WO2001007033A2 - Neuroprotective pharmaceutical reparations comprising p-fluoroselegiline - Google Patents
Neuroprotective pharmaceutical reparations comprising p-fluoroselegiline Download PDFInfo
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- WO2001007033A2 WO2001007033A2 PCT/HU2000/000084 HU0000084W WO0107033A2 WO 2001007033 A2 WO2001007033 A2 WO 2001007033A2 HU 0000084 W HU0000084 W HU 0000084W WO 0107033 A2 WO0107033 A2 WO 0107033A2
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- WIPO (PCT)
- Prior art keywords
- selegiline
- fluoro
- racemic
- optically active
- neurons
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- 229960003946 selegiline Drugs 0.000 claims abstract description 31
- 210000002569 neuron Anatomy 0.000 claims abstract description 30
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- 230000008929 regeneration Effects 0.000 claims abstract description 15
- 238000011069 regeneration method Methods 0.000 claims abstract description 15
- 102000010909 Monoamine Oxidase Human genes 0.000 claims description 12
- 108010062431 Monoamine oxidase Proteins 0.000 claims description 12
- 230000005764 inhibitory process Effects 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 239000002775 capsule Substances 0.000 claims description 9
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- 235000020357 syrup Nutrition 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 230000002427 irreversible effect Effects 0.000 claims description 8
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- 241000124008 Mammalia Species 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 13
- 239000004480 active ingredient Substances 0.000 claims 3
- 239000004615 ingredient Substances 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 8
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 230000000302 ischemic effect Effects 0.000 description 5
- 206010008120 Cerebral ischaemia Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229960003678 selegiline hydrochloride Drugs 0.000 description 4
- 230000004770 neurodegeneration Effects 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 230000010410 reperfusion Effects 0.000 description 3
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000699694 Gerbillinae Species 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000005779 cell damage Effects 0.000 description 2
- 208000037887 cell injury Diseases 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 description 1
- MUDUXRHPVDVWHU-UHFFFAOYSA-N 1-(4-fluorophenyl)-n-methyl-n-prop-2-ynylpropan-2-amine Chemical group C#CCN(C)C(C)CC1=CC=C(F)C=C1 MUDUXRHPVDVWHU-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010048964 Carotid artery occlusion Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001424413 Lucia Species 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 241000699684 Meriones unguiculatus Species 0.000 description 1
- 238000010826 Nissl staining Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 231100000318 excitotoxic Toxicity 0.000 description 1
- 230000003492 excitotoxic effect Effects 0.000 description 1
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- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000004694 hippocampus damage Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000006525 intracellular process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940037525 nasal preparations Drugs 0.000 description 1
- 101150006061 neur gene Proteins 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 238000011859 neuroprotective therapy Methods 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
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- 239000007935 oral tablet Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 210000002763 pyramidal cell Anatomy 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- 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
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
- A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
Definitions
- the object of the invention is the application of racemic or optically active p-fluoro- selegiline of the formula III and of its salts for the protection of neurons, the promotion of the regeneration of damaged neurons, advantageously with the simultaneous promotion of the irreversible inhibition of the MAO-B enzyme, of the protection of neurons and the regeneration of damaged neurons.
- the further objects of the invention are the pharmaceutical products suited for the above application and the modes of treatment performed with them.
- Nerve cell damages due to the ischaemic reperfusion process are different from the toxin- caused damaging processes since in that case cell damage is an endogenous process.
- excitotoxic amino acids are released in the nerve cells and in consequence of it the inflow of Ca 2 t" and Na + ions into the cells increases, which starts the formation of free radicals directly inducing cell degeneration.
- selegiline has neuroprotective effect in conditions of cerebral ischaemia /Eur.J. of Pharmacology 315 p. 19-30 /1996/, according to others /J. of Neur. Sciences J48 p.1-5 /1997/ it fails to protect against anoxic damage. According to our knowledge and measurements, selegiline has neuroprotective effect in very low doses, but in the higher dose range necessary for the inhibition of the MAO-B enzyme this effect no longer appears to be statistically significant. Thus, selegiline appears to be less advantageous in chronic neuroprotective therapy when applied at the dose inhibiting MAO-B.
- racemic and optically active p-fluoro-selegiline of formula III and of its salts we unexpectedly found that these compounds have very good neuroprotective effect advantageously in the dose range of 0,25 mg/kg bdwt to 2,5 mg/kg bdwt.
