WO2000032199A1

WO2000032199A1 - Use of galanthamine and galanthamine derivatives in the case of acute functional brain damage

Info

Publication number: WO2000032199A1
Application number: PCT/AT1998/000291
Authority: WO
Inventors: Martin Alois Hermann Mucke; Johannes Fröhlich; Ulrich Jordis
Original assignee: Sanochemia Pharmazeutika Aktiengesellschaft
Priority date: 1998-12-01
Filing date: 1998-12-01
Publication date: 2000-06-08
Also published as: AU1430099A

Abstract

The invention relates to the use of galanthamine and analogs thereof or acidic addition salts thereof in the production of medicaments for treating states arising from cerebro-vascular accidents or closed focal craniocerebral traumas or whiplash injuries.

Description

Use of galanthamine and galanthamine derivatives for acute functional brain damage

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). If this value drops below 5 ml / min / 100 g of tissue, nerve cells will perish and an infarct will develop. This ischemic nucleus is surrounded by a halo with critical low perfusion (pen umbra), in which certain neurotoxic substances are released and where, with rapid intervention, neurons can still be saved if the cascade of secondary damage spread can be interrupted. Acute therapeutic measures are therefore crucial for the outcome of a cerebral insult, which must begin in the first minutes to hours after the onset of symptoms.

Between 15,000 and 25,000 Austrians suffer a stroke each year, making it the third most common medical emergency and the most common cause of adult disability. Two thirds of all survivors remain disabled for life.

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. In addition to the 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. As a result, as well as intracranial bleeding, the blood vessels are narrowed and their functionality impaired, which leads to secondary ischemic damage. Further delayed damage is the uncontrolled release of neurotransmitters and neurotoxic compounds. To simplify matters, it can be assumed that within a few hours or days after the primary damage, a clinical picture will develop that is not unlike that of the stroke.

From a medicinal point of view, the condition after focal ischaemic insult has led to reperfusion of the affected brain region through the administration of generally vasodilating and metabolically stabilizing drugs (nootropics) and the reduction in blood viscosity through anticoagulants (heparin), especially recently the active resolution of the causing thrombus by lytic enzymes (streptokinase or tissue plasminogen activator - tPA) is sought. However, anticoagulation and thrombolysis therapy are associated with an increased risk of cerebral bleeding and are therefore absolutely contraindicated in the case of haemorrhagic insult, which means that time-consuming diagnostic clarification by means of imaging methods is required before the start of treatment.

After a focal craniocerebral trauma, however, the treatment is aimed primarily at normalizing the intracranial pressure and restoring the blood-brain barrier. Galanthamine with the formula

and some of its analogues have been known for many years as pharmaceutical active substances with an inhibitory effect on the synaptic enzyme acetylcholinesterase. 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.

Chemically speaking, galanthamine is an alkaloid of the morphine group, which can be obtained from snowdrops (Galanthus woronowii, G. nivalis, etc.) and other amaryllidaceae.

In addition to the production of galanthamine from plant sources, chemical synthesis processes for galanthamine and its analogs including their acid addition salts have also recently been proposed, reference being made to WO 95/27715 (= US Pat. No. 5,428,159) and WO 96/12692 . Further derivatives of galanthamine and their synthesis are described in WO 96/12692. The use of galanthamine for the manufacture of a medicament for the treatment of Alzheimer's disease and related dementias is known from EP 236 684 B1, its use in Down syndrome, myasthenia and related muscle disorders, in compression of peripheral nerves and in Glaucoma is described in WO 97/26887.

However, it could not have been foreseen that, according to the invention, 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. In particular, the application in both forms of stroke (ischemic and hemorrhagic) 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

a) the treatment of the condition after stroke,

b) the treatment of closed, focal traumatic brain injury,

c) the treatment of the condition after perinatal brain damage and

d) treatment after oxygen deficiency in the brain from suffocation, drowning or heart failure.

