WO2007065713A2

WO2007065713A2 - Use of 8-alpha-ergolines for the treatment of traumatic brain disorders

Info

Publication number: WO2007065713A2
Application number: PCT/EP2006/011865
Authority: WO
Inventors: Heinz Palla; Harald Mottl
Original assignee: AXXONIS PHARMA GmbH
Current assignee: AXXONIS PHARMA GmbH
Priority date: 2005-12-08
Filing date: 2006-12-08
Publication date: 2007-06-14
Anticipated expiration: 2008-06-08
Also published as: WO2007065713A3; WO2007065713A8; WO2007065713B1

Abstract

The present invention relates to 8-α-ergoline derived compounds and salts, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, hydrates, solvates and racemates and/or pharmaceutically acceptable salts of these compounds for use in pharmaceutical compositions together with pharmaceutically acceptable carriers, excipients and/or diluents. Said 8-α-ergoline derived compounds are useful for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of epileptic seizures, increased cranial pressure and brain edema in the acute or rehabilitation phase of a brain injury.

Description

Use of 8-α- ergolines

for the treatment of brain disorders

Description

The present invention relates to 8-α-ergoline derived compounds especially to lisuride and terguride and salts, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, hydrates, solvates and racemates and/or pharmaceutically acceptable salts of these compounds for use in pharmaceutical compositions together with pharmaceutically acceptable carriers, excipients and/or diluents for the treatment and prophylaxis of brain disorders wherein the brain disorders are characterised by increased cranial pressure or epileptic seizures or neural edema. Said ergoline derived compounds are useful for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above aspects of brain disorders. Furthermore, this invention relates especially to methods and compositions for treatment and/or prophylaxis of the above aspects of brain disorders by administering to the patient lisuride or one of its derivatives.

Background of the invention

Traumatic brain injury (TBI) is one brain disorder which is characterised by increased cranial pressure or epileptic seizures or neural edema. Traumatic brain injury (TBI) refers to brain damage after trauma by external mechanical forces. Clinically, TBI presents itself heterogeneously including diffuse axonal damage, focal contusions, space occupying epidural and subdural hematomas, and open or closed head injuries.

Secondary brain injury following traumatic brain injury is a result of direct and delayed mechanisms. A primary insult to the brain initiates metabolic and inflammatory processes which exacerbate the primary traumatic injury to neurons, leading to secondary brain injury. Such secondary brain injury can include neural edema, neuroinflammation, and neurodegeneration, traumatic brain injury associated ischemia, the production of reactive oxygen species and epileptic seizures. Acute traumatic brain injury is clinically graded as mild, moderate and severe based on the level of consciousness or the Glasgow Coma Scale (GCS) score after resuscitation. Severe TBI is characterized by coma or a GCS score lower than 9.

Of particular interest is the acute phase of TBI. The acute phase begins immediately after the primary brain injury and has a duration of up to four weeks. Most of the mortality happens during the acute phase of TBI either as a direct consequence of the primary lesions or as a consequence of the secondary brain injuries that reinforce the primary lesion Proportions of mortality increase with age: 21 % of patients younger than 35 years and 52% of patients older than 55 years do not survive a severe case of TBI. If a patient has survived the first four weeks after a severe acute TBI incident, the prognosis for survival improves considerably. During the acute phase of TBI numerous immune system mediators, such as TNF-α, TGF-β and interleukin 2 and interleukin 6, are released causing inflammation and an increase in intracranial pressure (ICP). This increase in intracranial pressure counteracts the central perfusion pressure and therefore decreases cerebral perfusion and oxygenation and contributes to additional ischemic injuries.

Current clinical management strategies of acute severe TBI focus therefore on managing cerebral pressure and cerebral perfusion by pharmacologically manipulating blood pressure and blood volume and osmolarity and through relieving ICP through decompressive craniectomy. An example of such a pharmacological strategy is the so- called volume targeted therapy, also known as the "Lund concept" which modulates the cerebral perfusion and pressure by a cocktail of a βrblocker like metoprolol, an c<₂- agonist like clonidine, fentanyl and low dose thiopental and a compound to treat acute migraine like dihydroergotamine or sumatriptan (Grande, P. -O. et al. (2002) Acta Anesthesia Scand 46:929-941 ).

