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WO2000032199A1 - Utilisation de galanthamine et de derives de galanthamine en cas de lesions cerebrales fonctionnelles aigues - Google Patents

Utilisation de galanthamine et de derives de galanthamine en cas de lesions cerebrales fonctionnelles aigues Download PDF

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Publication number
WO2000032199A1
WO2000032199A1 PCT/AT1998/000291 AT9800291W WO0032199A1 WO 2000032199 A1 WO2000032199 A1 WO 2000032199A1 AT 9800291 W AT9800291 W AT 9800291W WO 0032199 A1 WO0032199 A1 WO 0032199A1
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WO
WIPO (PCT)
Prior art keywords
hydrogen
galanthamine
sph
compound
general formula
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.)
Ceased
Application number
PCT/AT1998/000291
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German (de)
English (en)
Inventor
Martin Alois Hermann Mucke
Johannes Fröhlich
Ulrich Jordis
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.)
Sanochemia Pharmazeutika AG
Original Assignee
Sanochemia Pharmazeutika AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sanochemia Pharmazeutika AG filed Critical Sanochemia Pharmazeutika AG
Priority to PCT/AT1998/000291 priority Critical patent/WO2000032199A1/fr
Priority to AU14300/99A priority patent/AU1430099A/en
Publication of WO2000032199A1 publication Critical patent/WO2000032199A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the invention relates to the new use of galanthamine and chemical derivatives of galanthamine or pharmaceutically acceptable acid addition salt thereof for the manufacture of medicaments for the treatment of traumatic brain injury without fracture of the skull capsule (also referred to as intracranial trauma) and of stroke (acute cerebral in- sult).
  • the stroke is based on a sudden decrease in blood flow to one or more brain regions. This can be caused either by complete or partial occlusion of the supplying artery (focal ischemic insult, approx. 80% of cases) or by tearing of a vessel with subsequent bleeding in the brain or between the brain and the meninges (hemorrhagic insult, approx. 20 % of cases) occur. If the blood flow to the brain drops below 20 ml per minute and 100 grams of tissue, the first functional failures occur, which are initially still reversible and, in the most favorable cases, self-limiting (transient ischemic attack, TIA).
  • TIA transient ischemic attack
  • Acute traumatic brain injury always has an exogenous origin in Form of a massive, mechanical impact on the skull capsule, which results in a displacement of individual brain parts against each other and against the bony shell as well as bruises, even if there is no open skull fracture.
  • focal localized form which is usually associated with external head injuries, which is usually due to a fall or stroke
  • there is also a diffuse and only neurologically detectable form which is caused by the effect of strong acceleration forces on the head (so-called whiplash).
  • the cells of the brain matrix that are damaged during the primary event absorb more water and certain ions (especially calcium), which causes cerebral edema with increased internal pressure.
  • Galanthamine is therefore used pharmacologically for symptoms of paralysis as a result of poliomyelitis and for various chronic diseases of the nervous system.
  • Galanthamine and some of its derivatives are also used in the symptomatic treatment of Alzheimer's disease and related dementia.
  • Galanthamine is also used when the nervous system is damaged by injury.
  • galanthamine is an alkaloid of the morphine group, which can be obtained from snowdrops (Galanthus woronowii, G. nivalis, etc.) and other amaryllidaceae.
  • medicaments which contain galanthamine or chemical derivatives of galanthamine or salts thereof, which subsequently occur after a stroke or traumatic brain injury can significantly limit secondary brain damage.
  • This effect which affects both the intensity of the damage and the extent of the focus, appears to be largely independent of the ability of galanthamine to inhibit acetylcholinesterase, which is present at about the same time.
  • the application in both forms of stroke is possible without distinction in the initial phase, which enables faster intervention.
  • the invention relates to the use of galanthamine, derivatives or analogs of galanthamine and pharmaceutically acceptable acid addition salts thereof, for the manufacture of medicaments for
  • Analogs of galanthamine contemplated in the context of the invention are, starting from the above-mentioned formula of galanthamine, those compounds in which the hydroxyl group is replaced by a methoxy, ethoxy, low.
