridine hydrochloride (38% yield over 2 steps) in the same procedure as described in example 34.
  • Example 33 5-[2-(2,4-Difluorophenyl)ethenyl]-2-z-propyl-l,3-benzenediol (41). This material was prepared from l-(2,4-difluorophenyl)-2-(3,5-dimethoxy-4-z " -propylphenyl)ethene and pyridine hydrochloride in 44% yield in the same way as described in example 34.
  • PBMC peripheral blood mononuclear cells
  • PHA phytochemagglutinin
  • Compound 13 is 20 times more potent in inhibiting PBMC proliferation (Table 1). Similarly, compound 13 is more than 15 times more potent than is resveratrol in inhibition IFN- ⁇ production (Table 2). Similarly, the three fluorinated compounds, 37, 38 and 39 had IC 50 ⁇ 10 ⁇ M whereas that of resveratrol was > 50 ⁇ M the highest concentration tested. The fluorinated compounds had superior activity in inhibiting PBMC proliferation to that of resveratrol with >5 times more potency (Table 1).
  • IC 50 value of resveratrol is more than 9 times higher than that of the three fluorinated compounds, indicating that the fluorinated compounds are over 9 times more potent than resveratrol in inhibiting IFN- ⁇ production by human PBMC (Table 2).
  • Table 1 Effect of the novel compounds and resveratrol against human PBMC proliferation.
  • Human keratinocytes were cultured in the presence of IFN- ⁇ and titrated concentrations of drug or the vehicle.
  • the MTT assay was performed after 48 hours of culture.
  • a 0.8% agarose solution was prepared with complete RPMI-1640 cell culture medium. About 3.5 ml of this agarose solution was transferred to a glass slide before it solidified. Wells were made on the slide in a 3x6 array fashion (02 mm, inter-well distance 3mm) once the agarose had solidified. LTB4 was dissolved in anhydrous ethanol to 10 4 ng/ml and further diluted with the RPMI-1640 medium to 10 ng/ml for the test. Compound 39 was dissolved in DMSO, diluted with RPMI-1640 to 10 3 ⁇ g/ml and tested at the following concentrations: 100, 10, 1, 0.1 and 0.01 ⁇ g/ml.
  • Compound 39 showed potent inhibitory activity against WBC migration induced by leukotriene B4, a mediator that plays important role in inflammation, including the auto-immune response.
  • VEGF vascular endothelial growth factor
  • VEGF- ⁇ final concentration 100 ng/ml
  • test compound concentration 0.01-10 ⁇ g/ml
  • medium without test compound was the negative control.
  • the culture supernatant from each well was separately collected after an additional 24 h incubation and centrifuged at 2000rpm for 5 minutes before measuring the VEGF concentration.
  • VEGF concentration in the supernatant in each well was calculated based on measurements taken using an ELISA kit, according to the manufacturer's instructions.
  • Compound 39 had a significant inhibitory effect on VEGF expression in human keratinocytes.
  • Test compounds were dissolved and formulated in 50% PEG-400 in water.
  • mice ⁇ 20g were first injected separately intraperitoneally (IP) with 25 mg/kg of each test compound, then challenged by injection with 40 mg/kg lipopolysaccharide (LPS) (IP) 30 minutes later.
  • IP intraperitoneally
  • LPS lipopolysaccharide
  • One drug injection with 12.5 mg/kg of test compound was done at the same time as (LPS challenge and two subsequent sequential injections at 30 minutes intervals.
  • Positive control of dexamethasone was administered in a similar manner starting at 0.4 mg/kg and subsequently 0.2 mg/kg for three additional injections. Mice were sacrificed and blood collected by cardiac puncture
  • mice 150 minutes after LPS challenge The serum TNF- ⁇ levels were determined by ELISA. Each test group was comprised of six mice. Group of mice injected with the vehicle alone was used as negative control.
  • Ear thickness was measured 6 hours after TPA treatment to determine if edema was decreased.
  • replicated groups of TPA treated mice were treated with either 5-(2-phenylethenyl)-2-z ' -propyl- 1,3 -benzenediol, Calcitriol, compound 39 or only ethanol, and the levels of inhibition was obtained by measuring the thickness of the ear and expressing the difference in thickness of the treated ear from that of the ethanol treated ear, as a percentage.

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Abstract

L'invention concerne un nouveau groupe de dérivés de diphényl éthène, leurs sels pharmaceutiquement acceptables, le procédé de fabrication de ces composés, leur composition pharmaceutique et l'utilisation de ces composés en tant qu'agents pour traiter les maladies immunes, inflammatoires et auto-immunes.
PCT/CA2003/001497 1999-12-06 2003-09-30 Nouveaux composes bioactifs a base de diphenyl ethene et leur applications therapeutiques Ceased WO2004031117A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2004540416A JP2006508930A (ja) 2002-10-01 2003-09-30 新規生物活性ジフェニルエテン化合物およびその治療への適用
CA002501663A CA2501663A1 (fr) 2002-10-01 2003-09-30 Nouveaux composes bioactifs a base de diphenyl ethene et leur applications therapeutiques
EP03753179A EP1554236A1 (fr) 2002-10-01 2003-09-30 Nouveaux composes bioactifs a base de diphenyl ethene et leur applications therapeutiques
CN038235706A CN1688535B (zh) 2002-10-01 2003-09-30 新型生物活性的二苯乙烯化合物及其医疗用途
AU2003271470A AU2003271470B2 (en) 2002-10-01 2003-09-30 Novel bioactive diphenyl ethene compounds and their therapeutic applications
US10/893,863 US7321050B2 (en) 1999-12-06 2004-07-15 Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues
US11/865,935 US20080255245A1 (en) 1999-12-06 2007-10-02 Anti-Inflammatory and Psoriasis Treatment and Protein Kinase Inhibition by Hydroxystilbenes and Novel Stilbene Derivatives and Analogues
US11/949,529 US7868047B2 (en) 1999-12-06 2007-12-03 Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues
US12/638,618 US20100094041A1 (en) 1999-12-06 2009-12-15 Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US14886300A 2000-12-06 2000-12-06
US41463202P 2002-10-01 2002-10-01
US41463302P 2002-10-01 2002-10-01
US60/414,633 2002-10-01
US60/414,632 2002-10-01