- the racemic or optically active compounds of formula III and their salts are suitable for the production of pharmaceutical preparations and for the therapies performed by them, which ensure the protection of neurons and/or the regeneration of damaged neurons.
- the pharmaceutical preparations may be of optional dosage forms, advantageous are the oral dosage forms /tablet, capsule, solution, syrup or suspendable powder/ and the transdermally applicable form /patch/.
- the neuroprotective effect of racemic or optically active p-fluoro selegiline of formula III against ischaemic damage is not known from the literature. In the knowledge of the above we set the aim to find a compound which beside its irreversible MAO-B inhibitor effect is capable to ensure the protection of neurons and/or to promote the regeneration of damaged neurons in the same dose range.
- racemic or optically active p-fluoro-sclegiline of formula III and its salts administered in a determined dose range are capable to achieve the above aim and fulfil the set task, consequently they may be applicable for the treatment of acute or chronic neurodegenerative diseases.
- racemic optically active compounds of formula III and their salts are suitable for the production of pharmaceutical preparations and for the treatments performed with them which simultaneously promote the irreversible inhibition of MAO-B, the protection of neurons and/or the regeneration of the damaged neurons.
- p-fluoro-selegiline of formula III and/or its salts in the course of the treatment of mammals /including man/ at a dose range ensuring irreversible MAO-B inhibition, the protection of neurons and the promotion of the regeneration of the damaged neurons.
- This dose range is advantageously between 5 mg/day and 80 mg/day.
- the pharmaceutical preparations needed for the above treatment and their manufacturing also form a part of the solution described in our invention.
- the oral, nasal, rectally-, vaginally-, parenterally or locally applicable pharmaceutical preparations of our invention contain beside the compounds of general formula III and their salts the usual excipients and carrier substances, further their commercial package may contain an information leaflet indicating the applicable dose range.
- the orally applicable pharmaceutical forms according to our invention may be tablets, capsules, dragees, powders, granules, drinking solutions or syrups, which can be produced by the known methods.
- the nasal preparations may primarily be atomizable solid or fluid preparations.
- the parenterally applicable preparations are mainly injectable sterile solutions, suspendable powders, microcapsules and infusion solutions.
- the locally applicable preparations are e.g. patches, creams and gels.
- racemic p-fluoro-selegiline /p-fluoro-deprenyl/, N-//4-fluoro-phenyl-/isopropyl/-N- methyl-N-propinil-amine/, its optical isomers, the racemic compound and the salts, its biological effects /MAO-B inhibition, uptake inhibition/ as well as their production are described in the PCT patent application of publication No. WO-85/05617.
- mice Male Mongolian gerbils weighing 55-75 g were used for the experiments. The animals were anaesthetized with 1 % halothane in a mixture of 30 % dinitrogen-oxyde and 70 % oxygen. Body temperature was maintained at 37 °C by a heating blanket during the surgery. A midline incison was made in the ventral neck and carotid arteries were isolated. Global cerebral ischemia was evoked by 5 minute bilateral carotid occlusion. After release of microclips four days reperfusion was allowed. At the end of experiment animals were overanaesthetized with ether and intracardially perfused with 3.5 % phosphate buffered formaline.
- Gerbils were treated 6 times intraperitoneally, 5 and 30 minutes and 1-2-3 and 4 days after the termination of ischemia.
- Selegiline was applied in doses of 0.0001-0.001-0.01 and 0.25 mg/kg i.p.
- p-fluoro-selegiline was applied in doses of 0.001-0.01-0.25 and 2.5 mg/kg i.p.
- Figure 2 shows the area of CAl region of the /-/-selegiline hydrochloride treated animals and their controls.
- Figure 3 presents the hippocampal damage of the /-/-p-fluoro-selegiline treated and control animals.
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- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
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- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Hospice & Palliative Care (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Emergency Medicine (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention relates to the use of racemic or optically active p-fluoro-selegiline and/or its salts of formula (I) for the protection of neurons and/or for the promotion of the regeneration of damaged neurons.
Description
NEUROPROTECTIVE PHARMACEUTICAL PREPARATIONS
The object of the invention is the application of racemic or optically active p-fluoro- selegiline of the formula III and of its salts for the protection of neurons, the promotion of the regeneration of damaged neurons, advantageously with the simultaneous promotion of the irreversible inhibition of the MAO-B enzyme, of the protection of neurons and the regeneration of damaged neurons. The further objects of the invention are the pharmaceutical products suited for the above application and the modes of treatment performed with them.