  • Alkanyloxy e.g.
  • Acetyloxy-) group is replaced, the methoxy group by hydrogen, the ethoxy or a low.
  • Alkanoyloxy group (such as acetyloxy) is replaced and the methyl group substituted on the nitrogen atom by other straight or branched chain lower alkyl groups, such as ethyl, cyclopropylmethyl or cyclobutylmethyl, allyl, low.
  • Alkylphenol is replaced, the substituents fluorine, chlorine, bromine, low.
  • Alkyl, in which the substituents are on the phenyl ring, and compounds in which hydrogen atoms in the "ring" structure have been replaced by fluorine or chlorine groups are likely to have all or part of these properties.
  • R- L , R 2 are either the same or different and
  • R 4 , R 5 either both hydrogen or alternately any combination of hydrogen or one (Ar) alkyl-, (Ar) alkenyl- (Ar) alkynyl- with
  • R 8 is hydrogen or a lower (C 1 -C 10 ), optionally branched, optionally substituted (Ar) alkyl group
  • R 9 has the following meanings:
  • esters in particular also esters with the substitution pattern of amino acids, such as
  • R 10 is hydrogen, a lower ( ⁇ -C ⁇ , given- if branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or (Ar) alkylcarbonyloxy group as well as sulfonic acid such as eg tosyl and mesyl group
  • R X1 is hydrogen, a lower (C 1 -C 6 ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl group and sulfonic acid such as tosyl and mesyl.
  • Y 1 # Y 2 O, S, NH or NR 10 (surplus valences are each -H)
  • R 4 / H represents R s also OH or in the case that R s ⁇ H represents R 4 can also be OH.
  • G ; L , G 2 together or differently have the meaning:
  • R ⁇ 3 , R i4 is hydrogen, OH, a lower, optionally branched, optionally substituted (Ar) alkyl, aryl, (Ar) alkyloxy or aryloxy group or together an alkyl spiro group (C 3 to C 7 spiroring).
  • Aromatic an ortho, meta, or para disubst.
  • R 17 , R 18 , R 19 , and R 20 are individually or together, identical or different hydrogen, lower, optionally branched, optionally substituted (Ar) alkyl, cycloalkyl, or aryl groups, where R 17 and R 18 and R 19 and R 20 can together form a cycloalkyl group (ring size 3-8).
  • G 8 O, S, NH, NR 21 , - (CH 2 ) n -,
  • R 21 CHO, COOR 17 , or an unsubstituted, or by one or more F, Cl, Br, J, N0 2 , NH 2 , OH, alkyl, alkyloxy, CN, NC or CF 3 , CHO, COOH, COOalkyl, S0 3 H, SH, S-alkyl groups of identical or differently substituted (hetero) aryl radical, (with heteroaryl in particular 2-pyridyl, 4-pyridyl, 2-pyrimidinyl) or
  • a methyl group which is substituted by 1-3 unsubstituted or by one or more F, Cl, Br, J, NO 2 , NH 2 , alkyl, alkyloxy, CN, NC or CF 3 groups, the same or different substituted phenyl group (s) ,
  • G fi can also be:
  • R 7 is equal to R 6 or represents -0 (N-oxide) or a lone pair of electrons (e-pair), where R s and R 7 can also form a common ring of size 3-8, and [X] only then exists and represents an ion of a pharmacologically usable inorganic and organic acid if R s and R 6 are present and thus the nitrogen carries a positive charge.
  • the invention further encompasses the new, substituted bridged bases of the general formula (III) and their preparation, in particular 2, 5-diazabicyclo [2.2.1] heptanes: (Formula III)
  • a methyl group which is substituted by two unsubstituted or by one or more F, Cl, Br, J, N0 2 , NH 2 , OH, alkyl, alkyloxy, CN, NC or CF 3 , CHO, COOH, COOalkyl, S0 3 H, SH S-alkyl groups are substituted by the same or different substituted phenyl group (s),
  • R 17, R 18 , n, s have the meanings given in the general formula (I) and
  • G 4 and G s have the meanings given in the general formula (I) and G 9 is defined as:
  • Example a Example b
  • Galanthamine, an analogue, or an acid addition salt thereof can be administered in any suitable chemical or physical form.
