WO2006097744A2 - Phenol derivatives and their use to modulate pkb activity - Google Patents
Phenol derivatives and their use to modulate pkb activity Download PDFInfo
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- WO2006097744A2 WO2006097744A2 PCT/GB2006/000961 GB2006000961W WO2006097744A2 WO 2006097744 A2 WO2006097744 A2 WO 2006097744A2 GB 2006000961 W GB2006000961 W GB 2006000961W WO 2006097744 A2 WO2006097744 A2 WO 2006097744A2
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- pkb
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- pharmaceutically acceptable
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- 0 *c1cc(*)c(*)c(Cc2c(*)c(Cc3c(*)c(*)cc(*)c3)cc(*)c2)c1 Chemical compound *c1cc(*)c(*)c(Cc2c(*)c(Cc3c(*)c(*)cc(*)c3)cc(*)c2)c1 0.000 description 2
- XKUAPGKDSCPPJE-UHFFFAOYSA-N CC(c1cc(CCCl)ccc1O)=O Chemical compound CC(c1cc(CCCl)ccc1O)=O XKUAPGKDSCPPJE-UHFFFAOYSA-N 0.000 description 1
- HPGZZFCGNSOXFY-UHFFFAOYSA-N COCCOCCOCCOc1ccc(CCO)cc1 Chemical compound COCCOCCOCCOc1ccc(CCO)cc1 HPGZZFCGNSOXFY-UHFFFAOYSA-N 0.000 description 1
- PYWVWEBPONYFBV-UHFFFAOYSA-N COc1c(CO)cc(CCCl)cc1CO Chemical compound COc1c(CO)cc(CCCl)cc1CO PYWVWEBPONYFBV-UHFFFAOYSA-N 0.000 description 1
- NHOVBJTUKSSPGY-UHFFFAOYSA-N C[N+](C)(C)CCc(cc1)ccc1OC Chemical compound C[N+](C)(C)CCc(cc1)ccc1OC NHOVBJTUKSSPGY-UHFFFAOYSA-N 0.000 description 1
- BCPFFYSKRHEKDE-UHFFFAOYSA-N NCCCCCC(c1cc(CCCl)ccc1O)O Chemical compound NCCCCCC(c1cc(CCCl)ccc1O)O BCPFFYSKRHEKDE-UHFFFAOYSA-N 0.000 description 1
- FDLSQTOTBCBTCL-UHFFFAOYSA-N Oc1ccc(CCCl)cc1Cc(cc(CCCl)cc1)c1O Chemical compound Oc1ccc(CCCl)cc1Cc(cc(CCCl)cc1)c1O FDLSQTOTBCBTCL-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Definitions
- the present invention relates to novel compounds, which are useful as inhibitors and/or activators of protein kinase B (PKB/Akt). As such, these compounds will be useful in the treatment of cancer
- Phosphoinositide 3-kinases are an evolutionary conserved family of enzymes possessing lipid kinase activity who in response to extracellular stimuli are capable of generating a series of 3-phosphorylated phosphoinositide lipids with signalling potential.
- the resulting cellular effects of PI 3-kinase activity are diverse, including DNA synthesis, chemotaxis, glucose transport and vesicle trafficking.
- the activation of PI 3-kinases themselves takes place via a number of mechanisms, including receptor tyrosine kinases, Ras and heterotrimeric G-proteins.
- PKB/Akt protein kinase B
- T308 The first phosphorylation site, threonine-308 (T308) lies in the activation loop of PKB and is phosphorylated by phosphoinositide-dependent kinase-1 (PDK-I).
- S473 serine-473
- PDK-I mitogen- activated protein kinase-activated protein kinase 2
- ELK intergrin-linked kinase
- PKC ⁇ protein kinase C delta
- p70 S6K protein kinase C delta
- PKB protein kinase C delta
- Effectors of PKB include Bad, GSK-3 (glycogen synthase kinase-3) and mTOR (mammalian target of rapamycin) (Vivanco and Sawyers 2002).
- mTOR is a regulator of protein synthesis and is instrumental in PKC ⁇ activation (Parekh, Ziegler et al. 2000).
- mTOR activity is inhibited by rapamycin, via its binding to FKBP12, thus inhibiting events distal to mTOR (Sabers, Martin et al. 1995).
- Phosphoinositide signalling is a key element in controlling cell death, survival and fate.