There are two possible approaches of the treatment of acute and gradually developing chronic neurodegenerative diseases /cerebral ischaemia, Parkinson's disease, Alzheimer's disease, Huntington's chorea, etc./:
1. Rapid relief of the symptoms and
2. Slowing down or stopping the progression of the disease.
At present no drug exists which complies with both requirements. On the other hand, the true causes of the chronic neurodegenerative diseases are not known. The risk factors of stroke and the pathomechanism of the intracellular processes which follow stroke are relatively well known, but efficient medicinal treatment has as yet not been found.
It is known from the literature that selegiline //-/-N-1-phenyl-isopropyl-N-methyl-N- propinyl-amine/ shows neuroprotective effect against neurotoxins in in vivo systems by the inhibition of MAO-B and uptake.
Nerve cell damages due to the ischaemic reperfusion process are different from the toxin- caused damaging processes since in that case cell damage is an endogenous process. In the course of this process excitotoxic amino acids are released in the nerve cells and in consequence of it the inflow of Ca2 t" and Na+ ions into the cells increases, which starts the formation of free radicals directly inducing cell degeneration.
According to some authors selegiline has neuroprotective effect in conditions of cerebral ischaemia /Eur.J. of Pharmacology 315 p. 19-30 /1996/, according to others /J. of Neur. Sciences J48 p.1-5 /1997/ it fails to protect against anoxic damage.
According to our knowledge and measurements, selegiline has neuroprotective effect in very low doses, but in the higher dose range necessary for the inhibition of the MAO-B enzyme this effect no longer appears to be statistically significant. Thus, selegiline appears to be less advantageous in chronic neuroprotective therapy when applied at the dose inhibiting MAO-B.
We set the aim to find a compound with neuroprotective effect more efficiently applicable clinically than selegiline. In the course of the clinical studies of the racemic and optically active p-fluoro-selegiline of formula III and of its salts, we unexpectedly found that these compounds have very good neuroprotective effect advantageously in the dose range of 0,25 mg/kg bdwt to 2,5 mg/kg bdwt. According to our invention the racemic or optically active compounds of formula III and their salts are suitable for the production of pharmaceutical preparations and for the therapies performed by them, which ensure the protection of neurons and/or the regeneration of damaged neurons. The pharmaceutical preparations may be of optional dosage forms, advantageous are the oral dosage forms /tablet, capsule, solution, syrup or suspendable powder/ and the transdermally applicable form /patch/. The neuroprotective effect of racemic or optically active p-fluoro selegiline of formula III against ischaemic damage is not known from the literature. In the knowledge of the above we set the aim to find a compound which beside its irreversible MAO-B inhibitor effect is capable to ensure the protection of neurons and/or to promote the regeneration of damaged neurons in the same dose range. Surprisingly, we found that the racemic or optically active p-fluoro-sclegiline of formula III and its salts administered in a determined dose range are capable to achieve the above aim and fulfil the set task, consequently they may be applicable for the treatment of acute or chronic neurodegenerative diseases.
According to our invention, the racemic optically active compounds of formula III and their salts are suitable for the production of pharmaceutical preparations and for the treatments performed with them which simultaneously promote the irreversible inhibition of MAO-B, the protection of neurons and/or the regeneration of the damaged neurons.
Thus, according to our invention we proceed by applying p-fluoro-selegiline of formula III and/or its salts in the course of the treatment of mammals /including man/ at a dose range ensuring irreversible MAO-B inhibition, the protection of neurons and the promotion of the
regeneration of the damaged neurons. This dose range is advantageously between 5 mg/day and 80 mg/day. The pharmaceutical preparations needed for the above treatment and their manufacturing also form a part of the solution described in our invention. The oral, nasal, rectally-, vaginally-, parenterally or locally applicable pharmaceutical preparations of our invention contain beside the compounds of general formula III and their salts the usual excipients and carrier substances, further their commercial package may contain an information leaflet indicating the applicable dose range.
The orally applicable pharmaceutical forms according to our invention may be tablets, capsules, dragees, powders, granules, drinking solutions or syrups, which can be produced by the known methods.
The nasal preparations may primarily be atomizable solid or fluid preparations.
