WO2018068131A1 - Substituted hydroxystilbenes and their therapeutic applications - Google Patents
Substituted hydroxystilbenes and their therapeutic applications Download PDFInfo
- Publication number
- WO2018068131A1 WO2018068131A1 PCT/CA2017/051182 CA2017051182W WO2018068131A1 WO 2018068131 A1 WO2018068131 A1 WO 2018068131A1 CA 2017051182 W CA2017051182 W CA 2017051182W WO 2018068131 A1 WO2018068131 A1 WO 2018068131A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- disease
- compound
- group
- subject
- bromo
- Prior art date
Links
Classifications
-
- 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
- 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
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
-
- 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
- A61K31/055—Phenols the aromatic ring being substituted by halogen
-
- 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
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
-
- 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
- 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
- C07C39/42—Halogenated derivatives containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
Definitions
- the present invention pertains to substituted hydroxystilbenes and their therapeutic applications.
- the inflammatory response is mediated by cytokines, and cytokine activity and expression in turn are regulated by kinases.
- Aberrant kinase and cytokine activity play pivotal roles in chronic and acute inflammatory diseases.
- Aberrant kinase and cytokine activity also underly autoimmune diseases and different types of cancer.
- Kinase inhibitors are an established class of anticancer drugs (Chen, J Nat Prod, 2012, 75 (12):2269-2269) and anti-inflammation drugs (Wang et al, J Immunol, 2013,
- Janus Kinase 2 (JAK2) and Janus Kinase 3 (JAK3) are tyrosine kinases that regulate transcription of various target genes involved in growth and proliferation (Reiter et al, Cancer Res, 2005, 65(7):2662-2667; Takemoto et al, Proc Natl Acad Sci USA, 1997, 94(25): 13897-13902). JAK2 and JAK3 are also involved in mediating the signaling of many inflammatory cytokines involved in inflammation (Wang et al, J Immunol, 2013, 191(3): 1164-1174).
- JAK2 and JAK 3 inhibitors are therefore useful in treating cancers, and autoimmune and inflammatory diseases (Fridman et al, J Invest Dermatol, 2011, 131(9): 1838-1844).
- p38a p38 mitogen-activated protein kinase alpha
- MAP Mitogen-activated protein
- Glycogen synthase kinase 3 beta ( ⁇ 8 ⁇ 3 ⁇ ) is a serine-threonine kinase that regulates p53 function in proliferating cells such as cancer cells (WO2006/006939) and its inhibition down regulates inflammatory cytokines (Li et al, Cell Physiol Biochem, 2013, 32(6): 1720- 1728).
- Lymphocyte-specific protein tyrosine kinase is a Src tyrosine kinase involved in T cell activation and proliferation (Hanke et al, Inflamm Res, 1995, 44:357; Bolen et al, Ann Rev Immunol, 1997, 15:371). LCK inhibition has been successful in treatment of inflammatory diseases (Brisslert et al, Biochem Biophys Acta, 2014, 1842(11):2049-2059).
- Cytokines play important roles in initiating and regulating immune responses, and therefore their inhibition is a well-established approach to controlling autoimmune and inflammatory diseases (Kopf et al, Nature Reviews Drug Discovery, September 2010, 9:703- 718).
- exemplary cytokine targets include Interleukin- ⁇ (IL- ⁇ ) (Xu et al, Clin Exp Pharmacol Physiol, 2015, 42(10): 1075-83), Interleukin-2 (IL-2) (Roediger et al., J Allergy Clin Immunol, 2015, 136(6): 1653-63), Interleukin-6 (IL-6) (Scheller et al, Biochem
- Interleukin-8 (IL-8) (Aghazarian et al., Urology, 2015, 86(l):52-56), Interferon
- IFN- ⁇ gamma
- TNF-a Tumor necrosis factor alpha
- MIP-la Macrophage Inflammatory Protein la
- PDE4 inhibition is known to improve therapeutic treatment of a number of inflammatory, respiratory and allergic diseases and conditions (US6649633B2; Keren et al, J Dermatol Sci, January 2015, 77(l):74-76).
- FIG. 1 describes the constituents of compounds according to embodiments of the invention.