Lisuride is an ergot derived molecule, chemically related to dihydroergotamine, but it is not useful to treat acute migraine as are dihydroergotamine and sumatriptan. Lisuride is in fact useful to prevent the onset of migraine and would therefore not be expected to substitute for sumatriptan or dihydroergotamine in the volume targeted therapy based on what is known about its pharmacology. In addition lisuride is not associated with severe side effects and complications like dihydroergotamine.

Summarizing, 8-α-ergoline derived compounds have not been investigated for the treatment of the acute phase of traumatic brain injury in humans, where maintenance of haemodynamic stability and of ICP is of utmost importance to secure satisfactory cerebral perfusion.

Lisuride or other 8-α-ergolines are also useful for the therapy and prevention of epileptic seizures, which commonly occur during acute brain injury or in the rehabilitation phase after brain injury.

Epileptic seizures occur in patients with idiopathic and symptomatic epilepsy. Symptomatic epilepsy also occurs as a result of an injury to the brain. Idiopathic seizures can also occur spontaneously without a known or suspected cause. In an acute mouse model of convulsions induced by hyperbaric oxygen, the dopamine agonists lisuride, apomorphine, (-)3-PPP and Quinpirole, but curiously also the dopamine antagonist haloperidol reduced the latency of convulsions, but did not prevent or inhibit the occurrence of convulsions (Criborn, CO et al. (1988) Aviat. Space

Environmen. Med. 59:723-727; Criborn CO et al. (1987) J. Neural. Transm. 69:277-

285). Hyperbaric oxygen therapy is based on the principle of saturating hemoglobin with oxygen. It is not obvious for those skilled in the art how an animal model based on this principle should be predictive for a physiological situation like brain injury that is characterized by insufficient brain perfusion with oxygen.

Apomorphine, a dopamine agonist, was studied in epileptic patients in a double blind, placebo controlled study. Apormorphine was found to induce epileptic activity (Del Zompo, M. et al. (1983) Psychopharmacology (Berl) 79:209-214).

Summarizing, the analysis of the prior art demonstrates that our teaching is unprecedented. The use of lisuride or its derivatives for treatment of epileptic seizures in association with brain injury has not been described before. Surprisingly, we found that lisuride hydrogen maleate in a rat model of severe acute TBI reduced not only ICP but in addition also decreased the size of the brain edema and reduced frequency and magnitude of seizures. This accumulation of beneficial therapeutic effects in one molecule is unique for the treatment of acute traumatic brain injury and has not been described before in the art.

The term traumatic brain injury refers also to epileptic seizures and symptomatic epilepsy, indications which are implicitly disclosed when referring to the term TBI.

Brain injury occurs when perfusion of the whole brain or a part of the brain with oxygenated blood is reduced below a minimum threshold. This can happen for example by direct lack of oxygen to the body as in CO poisoning, as a result of an external mechanical impact to the brain as in accidents and as a result of occlusion or rupture of blood vessels either intrinsically such as in ischemic stroke or hemorrhagic stroke or extrinsically as a consequence of a surgical procedure like brain or heart surgery.

Further situations that can result in anoxia or hypoxia and subsequent brain injury are:

- airway obstruction

- aneurism - blood loss

- brain surgery

- carbon monoxide poisoning

- cardiac arrest

- choking

- coronary bypass graft surgery

- drowning

- electrical shock including lightning

- heart attack

- infectious disease

- ischemia

- meningitis

- perioperative complications during anesthesia

- shock

- strangulation

- vascular disruption

Clinically, the therapy of the brain injury incident happens in two distinct phases. In an acute phase the patient is normally admitted to an intensive care unit to treat the life- threatening symptoms. If the patient has survived this initial phase which is characterized by high mortality, treatment continues in a rehabilitation phase either in a specialized clinical setting or in an outpatient setting. Aspects of this invention are related to the use in the acute phase and/or the rehabilitation phase.

Object of the invention is to provide compounds useful for the treatment and/or prophylaxis of brain disorders wherein the brain disorder is characterized by increased cranial pressure, epileptic seizures, or neural edema The object of the invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, and the examples of the present application.

Surprisingly it was found that the 8-α-ergoline derivatives of the invention and especially lisuride, terguride and proterguride are useful for the treatment and/or prophylaxis of brain disorders wherein the brain disorder is characterized by increased cranial pressure, epileptic seizures or neural edema. Description of the invention

Herein we report ergoline compounds for the treatment of brain disorders. The ergoline derived compounds of the invention reduce neural edema, intracranial pressure and frequency and magnitude of epileptic seizures in acute TBI or the rehabilitation phase after a brain injury event.