- cell survival is an important mechanism of the natural defence against cancer.
- Cell survival is controlled by phosphoinositide 3-kinase products, which in turn activate a particular protein kinase, called PKB or Akt.
- PKB/ Akt is phosphorylated by other kinases subsequently leading towards full activation of its own catalytic abilities and thus progressing the cell survival signal through this protein kinase cascade. Unravelling the elements in control of PKB phosphorylation has been the focus of many research groups and drug development teams.
- the present invention provides the use of a compound of the formula:
- R 1 is C 1-5 alkoxy, OCOC I-3 Alkyl, O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 OMe, O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 0H or OH;
- R 2 is H, (CH 2 ) n OH, OCH 3 , Hal or
- R 3 is H or (CH 2 ) n OH
- R 4 is C 1-6 alkyl, optionally substituted by one or more of Hal, OH, COCH 3 , NH 2 ,
- halogen means F, Cl, I or Br, preferably Cl, I or Br.
- alkyl relates to both straight chain and branched alkyl radicals of 1 to 6 carbon atoms including but not limited to methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl n-pentyl, n-hexyl.
- alkyl relates to a group having 1, 2, 3, 4, 5 or 6 carbon atoms.
- alkyl also encompasses cycloalkyl radicals including but not limited to cyclopropyl, cyclobutyl, CH 2 -cyclopropyl, CH 2 -cyclobutyl, cyclopentyl or cyclohexyl.
- cycloalkyl relates to a group having 3, 4, 5 or 6 carbon atoms. Cycloalkyl groups may be optionally substituted or fused to one or more carbocyclyl or heterocyclyl group.
- the compounds of the present invention find use as inhibitors and/or activators of PKB, and thus as agents for use in the treatment of cancer.
- the compounds described herein find use in cancers where up regulation of PKB is implicated and more particularly where up-regulation together with mutation of PTEN is implicated.
- cancers such as ovarian, breast, prostrate, thyroid and pancreatic cancers are particular targets of the compounds.
- the present invention provides a pharmaceutical formulation comprising one or compounds as defined herein, optionally together with one or more pharmaceutically acceptable diluents, carriers and/or excipients.
- compositions of the invention may be presented in unit dose forms containing a predetermined amount of each active ingredient per dose.
- a unit may be adapted to provide 5-100mg/day of the compound, preferably either 5-15mg/day, 10-30mg/day, 25- 50mg/day, 40-80mg/day or 60-100mg/day.
- doses in the range 100-l000mg/day are provided, preferably either 100-400mg/day, 300-600mg/day or 500-l000mg/day.
- Such doses can be provided in a single dose or as a number of discrete doses. The ultimate dose will of course depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be at the doctor's discretion.
- compositions there may be cited all compositions usually employed for systemically or locally administering drugs.
- the pharmaceutically acceptable carrier should be substantially inert, so as not to act with the active component. Suitable inert carriers include water, alcohol, polyethylene glycol, mineral oil or petroleum gel, propylene glycol and the like. Said pharmaceutical preparations may be formulated for administration in any convenient way for use in human or veterinary medicine.
- compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam.
- oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue
- parenteral administration for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension
- topical application for example
- the subject agents may be simply dissolved or suspended in sterile water.
- the pharmaceutical preparation is non-pyrogenic, i.e., does not elevate the body temperature of a patient.
- effective amount means that amount of one or more agent, material, or composition comprising one or more agents of the present invention which is effective for producing some desired effect in an animal. It is recognized that when an agent is being used to achieve a therapeutic effect, the actual dose which comprises the "effective amount” will vary depending on a number of conditions including the particular condition being treated, the severity of the disease, the size and health of the patient, the route of administration, etc. A skilled medical practitioner can readily determine the appropriate dose using methods well known in the medical arts.
- phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body.
- a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body.
- Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
- materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
- one or more agents may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
- pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
- Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like (Berge, Bighley et al. 1977).
- the pharmaceutically acceptable salts of the agents include the conventional non-toxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
- such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
- inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like
- organic acids such as acetic, propionic, succinic, glycolic, stearic,
- the one or more agents may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
- These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
- Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
- Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., supra).
- Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
- antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
- water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
- oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
- Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and ublingual), rectal, vaginal and/or parenteral administration.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
- the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
- the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
- Methods of preparing these formulations or compositions include the step of bringing into association an agent with the carrier and, optionally, one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association an agent of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
- Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), 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 (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
- lozenges using a flavored basis, usually sucrose and acacia or tragacanth
- a compound of the present invention may also be administered as a bolus, electuary or paste.
- the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, olyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerator
- the pharmaceutical compositions may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin apsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross- linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
- compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
- These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
- embedding compositions which can be used include polymeric substances and waxes.
- the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
- Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
- Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the agents.
- suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the agents.
- Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be
- Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
- the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
- the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
- Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
- Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the agents in the proper medium. Absorption enhancers can also be used to increase the flux of the agents across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
- compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
- aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
- polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
- vegetable oils such as olive oil
- injectable organic esters such as ethyl oleate.
- Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
- compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of an agent, it is desirable to slow the absorption of the agent from subcutaneous or intramuscular injection.
- adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
- Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutano
- Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of agent to polymer, and the nature of the particular polymer employed, the rate of agent release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the agent in liposomes or microemulsions which are compatible with body tissue.
- compositions containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
- covers e.g., plasters, bandages, dressings, gauze pads and the like, containing an appropriate amount of a therapeutic.
- therapeutic compositions may be administered/ delivered on stents, devices, prosthetics, and implants.
- the present invention provides a compound as defined herein for use in medicine, particularly in the treatment of cancer.
- R 5 is C 1-5 alkoxy or OH
- R 6 is C 1-5 alkyl, optionally substituted by Hal, NHCH 3 , CO 2 H or esters or amides thereof;
- R 7 and R 8 are independently (CH 2 ) q OH where q is 2-5; and pharmaceutically acceptable salts thereof.
- the use of such compounds in the manufacture of a medicament for use in modulating PKB activity is also provided.
- Figure 1 provides compounds of the invention
- Figure 2 provides the results of western blots, illustrating phosphorylation of PKB when treated with various compounds of the invention
- Figure 3 illustrates that compound Q of the invention induces phosphorylation of PKB. Overlay of green and blue fluorescence channels where phosphorylation of PKB on S473 is indicated by the increase of green staining with a FITC labelled phospho- specific antibody and dapi stained nuclei are shown in false colour red. Upper panel: where indicated starved Cos6 cells were treated with serum and/or 15 ⁇ g/ml cQ for 10 min.
- FIG. 4 illustrates that compound Q inhibits insulin-stimulated actin remodelling. Overlay of red (F-actin) and blue (nuclei) fluorescence channels. Where indicated, starved Cos6 cells were stimulated with 15 ⁇ g/ml cQ and/or 5 ⁇ g/ml insulin for 10 min. c) Cells were preincubated with 100 ⁇ M LY294002 for 30 min, before stimulation. Rhodamine-labelled phalloidin staining demonstrated that a) starved Cos6 fibroblasts form stress fibers which are remodelled after d) insulin stimulation into polymerised F-actin juxtaposed to the plasma membrane, b) c A also induces the loss of stress fibers in starved fibroblasts. But unlike insulin, cQ is capable of reorganising the cytoskeleton c) independent of PI3-kinase and e) interferes with insulin-stimulated stress fiber breakdown; and
- Figure 5 provides the results of further western blots, illustrating activation of PKB with various compounds of the invention.
- Infrared spectra were recorded using a Shamadazu FTIR-8700 infrared spectrophotometer. Melting points were determined on a Gallenkamp melting point apparatus and are uncorrected. Mass spectra were recorded using a Micromass LCT- KAl 11 electrospray mass spectrometer. Accurate molecular weights were carried out by staff at the Department of Chemistry, University College London.
- Step 1 To a suspension of wang (polymer-bound p-benzyloxybenzyl alcohol) resin (3.07 g, 4.5 mmol) in dry dichloromethane (30 ml), was added trichloroacetonitrile (4.5 ml, 44.88 mmol). The mixture was cooled to 0 °C, l,8-diazabicyclo[5.4.0]undec- 7-ene (DBU) (0.3 ml, 2.00 mmol) was added dropwise and the reaction mixture was shaken for 1 h at 0 °C.
- DBU l,8-diazabicyclo[5.4.0]undec- 7-ene
- boron-triflouride dietherate (0.093 ml, 0.76 mmol) was added dropwise and the resin suspension was left shaking at room temperature for 18 h.