- FIG. 2 shows the structures of compounds according to embodiments of the invention.
- FIG. 3 shows the synthetic process for making compounds according to embodiments of the invention.
- FIG. 4 shows the efficacy of a compound according to an embodiment of the invention in dextran sodium sulphate (DSS)-induced model of inflammatory bowel disease (IBD)/colitis in mice.
- DSS dextran sodium sulphate
- IBD inflammatory bowel disease
- autoimmune disease refers to the physiological condition in mammals that is typically characterized by the immune system's reaction to inappropriate targets such as normal tissues.
- the term "autoimmune disease” includes Addison's disease, ankylosing spondylitis, celiac disease, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, pemphigus, rheumatoid arthritis, Sjogren syndrome, systemic lupus erythematosus, Type 1 diabetes, IBD, psoriasis, vitiligo, alopecia areata and vasculitis.
- cancer refers to the physiological condition in mammals that is typically characterized by unregulated cell growth.
- cancer includes cancer of any origin, including benign and malignant cancers, metastatic and non-metastatic cancers, and primary and secondary cancers.
- cancer includes reference to cancer cells.
- cancers include, but are not limited to, cancers of the bladder, bone, brain/CNS, breast, cervix, colon, duodenum, esophagus, eye, gall bladder, heart, kidney, larynx, liver, lung, mouth, ovary, pancreas, pharynx, prostate, rectum, stomach, testis, uterus, as well as AIDS-related cancers, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, melanoma, leukemia (including lymphocytic leukemia, hairy cell leukemia, and acute myelogenous leukemia), choriocarcinoma, rhabdomyosarcoma, and neuroblastoma.
- AIDS-related cancers Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, melanoma
- leukemia including lymphocytic leukemia
- an "effective amount” as used herein refers to the amount of active agent sufficient to elicit a desired biological response or, equivalently, to inhibit an undesired biological response.
- An amount of a particular active agent that is effective may vary depending on such factors as the desired biological response, severity of the disease, the activity of the active agent to be delivered, the route of administration, the rate of excretion of the active agent being employed, the duration of the treatment, other drugs, compounds or materials used in combination with the particular active agent employed, the subject's age, sex, weight, condition, general health and prior medical history of the subject, and like factors well known in the medical arts.
- an "effective amount” will be that amount of the active agent that is the lowest dose effective to produce the desired biological response.
- an “effective amount” will generally depend upon the factors described above. Generally, an “effective amount” will range from about 1 to about 400 mg per kilogram of body weight per day, more preferably from about 10 to about 50 mg per kg per day. If desired, daily dosage in an “effective amount” may be administered as one dose, or two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
- inflammatory disease refers to the physiological condition in mammals that is typically characterized by the immune system's excessive reaction to innocuous targets or reaction to inappropriate targets.
- inflammatory disease includes Alzheimer's disease, amyotrophic lateral sclerosis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, eczema, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, osteoarthritis, Parkinson's disease, periodontal disease, psoriasis and sun burn.
- a "package insert" as used herein refers to instructions customarily included in commercial packages of medicaments that contain information about the indications, usage, dosage, administration, contraindications, other medicaments to be combined with the packaged product, and/or warnings concerning the use of such medicaments, and the like.
- pharmaceutically acceptable carrier refers to one or more excipients, stabilizers, fillers, binders, humectants, disintegrating agents, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, coloring agents, diluents, emulsifiers, preservatives, solubilizing agents, suspending agents and the like that are suitable for use with the subject being exposed thereto at the dosages and concentrations employed without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable carrier refers to one or more excipients, stabilizers, fillers, binders, humectants, disintegrating agents, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, coloring agents, diluents, emulsifiers, preservatives, solubilizing agents, suspending agents and the like that are suitable for use with the subject being exposed thereto
- Examples of pharmaceutically acceptable carriers include water, citrate or phosphate buffers, starches, lactose, sucrose, glucose, mannitol, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, glycerol, agar, calcium carbonate, alginic acid, sodium carbonate, paraffin, quaternary ammonium compounds, cetyl alcohol, glycerol monostearate, kaolin and bentonite clay, talc, calcium stearate, magnesium stearate, polyethylene glycols, sodium lauryl sulfate, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils, tetrahydrofuryl alcohol, fatty acid esters, thioxylated isostearyl alcohols, polyoxyethylene sorbitol and
- salts refers to toxicologically compatible organic or inorganic salts of the active agent.
- exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate
- a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
- the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or
- suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
- proliferative disease refers to the physiological condition in mammals that is characterized by the excessive proliferation of cells and turnover of cellular matrix.
- proliferative disease includes cancer, graft-versus-host disease, restenosis, hamartoma syndromes (e.g., tuberous sclerosis or Cowden Syndrome), encephalomyelitis, arthritis, scleroderma, pulmonary fibrosis, renal fibrosis, cystic fibrosis, pulmonary hypertension, hypertrophic cardiomyopathy, Parkinson-White syndrome and wet and dry macular degeneration.
- subject refers to an individual to whom an active agent is to be delivered, e.g., for treatment purposes.
- the term “subject” includes mammals, in particular humans, and other mammals including companion animals such as cats and dogs, livestock animals such as cows, pigs, horses, sheep and goats, zoo animals, and research animals, such as rodents.
- the "subject” also includes in vitro cultured cells.
- Desired clinical results can include, but are not limited to, reduction or alleviation of at least one symptom of a disease.
- treatment can be diminishment of at least one symptom of disease, diminishment of extent of disease, stabilization of disease state, prevention of spread of disease, delay or slowing of disease progression, palliation of disease, diminishment of disease reoccurrence, remission of disease, prolonging survival with disease, or complete eradication of disease.
- AKT1 RAC-alpha serine/threonine -protein kinase
- G-CSF Granulocyte colony stimulating factor
- GM-CSE Granulocyte macrophage colony stimulating factor
- GSK3 Glycogen synthase kinase 3 beta
- IBD Inflammatory bowel disease
- IFN- ⁇ Interferon gamma
- IL- ⁇ Interleukin-1 beta
- IL-2 Interleukin-2
- IL-8 Interleukin-8
- JAK3 Janus Kinase 3
- LCK Lymphocyte specific protein tyrosine kinase
- MIP- ⁇ Macrophage inflammatory protein 1 alpha
- PBMC Peripheral blood mononuclear cell
- p38a p38 mitogen activated protein kinase alpha
- ⁇ 38 ⁇ p38 mitogen activated protein kinase beta
- PHA Phytohaemagglutinin
- TNF-a Tumor necrosis factor alpha
- R 1 is selected from H, halogen and CN
- R 2 is selected from H, halogen and CN
- R 3 is selected from H, halogen and CN
- R 4 is H
- R 5 is selected from H, halogen and CN
- R 6 is alkyl or cycloalkyl
- the compound may be one of exemplary Compounds 1 to 27 set out in FIG. 1.
- FIG. 2 shows the structure of exemplary Compounds 1. 2. 7, 10, 12, 18, 20. 24 and 27.
- the compound may have Formula I wherein R 1 is selected from H, F and CN; R 2 is H or CN; R 3 is selected from H, F and CN; R 4 is H; R 5 is H or F; and R 6 is selected from iso-propyl, cyclopropyl, cyclopentyl. cyclohexyl and cycloheptyl.
- the compound may have Formula I wherein R 1 is H; R 2 is H or CN; R 3 is selected from H, F and CN; R 4 is H; R 5 is H; and R 6 is selected from iso-propyl, cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
- the compound may have Formula I wherein R 1 is H; R 2 is H; R 3 is F; R 4 is H; R 5 is H; and R 6 is selected from iso-propyl, cyclopropyl and cyclopentyl.
- the compound may be 3-hydroxy-4-isopropyl-4'-fluoro-(£)- stilbene.
- the compound having Formula I may be provided as a pharmaceutically acceptable salt.
- compositions comprising a compound having Formula I and a pharmaceutically acceptable carrier.
- compositions comprising compounds of Formula I may be provided in unit dosage form.