A number of studies in the scientific literature have described seizures as one of the sequelae of brain injury. It was estimated that traumatic brain injury alone accounts for 20% of symptomatic epilepsy in the general population and 5% of all epilepsy. Stroke has been reported to cause 22% of all cases of epilepsy in adults. Epileptic seizures in patients having suffered a stroke occur with a frequency of about 5%. For TBI a similar incidence of seizures is reported.

Seizures are common during the acute phase of brain injury and can occur unpredictably in the rehabilitation phase. Seizures during acute brain injury are typically treated with traditional anticonvulsants (phenytoin, carbamazepine, sodium valproate, ethosuximide, primidone, clonazepam, phenobarbital).

Disadvantages of these therapies are that they cause cognitive impairment at the therapeutic concentrations employed (Martin, R et al. (1999) Neurology 52:321-327;

Gilham, RA et al. (1988) J Neurol Neurosurg Psychiatry 51 :929-933; Meador K et al.

(1999) Epilepsia 40:1279-1285). Traditional anticonvulsants have shown little benefit in preventing seizures in patients with brain injury (McQueen, JK et al. (1983) J Neurol

Neurosurg Psychiatry 46:899-904; Perry, JK et al. (1979) Neurology 29:600-601 ; Temkin N (2001 ) Epilepsia 42:515-524; Young B et al. (1983) Neurosurgery 58:236-

241 ). In fact, the American Association of Neurological Surgeons together with the

Brain Trauma Foundation in their Guidelines for Management and Prognosis of Severe

Traumatic Injury (2000) does not recommend the use of phenytoine, carbamazepine, phenobarbital or valproate for preventing late posttraumatic seizures, occurring seven days after brain injury.

The present invention addresses the shortcomings of current therapies. Lisuride is not known to cause cognitive impairment and is safe when used over many years. The treatment with lisuride can therefore be applied in the rehabilitation phase when current anticonvulsants are not indicated and no cognitive changes are induced in patients.

In this invention we disclose that a 6 month treatment of stroke patients with lisuride during a placebo controlled trial completely reduced the occurrence of epileptic seizures did not lead to cognitive impairment or other side effects that would preclude the use of lisuride as an agent to prevent epileptic seizures after brain injury.

The use of lisuride, terguride and proterguride or its derivatives for treatment of epileptic seizures which occur as sequelae of a brain injury in the rehabilitation phase of the condition have not been described before. Thus, the present invention relates to methods and compositions for treatment and prophylaxis of epileptic seizures which occur in the rehabilitation phase after a brain injury event by administering to the patient a pharmacologically effective amount of lisuride or one of its derivatives.

A specific brain injury event disclosed herein where lisuride was effective in preventing symptomatic seizures is stroke. Symptomatic seizures are common in the rehabilitation phase after stroke, traumatic brain injury and other types of brain injury. The characteristics of seizures that occur in the rehabilitation phase after stroke can not be distinguished medically or pharmacologically from the seizures that occur after traumatic brain injury. Therefore the use of lisuride and related compounds is claimed not only for the prophylaxis of seizures that occur in the rehabilitation phase after stroke but more generally for seizures that occur in the rehabilitation phase after a brain injury. In the Example 1 the pharmacological amount that was used was 150 μg lisuride hydrogen maleate per day, equivalent to about 2 μg/kg lisuride hydrogen maleate per day. When given orally, Lisuride has a bioavailability of only 25%. The oral dose of lisuride of 2 μg/kg is therefore equivalent to a dose of 0.5 μg/kg when the drug is applied parenterally or transdermally.

Transdermal as well as subcutaneous applications of lisuride have been described and Parkinson patients tolerate subcutaneous daily infusions of 1000 - 2000 μg/kg without serious adverse side effects. Preferred are therefore doses of lisuride for treatment of symptomatic epilepsy ranging from 0.5 μg/kg per day up to 25 μg/kg day.

The time of treatment of epileptic seizures that occur in the rehabilitation phase after a brain injury event was limited to 6 months in the example herein. However, lisuride is a molecule with an established safety profile and patients have been under high dose parenteral therapy with lisuride for more than 10 years. Preferred is therefore a longterm chronic treatment of symptomatic epilepsy resulting from brain injury. Such a method comprises administering to a patient in need of such treatment or such prophylaxis a pharmacologically effective amount of lisuride, terguride and proterguride or another 8-α-ergoline compound which is effective to treat and/or prevent epileptic seizures.