- the resin was collected in a sintered glass funnel and washed sequentially with tetrahydrofuran, tetrahydrofuran/methanol (1:1), methanol, tetrahydrofuran/methanol (1:1), tetrahydrofuran and dichloromethane.
- Step 3 To a supension of the resin in dry dichloromethane the resin was washed as before.
- the resin (0.17 g, 0.25 mmol) was re-suspended in a solution of 1% trifluoroacetic acid/ dichloromethane (5.0 ml). The resin suspension was shaken for 4 h and then washed sequentially with dichloromethane, tetrahydrofuran, tetrahydrofuran/methanol (1:1), methanol, tetrahydrofuran/methanol (1:1), tetrahydrofuran and dichloromethane. The organic layer was washed with water (2 x 50 ml) and brine (2 x 40 ml), dried with magnesium sulfate and reduced in vacuo.
- the product was concentrated in vacuo to afford the O-methoxy bis-acetylated intermediate (2.13 g, 78%).
- Anhydrous methanol (7 ml) was added to the O-methoxy intermediate (0.65 g, 2.55 mmol) under nitrogen and then cooled to 0°C in ice. 13% Sodium hypochlorite (24 ml, 20.55 mmol) was added dropwise and the mixture was left to stir at room temperature for 18h. Then 18.5% aqueous hydrochloric acid (5 ml) was added slowly and the mixture was left to stir at room temperature for 3 h. The reaction mixture was then concentrated in vacuo and redissolved in anhydrous methanol (10 ml) under nitrogen.
- Aluminium chloride (764 mg, 5.73 mmol) was added to solution of 4- methoxyphenethyl chloride (0.4 ml, 2.64 mmol) in dichloromethane under nitrogen. The mixture was cooled in ice to 0 °C and then acetyl chloride (0.41 ml, 5.76 mmol) was added dropwise. The reaction mixture was left to stir at room temperature for 24 h. The mixture was cautiously poured into ice and the organic layer was extracted using dichloromethane (3 x 30 ml). The combined organic extracts was washed with brine, dried with magnesium sulfate and concentrated in vacuo.
- Acetyl chloride (0.24 ml, 3.38 mmol) was added to a stirring solution of 4-(2-chloro- ethyl)-phenol (261 mg, 1.67 mmol), pyridine (0.68 ml, 8.41 mmol) and 4- dimethylaminopyridine (20 mg, 0.16 mmol) in dichloromethane (6 ml) at 0 °C and the reaction mixture was allowed to warm slowly to room temperature and stirred for 17h. The reaction mixture was quenched with water (8 ml).
- PKB is a protein downsteam effector of PI3K, and becomes phosphorylated on
- NCS Natal Calf Serum
- NCS Natal Calf Serum
- NIH3T3 cells were grown in media (GibcoBRL) containing 10% NCS to near confluency in six well plates. The cells were starved using 0.5% serum for 2-3 days. The media was then removed and replaced with serum free media for 15 minutes. Subsequently, 1% NCS was added to reaction wells, and 0%, 1% and 10% 5 NCS to control wells. After 20 minutes incubation, the compound was added, and the wells incubated for a further 15 minutes. Media was removed and sample buffer was added and the cells lysed, boiled, centrifuged.
- NIH 3T3 of Cos6 fibroblasts growing on PLL coated coverslips in DMEM containing 10% FCS were starved for 24 hours. Stimulation with c48/80 [10 ⁇ g/ml] was always carried out in the pesence of 1% FCS for 10 min. Whereas cells growing in DMEM completely depleted of serum were used for experiments with cQ [15 ⁇ g/ml]. Where indicated, cells were pretreated with 100 ⁇ M LY294002 for 30 min or 500 nM RV001 for 15 min. After treatment cells were washed with PBS, fixed with 4% PFA and permeabilised with 0.25 % Triton-X/PBS and washed extensively.