- the amounts of compounds of Formula I that can be combined with a pharmaceutically acceptable carrier to produce a single dosage form will generally be the amount that produces a therapeutic effect. In some embodiments, out of one hundred percent, this amount will range from about 0.1 percent to about 99 percent of active agent, from about 5 percent to about 70 percent of active agent, or from about 10 percent to about 30 percent of active agent.
- aspects relate to methods of treating a condition by administration to a subject of an effective amount of a compound having Formula I. While it is possible for compounds of Formula I to be administered alone, it may be preferable to administer them in combination with one or more pharmaceutically acceptable carriers as a composition. In some
- the methods comprise administering to the subject at least one compound having Formula I either alone in or in combination with at least one additional therapeutic agent.
- compounds having Formula I inhibit cell proliferation, inhibit PDE4, inhibit a range of kinases, and inhibit a range of cytokines.
- Suitable diseases may be treated with compounds having Formula I. Suitable diseases that may be treated include cancers, autoimmune diseases and inflammatory diseases.
- the subject to be treated may be any subject diagnosed as having one of the indicated conditions.
- the subject to be treated may be in need of treatment for one of the indicated conditions because of a diagnosis of the condition or because of an assessment of risk for developing the condition.
- the subject may be diagnosed with the condition using diagnostic or clinical tests that are well known.
- the administration route of compounds of Formula I, alone or in a composition, in terms of effect may be local or systemic (enteral or parenteral), and in terms of location may for example be buccal, epi cutaneous, epidural, intraartciular, intracardiac, intracavemous, intracerebral, intracerebroventricular, intradermal, intramuscular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravenous, intravesical, intravitreal, nasal, oral, rectal, subcutaneous, sublingual, sublabial, transdermal, transmucosal, and the like.
- oral administration may be in the form of capsules, cachets, pills, tablets, lozenges, pastes, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles or as mouth washes and the like.
- compositions in solid dosage forms for oral administration include capsules, tablets, pills, dragees, powders, granules and the like.
- the solid dosage forms may be scored or prepared with coatings and shells, such as enteric coatings and other coatings.
- compositions in liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- topical or transdermal administration may be in the form of powders, sprays, ointments, pastes, creams, lotions, gels, solutions, controlled-release patches and inhalants.
- parenteral administration e.g. intravenous administration
- compounds of Formula I are formulated into pharmaceutically acceptable dosage forms by conventional methods.
- kits comprising compounds of Formula I, and a package insert comprising instructions for using compounds of Formula I to treat a condition in a subject.
- Suitable conditions that may be treated include cancers, autoimmune diseases and inflammatory diseases.
- FIG. 3 illustrates a synthetic method used to prepare compounds of Formula I according to an embodiment of the invention.
- the compounds are synthesized in six steps from the commercially available starting material, 3-methoxybenzyl alcohol, as follows.
- Step 1 3-Methoxybenzyl alcohol was brominated with one molar equivalent of N- bromosuccinimide in tetrahydrofuran (THF) at room temperature to afford 4-bromo-3- methoxybenzyl alcohol.
- Step 2 4-bromo-3-methoxybenzyl alcohol was converted to the corresponding benzyl chloride with an excess of thionyl chloride in dimethylformamide (DMF) at room
- Step 3 The benzyl chloride from Step 2 was converted to diethyl 4-bromo-3- methoxybenzylphosphonate with an excess of tri ethyl phosphite upon heating at 150 °C for 16 hours.
- Step 4 The diethyl 4-bromo-3-methoxybenzylphosphonate from Step 3 was reacted with an excess of sodium hydride and a substituted benzaldehyde in THF to afford the substituted trans-4-bromo-3-methoxystilbene (Horner-Wadsworth-Emmons Reaction).
- Step 5 The substituted trans-4-bromo-3-methoxystilbene from Step 4 was reacted with an alkyl Grignard reagent in the presence of a catalytic amount of N1CI2DPPE
- Step 6 The substituted trans-4-alkyl-3-methoxystilbene from Step 5 was reacted with an excess of boron tribromide in dichloromethane (DCM) at room temperature to afford the substituted trans-4-alkyl-3-hydroxystilbene.
