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  • A61P7/10—Antioedematous agents; Diuretics

Definitions

• the present invention relates to a new PTEN inhibitor or a new Maxi-K channels opener. More particularly, it relates to a PTEN inhibitor or new Maxi-K channels opener, which comprises as an active ingredient a tetrazolylalkoxy- dihydrocarbostyril compound of the formula (I) :
• R is a oycloalkyl group
• A is a lower alkylene group
• the bond between 3- and 4-positions of the carbostyril nucleus means a single bond or a double bond, or a salt thereof.
• PTEN Phosphatase and Tensin homolog deleted on chromosome Ten
• PTEN gene product exhibits a new phosphatase activity, i.e. it is able to dephosphorylate a phosphatidylinositol 3, 4, 5-trisphosphate (PIP3) substrate, which is a lipid second messenger, at D3 position thereof (cf. Beitner-Johnson D, Millhorn DE, J. Biol. Chem., 273: pp. 13375-13378, 1998) .
• PTEN In view of the functions of PTEN, it is expected that when inhibition of PTEN will be effective for promotion of the survival of normal cells, brain cells, heart cells, and skin, and further effective for inhibiting of Gram negative sepsis and cell migration and cell invasion.
• Maxi-K channel is a class of large conductance calcium sensitive potassium channels, and the activity of Maxi-K channels is controlled by intracellular calcium concentration and membrane potential, etc.
• the Maxi-K channels are widely distributed within the living body such as neurons, heart cells, smooth muscle cells, and the opening of the Maxi-K channels induces hyperpolarization of cells.
• the opening of the Maxi-K channels is useful for the treatment of neuronal disorders, for example, as a medicament such as (1) an anticonvulsant, (2) a medicine for neuroprotection, for treatment of regional cerebral edema and neurologic motor impairment, cognitive disorders, traumatic brain injury, Parkinson's disease, epilepsy, migraine, and Alzheimer's disease, (3) a medicine for control of a pain, (4) a medicine for treating urge urinary incontinence, intestinal hypermotility, uterine contractility, anxiety, and depression.
• a medicament such as (1) an anticonvulsant, (2) a medicine for neuroprotection, for treatment of regional cerebral edema and neurologic motor impairment, cognitive disorders, traumatic brain injury, Parkinson's disease, epilepsy, migraine, and Alzheimer's disease, (3) a medicine for control of a pain, (4) a medicine for treating urge urinary incontinence, intestinal hypermotility, uterine contractility, anxiety, and depression.
• the present inventor has found that the tetrazolylalkoxy-dihydrocarbostyril compounds of the formula (I) or a salt thereof as mentioned above, particularly 6- [4- (l-cyclohexyl-lH-tetrazol-5- yl)butoxy] -3, 4-dihydro-carbostyril or a salt thereof, which are known to have platelet aggregation inhibitory activity and vasodilating activity, exhibit an activity of inhibiting PTEN and hence are useful as a PTEN inhibitor, and then the present invention has been accomplished.
• the present inventor has found that the tetrazolylalkoxy-dihydrocarbostyril compounds of the formula (I) or a salt thereof as mentioned above, particularly 6- [4- (l-cyclohexyl-lH-tetrazol-5-yl) butoxy] - 3, 4-dihydrocarbostyril or a salt thereof, which are known to have platelet aggregation inhibitory activity and vasodilating activity, exhibit an activity of opening of Maxi-K channels and hence are useful as a Maxi-K channels opener, and then the present invention has been accomplished.
• Fig. 1 shows a suppression of the TNF- ⁇ (50 ng/ml)- stimulated increased PTEN phosphorylation level by cilostazol (tradename of 6- [4- (l-cyclohexyl-lH-tetrazol-5- yl)butoxy] -3, 4-dihydro-carbostyril) .
• Fig. 2 shows effects of drugs on opening of calcium- activated K + current in SK-N-SH cells
• Fig. 2A shows the effects of cilostazol (tradename of 6- [4- (1-cyclohexyl- lH-tetrazol-5-yl)butoxy] -3, 4-dihydrocarbostyril)
• Fig. 2B shows effects of cilostazol and/or glibenclamide (abbreviated as "GBC”, which is commercially available antidiabetics, suggestive of absence of opening of ATP- sensitive K + channels)
• Fig. 2C shows effects of cilostazol and/or iberiotoxin (abbreviated as "Ibtx”, which is known as Maxi-K + channel blocker, suggestive of opening of Maxi-K + channels) .
• Fig. 3 shows total amyloid-beta concentration (A-Beta 40 and A-Beta 42 levels) in brains of mice in the control and cilostazole treated groups which were detected by ELISA.