  • it can be administered as the hydrobromide, hydrochloride, methyl sulfate or methiodide.
  • Galanthamine, an analogue, a derivative or their pharmaceutically acceptable acid addition salts can be administered intravenously to a patient suffering from stroke or traumatic brain injury by injection or infusion or intracerebroventricularly by means of an implanted container.
  • Typical dosage rates when these active ingredients are administered depend on the nature of the compound used and, in the case of intravenous administration, are in the range from 0.1 to 2.0 mg per day and kg of body weight, depending on the physical condition and other medication of the patient.
  • Liquid formulation for intracerebroventricular administration in a concentration of 1 or 5 mg of active ingredient / ml.
  • This experiment was carried out on isolated cortical neurons from nine-day-old chicken bryons (white leghorn hybrid strain).
  • test substances were the galanthamine derivatives listed below with the structural formulas:
  • test substances and the internal standard were administered from the first day over the entire test period of eight days.
  • the substances were tested on two different days. Two identical microplates with two wells per substance and dosage were prepared each day. Twelve specific values for blind tests were generated on each microplate.
  • One day old, 'fertilized eggs were kept at 12 + 0.1 ° C and 80 + 5% humidity in an incubator for eight days. On embryonic day 0, the eggs were placed in a incubator and kept at 38 + 0.5 ° C and 55 + 5% moisture until embryonic day 8.
  • the cortical neuron cultures of the eight day old chicken embryos were prepared as described in SOP F1505-01.
  • the described cortical neuron cultures of the chicken embryos were kept in this medium for eight days, ie with a large amount of deprivation, of the fetal calf serum necessary for survival. 5
  • a vitality assay was used to quantitatively check whether the addition of test substances during serum withdrawal could reduce cell death compared to the untreated controls.
  • galanthamine achieves a protective effect which can no longer be improved and which roughly corresponds to a doubling of the surviving cells.
  • the galanthamine derivative SPH-1286 ((-) N- (3-piperidinopropyl) -N-demylgalanthamine has a better effect at 0.1 mM (factor about 2.5).
  • the same derivative as racemate ( +/-) an equally strong protective effect at a concentration of only 0.0125 mM, although the cholinesterase inhibitory effect of this mixture of the two stereoisomers is only a quarter of that observed with the (-) - epimer SPH-1286.
  • mice were trained in a cognitive test model ("passive avoidance") and then anesthetized with carbon dioxide, which causes a loss of memory due to the lack of oxygen supply to the brain.
  • the aim of this experiment is to determine whether the invention in
  • hypoxia test Groups of ten mice were described in the table below using a constant volume dose of 10 ml / kg with varying concentrations of the substance tested.
  • test substance was administered one hour before the acquisition attempt (see below):
  • the apparatus consists of a 16 x 15 x 15 cm chamber with opaque walls and a grid floor.
  • a 4 cm wide, 11.5 cm long raised bridge extends from one side of the chamber and is illuminated.
  • the chamber is kept dark.
  • a mouse placed on the bridge can reach the chamber through a 3 x 3 cm opening. Electric shocks can be given on the legs of the dark chamber.
  • the animals were placed on the dock and entry latency is recorded.
  • the animals (except Groups 1 and 5) received electric shocks 10 seconds after they entered the dark room.
  • the animals were anesthetized with carbon dioxide (groups 5 to 10) or subjected to the sham anesthetic treatment (groups 1 to 4).
  • the anesthetic treatment consists of placing the mice in a chamber filled with C0 2 until breathing stopped. The mice were then resuscitated by artificial respiration.
  • the sham treatment was done by placing the mice in an identical chamber without CO 2 .
  • Piracetam was used as the substance for the positive control.
  • test compounds were prepared in 0.5% w / v carboxymethyl cellulose, with lower concentrations being prepared by dilution with 0.5% w / v carboxymethyl cellulose.