- DCM dichloromethane
- reaction mixture was quenched with water (5 mL), diluted with additional ether (60 mL) and the resultant mixture was washed first with a saturated aqueous solution of sodium thiosulfate and then with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the crude product which was purified by recrystallization from hexanes to afford the title compound as a light yellow crystalline solid (874 mg, 66%).
- DMEM containing 10% FBS (A549 and MDA-MB-435).
- l-5xl0 4 cells per well in 100 of the cell culture medium containing 0.5% FBS were seeded into a 96-well flat bottom plate.
- the test compounds were added to the culture at different concentrations in triplicates.
- the controls include triplicates of no compound treatment and cell culture medium without cells.
- the cells were incubated at 5% C0 2 , 37 °C for 48 hours.
- MTS reagent was added to each well and incubated at 37 °C for 4 hours.
- the absorbance was read at 490 nm.
- the percentage of inhibition was calculated using the formula: [1 -(experiment reading-background reading)/(negative control reading-background reading)] x 100.
- the determined cell viability IC50 values are listed in Table 1.
- Cells were cultured in RPMI-1640 containing 10% FBS (Jurkat) or DMEM containing 10% FBS (MDA-MB-435).
- lxlO 4 cells were seeded into one well of a 96-well white ISOPLATETM with 0.5% FBS.
- the cells were cultured at 5% C0 2 , 37 °C overnight.
- the diluted test compounds were added into each well in a total volume of 100 of cell culture medium.
- For each cell line were set up three wells containing cells and only diluted DMSO as a negative (vehicle) control, and three wells without cells but containing the same volume and type of cell culture medium as background control.
- the cells were incubated at 5% C0 2 , 37 °C for 24 hours. On Day 3, 1 of [3 H ] -thymidine was added into each well and incubation at 5% C0 2 , 37 °C was continued for another 24 hours. On Day 4, 30 of 50% TCA was added into each well and was incubated at 4 °C for 4 hours. Plates were washed with ddH 2 0 four times and then air dried for 30 minutes followed by the addition of 100 ⁇ . of scintillation fluid into each well. The radioactivity was read using
- kinases profiling was conducted using different recombinant kinase targets against the compounds at 5 uM ATP.
- the kinases tested included AKTl (RAC-alpha serine/threonine- protein kinas 1), JAK2, JAK3, ⁇ 38 ⁇ , ⁇ 38 ⁇ (p38 mitogen-activated protein kinase beta), GSK3fi, SYK (Spleen tyrosine kinase), LCK, IKKa and ⁇ and CLK4.
- the test compounds were tested at 5 ⁇ and 50 ⁇ in triplicates. The results are shown in Table 3.
- Assays were performed using recombinant human PDE4B1 enzyme expressed in a baculoviral system.
- the radiometric assay is a modification of the 2-step method of Thompson and Appleman (Biochemistry 10, 1971, 311-316). The reactions were performed at 1 ⁇ of cAMP.
- the test articles were each tested at 0.2 ⁇ and 20 ⁇ in triplicates.
- the percentage inhibition values for the reference inhibitor, rolipram were also determined and compared to historical assay values to ensure it was in an acceptable range. The results are shown in Table 4.
- PBMC cells were used to test the effects of the compounds on the production multiple cytokines.
- PBMC human PBMC
- FBS fetal bovine serum
- Cytokine production was induced with a combination of PMA and PHA 30 minutes post the compound treatments.
- Cells were treated with various concentrations of the compounds for 24 hours at 37 °C.
- the culture supernatants were collected from drug-treated or control samples.
- Cytokines tested include: IL- la, IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17A, IFN- ⁇ , TNF-a, G- CSF(Granulocyte -colony -stimulating factor), GM-CSF(Granulocyte-macrophage colony- stimulating factor), TGF- ⁇ 1 and ⁇ .
- EXAMPLE 8 Effect on inflammatory bowel disease (IBD)/colitis in mice
- DSS dextran sodium sulphate
- IBD inflammatory bowel disease
- Rolipram was used as a positive control in this experiment.
- Colitis was induced in the mice by providing drinking water containing DSS (3.5%, M. Wt. 30,000-50,000) from Day 0 to Day 8.
- the test compounds were administered as per their respective groups at specific dose levels starting from Day 0 through to Day 8.