The parenterally applicable preparations are mainly injectable sterile solutions, suspendable powders, microcapsules and infusion solutions. The locally applicable preparations are e.g. patches, creams and gels.
The racemic p-fluoro-selegiline /p-fluoro-deprenyl/, N-//4-fluoro-phenyl-/isopropyl/-N- methyl-N-propinil-amine/, its optical isomers, the racemic compound and the salts, its biological effects /MAO-B inhibition, uptake inhibition/ as well as their production are described in the PCT patent application of publication No. WO-85/05617.
We present below further details of our invention by the following examples without aiming at restriction.
Biological example
In the following experiment we compared the neuroprotective and/or the regeneration promoting effect of damaged neurons exerted by /-/-p-fluoro-selegiline hydrochloride and /-/-selegiline hydrochloride at single doses ranging from 0,0001 mg/kg bdwt to 2,5 mg/kg bdwt.
Description of the experiment
Comparative study of selegiline and p-F-selegiline in global cerebral ischemia model in gerbils
Male Mongolian gerbils weighing 55-75 g were used for the experiments. The animals were anaesthetized with 1 % halothane in a mixture of 30 % dinitrogen-oxyde and 70 % oxygen. Body temperature was maintained at 37 °C by a heating blanket during the surgery. A midline incison was made in the ventral neck and carotid arteries were isolated. Global cerebral ischemia was evoked by 5 minute bilateral carotid occlusion. After release of microclips four days reperfusion was allowed. At the end of experiment animals were overanaesthetized with ether and intracardially perfused with 3.5 % phosphate buffered formaline. Following fixation brains were dissected and histologically processed, frontal sections of 30 μm thickness were made by freezing microtome at the level of rostral hippocampus. After Nissl staining the ischemia/reperfusion-induced neuronal damage was valuated in the CAl region of the hippocampus. Area of the CAl pyramidal cell layer was measured by computerized image analyzer system (Lucia 3.1).
Experimental groups were the following:
• sham operated, vehicle treated control
• ischemic, vehicle treated control
• ischemic, selegiline treated • ischemic, p-fluoro-selegiline treated.
Gerbils were treated 6 times intraperitoneally, 5 and 30 minutes and 1-2-3 and 4 days after the termination of ischemia.
Selegiline was applied in doses of 0.0001-0.001-0.01 and 0.25 mg/kg i.p. p-fluoro-selegiline was applied in doses of 0.001-0.01-0.25 and 2.5 mg/kg i.p.
Figure 2 shows the area of CAl region of the /-/-selegiline hydrochloride treated animals and their controls. Figure 3 presents the hippocampal damage of the /-/-p-fluoro-selegiline treated and control animals.
An example of the pharmaceutical preparation /10 mg tablet/
10 g /-/-p-fluoro-selegiline hydrochloride 6 g talcum
6 g magnesium stearate 20 g polividone 90 g maize starch 170 g lactose were homogenized, granulated then 1000 tablets were pressed from the obtained granulate.
Claims
1. Use of racemic or optically active p-fluoro-selegiline of the formula (I) (Figure 1) and/or its salt for the manufacture of a pharmaceutical composition for the protection of neurons and/or for the promotion of the regeneration of damaged neurons.
2. A use according to claim 1, characterized in that, the pharmaceutical composition is manufactured in an oral or a transdermal form as tablet, capsule, patch, retard tablet, solution or syrup.
3. A use according to claim 1, characterized in that, the pharmaceutical composition is manufactured in a form, which ensures the administration of racemic or optically active p-fluoro-selegiline or its salt in a dose between 5 mg/day - 80 mg/day.
4. Method of treatment for the protection of neurons and/or for the promotion of the regeneration of damaged neurons characterized in that, the therapeutically effective amount of racemic or optically active p-fluoro-selegiline and/or its salt is used.
5. A method according to claim 4, characterized in that, the racemic or optically active p- fluoro-selegiline and/or its salt is used orally or transdermally in the form of tablet, capsule, retard tablet, solution or syrup.
6. A method according to claim 4, characterized in that, the racemic or optically active p- fluoro-selegiline in a dose between 5 mg day - 80 mg/day is used.
7. Pharmaceutical composition for the protection and/or for the promotion of the regeneration of damaged neurons, characterized in that, it contains racemic or optically active p-fluoro-selegiline of the formula (I) and/or its salt as active ingredient together with auxiliary ingredients commonly used in the pharmaceutical compositions.