  • Piracetam was prepared in 0.5% w / v carboxymethyl cellulose in the desired concentration.
  • test substance SPH-1286 was able to completely prevent amnesia, which has not yet been described for a cholinesteras inhibitor.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Utilisation de galanthamine et d'analogues de celle-ci ou bien de ses sels d'addition d'acide pour la fabrication de médicaments destinés au traitement de l'état post-apoplexie cérébral ou du traumatisme craniocérébral focal fermé ou bien du traumatisme par projection.
PCT/AT1998/000291 1998-12-01 1998-12-01 Utilisation de galanthamine et de derives de galanthamine en cas de lesions cerebrales fonctionnelles aigues Ceased WO2000032199A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/AT1998/000291 WO2000032199A1 (fr) 1998-12-01 1998-12-01 Utilisation de galanthamine et de derives de galanthamine en cas de lesions cerebrales fonctionnelles aigues
AU14300/99A AU1430099A (en) 1998-12-01 1998-12-01 Use of galanthamine and galanthamine derivatives in the case of acute functionalbrain damage

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/AT1998/000291 WO2000032199A1 (fr) 1998-12-01 1998-12-01 Utilisation de galanthamine et de derives de galanthamine en cas de lesions cerebrales fonctionnelles aigues

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WO2000032199A1 true WO2000032199A1 (fr) 2000-06-08

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074820A1 (fr) * 2000-03-31 2001-10-11 Sanochemia Pharmazeutika Aktiengesellschaft Nouveaux derives et analogues de la galanthamine
WO2005030333A3 (fr) * 2003-09-29 2005-06-23 Sanochemia Pharmazeutika Ag Nouveaux derives de 4a,5,9,10,11,12-hexahydrobenzofuro[3a,3,2] [2]- benzazepine, procede pour les preparer et leur utilisation pour la preparation de produits pharmaceutiques
US7101890B2 (en) 1996-04-19 2006-09-05 Sanochemia Ltd. Benzazepine derivatives, drugs containing these and use of the same for producing drugs
WO2007016793A1 (fr) * 2005-08-11 2007-02-15 Universite De Montreal La galantamine en tant que médicament neuroprotecteur pour les cellules ganglionnaires de la rétine
AT500332B1 (de) * 2003-09-29 2008-09-15 Sanochemia Pharmazeutika Ag Neue derivate des (4as,8as)-d5,6-4a,5,9,10,11,12- hexahydro-11-methyl-3-methoxy-benzofuro(3a,3,2- f)(2)benzazepin, verfahren zu deren herstellung sowie deren verwendung zur herstellung von arzneimitteln
WO2009127218A1 (fr) 2008-04-14 2009-10-22 Galantos Pharma Gmbh Dérivés de galantamine comme promédicaments pour le traitement de maladies du cerveau humain
US9763953B2 (en) 2005-09-22 2017-09-19 Neurodyn Life Sciences Inc. Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3231571A1 (de) * 1982-08-25 1984-03-01 Naučno-issledovatel'skij institut po biologičeskim ispytanijam chimičeskich soedinenij, Staraja Kupavna, Moskovskaja oblast' Arzneipraeparat als stimulator der nervmuskeluebertragung, der glatten muskel, der erregungsleitung in dem peripherischen und zentralnervensystem
EP0449247A2 (fr) * 1990-03-29 1991-10-02 LTS Lohmann Therapie-Systeme GmbH & Co. KG Composition pharmaceutique renfermant de la Galanthamine dans le traitement de l'alcoolisme
JPH0466571A (ja) * 1990-07-03 1992-03-02 Meiji Seika Kaisha Ltd 脳及び心機能障害改善剤
US5294625A (en) * 1989-01-13 1994-03-15 Takeda Chemical Industries, Ltd. Benzylpiperidine compounds and their use
WO1997026887A1 (fr) * 1996-01-26 1997-07-31 Sanochemia Ltd. Utilisation de galanthamine pour preparer de nouveaux medicaments