- Compound 2 was tested at 10 and 30 mg/kg and Rolipram was tested at 5 mg/kg.
- Colitis was consistently induced in most of the mice, with onset of disease (stool consistency) from Day 2 and drastic reduction in body weight, diarrhea and severe rectal bleeding at Day 5-7 demonstrating the severity of disease.
- Compound 2 was dissolved in vehicle (1.5% Cremophor EL) at 3 mg/mL and 1 mg/mL for the 30 and 10 mg/kg doses, respectively.
- Rolipram was dissolved in 1% DMSO/99% PBS at 0.5 mg/mL for the 5 mg/kg dose. All doses were administered by oral gavage.
- DAI disease activity index
- EXAMPLE 9 Efficacy against the inflammatory skin conditions psoriasis and eczema
- a topical cream containing compound 2 was prepared as follows: Compound 2 was dissolved in propylene glycol at a concentration of 11.0% w/w and this solution was then mixed with the appropriate amount of Glaxal base cream to afford a 1.0% w/w cream of compound 2.
- 10 subjects with psoriasis and 5 subjects with eczema were treated with the cream twice daily for a period of 2-12 weeks.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201780062107.0A CN109890784B (en) | 2016-10-13 | 2017-10-04 | Substituted hydroxystyrenes and therapeutic uses thereof |
EP17860520.0A EP3526186B1 (en) | 2016-10-13 | 2017-10-04 | Substituted hydroxystilbenes and their therapeutic applications |
ES17860520T ES2924065T3 (en) | 2016-10-13 | 2017-10-04 | Substituted hydroxystilbenes and their therapeutic applications |
JP2019520644A JP6936319B2 (en) | 2016-10-13 | 2017-10-04 | Substituted hydroxystilbenes and their therapeutic applications |
CA3038575A CA3038575C (en) | 2016-10-13 | 2017-10-04 | Substituted hydroxystilbenes and their therapeutic applications |
AU2017344103A AU2017344103B2 (en) | 2016-10-13 | 2017-10-04 | Substituted hydroxystilbenes and their therapeutic applications |
KR1020197009817A KR102419043B1 (en) | 2016-10-13 | 2017-10-20 | Substituted hydroxystilbenes and therapeutic uses thereof |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662407886P | 2016-10-13 | 2016-10-13 | |
US62/407,886 | 2016-10-13 | ||
US15/338,232 | 2016-10-28 | ||
US15/338,232 US9725406B1 (en) | 2016-10-13 | 2016-10-28 | Substituted hydroxystilbenes and their therapeutic applications |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018068131A1 true WO2018068131A1 (en) | 2018-04-19 |
Family
ID=59411070
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CA2017/051182 WO2018068131A1 (en) | 2016-10-13 | 2017-10-04 | Substituted hydroxystilbenes and their therapeutic applications |
Country Status (9)
Country | Link |
---|---|
US (2) | US9725406B1 (en) |
EP (1) | EP3526186B1 (en) |
JP (1) | JP6936319B2 (en) |
KR (1) | KR102419043B1 (en) |
CN (1) | CN109890784B (en) |
AU (1) | AU2017344103B2 (en) |
CA (1) | CA3038575C (en) |
ES (1) | ES2924065T3 (en) |
WO (1) | WO2018068131A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9725406B1 (en) * | 2016-10-13 | 2017-08-08 | Resolvex Pharmaceuticals Inc. | Substituted hydroxystilbenes and their therapeutic applications |
SG11202008361YA (en) * | 2018-03-27 | 2020-09-29 | Neuropore Therapies Inc | Compounds as modulators of tlr2 signaling |
CN110183311B (en) * | 2019-07-25 | 2019-10-29 | 江西中医药大学 | A kind of isopentene group stilbene and its purposes in preparation treatment diseases associated with inflammation drug |
CN110496117B (en) * | 2019-09-30 | 2022-09-06 | 中国科学院微生物研究所 | New application of small molecular compound in resisting African swine fever virus infection |
