EP2121571A1 - Amphetamines fluoro-substituees et derives d'amphetamines fluoro-substituees et leur utilisation - Google Patents

Amphetamines fluoro-substituees et derives d'amphetamines fluoro-substituees et leur utilisation

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Publication number
EP2121571A1
EP2121571A1 EP08716621A EP08716621A EP2121571A1 EP 2121571 A1 EP2121571 A1 EP 2121571A1 EP 08716621 A EP08716621 A EP 08716621A EP 08716621 A EP08716621 A EP 08716621A EP 2121571 A1 EP2121571 A1 EP 2121571A1
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EP
European Patent Office
Prior art keywords
amphetamine
fluorine
substituted
derivative
phenyl ring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP08716621A
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German (de)
English (en)
Inventor
Ulrich Nagel
Werner Jürgen SCHMIDT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eberhard Karls Universitaet Tuebingen
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Eberhard Karls Universitaet Tuebingen
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Application filed by Eberhard Karls Universitaet Tuebingen filed Critical Eberhard Karls Universitaet Tuebingen
Publication of EP2121571A1 publication Critical patent/EP2121571A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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

Definitions

  • the present invention relates to fluorine-substituted amphetamines and amphetamine derivatives, their use as active ingredient and a pharmaceutical composition comprising at least one fluorine-substituted amphetamine or amphetamine derivative.
  • Parkinson's disease can affect many parts of the human body, starting from the brain.
  • the four main symptoms of Parkinson's disease are rigor (stiff muscles), tremor (muscle tremors) and hypokinesia (physical aggressiveness), which can lead to akinesia (immobility), as well as postural instability (postural instability).
  • rigor stiff muscles
  • tremor muscle tremors
  • hypokinesia physical aggressiveness
  • akinesia immobility
  • postural instability postural instability
  • cognitive deficits especially deficits in implicit learning.
  • L-DOPA the most well-known anti-Parkinson's drug
  • L-DOPA absorption in the gut and disciplined medication Long-term observations of the course of illness-related disorders are necessary. Recurring, regular checks must be performed to ensure adequate patient medication, especially one ensure adequate drug adjustment. For the affected persons, this means an increased compulsion to forward-looking life planning, combined with a severe restriction of the quality of life.
  • Ph is a phenyl ring.
  • An amphetamine derivative is to be understood as meaning a compound having the above structure which has at least one radical other than H and / or on the phenyl ring (in addition to fluorine) at least one substituent other than hydrogen.
  • An inventive fluorine-substituted amphetamine or amphetamine derivative has the formula (I) (I)
  • radicals R 1 or R 2 where at least one of the radicals R 1 or R 2 is other than H and Ph is a phenyl ring which is substituted at least at one position by fluorine or the radicals R 1 and R 2 are independently H or different from H and Ph is a phenyl radical Ring which is substituted with fluorine in at least three positions or the radicals R1 and R2 are each independently H or different from H and Ph is a phenyl ring which is substituted at least at one position with fluorine and at least one further Position has a different substituent from H.
  • Degradation is subject or is metabolized by the metabolism. This could be due to the fact that the fluorine-substituted phenyl ring of the amphetamine or amphetamine derivative according to the invention has an increased stability to the oxysubstituted phenyl ring of MDMA. causes a metabolism of the amphetamine or amphetamine derivative according to the invention.
  • the fluoro-substituted amphetamine or amphetamine derivative is excreted unchanged during or after the treatment.
  • the fluorine-substituted amphetamine or amphetamine derivative of the present invention preferably has a so-called sustained release action, i. it stays longer in the body of an animal or men.
  • a sudden high concentration of active ingredients active ingredient tips
  • the fluorine-substituted amphetamine or amphetamine derivative can be used in a relatively low dose in therapy or treatment.
  • the fluorine-substituted amphetamine or amphetamine derivative according to the invention can also be present in particular as a salt, particularly preferably in physiologically compatible form.
  • the salt may in particular be a water-soluble salt, for example a hydrochloride, sulfate or nitrate.
  • the fluorine-substituted amphetamine or amphetamine derivative according to the invention is present as an enantiomeric mixture, ie as a racemate.
