Claims
- 1. A piperidine compound selected from those having the formula I ##STR15## wherein R.sup.3 is 3,4-methylenedioxyphenyl, naphthyl or phenyl which may be substituted with one or more C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, C.sub.3-8 -cycloalkyl, C.sub.3-5 -alkylene, or benzyloxy groups, R.sup.1 is straight or branched C.sub.5-8 -alkyl, C.sub.4-8 -alkenyl, C.sub.4-7 -cycloalkyl, C.sub.4-8 -cycloalkylalkyl, phenyllower-alkyl, phenyloxylower-alkyl, and lower-alkoxy-lower-alkyl,
- X is hydrogen or 4-fluoro and wherein
- Y is O or S,
- and a salt thereof with a pharmaceutically-acceptable acid.
- 2. A compound of claim 1 which is (-)-trans-4-(-4-fluorocyclopentyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpiperidine hydrochloride.
- 3. A compound of claim 1 which is (+)-trans-4-phenyl-3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpiperidine hydrochloride.
- 4. A compound of claim 1 which is (-)-trans-4-(-4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-1-pentylpiperidine hydrochloride.
- 5. A compound of claim 1 which is (-)-trans-4(-4-fluorophenyl)-3-(5,6,7,8-tetrahydro-2-naphthoxymethyl)-1-pentylpiperidine hydrochloride.
- 6. A pharmaceutical composition suitable for use in preventing calcium overload in brain cells of mammals, including humans, comprising an amount of a compound of claim 1, which is effective for inhibiting calcium uptake into brain cells, together with a pharmaceutically-acceptable carrier or diluent.
- 7. A pharmaceutical composition according to claim 6 in the form of an oral dosage unit containing 1-100 mg of the active compound.
- 8. A compound of claim 1 which is (-)-trans-4-(4-fluorophenyl)-3(3,4-methylenedioxyphenoxymethyl)-1-pentylpiperidine or a pharmaceutically-acceptable salt thereof.
- 9. A compound of claim 1 which is (-)-trans-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpiperidinee hydrochloride.
Priority Claims (2)
| Number |
Date |
Country |
Kind |
| 5232/86 |
Nov 1986 |
DKX |
|
| 3234/87 |
Jun 1987 |
DKX |
|
PRINCIPLE
This is a division of application Ser. No. 106,154, filed Oct. 8, 1987, now U.S. Pat. No. 4,877,799.
The present invention relates to therapeutically active piperidine compounds, a method of preparing the same, pharmaceutical compositions comprising the compounds and to a method of treating therewith The novel compounds are useful in the treatment of anoxia, ischemia, migraine and epilepsy.
It is well known that accumulation of calcium in the brain cells (calcium overload) is seen after periods of uncontrolled hyperactivity in the brain, such as after convulsions, migraine, anoxia and ischemia. As the concentration of calcium in the cells is of vital importance for the regulation of cell function, an uncontrolled high concentration of the cell calcium will lead to, or indirectly cause the symptoms and possibly also the degenerative changes combined with the above diseases.
Therefore calcium overload blockers selective for brain cells will be useful i n the treatment of anoxia, ischemia, migraine and epilepsy.
Well known calcium antagonists such as nifedipine, verapamil and diltiazem have activity against pheripheral calcium uptake, e.g. in blood vessels and the heart, however have shown only very low activity against calcium overload in brain cells.
Accordingly it is an object of the invention to provide novel compounds having activity against calcium overload in brain cells.
The novel compounds of the invention are piperidine compounds having the general formula I ##STR2## wherein R.sup.3 is 3 4-methylenedioxyphenyl, aryl or heteroaryl which are optionally substituted with one or more C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, C.sub.3-8 -cycloalkyl, C.sub.3-5 -alkylene or aralkoxy,
R.sup.1 is straight or branched C.sub.4-8 -alkoxy-C.sub.1-8 -alkoxy-C.sub.4-8 -alkyl, C.sub.4-7 -cycloalkyl, aryloxy-C.sub.3-8 -alkyl C.sub.4-8 -alkenyl, or C.sub.4-8 -cycloalkylalkyl, or R.sup.1 may also be hydrogen or C.sub.1-3 -alkyl, when R.sup.3 is aryl, which is substituted with two or more of C.sub.1-6 - alkyl C.sub.1-6 -alkoxy, C.sub.3-8 -cycloalkyl, aralkoxy, or with C.sub.3-5 - alkylene.
Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts.
The invention also relates to a method of preparing the above mentioned compounds. This methods comprises
The pharmacological properties of the compounds of the invention can be illustrated by determining their capability to inhibit calcium uptake into brain synaptosomes.
Depolarization of neuronal membranes leads to an opening of socalled `voltage operated calcium channels` (VOC) in the membranes which allows a massive influx of calcium from the extracellular space. A crude synaptosomal preparation (socalled P.sub.2 fraction) contains small vesicles surrounded by neuronal membrane and it is possible in such a preparation to study a depolarization-induced opening of VOC. In the present model .sup.45 Ca influx is induced in the synaptosomes by depolarization with elevated potassium concentrations, and the effect of test substances on this stimulated uptake is studied (Nachshen, D.A. and Blaustein M P. Mol. Pharmcol. 16, 579 (1979)).