WO2023175177A1 (en) * | 2022-03-18 | 2023-09-21 | Institut Curie | Differential diagnosis of crohn's disease and ulcerative colitis |
CN117229208B (en) * | 2023-11-13 | 2024-02-23 | 上海泽德曼医药科技有限公司 | Condensed ring compound, preparation method and medical application thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6649633B2 (en) | 2001-01-31 | 2003-11-18 | Pfizer Inc | Nicotinamide biaryl derivatives useful as inhibitors of PDE4 isozymes |
US20080255245A1 (en) | 1999-12-06 | 2008-10-16 | Welichem Biotech Inc. | Anti-Inflammatory and Psoriasis Treatment and Protein Kinase Inhibition by Hydroxystilbenes and Novel Stilbene Derivatives and Analogues |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7321050B2 (en) * | 1999-12-06 | 2008-01-22 | Welichem Biotech Inc. | Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues |
JP4880847B2 (en) * | 1999-12-06 | 2012-02-22 | ウェリケム,バイオテック インコーポレーテッド | Anti-inflammatory and psoriasis treatments and protein kinase inhibition with hydroxylstilbene and novel stilbene derivatives and analogs |
CN1955153A (en) * | 2005-10-24 | 2007-05-02 | 南京莱因医药科技有限公司 | Synthetic method of pterostilbene |
US9725406B1 (en) * | 2016-10-13 | 2017-08-08 | Resolvex Pharmaceuticals Inc. | Substituted hydroxystilbenes and their therapeutic applications |
-
2016
- 2016-10-28 US US15/338,232 patent/US9725406B1/en active Active
-
2017
- 2017-06-29 US US15/638,208 patent/US10166201B2/en active Active
- 2017-10-04 EP EP17860520.0A patent/EP3526186B1/en active Active
- 2017-10-04 WO PCT/CA2017/051182 patent/WO2018068131A1/en unknown
- 2017-10-04 CA CA3038575A patent/CA3038575C/en active Active
- 2017-10-04 JP JP2019520644A patent/JP6936319B2/en active Active
- 2017-10-04 ES ES17860520T patent/ES2924065T3/en active Active
- 2017-10-04 AU AU2017344103A patent/AU2017344103B2/en active Active
- 2017-10-04 CN CN201780062107.0A patent/CN109890784B/en active Active
- 2017-10-20 KR KR1020197009817A patent/KR102419043B1/en active IP Right Grant
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080255245A1 (en) | 1999-12-06 | 2008-10-16 | Welichem Biotech Inc. | Anti-Inflammatory and Psoriasis Treatment and Protein Kinase Inhibition by Hydroxystilbenes and Novel Stilbene Derivatives and Analogues |
US6649633B2 (en) | 2001-01-31 | 2003-11-18 | Pfizer Inc | Nicotinamide biaryl derivatives useful as inhibitors of PDE4 isozymes |
Non-Patent Citations (12)
Title |
---|
AGHAZARIAN ET AL., UROLOGY, vol. 86, no. 1, 2015, pages 52 - 56 |
BAUER ET AL.: "Studies in Relation to Biosynthesis", AUSTRALIAN JOURNAL OF CHEMISTRY, 1955, pages 534 - 538, XP009514079, ISSN: 0004-9425 * |
DI BARI, CLIN TER, vol. 166, no. 3, 2015 |
JAIN ET AL., CURR DRUG TARGETS, vol. 15, no. 5, 2014, pages 539 - 550 |
KEREN ET AL., J DERMATOL SCI, vol. 77, no. 1, January 2015 (2015-01-01), pages 74 - 76 |
KOPF ET AL., NATURE REVIEWS DRUG DISCOVERY, vol. 9, September 2010 (2010-09-01), pages 703 - 718 |
NOVOSELOVA ET AL., MEDIATORS INFLAMM, vol. 2014, 2014, pages 728619 |
ROEDIGER ET AL., J ALLERGY CLIN IMMUNOL, vol. 136, no. 6, 2015, pages 1653 - 63 |
ROUBILLE ET AL., ANN RHEUM DIS, vol. 74, no. 3, 2015, pages 480 - 489 |
SCHELLER ET AL., BIOCHEM BIOPHYSICA ACTA (BBA) - MOLECULAR CELL RESEARCH, vol. 1813, no. 5, May 2011 (2011-05-01), pages 878 - 888 |
See also references of EP3526186A4 |
XU ET AL., CLIN EXP PHARMACOL PHYSIOL, vol. 42, no. 10, 2015, pages 1075 - 83 |
Also Published As
Publication number | Publication date |
---|---|
ES2924065T3 (en) | 2022-10-04 |
CA3038575C (en) | 2023-08-01 |
EP3526186A1 (en) | 2019-08-21 |
EP3526186A4 (en) | 2020-04-29 |
US10166201B2 (en) | 2019-01-01 |