  • the enantiomers may be present in the racemate in principle in each Amount ratio to each other. It may be preferred that one of the enantiomers is in excess. Furthermore, it may be preferred that the fluorine-substituted amphetamine or amphetamine derivative is present in enantiomerically pure form.
  • the residues other than H which the amphetamine or amphetamine derivative according to the invention may have are preferably alkyl groups. Particular preference is given to alkyl groups having one to ten carbon atoms, in particular methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl groups.
  • the alkyl groups can in principle be cyclized, straight-chain or branched. Particularly preferred, however, are short-chain (up to 5 C atoms) and unbranched alkyl groups, in particular methyl and / or ethyl groups.
  • the at least one substituent other than H on the phenyl ring is also preferably an alkyl group.
  • the above statements concerning the non-H residues which may comprise the amphetamine or amphetamine derivative of the present invention may be fully incorporated by reference.
  • an amphetamine or amphetamine derivative according to the invention may also have one or more alkyl groups in addition to one or more such substituents.
  • the fluorine-substituted amphetamine or amphetamine derivative according to the invention has a phenyl ring of the formula (II)
  • substituents R3 to R7 are fluorine and at least one of the radicals R1 or R2 is different from H.
  • the radical R1 and / or the radical R2 is preferably an ethyl group in this embodiment. Particularly preferably, in particular one of the two radicals is an ethyl group and the other H.
  • the preferred amphetamine or amphetamine derivative according to the invention has the formula (III)
  • the amphetamine or amphetamine derivative according to the invention has a phenyl ring of the formula (II)
  • R3 to R7 are fluorine, one of R1 or R2 is H and the other is H or H, in particular an alkyl group.
  • the radicals R1 and R2 are preferably equal to H. in this embodiment.
  • the amphetamine or amphetamine derivative according to the invention in this further particularly preferred embodiment has the formula (IV)
  • the amphetamine or amphetamine derivative according to the invention has a phenyl ring of the formula (II)
  • substituents R3 to R7 are fluorine and at least one further is an alkyl group.
  • at least R 4 is fluorine and at least R 5 is an alkyl group or at least R 5 is fluorine and at least R 4 is an alkyl group.
  • the at least one alkyl group is preferably a methyl group.
  • one of the radicals R 1 or R 2 is preferably H, while the other is H or different from H, in particular an alkyl group.
  • radicals R1 and R2 equal H.
  • the amphetamine or amphetamine derivative according to the invention in this third, particularly preferred embodiment has the formulas (V) or (VI)
  • the preparation of amphetamines or amphetamine derivatives according to the invention can in principle be carried out in various ways.
  • the particularly preferred methods for producing Development of amphetamines or amphetamine derivatives are also the subject of the present invention.
  • the preparation is particularly preferred starting from fluorine-substituted benzaldehydes. These can be reacted with nitroethane in the manner of an aldol reaction, followed by reduction of the resulting double bond and the nitro group.
  • the reduction is preferably carried out by means of a complex hydride, in particular with lithium aluminum hydride.
  • the resulting amino group can then be alkylated by customary methods, for example by means of methyl formate or acetic anhydride (the intermediates obtained after reaction of the amino compound with these reagents must of course be reduced, for example with lithium aluminum hydride).
  • Another particularly preferred method for preparing inventive amphetamines or amphetamine derivatives is based on fluorine-substituted benzene derivatives which are reacted with an alanine derivative.
  • Particularly suitable alanine derivatives are alanine hydrochloride and phthaloylalanine.
  • the alanine derivative can substitute an H on the benzene ring using suitable Lewis acidic catalysts.
  • a carbonyl compound is formed, which can subsequently be reduced. This gives a fluorine-substituted amphetamine, which can then be modified on the nitrogen, if desired.
  • the present invention further includes the use of a fluorine-substituted amphetamine or amphetamine derivative as a medicament, in particular for the treatment of neurological diseases, their consequences and / or for the treatment of side effects of a therapy of neurological diseases, and in particular also the use of a fluorine-substituted amphetamine or amphetamine derivative for the preparation of a medicament , in particular a medicament for the treatment of neurological diseases, their consequences and / or for the treatment of side effects of a therapy of neurological diseases.