8. The oral or transdermal pharmaceutical composition according to claim 7, in the form of tablet, capsule, patch, solution or syrup.
9. The use of the racemic or optically active p-fluoro-selegiline of the formula (I) and/or its salt as an active ingredient in the preparation of a pharmaceutical composition simultaneously suitable for the irreversible inhibition of MAO-B enzyme for the protection of neurons and for the promotion of the regeneration of damaged neurons.
10. A use according to claim 9, characterized in that, the pharmaceutical composition is prepared in the form of tablet, capsule, patch, retard tablet, solution or syrup.
11. Method of treatment for the irreversible inhibition of MAO-B enzyme, for the protection of neurons and/or for the promotion of the regeneration of damaged neurons, characterized in that, the therapeutically active amount of racemic or optically active p- fluoro-selegiline of the formula (I) and/or its salt is used.
12. A method according to claim 1 1, characterized in that, the racemic or optically active p- fluoro-selegiline of the formula (I) is used orally or transdermally preferably in the form of tablet, capsule, patch, solution or syrup.
13. A method according to claim 1 1, characterized in that, the racemic or optically active p- fluoro-selegiline of the formula (I) in a dose between 5 mg/day - 80 mg-day is used.
14. Pharmaceutical composition for the irreversible inhibition of MAO-B enzyme, for the protection of neurons and/or for the promotion of the regeneration of damaged neurons, characterized in that, it contains racemic or optically active p-fluoro-selegiline of the formula (I) and/or its salt as active ingredient together with auxiliary ingredients commonly used in the pharmaceutical compositions.
15. The oral or transdermal pharmaceutical composition according to claim 14, in the form of tablet, capsule, patch, solution or syrup.
16. A packed pharmaceutical composition suitable for sale, characterized in that, it consists of an optional dose form containing the racemic or optically active p-fluoro-selegiline and/or its salt and an information carrier, which states that p-fluoro-selegiline and/or the equivalent amount of its salt in a dose between 5 mg/day - 80 mg/day is suitable simultaneously for irreversible inhibition of MAO-B enzyme, for protection of neurons and/or for the promotion of regeneration of damaged neurons in case of mammals (including the man).
17. A pharmaceutical composition according to claim 16, characterized in that, the dose form is an orally or transdermally applicable form.
18. An orally applicable dose form according to claim 16, characterized in that, the dose form is tablet, capsule, solution, syrup or suspendable powder.
19. A transdermally applicable dose form according to claim 16, characterized in that, the dose form is a patch.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU65856/00A AU6585600A (en) | 1999-07-22 | 2000-07-21 | Neuroprotective pharmaceutical preparations |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP9902482 | 1999-07-22 | ||
| HU9902482A HUP9902482A2 (en) | 1999-07-22 | 1999-07-22 | Use of p-fluoro-selegiline for producing neuroprotective pharmaceutical compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2001007033A2 true WO2001007033A2 (en) | 2001-02-01 |
| WO2001007033A3 WO2001007033A3 (en) | 2001-08-16 |
Family
ID=89998823
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2000/000084 WO2001007033A2 (en) | 1999-07-22 | 2000-07-21 | Neuroprotective pharmaceutical reparations comprising p-fluoroselegiline |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU6585600A (en) |
| HU (1) | HUP9902482A2 (en) |
| WO (1) | WO2001007033A2 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU207282B (en) * | 1984-05-31 | 1993-03-29 | Chinoin Gyogyszer Es Vegyeszet | Process for producing phenyl-alkyl-amine derivatives and pharmaceutical compositions containing them |
| HUT63579A (en) * | 1991-12-20 | 1993-09-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing double-phase pharmaceutical compositions suitable for treating diseases occurring during neurodegenerative processes |
-
1999
- 1999-07-22 HU HU9902482A patent/HUP9902482A2/en unknown
-
2000
- 2000-07-21 WO PCT/HU2000/000084 patent/WO2001007033A2/en active Application Filing
- 2000-07-21 AU AU65856/00A patent/AU6585600A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| HU9902482D0 (en) | 1999-10-28 |
| WO2001007033A3 (en) | 2001-08-16 |
| HUP9902482A2 (en) | 2002-04-29 |
| AU6585600A (en) | 2001-02-13 |
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