• Fig. 4 shows a summary of experimental results obtained from the Y-maze behavior paradigm for testing the effects on Alzheimer's disease of the compound of the present invention.
• the present invention provides a new PTEN inhibitor or new Maxi-K channels opener which comprises as an active ingredient a tetrazolylalkoxy-carbostyril compound of the formula (I) or a salt thereof.
• the present invention further provides a method for inhibiting PTEN and a method for opening Maxi-K channels, which comprises administering the tetrazolylalkoxy-carbostyril compound (I) or a salt thereof to a patient in need of such treatments, and further provides a use of the tetrazolylalkoxy-carbostyril compound (I) or a salt thereof for inhibiting PTEN as well as for opening Maxi-K channels.
• the compound of the formula (I) or a salt thereof has excellent PTEN inhibitory effect and hence the PTEN inhibitor of the present invention comprising as an active ingredient the compound of the formula (I) or a salt thereof is useful as a medicament for promotion of the survival of normal cells, brain cells, heart cells, and skin, and further for inhibiting of Gram negative sepsis and cell migration and cell invasion without any side effect due to inhibition of PTEN.
• the compound of the formula (I) or a salt thereof has excellent effect of opening of a large conductance calcium-activated K + channel (Maxi-K channels) and hence the Maxi-K channel opener of the present invention comprising as an active ingredient the compound of the formula (I) or a salt thereof is useful as a medicament for the treatment of neuronal disorders, for example, an anticonvulsant, a neuroprotecting agent, a medicament for treatment of regional cerebral edema and neurologic motor impairment, cognitive disorders, traumatic brain injury, Parkinson's disease, epilepsy, migraine, and Alzheimer's disease, pain, urge urinary incontinence, intestinal hypermotility, uterine contractility, anxiety, and depression.
• neuronal disorders for example, an anticonvulsant, a neuroprotecting agent, a medicament for treatment of regional cerebral edema and neurologic motor impairment, cognitive disorders, traumatic brain injury, Parkinson's disease, epilepsy, migraine, and Alzheimer's disease, pain, urge urinary incontinence, intestinal hypermotility, uterine
• the "cycloalkyl group” includes C 3 _ 8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. but preferable one is cyclohexyl.
• the "lower alkylene group” includes ⁇ . e alkylene groups such as methylene, ethylene, propylene, butylene, etc. but preferable one is butylene.
• Particularly preferred compound is 6- [4- (1-cyclohexyl- lH-tetrazol-5-yl)butoxy] -3, 4-dihydro-carbostyril, which has been sold as a vasodilator under a tradename of cilostazol.
• the compound of the formula (I) of the present invention can be used in bulk or preferably in the form of a pharmaceutical preparation with a conventional pharmaceutical carrier or diluent.
• the dosage form is not limited to a specific form, but may be in any conventional dosage forms, for example, preparations for oral administration, such as tablets, capsules, granules, various liquid preparations suitable for oral administration, or preparations for parenteral administration, such as injections, suppositories.
• the dosage is not limited to a specific range but is usually in the range of 100 to 400 mg per day in adult (50kg of body weight) which is administered once or being divided in one to several times.
• the active compound is preferably contained in the preparation in an amount of 50 to 100 mg per dosage unit.
• the preparation for injection is usually prepared in the form of a liquid preparation, an emulsion, or a suspension, which are sterilized and further are preferably made isotonic to the blood.
• the preparations in the form of a liquid, emulsion or suspension are usually prepared by using conventional pharmaceutical diluents, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters.
• These preparations may be incorporated with an isotonic agent such as sodium chloride, glucose, glycerin in an amount sufficient for making isotonic and may further incorporated with conventional solubilizers, buffers, anesthetizing agents, and optionally colorants, preservatives, fragrant materials, flavors, sweetening agents, and other medicaments.
• the preparations such as tablets, capsules, liquid for oral administration may be prepared by a conventional method.
• the tablets may be prepared by mixing with conventional pharmaceutical carriers such as gelatin, starches, lactose, magnesium stearate, talc, gum arabic, and the like.
• the capsules may be prepared by mixing with inert pharmaceutical fillers or diluents and filled in a hard gelatin capsule or a soft capsule.
• the oral liquid preparations such as syrups or elixirs are prepared by mixing the active compound and sweetening agents (e.g. sucrose), preservatives (e.g. methylparaben, propylparaben) , colorants, flavors, and the like.
• the preparations for parenteral administration may also be prepared by a conventional method, for example, by dissolving the compound (I) of the present invention in a sterilized aqueous carrier, preferably water or a saline solution.