  • any amphetamine or amphetamine derivative is suitable which has a phenyl ring which is substituted at at least one position by fluorine.
  • an amphetamine or amphetamine derivative whose phenyl ring is substituted at the at least one position by fluorine and at at least one further position has a substituent other than H, in particular an alkyl group.
  • the amphetamine or amphetamine derivative which can be used according to the invention preferably has at least one radical other than H, in particular an alkyl group, on the nitrogen.
  • the amphetamine or amphetamine derivative which can be used according to the invention is particularly preferably the fluorine-substituted amphetamines or amphetamine derivatives as already described above, in particular the compounds (III), (IV), (V) and (VI), among which the Compound (III) is particularly preferred.
  • the fluorine-substituted amphetamine or amphetamine derivative according to the invention has outstanding suitability, in particular for the treatment of neurological diseases and their consequences.
  • the fluorine-substituted amphetamine or amphetamine derivative are particularly suitable for the treatment of side effects of a therapy of neurological diseases.
  • the fluoro-substituted amphetamine or amphetamine derivative according to the invention can also be administered in the therapy of neurological diseases for the prevention of side effects.
  • the fluorine-substituted amphetamine or amphetamine derivative according to the invention can surprisingly be used both in the case of several simultaneously occurring indications.
  • Trems in particular Parkinson's disease, to emphasize, particularly preferably idiopathic Parkinson's disease.
  • the treatable consequences of the neurological diseases and / or the side effects are, in particular, movement disorders, multiple system atrophies, dystonic syndromes, dyskinetic syndromes and Parkinson's symptoms, such as tremor.
  • the therapy is preferably a medicamentous therapy, in particular with at least one anti-Parkinson's active ingredient, in particular from the group with dopamine precursors, decarboxylase inhibitors, dopamine agonists, all active ingredients which act via a stimulation of the dopamine receptors, Catechol O-methyltransferase (COMT) inhibitors, monoamine oxidase (MAO) inhibitors, and N-methyl-D-aspartate (NMDA) receptor antagonists.
  • CCT Catechol O-methyltransferase
  • MAO monoamine oxidase
  • NMDA N-methyl-D-aspartate
  • Suitable decarboxylase inhibitors are, in particular, benserazide or carbidopa.
  • dopamine agonists particular mention may be made of bromocriptine, apomorphine, cabergoline, pramipexole, ropinirole, pergolide, dihydro-alpha-ergocriptine or lisuride.
  • Suitable inhibitors of catechol-O-methyltransferase (COMT) include, in particular, entacapone or tolcapone.
  • As an example of inhibitors of monoamine oxidase (MAO) should be mentioned in particular.
  • Particularly suitable antagonists of N-methyl-D-aspartate (NMDA) receptors are amantadine or budipin.
  • drugs with said anti-Parkinson drugs are in particular all types of dyskinesias, in particular chorea, dystonic, ballistic and muscle spasmodic dyskinesia, as well as motor (reaction) fluctuations or psychotic states.
  • amphetamines or amphetamine derivatives according to the invention may also be used for the treatment of so-called tardive dyskinesias, which may be induced by neuroleptics.
  • the use according to the invention comprises the treatment of L-DOPA-induced side effects, in particular of L-DOPA-induced dyskinesias.
  • the fluorine-substituted amphetamine and amphetamine derivative according to the invention are suitable for the treatment of extrapyramidal movement disorders of all kinds.
  • Parkinson's syndromes dyskinetic, chorea- or dystonic syndromes (in particular Huntington's disease)
  • extrapyramidal adverse effects of neuroleptics tremor, Gilles de Ia Tourette Syndrome, Ballism, Muscle Spasm, Restless Legs Syndrome, or Wilson's Disease.
  • a pharmaceutical composition is also the subject of the present invention. This comprises according to the invention as active ingredient at least one fluorine-substituted amphetamine or amphetamine derivative.
  • the at least one fluorine-substituted amphetamine or amphetamine derivative has already been described in the context of the description of the use according to the invention.
  • the relevant embodiments are hereby incorporated by reference.