WO1997040049A1 (fr) * 1996-04-19 1997-10-30 Sanochemia Ltd. Derives de benzazepine, medicaments contenant ces derives et leur utilisation pour produire des medicaments

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3231571A1 (de) * 1982-08-25 1984-03-01 Naučno-issledovatel'skij institut po biologičeskim ispytanijam chimičeskich soedinenij, Staraja Kupavna, Moskovskaja oblast' Arzneipraeparat als stimulator der nervmuskeluebertragung, der glatten muskel, der erregungsleitung in dem peripherischen und zentralnervensystem
US5294625A (en) * 1989-01-13 1994-03-15 Takeda Chemical Industries, Ltd. Benzylpiperidine compounds and their use
EP0449247A2 (fr) * 1990-03-29 1991-10-02 LTS Lohmann Therapie-Systeme GmbH & Co. KG Composition pharmaceutique renfermant de la Galanthamine dans le traitement de l'alcoolisme
JPH0466571A (ja) * 1990-07-03 1992-03-02 Meiji Seika Kaisha Ltd 脳及び心機能障害改善剤
WO1997026887A1 (fr) * 1996-01-26 1997-07-31 Sanochemia Ltd. Utilisation de galanthamine pour preparer de nouveaux medicaments
WO1997040049A1 (fr) * 1996-04-19 1997-10-30 Sanochemia Ltd. Derives de benzazepine, medicaments contenant ces derives et leur utilisation pour produire des medicaments

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEN Y ET AL: "Rivastigmine, a brain-selective acetylcholinesterase inhibitor, ameliorates cognitive and motor deficits induced by closed-head injury in the mouse.", J NEUROTRAUMA, APR 1998, 15 (4) P231-7, UNITED STATES, XP002117433 *
MANKOVSKII NB ET AL: "Effectiveness of gammalon and anticholinesterase preparations in the restorative and residual periods of ischemic stroke in old age", VRACH DELO, 1976, (5) P15-9, USSR, XP002112706 *
MUCKE H.A.M.: "Preclinical studies with galanthamine", DRUGS OF TODAY_(_DRUGS TODAY_), 33/4 (259-264), Spain, XP002112707 *
PATENT ABSTRACTS OF JAPAN vol. 016, no. 273 (C - 0953) 18 June 1992 (1992-06-18) *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101890B2 (en) 1996-04-19 2006-09-05 Sanochemia Ltd. Benzazepine derivatives, drugs containing these and use of the same for producing drugs
WO2001074820A1 (fr) * 2000-03-31 2001-10-11 Sanochemia Pharmazeutika Aktiengesellschaft Nouveaux derives et analogues de la galanthamine
US7166588B2 (en) 2000-03-31 2007-01-23 Sanochemia Pharmazeutika Aktiengesellschaft Derivatives and analogs of galanthamine
WO2005030333A3 (fr) * 2003-09-29 2005-06-23 Sanochemia Pharmazeutika Ag Nouveaux derives de 4a,5,9,10,11,12-hexahydrobenzofuro[3a,3,2] [2]- benzazepine, procede pour les preparer et leur utilisation pour la preparation de produits pharmaceutiques
AT500332B1 (de) * 2003-09-29 2008-09-15 Sanochemia Pharmazeutika Ag Neue derivate des (4as,8as)-d5,6-4a,5,9,10,11,12- hexahydro-11-methyl-3-methoxy-benzofuro(3a,3,2- f)(2)benzazepin, verfahren zu deren herstellung sowie deren verwendung zur herstellung von arzneimitteln
WO2007016793A1 (fr) * 2005-08-11 2007-02-15 Universite De Montreal La galantamine en tant que médicament neuroprotecteur pour les cellules ganglionnaires de la rétine
US9763953B2 (en) 2005-09-22 2017-09-19 Neurodyn Life Sciences Inc. Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment
US10265325B2 (en) 2005-09-22 2019-04-23 Neurodyn Life Sciences Inc. Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment
WO2009127218A1 (fr) 2008-04-14 2009-10-22 Galantos Pharma Gmbh Dérivés de galantamine comme promédicaments pour le traitement de maladies du cerveau humain

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