• Preferred liquid preparation suitable for parenteral administration is prepared by dissolving about 50 - 100 mg of the active compound (I) in water and an organic solvent and further in a polyethylene glycol having a molecular weight of 300 to 5000, which is preferably incorporated with a lubricant such as sodium carboxy-methylcellulose, methyl-cellulose, polyvinylpyrr ⁇ lidone, and polyvinyl alcohol.
• the above liquid preparations may preferably be further incorporated with a disinfectant (e.g.
• the preparation for parenteral administration may be filled in a capsule, followed by removing the aqueous medium by a conventional lyophilizing technique, and is recovered into a liquid preparation by dissolving in an aqueous medium when used.
• SK-N-SH KCLB 30011, human brain neuroblastoma
• MEM Eagle's minimum essential medium
• L-glutamine 2 mM L-glutamine
• 1.0 mM sodium pyruvate supplemented with 10% heat-inactivated fetal bovine serum.
• Cells were grown to confluence at 37 °C in 5% C0 2 and used for experiments at no greater than passage 20.
• TNF- ⁇ solution TNF- ⁇ (Upstate Biotechnology, Inc., Lake Placid, NY) was dissolved in the phosphate buffered saline as a 10 ⁇ g/ml stock solution.
• the cells were lysed in lysis buffer containing 50 mM Tris-Cl (pH 8.0), 150 mM NaCl, 0.02% sodium azide, 100 ⁇ g/ml phenylmethylsulfonyl fluoride, 1 ⁇ g/ml aprotinin and 1% Triton X-100. Following centrifugation at 12,000 rpm, 50 ⁇ g of total protein was loaded into 8 or 10% SDS-PAGE gel, and transferred to nitrocellulose membrane (Amersham Pharmacia Biotech, Piscataway, NJ) .
• the blocked membranes were then incubated with the indicated antibody, and the immunoreactive bands were visualized using chemiluminescent reagent as recommended by Supersignal West Dura Extended Duration Substrate Kit (Pierce, Rockford, IL) .
• the signals of the bands were quantified using a GS-710 Calibrated imaging Densitomerter (Bio-Rad Laboratories, Hercules, CA) .
• the results were expressed as a relative density.
• Polyclonal antibodies against PTEN, phospho-PTEN (Ser 380/Thr382/383) were from the Cell Signaling Technology (Beverly, MA) .
• cilostazol (1, 10 and 100 ⁇ M) concentration-dependently suppressed the TNF- ⁇ (50 ng/ml)- stimulated increased PTEN phosphorylation level.
• SK-N-SH KCLB 30011, human brain neuroblastoma
• MEM Eagle's minimum essential medium
• Test drugs were grown to confluence at 37 °C in 5% C0 2 and used for experiments at no greater than passage 20.
• Cilostazol (a compound of the present invention, a tradename of 6- [4- (l-cyclohexyl-lH-tetrazol-5-yl) -butoxy] - 3, 4-dihydro-carbostyril) .
• Glibenclamide abbreviated as "GBC”
• GPC Glibenclamide
• Iberiotoxin abbreviated as "Ibtx”, which is known as Maxi-K + channel blocker
• Electrode resistance was kept below 3 M ⁇ . Junction potentials were zeroed with the electrode in the standard bath solution. Gigaohm seal formation was achieved by suction and, after establishing the whole cell configuration, the capacitive transients elicited by symmetrical 10 mV voltage clamp steps from -80 mV were recorded at 50 kHz for calculation of cell capacitance.
• the normal bath solution for the whole-cell recordings was: NaCl 130 mM, KC1 5 mM, MgCl 2 1.2 mM, CaCl 2 1.8 mM, HEPES 10 mM, glucose 5.2 mM and the pH was adjusted to 7.4 with NaOH.
• Pipettes were filled with KC1 140 mM, MgCl 2 0.5 mM, CaCl 2 0.1 mM, ethylenebis (oxonitrilo) tetra-acetic acid (EGTA) 0.09 mM, HEPES 10 mM, glucose 10 mM and the pH was adjusted to 7.4 with KOH.
• KC1 140 mM MgCl 2 0.5 mM, CaCl 2 0.1 mM
• EGTA ethylenebis (oxonitrilo) tetra-acetic acid
• HEPES 10 mM glucose 10 mM
• the pH was adjusted to 7.4 with KOH.
• Fig. 2A shows the effects of cilostazol
• Fig. 2B shows effects of cilostazol and/or glibenclamide ("GBC”, suggestive of opening of Maxi-K + channels)
• Fig. 2C shows effects of cilostazol and/or iberiotoxin ("Ibtx"
• the current was significantly increased by cilostazol, but on the other hand, it reversibly blocked by addition of iberiotoxin (100 nM) to the bath, but not by glibenclamide (10 uM) .