  • the treatment of a neurological disorder with a pharmaceutical composition according to the invention can completely replace a treatment with a medicament containing one of the abovementioned conventional active ingredients.
  • the fluorine-substituted amphetamine or amphetamine derivative is present in a composition according to the invention. as the sole active ingredient.
  • a mixture of different fluorine-substituted amphetamines or amphetamine derivatives it is also possible to use a mixture of different fluorine-substituted amphetamines or amphetamine derivatives.
  • a pharmaceutical composition according to the invention comprises at least one pharmaceutically acceptable carrier.
  • suitable carriers are known to the person skilled in the art.
  • the pharmaceutical composition according to the invention comprises a combination of the at least one fluorine-substituted amphetamine or amphetamine derivative and at least one conventional active ingredient, in particular at least one conventional anti-Parkinson's active ingredient.
  • At least one active ingredient from the group comprising dopamine precursors, decarboxylase inhibitors, dopamine agonists, all active ingredients which act via stimulation of the dopamine receptors, inhibitors of catechol-O-methyltransferase (COMT), inhibitors of monoamine oxidase are suitable for this purpose (MAO) and antagonists of N-methyl-D-aspartate (NMDA) receptors.
  • Preferred decarboxylase inhibitors dopamine agonists, catechol O-methyltransferase inhibitors, monoamine oxidase (MAO) inhibitors, and N-methyl D-aspartate (NMDA) receptor antagonists have been mentioned previously. The corresponding statements are hereby incorporated by reference.
  • the at least one anti-parkinsonian active ingredient is particularly preferably the L-DOPA, which has already been mentioned several times.
  • Amphetamines or amphetamine derivatives according to the invention can be prepared basically in several ways. Particular preference is given to syntheses starting from benzaldehydes which lead via 1- (fluorophenyl) -2-nitropropenes to 1- (fluorophenyl) -2-aminopropanes. If appropriate, these can be reacted further, in particular functionalized on the amino group.
  • aldehyde (3,4-difluorobenzaldehyde, 3-fluoro-4-methylbenzaldehyde, 3-methyl-4-fluorobenzaldehyde, 2,5-difluorobenzaldehyde or 2,4,5-TNfluorobenzaldehyde)
  • 208 mmol (16.2 g , 15.5 ml) of nitroethane 44 mmol (10 g, 10.6 ml) of ⁇ -aminopropyltriethoxysilane and 44 mmol (2.6 g, 2.5 ml) of glacial acetic acid in 25 ml of methanol for several days.
  • crystals are formed. These are filtered off, washed with cold aqueous methanol (10% water) and dried. Otherwise it is diluted with water and extracted three times with diethyl ether.
  • step 2 In prepared according to step 2 1- (fluoro-phenyl) -2-aminopropane can be introduced in a subsequent step, a methyl group.
  • a methyl group In particular, it is possible to proceed as follows: 0.1 mol of 1- (3,4-difluorophenyl) -2-aminopropane hydrochloride is dissolved in water. The solution is basified with caustic soda, extracted three times with diethyl ether, and the combined extracts are dried over solid potassium hydroxide. The solution is decanted from the desiccant and the ether removed in vacuo. The remaining oil is taken up in methyl formate and stirred at 20 bar H 2 pressure and 70 0 C in an autoclave overnight.
  • the solution is concentrated, taken up with tetrahydrofuran and added dropwise to 0.1 mol (3.8 g) of lithium aluminum hydride in tetrahydrofuran and stirred at 45 ° C. for 24 h. Then it is hydrolyzed with 4 ml of water, 4 ml of 15% sodium hydroxide solution and 12 ml of water. The precipitated aluminum hydroxide is filtered off and the aluminum hydroxide is washed three times with diethyl ether. From the combined ether phases, the solvent is removed in vacuo and the residue taken up in the just sufficient amount of dilute hydrochloric acid.
  • This solution is extracted twice with ethyl acetate, then twice with diethyl ether, the extracts are discarded.
  • the aqueous solution is basified with sodium hydroxide and extracted three times with diethyl ether.
  • the combined ether extracts are mixed with hydrochloric acid with vigorous stirring until the emulsion is neutral.
  • the solvents are removed in vacuo and the dried residue is recrystallized from ethyl acetate. The yield was usually about 80%.
  • 0.1 mol of 1- (3,4-difluorophenyl) -2-aminopropane hydrochloride is converted into the free base analogously to step 3.
  • the ethereal solution decanted from the potassium hydroxide is added with 0.1 mol (7.91 g, 8.1 ml) of pyridine.
  • 0.1 mol (10.2 g, 9.5 ml) of acetic anhydride is now added in portions and the mixture is stirred overnight at room temperature.
  • the reaction is washed three times with 2N hydrochloric acid, once with potassium bicarbonate solution, three times with water, dried and concentrated. The residue is taken up in tetrahydrofuran and as in