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. Alkylphenyl- or substituted nied. Alkylphenol is replaced, the substituents fluorine, chlorine, bromine, low. Alkoxy, hydroxy, nitro, amino, low. alkyl or acylamino with 1 to 5 carbon atoms or unsubstituted and halogen-substituted benzoyl, nied. 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.

In the context of the invention, compounds of the general formula (I)

Formula (I)

considered, where

R- _L , R _{2 are} either the same or different and

Hydrogen, F, Cl, Br, J, CN, NC, OH, SH, N0 ₂ , S0 ₃ H, NH ₂ , CF ₃ or

a lower one

, optionally branched, optionally substituted (Ar) alkyl or (Ar) alkyloxy group or

an amino group which is substituted by one or two identical or different lower (0. ^ - 0. ^), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or (Ar) alkyloxycarbonyl groups or

a COOH, COO (Ar) alkyl, CONH, CON (Ar) alkyl group or

- (CH ₂ ) _n -Cl, - (CH ₂ ) _n -Br, - (CH ₂ ) _n -OH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -CN, - (CH ₂ ) _n - NC, where

R ₁ -R _{2 can} also be defined together as -CH = CH-CH = CH-, -O- (CH ₂ ) _n -0-, with n = l-3.

R ₃ = R ₁ , especially OH and 0CH ₃ , further R ₂ -R ₃ together: -O- (CH ₂ ) _n -0- can form, where n = l-3

R ₄ , R ₅ : either both hydrogen or alternately any combination of hydrogen or one (Ar) alkyl-, (Ar) alkenyl- (Ar) alkynyl- with

SR ₈ , where R _{8 is} hydrogen or a lower (C ₁ -C ₁₀ ), optionally branched, optionally substituted (Ar) alkyl group

SO-R ₈ , S0 ₂ R ₈

OH, O protecting group (such as TMS, TBDMS),

0-CS-NR ₈ (thiourethane),

0-CO-NR ₉ , where R _{9 has} the following meanings:

0-CO-R ₈ (esters, R ₈ see above), in particular also esters with the substitution pattern of amino acids, such as

further: R ₄ , R ₅ = together hydrazones (= N-NH-R ₁₀ , = NN (R ₁₀ , R _1X ), oximes ( ₌ NoR ₁₁ ) where 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 and 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.

as well as substituents of the type:

Y

Y _{1 #} Y ₂ = O, S, NH or NR ₁₀ (surplus valences are each -H)

where in the case that R ₄ / H represents R _s also OH or in the case that R _s Φ H represents R _{4 can} also be OH.

G _{; L} , G ₂ : together or differently have the meaning:

-C (R ₁₃ , R ₁₄ ) -, where R _ι3 , 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).

Furthermore G and G ₂ together

with m = 1 to 7.

G ₃ : -CH ₂ - or = CO represents.

R _{6 represents} a group - (G ₄ ) _p - (G ₅ ) _q - G ₆ with p, q = 0-1, in which

G ₄ fulfills the following definition:

- (CH ₂ ) _r -, -C (R _1S , R ₁₆ ) - (CH ₂ ) _r -, with r = 1-6 and R ₁₅ , R ₁₆ = hydrogen, lower, optionally branched, optionally substituted (Ar) Alkyl, cycloalkyl, aryl group, -O- or -NR 15

-CH CH-

\ /

(CH ₂ ) t

with s 1-4, t = 0 -4

, an ortho, meta, or para disubst. Aromatic

, where G ₇ = NR ₁₅ , O or S,

G _{5 may be the} same or different from G ₄ and, in the event that p = 1, additionally represents -S-,

G ₆ fulfills the following definition:

With

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:

respectively.

-CHO, COOR ₁₇ , -CONR ₁₇

a low, optionally branched, optionally substituted (Ar) alkyl, (AR) alkenyl, (AR) alkynyl, cycloalkyl,

or aryl group,

-0-R ₁₇ , -NR ₁₇ R ₁₈ , phthalimido, -CN, or -NC.

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.

Z = N or N ⁺ for the case that R ₆ and R ₇ are present together and R _{7 is} not equal to 0 ^" .