CN109890784A (en) | 2019-06-14 |
CA3038575A1 (en) | 2018-04-19 |
US9725406B1 (en) | 2017-08-08 |
AU2017344103A1 (en) | 2019-04-04 |
JP2019532076A (en) | 2019-11-07 |
JP6936319B2 (en) | 2021-09-15 |
US20180118667A1 (en) | 2018-05-03 |
KR20190101953A (en) | 2019-09-02 |
CN109890784B (en) | 2022-04-29 |
KR102419043B1 (en) | 2022-07-07 |
AU2017344103B2 (en) | 2021-07-01 |
EP3526186B1 (en) | 2022-05-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2017344103B2 (en) | Substituted hydroxystilbenes and their therapeutic applications | |
JP7085566B2 (en) | Apoptosis inducer | |
US20130281396A1 (en) | Treatment of diseases by epigenetic regulation | |
EP3705480B1 (en) | Class of amino-substituted nitrogen-containing fused ring compounds, preparation method therefor, and use thereof | |
CN102603743A (en) | Anti-tumor benzazepine[f]azulene derivative, preparation method thereof, and purpose thereof | |
DE60117835T2 (en) | Amino-substituted tetracyclic compounds useful as anti-inflammatory agents and drugs containing them | |
CN111116469A (en) | HDAC inhibitor, preparation method, pharmaceutical composition and application thereof | |
US11000485B2 (en) | Substituted hydroxystilbenes as AhR and Nrf2 modulators and their therapeutic applications | |
US20150299185A1 (en) | Novel imidazopyridine derivatives as a tyrosine kinase inhibitor | |
EA003941B1 (en) | 2-aminopyridines containing fused ring substituents | |
CN110054627A (en) | A kind of novel IDO inhibitor, preparation method, medical composition and its use | |
JP7117029B2 (en) | 2-Substituted pyrazoleamino-4-substituted amino-5-pyrimidineformamide compounds, compositions and uses thereof | |
JP2022527279A (en) | Quinoline derivatives and their use for the treatment of cancer | |
CN111116551A (en) | 1-azaspiro [5.5] undecan-3-ones and 1-azaspiro [5.5] undecan-3-ols | |
JP2009507858A (en) | Quinoline derivatives and use as antitumor agents | |
CN113549046B (en) | Bisbecklonin S derivative and preparation method and application thereof | |
CN113801110B (en) | 1,2, 4-oxadiazole heterocyclic compound and application thereof | |
CN111039940B (en) | Aurora A kinase inhibitor, preparation method, pharmaceutical composition and application thereof | |
CN107281180A (en) | Application of the 8- alkyl berberine salts in prevention and treatment lung-cancer medicament is prepared | |
CN101317845A (en) | Pharmaceutical use of 6-aryl substituted pyridine compounds | |
CN106986821B (en) | A kind of aminomethyl pyridine analog derivative and its preparation method and application | |
WO2020228463A1 (en) | Preparation method for and use of anti-leukemia selenium-substituted noscapine derivatives | |
NZ199887A (en) | Phenanthroline derivatives and pharmaceutical compositions | |
CN101284007B (en) | Pharmaceutical use of aryl group substituted pyridone derivates in preparing medicine for tumour | |
CN117304148A (en) | 3, 4-disubstituted gamma-butyrolactone derivative, preparation method thereof and application of 3, 4-disubstituted gamma-butyrolactone derivative in preparation of antitumor drugs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17860520 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3038575 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2017344103 Country of ref document: AU Date of ref document: 20171004 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20197009817 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2019520644 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2017860520 Country of ref document: EP Effective date: 20190513 |