  • Step 3 reduced with lithium aluminum hydride and worked up.
  • the yield was usually about 80% here as well
  • Another particularly preferred route for preparing amphetamines or amphetamine derivatives according to the invention is based on substituted benzenes. The following is the synthesis of
  • 1-hydroxy-2-aminopropane methanesulfonate filtered off.
  • This metal methanesulfonate is hydrogenated in 30 ml methanesulfonic acid at 90 0 C and 1 bar with 2 g of 10% Pd / C as catalyst overnight. For workup, it is diluted with 200 ml of water, the pH is brought to 3 with sodium hydroxide and extracted three times with diethyl ether.
  • aqueous phase is made strongly alkaline, extracted three times with ether and worked up the combined ether phases as above on the 1- (2,5-difluorophenyl) -2-aminopropane-methanesulfonate. After recrystallization from ethyl acetate, which contains little ethanol, gives 4.7 g (37% of theory)
  • the methanesulfonate of this compound can be specified in methanesulfonic acid at 90 0 C and hydrogenated be as hydrochloride gerei- nigt as in (3).
  • hydrochloride gerei- nigt as in (3).
  • 1- (3,4-Difluorophenyl) -2-aminopropane hydrochloride is obtained in 55% yield based on the alanine used.
  • Parkinson's disease is the degeneration of dopaminergic neurons. As a result, there is a depletion of dopamine in the basal ganglia of the brain (dopamine hypofunction).
  • Parkinson's disease can be examined in animal models.
  • reduced functional dopamine activity can be achieved by blocking dopamine receptors or by destroying dopaminergic neurons.
  • rats Sprague-Dawley rats, Charles River, Sulzfeld, Germany
  • rats were established as an animal model. In the case of The rats were kept in constant, reproducible conditions.
  • the Sprague-Dawley rats were used in the experiment with a weight of about 220 to 300 g.
  • the rats were kept in groups. A light cycle of 12:12 hours was observed (switched on light from 07:00 to
  • Haloperidol-induced catalepsy is used herein as a model for Parkinsonism.
  • Haloperidol is a dopamine receptor blocking drug.
  • the catalepsy induced in this way includes akinesia and rigor.
  • the haloperidol model is treatable by all known clinically effective anti-Parkinsonian drugs as described above.
  • the haloperidol (Haldol, Janssen®, Germany) was supplemented with a phosphate buffered saline (phosphate buffered saline, PBS; Sigma, Deisenhofen, Germany) to a concentration of 0.5 mg per ml. Twelve rats each received an intraperitoneal (ip) injection of this solution with an absolute amount of the haloperidol of 0.5 mg per kilogram of body weight and an injection with PBS.
  • phosphate buffered saline phosphate buffered saline, PBS; Sigma, Deisenhofen, Germany
  • Schmidt et al. Wang J. Schmidt, Andreas Mayerhofer, Anja Meyer, Karl-A Kovar, "Ecstasy counteracts catalepsy in rats, anti-parkinsonian effect?", Neuroscience Letters
  • Fig. 1 the results of the descent tests are shown clearly. It was found that catalepsy was clearly pronounced in rats after treatment with haloperidol (HALO 1 0.5 mg / kg) followed by injection of PBS (vehicle control) with a descent latency of approximately 130 seconds. The descent latency of rats treated with MDMA (5 mg / kg) was much lower at about 30 seconds, but was still lower than that with 1- (3,4-difluorophenyl) -2- (N-ethylamino) -propane ( fMDE, formula (IM), 5 mg / kg) treated rats were slightly below.
  • HALO 1 haloperidol
  • PBS vehicle control
  • mice 24 rats were placed in deep anesthesia. One half of the rats were each treated with the neurotoxin 6-hydroxy-dopamine, which destroyed dopaminergic neurons in this brain half. On the body side, which is contralateral to the damaged hemisphere, animals treated in this way displayed Parkinson's symptoms (Hemi-Parkinson). The animals were then treated twice daily for twenty-five days with an anti ⁇
  • Parkinson's drug treated intraperitoneally. These were L-DOPA methyl ester in an amount of 10 mg per kg body weight with benserazide in an amount of 7.5 mg per kg body weight (Sigma, Deisenhofen, Germany). Under this treatment, the rats developed dyskinesia of the contralateral forepaw.
  • the other twelve rats were additionally fluorinated
  • Amphetamine derivative 1- (3,4-difluorophenyl) -2- (N-ethylamino) -propane (Formula III).
  • FIG. 2 clearly shows the results for the treatment.
  • the hemiparcinogenic, chronic L-DOPA pretreated rats were injected with PBS as a vehicle control after treatment with the anti-Parkinson's drug (L-DOPA methyl ester with benzoic acid (10 + 7.5 mg / kg)).
  • the dyskinesia quantification of the test group ie the animals additionally treated with 1- (3,4-difluorophenyl) -2- (N-ethylamino) -propane (formula (III), fMDE, 5 mg / kg), observed.