• iberiotoxin 100 nM
• glibenclamide 10 uM
• the increase in Maxi-K channel-medicated currents was given by cilostazol even in co-existence of glibenclamide, while glibenclamide alone could not increase the Maxi-K channel- mediated currents.
• Maxi-K channel blocker increase of the current was rather less than iberiotoxin alone.
• CMC carboxy- methylcellurose
• mice were genotyped at the beginning and end of the study.
• mice were subjected to the Y-maze behavior paradigm prior to completing the in-life phase.
• the mice were sacrificed at 14 weeks of age.
• e. Upon sacrifice, 1 ml of blood was collected for cilostazol blood concentration measurement, and APP/PSl mice were perfused with saline. Brains were hemisected with one hemisphere fixed and the other hemisphere frozen.
• the frozen hemisphere was homogenized and analyzed for total amyloid-beta concentration via ELISA.
• mice Total A-Beta 40 and total A-Beta 42 levels in brains of mice were detected in the control group and ⁇ in cilostazol treated group. The results are shown in the accompanying Fig. 3. 3.
• Procedure The following procedure outlines the steps taken to perform the test "Spontaneous Alternation in the Y-maze" .
• Mice have an _innate tendency to explore their environment. Successful exploration depends on the ability to avoid places recently visited, where food may have been depleted or absent (* spontaneous alternation").
• the Y-maze is an ethologically based test that does not involve reward delivery. Mice with compromised N ⁇ working memory" function cannot hold information regarding places just visited in their working memory; therefore they show decreased spontaneous alternation. Published results have shown decreased spontaneous alternation and increased exploration in certain transgenic mouse strains, for example APP/PSl mice.
• Cilostazol has an anti-platelet and vaso-dilating action, which has an indication for ASO and prevention of secondary brain infarction.
• Cilostazol may contribute to reduce the deposition of amyloid-beta protein, and improve a behavior of Alzheimer's dementia. i. Bring mice to be tested into the testing room.
• mice Avoid bringing many mice (more than three cages) into the testing area at once, as this may influence their behavior.
• mice may be tested out of its home cage by the base of the tail, and weigh it. Record the weight in the Y-Maze Data Spreadsheet. Place the mice back in the cage. (Alternatively, mice may be weighed before the start of the experiment, e.g. on the previous day) iv. Leave the mice undisturbed for 1 hour before the testing starts so that they can acclimate to the room. Extra care should be taken to ensure that cages are not left adjacent to one particular arm, as the smell, for example, may influence the entry of a mouse into a single arm.
• mice by the tail and place them in their home cage. Record the number of boli and whether or not the mice urinated in the Y-maze spreadsheet. Wipe the inside of the Y-maze with isopropanol. Use brush to get in corners, clean both walls and floor. Make sure that the Y-maze is clean and clear of any smell, bedding or food that may have been brought into the maze by a previous mouse. Make sure the Y-maze is dry after cleaning with alcohol. Make sure no cleaning material (such as tissue) is left behind in the maze. ix. Repeat steps for all of the mice to be tested. x. After the test, transfer data from hard copy to Excel spreadsheet.
• the tetrazolylalkoxy-dihydrocarbostyril compounds (I) or a salt thereof of the present invention is effective for opening Maxi-K Channels and is useful for the treatment of neuronal disorders, particularly for the treatment of Alzheimer's disease.
• the present invention provides a composition
• a composition comprising as an active ingredient a tetrazolylalkoxy- dihydrocarbostyril compound (I) or a salt thereof, which has excellent PEN inhibitory effects and is useful as a medicament for promotion of the survival of normal cells, brain cells, heart cells, and skin, and further for inhibiting of Gram negative sepsis and cell migration and cell invasion without any side effect due to inhibition of PTEN.
• composition of the present invention is further useful as an opener of a large conductance Ca 2+ -activated K + channel (Maxi-K channel) and hence as a medicament for the treatment of neuronal disorders, for example, an anticonvulsant, a neuroprotecting agent, a medicament for treatment of regional cerebral edema and neurologic motor impairment, cognitive disorders, traumatic brain injury, Parkinson's disease, epilepsy, migraine, and Alzheimer's disease, etc.
• a large conductance Ca 2+ -activated K + channel for example, an anticonvulsant, a neuroprotecting agent, a medicament for treatment of regional cerebral edema and neurologic motor impairment, cognitive disorders, traumatic brain injury, Parkinson's disease, epilepsy, migraine, and Alzheimer's disease, etc.

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