A special case of the new compounds of the general formula (I) are the compounds of the general formula (II)

(Formula (II)

wherein the radicals have the meanings described for formula (I). This formula is formally derived from formula (I) by breaking the bond of C _r to the "furan" oxygen and instead forming C directly on Z.

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)

where R ₂₂

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 or

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

R ₂₃ = AG ₅ ) _q - (G ₄ ) _p - G ₉

where G ₄ and G _{s have} the meanings given in the general formula (I) and G _{9 is} defined as:

Hydrogen, F, Cl, Br, J, OH, O-Ts, O-Ms, O-triflate, COOH, COCL CHO, -0-R ₁₇ , -NR ₁₇ R ₁₈ , phthalimido, -CN, or -NC or other groups suitable for nucleophilic substitutions, addition reactions, condensation reactions etc.

Examples of these connection types:

Example a Example b

These compounds of the general formula (III) not only represent an interesting class of compounds pharmaceutically, but are also used as substituents in a large number of base bodies. Examples are compounds 105 to 109.

Overview of compounds of the type of the general formula I:

IQ -

Compounds of the general formula (II) are also considered within the scope of the invention:

Formula (II)

which is a special case of the general formula (I),

DB = double bond

Note: "Chiral." indicates the chirality of the respective educt in the entire table.

Galanthamine, an analogue, or an acid addition salt thereof can be administered in any suitable chemical or physical form. For example, 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.

The following specific formulations can be used to treat the condition after stroke or traumatic brain injury: Solution for parenteral administration containing 1 mg active ingredient / ml.

Liquid formulation for intracerebroventricular administration, in a concentration of 1 or 5 mg of active ingredient / ml.

In order to demonstrate the effect of galanthamine, derivatives and analogues of galanthamine in acute functional brain damage, the effects of the stroke were simulated.

A) Protective effect against apoptotic cell death when nutrients are withdrawn in vitro.

This experiment was carried out on isolated cortical neurons from nine-day-old chicken bryons (white leghorn hybrid strain).

The test substances were the galanthamine derivatives listed below with the structural formulas:

SPH- 1068:

Structural formula: OH

Compound from example no. :

SPH-1088: structural formula:

Compound from example no.

SPH-1092: structural shapes

Compound from example no.

SPH-1096:

Structural formula

Compound from example no .: 69

SPH-1099: structural formula:

Compound from example no .: 73

SPH-1107: structural formula:

Compound from example no. : 95

SPH- 1221:

Structural formula:

Compound from example no.

Compound from example no .: 4 and

SPH-1286: structural formula

Compound from Example No.: 95

Galanthamine was used as the internal standard.

The test substances and the internal standard (galanthamine) 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.

Storage and incubation of fertilized eggs:

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.

A fresh medium prepared under sterile conditions with the following composition was used as culture medium: 100 ml EMEM (= cell culture medium (modified eagles edium) with 1 g glucose / 1, 2% FCS (= fetal calf serum), 0.01% gentamycin and 2 mM L-glutamine. 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

On the eighth day, 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. The vitality test is based on the metabolic reduction of MTT (= a chromophore), a substance with a yellow color, to a blue formazan product by mitochondrial dehydrogenase. Only vital cells are able to catalyze this reaction. The vitality was measured with an ELISA reader (570 nm).

15

The results are summarized in the table below:

coπt ~ 3 6.25μ 12.5μ 25μM 50μM tOOμW 200μM 400μM

Galanrthamine 0.065 0.065 0.065 0.073 0.074 0.084 0.117 0.156 0.167

SPH-1068 0.066 0.069 0.072 0.074 0.081 0.107 0.139 0.184

SPH-1088 0.063 0.067 0.084 0.082 0.105 0.159 0.238 0.242

SPH-1092 0.069 0.077 0.083 0.103 0.155 0.235 0.159 0.048

SPH-1096 0.066 0.067 0.068 0.076 0.081 0.108 0.167 0.224

SPH-1099 0.058 0.059 0.059 0.061 0.056 0.059 0.052 0.074

DMSO 0.067 0.068 0.066 0.064 0.067 0.069 0.077 0.107

cont ~ 3yM 6.25μM 125μM 25μM 50μM 100μ 20DμM 4θ0μM

Galanthamins 0.063 0.065 0.066 0.067 0.072 0.085 0.130 0.164 0.047

SPH-1067 0.061 0.063 0.068 0.070 0.080 0, 125 0, 158 0.049

DMSO 0.061 0.064 0.064 0.066 0.069 0.095 0, 183 P, ζ>? 7 cont ~ 3μM 6.25μM! 25μM 25μM 50μ 100μM: 2C0μM 400μM