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Abstract

L'invention concerne des amphétamines fluoro-substituées ou des dérivés d'amphétamines fluoro-substituées de formule (I) dans laquelle au moins l'un des restes R1 ou R2 est différent de H, et Ph désigne un noyau phényle qui est substitué, en au moins une position, par un fluor, ou bien les restes R1 et R2 désignent H, indépendamment l'un de l'autre, ou sont différents de H, et Ph désigne un noyau phényle qui est substitué, en au moins trois positions, par un fluor, ou bien les restes R1 et R2 désignent H, indépendamment l'un de l'autre, ou sont différents de H, et Ph désigne un noyau phényle qui est substitué, en au moins une position, par un fluor, et qui présente en une autre position, un substituant différent de H. L'invention concerne en outre l'utilisation d'amphétamine fluoro-substituée ou des dérivés d'amphétamine fluoro-substituée, comme médicaments, en particulier pour le traitement de maladies neurologiques et leurs suites, et/ou pour le traitement d'effets secondaires d'une thérapie de maladies neurologiques, ainsi qu'une composition pharmaceutique comprenant, comme principe actif, au moins une amphétamine fluroro-substituée ou un dérivé d'amphétamine fluoro-substituée.
EP08716621A 2007-03-19 2008-03-19 Amphetamines fluoro-substituees et derives d'amphetamines fluoro-substituees et leur utilisation Withdrawn EP2121571A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007014286A DE102007014286A1 (de) 2007-03-19 2007-03-19 Fluorsubstituierte Amphetamine und Amphetaminderivate und deren Verwendung
PCT/EP2008/002188 WO2008113565A1 (fr) 2007-03-19 2008-03-19 Amphétamines fluoro-substituées et dérivés d'amphétamines fluoro-substituées et leur utilisation

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EP2121571A1 true EP2121571A1 (fr) 2009-11-25

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US (1) US20100179221A1 (fr)
EP (1) EP2121571A1 (fr)
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NZ595542A (en) 2009-03-30 2013-05-31 Dong A Pharm Co Ltd Improved method for preparing dipeptidyl peptidase-iv inhibitor and intermediate
GB2571696B (en) 2017-10-09 2020-05-27 Compass Pathways Ltd Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced
CN113993523A (zh) 2019-04-17 2022-01-28 指南针探路者有限公司 用赛洛西宾治疗抑郁症和其他各种病症

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FR104F (fr) * 1960-11-05
BE609630A (fr) * 1960-11-05 1962-04-26 Science Union & Compagnie Soc Nouveaux produits anorexiants
HU209605B (en) * 1991-04-15 1994-09-28 Chinoin Gyogyszer Es Vegyeszet Process for production of wather-free transdermal preparation
US7625909B2 (en) * 2003-05-23 2009-12-01 Novartis Vaccines And Diagnostics, Inc. Substituted quinazolinone compounds

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DE102007014286A1 (de) 2008-09-25
US20100179221A1 (en) 2010-07-15

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