Another method comprises administering to a patient in need of such treatment a pharmacologically effective amount of lisuride, terguride and proterguride or another 8- α-ergoline compound which is effective to treat epilepsy, neural edema and traumatic brain injury associated ischemia.

In addition the 8-α-ergoline derived compounds of the invention offer pharmacokinetic advantages over oral drugs as they can be administered as an intravenous or subcutaneous infusion or via a transdermal route, e.g. via a transdermal patch. This allows for stable and easily controllable plasma drug levels in a patient population that frequently has resorption and bioavailability problems.

Thus, the invention relates to the use of the compounds of the general formula (I)

wherein

R¹ and R⁴ represent independently from each other -H, -CHO, -COCH₃, -COC₂H₅, -COC₃H₇, -CO-cyclo-C₃H₅, -COCH(CH₃)₂, -COC(CH₃)₃, -COOH, -COOCH₃, -COOC₂H₅, -COOC₃H₇, -COO-cyclo-C₃H₅,

-COOCH(CHa)₂, -COOC(CH₃)₃, -CONH₂, -CONHCH₃, -CONHC₂H₅, -CONHC₃H₇, -CONH-cyclo-C₃H₅, -CONH[CH(CH₃J₂], -CONH[C(CHa)₃], -CON(CH₃)₂, -CON(C₂Hs)₂, -CON(C₃H₇)₂, -CON(cyclo-C₃H₅)₂,

-CON[CH(CH₃)₂]₂, -CON[C(CH₃)₃]₂, -NH₂, -NHCH₃, -NHC₂H₅, -NHC₃H₇, -NH-cyclo-C₃H_5l -NHCH(CH₃)₂, -NHC(CH₃)₃, -N(CH₃J₂, -N(C₂Hs)₂, -N(C₃H₇J₂, -N(cyclo-C₃Hs)₂, -N[CH(CH₃)₂]₂, -N[C(CH₃)₃]₂, -SOCH₃, -SOC₂H₅, -SOC₃H₇, -SO-cyclo-C₃H₅, -SOCH(CH₃)₂, -SOC(CH₃)₃, -SO₂CH₃, -SO₂C₂H₅, -SO₂C₃H₇, -SO₂-CyCIo-C₃H₅, -SO₂CH(CH₃)₂, -SO₂C(CHa)₃, -SO₃H, -SO₃CH₃, -SO₃C₂H₅, -SO₃C₃H₇, -SO₃-cyclo-C₃H₅, -SO₃CH(CH₃)₂, -SO₃C(CH₃)₃, -CH₂F, -CHF₂, -CF₃, -CH₂CI, -CH₂Br, -CH₂I, -CH₂-CH₂F, -CH₂-CHF₂, -CH₂-CF₃, -CH₂-CH₂CI, -CH₂-CH₂Br, -CH₂-CH₂I, -CH₃, -C₂H₅, -C₃H₇, -CH(CH₃)₂, -C(CH₃J₃, -C₄H₉, -CH₂-CH(CH₃)₂, -CH(CH₃)-C₂H₅, -C₅H-₁₁, -CeHi₃, -C₇Hi₅, -CeHi₇, -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-CβH-n, -Ph, -CH₂-Ph, -CPh₃, -CH=CH₂, -CH₂-CH=CH₂, -C(CH₃)=CH₂, -CH=CH-CH₃,

-C₂H₄-CH=CH₂, -CH=C(CH₃)₂, -C≡CH, -C≡C-CH₃₎ -CH₂-C=CH;

R² and R³ represent independently from each other -R⁶, -R⁷, a linear or branched, saturated or unsaturated alkyl residues with 1 - 10 carbon atoms, which can be substituted with one or more of the residues R⁸ - R⁴³; a linear or branched, saturated or unsaturated -CO-alkyl residue with 1 - 10 carbon atoms, which can be substituted with one or more of the residues R⁸ - R⁴³; a linear or branched, saturated or unsaturated -NH-CO-alkyl residue with 1 - 10 carbon atoms, which can be substituted with one or more of the residues R⁸ - R⁴³; a linear or branched, saturated or unsaturated -NH-CO— NH-alkyl residue or -NH-CO— N(dialkyl residue) with alkyl residues with 1 - 10 carbon atoms, which can be substituted with one or more of the residues R⁸ - R⁴³; an aryl residue or cycloalkyl residue or bicyclic or tricyclic carbocyclus, which can be substituted with one or more of the residues R⁸ - R⁴³; a heteroaryl residue or heterocyclyl residue or a bicyclic or tricyclic saturated or unsaturated heterocyclus, which can be substituted with one or more of the residues R⁸ - R⁴³;