- Insulin-stimulated actin remodeling is inhibited by cQ
- Colony stimulating factor-1 (CSF-I) is a lineage-specific growth factor
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AU2006224314A AU2006224314A1 (en) | 2005-03-17 | 2006-03-17 | Phenol derivatives and their use to modulate PKB activity |
CA002601503A CA2601503A1 (en) | 2005-03-17 | 2006-03-17 | Phenol derivatives and their use to modulate pkb activity |
JP2008501412A JP2008538207A (en) | 2005-03-17 | 2006-03-17 | Compound |
US11/908,671 US20090221702A1 (en) | 2005-03-17 | 2006-03-17 | Compounds |
EP06726411A EP1879562A2 (en) | 2005-03-17 | 2006-03-17 | Phenol derivatives and their use to modulate pkb activity |
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GBGB0505509.0A GB0505509D0 (en) | 2005-03-17 | 2005-03-17 | Compounds |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009150137A2 (en) | 2008-06-10 | 2009-12-17 | Novartis Ag | Organic compounds |
EP2603215A4 (en) * | 2010-08-11 | 2015-08-05 | Philadelphia Health & Educatio | Novel d3 dopamine receptor agonists to treat dyskinesia in parkinson's disease |
WO2016038379A1 (en) * | 2014-09-10 | 2016-03-17 | Royal Holloway And Bedford New College | An anticonvulsant compound |
US9861594B2 (en) | 2013-10-28 | 2018-01-09 | Drexel University | Treatments for attention and cognitive disorders, and for dementia associated with a neurodegenerative disorder |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2745876A1 (en) * | 2012-12-21 | 2014-06-25 | Prous Institute for Biomedical Research, S.A. | Hydroxy aliphatic substituted phenyl aminoalkyl ether derivatives |
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-
2005
- 2005-03-17 GB GBGB0505509.0A patent/GB0505509D0/en not_active Ceased
-
2006
- 2006-03-17 JP JP2008501412A patent/JP2008538207A/en not_active Withdrawn
- 2006-03-17 EP EP06726411A patent/EP1879562A2/en not_active Withdrawn
- 2006-03-17 AU AU2006224314A patent/AU2006224314A1/en not_active Abandoned
- 2006-03-17 US US11/908,671 patent/US20090221702A1/en not_active Abandoned
- 2006-03-17 WO PCT/GB2006/000961 patent/WO2006097744A2/en active Application Filing
- 2006-03-17 CN CNA2006800170877A patent/CN101222916A/en active Pending
- 2006-03-17 CA CA002601503A patent/CA2601503A1/en not_active Abandoned
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Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2009150137A2 (en) | 2008-06-10 | 2009-12-17 | Novartis Ag | Organic compounds |
EP2603215A4 (en) * | 2010-08-11 | 2015-08-05 | Philadelphia Health & Educatio | Novel d3 dopamine receptor agonists to treat dyskinesia in parkinson's disease |
US9289400B2 (en) | 2010-08-11 | 2016-03-22 | Drexel University | D3 dopamine receptor agonists to treat dyskinesia in parkinson's disease |
US9675565B2 (en) | 2010-08-11 | 2017-06-13 | Drexel University | D3 dopamine receptor agonists to treat dyskinesia in parkinson's disease |
US10543180B2 (en) | 2010-08-11 | 2020-01-28 | Drexel University | D3 dopamine receptor agonists to treat dyskinesia in Parkinson's disease |
US11266612B2 (en) | 2010-08-11 | 2022-03-08 | Drexel University | D3 dopamine receptor agonists to treat dyskinesia in Parkinson's disease |
US9861594B2 (en) | 2013-10-28 | 2018-01-09 | Drexel University | Treatments for attention and cognitive disorders, and for dementia associated with a neurodegenerative disorder |
US10695302B2 (en) | 2013-10-28 | 2020-06-30 | Drexel University | Treatments for attention and cognitive disorders, and for dementia associated with a neurodegenerative disorder |
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WO2016038379A1 (en) * | 2014-09-10 | 2016-03-17 | Royal Holloway And Bedford New College | An anticonvulsant compound |
US10301263B2 (en) | 2014-09-10 | 2019-05-28 | Royal Holloway And Bedford New College | Anticonvulsant compound |
Also Published As
Publication number | Publication date |
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AU2006224314A1 (en) | 2006-09-21 |
WO2006097744A3 (en) | 2007-02-01 |
CN101222916A (en) | 2008-07-16 |
GB0505509D0 (en) | 2005-04-27 |
JP2008538207A (en) | 2008-10-16 |
CA2601503A1 (en) | 2006-09-21 |
US20090221702A1 (en) | 2009-09-03 |
EP1879562A2 (en) | 2008-01-23 |
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