Related Parent Applications (4)

Application Number Title Priority Date Filing Date
PCT/CA2000/001433 Continuation-In-Part WO2001042231A2 (fr) 1999-12-06 2000-12-06 Traitement anti-inflammatoire et psoriasique et inhibition de la proteine kinase par des hydroxylstilbenes et de nouveaux derives de stilbene ou analogues
US14886300A Continuation-In-Part 2000-10-06 2000-12-06
US10/148,863 Continuation-In-Part US20030171429A1 (en) 1999-12-06 2000-12-06 Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxyltilbenes and novel stilbene derivatives and analogues
US11/949,529 Continuation-In-Part US7868047B2 (en) 1999-12-06 2007-12-03 Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues

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GB2411353A (en) * 2004-02-25 2005-08-31 Univ Hertfordshire Resveratrol Analogues
FR2898124A1 (fr) * 2006-03-03 2007-09-07 Centre Nat Rech Scient Derive de resveratol a longue chaine hydroxylee utiles comme neurotrophiques
US8487009B2 (en) 2001-01-18 2013-07-16 Glaxo Group Limited 1,2-diphenylethene derivatives for treatment of immune diseases
CN111148729A (zh) * 2017-09-30 2020-05-12 北京文丰天济医药科技有限公司 苯烯莫德的晶型及其用途与制备方法
US10961175B2 (en) 2017-11-10 2021-03-30 Dermavant Sciences GmbH Process for preparing tapinarof
WO2021236709A1 (fr) 2020-05-19 2021-11-25 Teva Pharmaceuticals International Gmbh Formes à l'état solide de tapinarof
WO2023125536A1 (fr) * 2021-12-28 2023-07-06 上海泽德曼医药科技有限公司 Composé pour inhiber la croissance endothéliale vasculaire et son utilisation
WO2025031935A1 (fr) 2023-08-04 2025-02-13 Sandoz Ag Formes cristallines de tapinarof
IT202300023508A1 (it) 2023-11-08 2025-05-08 Procos Spa Processo per la preparazione della forma polimorfa iii di tapinarof

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CN101544591B (zh) * 2009-05-06 2013-07-10 河北科技大学 (e)-取代苯乙烯类化合物及其制备方法
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CN102675060A (zh) * 2011-10-31 2012-09-19 栗艳艳 高藜芦醇的醚衍生物和医疗用途
CN103172512B (zh) * 2011-12-23 2016-08-03 中国医学科学院医药生物技术研究所 一组木豆素结构类似化合物、制备方法和应用
CN103483158B (zh) * 2013-10-14 2016-06-08 武汉英纳氏药业有限公司 一种二苯乙烷衍生物及其应用
WO2016092493A1 (fr) * 2014-12-12 2016-06-16 Glaxosmithkline Intellectual Property Development Limited Nouvelle méthode d'utilisation
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US8487009B2 (en) 2001-01-18 2013-07-16 Glaxo Group Limited 1,2-diphenylethene derivatives for treatment of immune diseases
GB2411353A (en) * 2004-02-25 2005-08-31 Univ Hertfordshire Resveratrol Analogues
FR2898124A1 (fr) * 2006-03-03 2007-09-07 Centre Nat Rech Scient Derive de resveratol a longue chaine hydroxylee utiles comme neurotrophiques
WO2007099162A3 (fr) * 2006-03-03 2007-11-29 Centre Nat Rech Scient Derive de resveratrol a longue chaine hydroxylee utiles comme neurotrophiques
JP2009528330A (ja) * 2006-03-03 2009-08-06 サントル・ナシオナル・ドゥ・ラ・ルシェルシュ・シアンティフィーク（セーエヌエールエス） 神経栄養剤として有用なヒドロキシル化長鎖レスベラトロール誘導体
CN111148729A (zh) * 2017-09-30 2020-05-12 北京文丰天济医药科技有限公司 苯烯莫德的晶型及其用途与制备方法
US10961175B2 (en) 2017-11-10 2021-03-30 Dermavant Sciences GmbH Process for preparing tapinarof
US11597692B2 (en) 2017-11-10 2023-03-07 Dermavant Sciences GmbH Process for preparing tapinarof
US12275696B2 (en) 2017-11-10 2025-04-15 Dermavant Sciences GmbH Process for preparing tapinarof
WO2021236709A1 (fr) 2020-05-19 2021-11-25 Teva Pharmaceuticals International Gmbh Formes à l'état solide de tapinarof
WO2023125536A1 (fr) * 2021-12-28 2023-07-06 上海泽德曼医药科技有限公司 Composé pour inhiber la croissance endothéliale vasculaire et son utilisation
WO2025031935A1 (fr) 2023-08-04 2025-02-13 Sandoz Ag Formes cristallines de tapinarof
IT202300023508A1 (it) 2023-11-08 2025-05-08 Procos Spa Processo per la preparazione della forma polimorfa iii di tapinarof
WO2025099634A1 (fr) * 2023-11-08 2025-05-15 Procos S.P.A. Procédé de préparation de la forme polymorphe iii de tapinarof

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CN1688535B (zh) 2011-11-09
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AU2003271470A1 (en) 2004-04-23

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