Galanthamine 0.065 0.065 0.065 0.073 0.074 0.084 0.17 0.156 0.167

SPH-1107 0.083 0.152 0.211 0.221 0.158 0.080 0.046 0.044

SPH-1221 0.061 0.066 0.069 0.070 0.086 0.117 0.157 0.138

SPH-1241 0.061 0.067 0.071 0.087 0.097 0.114 0.122 0.066

SPH-1286 0.065 0.078 0.092 0.132 0.190 0.205 0.145 0.058

DMSO 0.067 0.068 0.066 0.064 0.067 0.069 0.077 0.107 Discussion of the results:

This experiment shows that there is no direct connection between the inhibitory effect against acetylcholinesterase and the anti-apoptotic effect when the nutrient is removed from the cell culture (simulation of a stroke). It is therefore an activity not previously known for galanthamine and its derivatives.

At a concentration of 0.2 mM, 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). Remarkably, however, 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. that the neuroprotective effect is more pronounced in the (+) epimer, which in turn has a lower cholinesterase inhibitory activity Another indication of the difference between the neuroprotective activity (according to the invention) and esterase inhibiting activity is that it is inactive as an esterase inhibitor Epi-galanthamine is as neuroprotective as natural (-) -galanthine.

B. Hypoxia Trial:

In this experiment, 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

Compounds considered are able to prevent amnesia.

Description of the 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.

Group El ektroCO Oral administration dose shock exposure exposure (mg / kg)

1 No No Sa ne -

2 yes no cream -

3 Yes No SPH-1286 100

4 Yes No Piracetam 300

5 No Yes Saline -

6 Yes Yes Saline -

Yes Yes SPH- 1286 10

S Yes Yes SPH- 1286 30

Q Yes Yes SPH-1 286 100

'0 Yes Yes Piracetam 300

Laboratory animals:

Male mice of the strain ICR-CD-1 with a body weight of 18 to 22 g and an age of about 4 weeks were used in the experiment.

The 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.

Execution of the experiment:

On day 1, the animals are trained by placing them on the jetty and recording the time (latency) until they are enter the dark room. This is repeated once. Only animals that easily enter the dark room are used in the experiment.

Acquisition training was carried out on day 2. The animals are 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. Immediately after the electric shock, 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 .

The effects of amnesia were tested on day 3. The animals were placed on the footbridge and the entry latency was recorded. Animals that did not go into the dark chamber within 180 seconds were removed from the dock and a latency of more than 180 seconds was recorded.

Piracetam was used as the substance for the positive control.

The 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.

The test results are summarized in the table below:

Average entry latency:

troschocks time (min) until the mouse enters the chamber

Group treatment and co ₂ hek exposed dose exposed 1st day

(mg / kg p.o.) (0.25 A; 2nd day 3rd day 10 seconds) Trial 1 Trial 2 Trial 3

1 Vehiclc No No 0.043 0.028 0.016 0013 0.021

2 Vehiclc - No Ye'i 0.060 0.043 0.030 0.022> 2.491

3 SPH-1286 100 No Yes 0.047 0.053 0.025 0.018> 2.618

4 Piracetam 300 No Yes 0052 0.042 0.026 0.020> 2.880

5 Vehicle - Yes No 0.066 0.034 0.028 0.020 0.026

6 Vehiclc - Yes Yes 0.064 0.040 0.023 0.O16 0.038

7 SPH-1286 10 Yes Yc * 0045 0.024 0.019 0.017 0.253

8 SPH-1286 30 Yes Yes 0.056 0.028 0.020 0.016> 1,852 **

9 SPH-1286 100 Yes Yes 0.062 0.033 0.016 0.016> 2.546 * '

10 Piracetam 300 Yes Yes 0.052 0.030 0.018 0.017> 2.812 **

Statistical sigαiftcance ofdiffe: rεnce frorn vehicle-trcutcd | group (Group 6): ** /?<0.0l)

Discussion of the test result:

In hypoxia mode11, the test substance SPH-1286 was able to completely prevent amnesia, which has not yet been described for a cholinesteras inhibitor.