A male Wistar rat is decapitated and the cerebral cortex removed and homogenized in 20 ml. of ice-cold 0.32 M sucrose using a glass homogenizer with a teflon pestle. All subsequent steps for isolation of synaptosomes are done at 0.degree.-4.degree. C. The homogenate is centrifuged at 1000.times.g for 10 min and the resulting supernatant is re-centrifuged at 18000.times.g for 20 min. This pellet (P.sub.2) is resuspended in 0.32 M sucrose (10 ml per g of original tissue) with a teflon pestle.
Aliquots (0.050 ml) of this crude synaptosomal suspension are added to glass tubes containing 0.625 ml of NaCl buffer (136 mM NaCl, 4 mM KCl, 0.35 mM CaCl.sub.2, 1.2 mM MgCl.sub.2, 20 mM Tris HCl, 12 mM glucose, pH 7.4) and 0.025 ml of various drug solutions in 48% Ethanol. The tubes are pre-incubated for 30 min on ice and then for 6 min at 37.degree. C. in a water bath.
The uptake is immediately initiated by adding 0.4 ml of .sup.45 CaCl.sub.2 (specific activity=29-39 Ci/g; 0.5 Ci/assay), in 145 mM NaCl for non-depolarized samples and in 145 mM KCl for depolarized samples. The incubation is continued for 15 s.
The uptake is terminated by rapid filtration through GF-C glass fiber filters which are washed three times with 5 ml of a cold solution containing 145 mM KCl, 7 mM EGTA and 20 mM Tris HCl, pH 7.4. The amount of radioactivity on the filter disc is determined by liquid scintillation spectrometry.
Test substances are dissolved in 10 ml of 48% ethanol at a concentration of 0.44 mg/ml. Dilutions are made in 48% ethanol to give final concentrations of 0.1, 0.3, 1, 3 and 0 10 .mu.g/ml. Experiments are performed in duplicate. Controls for depolarized and nondepolarized samples are included in the assay and test substances are only tested in depolarized samples. 25-75% inhibition of stimulated uptake must be obtained before calculating the IC.sub.50 value.
The test value will be given as IC.sub.50 (the concentration (.mu.g/ml) of test substance which inhibit 50% of stimulated uptake of .sup.45 Ca (uptake in depolarized samples corrected for basal uptake in nondepolarized samples )). The IC.sub.50 value is estimated from dose response curves.
Test results obtained by testing some compounds of the present invention will appear from the following table 1.
The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically-acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and, in such form may be employed as solids, such as tablets or filled capsules; or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; in the form of suppositories for rectal administration: or in the form of sterile injectable solutions for parenteral (including subcutneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective calcium overload blocking amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing ten (10) milligrams of active ingredient or, more broadly, ten (10) to hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g., for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.
Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Ampoules are convenient unit dosage forms.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch, are particularly suitable for oral application. A syrup, elixirs or the like can be used in cases where a sweetened vehicle can be employed.
Generally, the compounds of this invention are dispensed in unit form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
The dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 10-100 mg/day, when administered to patients, e.g. humans, as a drug.
A typical tablet which may be prepared by conventional tabletting techniques contains:______________________________________Active compound 5.0 mgLactosum 67.8 mg Ph.Eur.Avicel .TM. 31.4 mgAmberlite .TM. IRP 88 1.0 mgMagnesii stearas 0.25 mg Ph.Eur.______________________________________
Due to the high calcium overload blocking activity , the compounds of the invention are extremely useful in the treatment of symptoms related to an accumulation of calcium in brain cells of mammals , when administered in an amount effective for blocking calcium overload in brain cells . The important calcium overload blocking activity of compounds of the invention includes both activity against anoxia, ischemia, migraine and epilepsy . The compounds of the invention may accordingly be administered to a subject, e.g., a living animal body, including a human, in need of a calcium overload blocker , and if desired in the form of a pharmaceutically-acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulfate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically-acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective calcium overload blocking amount, and in any event an amount which is effective for the treatment of anoxia, ischemia, migraine or epilepsy due to their calcium overload blocking activity. Suitable dosage ranges are 1-200 milligrams daily, 10-100 milligrams daily and especially 30-70 milligrams daily depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
| 3912743 |
Christensen |
Oct 1975 |
|
| 4007196 |
Christensen et al. |
Feb 1977 |
|
Foreign Referenced Citations (2)
| Number |
Date |
Country |
| 152273 |
Jul 1984 |
EPX |
| 223403 |
Oct 1985 |
EPX |
Divisions (1)
|
Number |
Date |
Country |
| Parent |
106154 |
Oct 1987 |
|
Patent Grant
5019582