Claims

Claims:

1. Use of galanthamine, derivatives or analogs of galanthamine, or pharmaceutically acceptable acid addition salts thereof, for the manufacture of a medicament for the treatment of the condition after stroke.

2. Use of galanthamine, derivatives or analogs of galanthamine, or pharmaceutically acceptable acid addition salts thereof, for the manufacture of a medicament for the treatment of closed skull-brain trauma.

3. Use of galanthamine, derivatives or analogs of galanthamine, or pharmaceutically acceptable acid addition salts thereof, for the manufacture of a medicament for the treatment of perinatal brain damage.

4. Use of galanthamine, derivatives or analogs of galanthamine, or pharmaceutically acceptable acid addition salts thereof, for the manufacture of a medicament for the treatment of brain damage after deficiency in the supply of oxygen to the brain after suffocation, drowning or heart failure.

5. Use according to one of claims 1 to 4, characterized in that the compound is selected from the group consisting of:

a) Compound of the general formula I, in which means

R is hydrogen

R _r hydrogen

R ₃ methyl R ₄ hydrogen

R _s hydroxy R ₆ methyl Z nitrogen G ₃ methylene (SPH-1068),

b) Compound of the general formula I, in which:

R _x hydrogen

R _{2 is} hydrogen

R ₃ hydrogen R ₄ hydroxy

R _{5 is} hydrogen

R _ε hydrogen

Z nitrogen

G ₃ methylene (SPH-1088),

c) Compound of the general formula I, in which:

R _x hydrogen

R ₂ hydrogen R ₃ methyl

R _{4 is} hydrogen

R _{5 is} hydrogen

R ₆ methyl

Z nitrogen G ₃ methylene

(as hydrobromide) (SPH-1092),

d) Compound of the general formula I in which: R _x hydrogen R ₂ hydrogen R ₃ methyl R ₄ hydroxy R ₅ hydrogen R ₆ -CH ₂ -CH ₂ OH Z nitrogen G ₃ methylene (SPH-1096),

e) Compound of the general formula I, in which R _{x is} hydrogen R _{2 is} hydrogen

R _{3 is} hydrogen

R ₄ hydroxy

R _{5 is} hydrogen

R ₆ -CH ₂ -CN Z nitrogen

G ₃ methylene

(SPH-1099),

f) Compound of the general formula I, in which: R 1 is hydrogen

R _{2 is} hydrogen

R ₃ methyl

R ₄ hydroxy

R ₅ hydrogen R ₆ -N ₃ -piperidinopropyl

Z nitrogen

G ₃ methylene

(as hydrochloride) (SPH-1107),

g) Compound of the general formula I, in which: R _x denotes hydrogen R ₂ hydrogen R ₃ methyl R ₄ hydroxy R _s hydrogen R ₆ -CO-NH-C (CH ₃ ) ₃ Z nitrogen G ₃ methylene hydrochloride (SPH-1221),

h) compound of the general formula I in which:

R _x bromine

R _{2 is} hydrogen

R ₃ methyl

R ₄ hydroxy R ₅ hydrogen

R _{6 is} hydrogen

Z nitrogen

G ₃ methylene (SPH-1241) and

i) compound of the general formula I, in which:

R _λ hydrogen

R _{2 is} hydrogen

R ₃ methyl R ₄ hydroxy

R _{5 is} hydrogen

R ₆ 3-piperidinopropyl

Z nitrogen

G ₃ methylene. (SPH-1286)