R⁵ represents one of the residues -H, -F, -Cl₁ -Br, -I, -CN or -NO₂;

R⁶ - R⁴⁵ represent independently from each other -H, -OH, -OCH₃, -OC₂H₅, -OC₃H₇, -O-cyclo-C₃H₅, -OCH(CH₃J₂, -OC(CH₃)₃, -OC₄H₉, -OPh, -OCH₂-Ph, -OCPh₃, -SH, -SCH₃, -SC₂H₅, -SC₃H₇,

-S-cyclo-C₃H₅, -SCH(CH₃)₂₎ -SC(CH₃)₃, -NO₂, -F₁ -Cl, -Br, -I₁ -N₃, -CN₁ -OCN, -NCO, -SCN₁ -NCS₁ -CHO₁ -COCH₃, -COC₂H₅, -COC₃H₇, -CO-CyClO-C₃H₅, -COCH(CH₃)₂, -COC(CH₃)_3l -COOH, -COCN, -COOCH₃, -COOC₂H₅, -COOC₃H₇, -COO-cyclo-C₃H_5l -COOCH(CH₃)_2l -COOC(CH₃)_3l -0OC-CH₃, -0OC-C₂H₅, -0OC-C₃H₇, -OOC-cyclo-C₃H_5l -OOC-CH(CH₃)₂, -OOC-C(CH₃)_3l -CONH₂, -CONHCH₃, -CONHC₂H₅, -CONHC₃H₇, -CONH-CyClO-C₃H₅, -CONH[CH(CH₃)₂], -CONH[C(CH₃)₃], -CON(CH₃)₂, -CON(C₂Hs)₂, -CON(C₃H₇)₂, -CON(cyclo-C₃H₅)₂,

-CON[CH(CH₃)₂]_2l -CON[C(CH₃)₃]₂, -NH₂, -NHCH₃, -NHC₂H₅, -NHC₃H₇, -NH-cyclo-C₃H₅, -NHCH(CH₃)₂, -NHC(CH₃)₃, -N(CH₃J₂, -N(C₂H₅J₂, -N(C₃H₇J₂, -N(cyclo-C₃H₅)₂, -N[CH(CH₃)₂]₂, -N[C(CH₃Ja]₂, -SOCH₃, -SOC₂H₅, -SOC₃H₇,

-SO-CyCIo-C₃H₅, -SOCH(CH₃J₂, -SOC(CH₃J₃, -SO₂CH₃, -SO₂C₂H₅, -SO₂C₃H₇, -SO₂-CyClO-C₃H₅, -SO₂CH(CH₃J₂, -SO₂C(CH₃J₃, -SO₃H, -SO₃CH₃, -SO₃C₂H₅, -SO₃C₃H₇, -SO₃-CyCIo-C₃H₅, -SO₃CH(CH₃J₂, -SO₃C(CHa)₃, -OCF₃, -OC₂F₅, -0-COOCH₃, -0-COOC₂H₅,

-0-COOC₃H₇, -0-COO-CyClO-C₃H₅, -O-COOCH(CH₃)₂₎ -O-COOC(CH₃)₃, -NH-CO-NH₂, -NH-CO-NHCH₃, -NH-CO-NHC₂H₅, -NH-CO-NHC₃H₇, -NH-CO-NH-cyclo-C₃H₅₎ -NH-CO-NH[CH(CH₃)₂], -NH-CO-NH[C(CH₃)₃], -NH-CO-N(CH₃)₂, -NH-CO-N(C₂H₅)₂, -NH-CO-N(C₃H₇J₂,

-NH-CO-N(cyclo-C₃H₅)_2> -NH-CO-N[CH(CH₃)₂]₂, -NH-CO-N[C(CH₃)₃]_2|

-NH-CS-NH₂, -NH-CS-NHCH₃, -NH-CS-NHC₂H₅, -NH-CS-NHC₃H₇, -NH-CS-NH-cyclo-C₃H₅, -NH-CS-NH[CH(CH₃)₂], -NH-CS-NH[C(CH₃)₃],

-NH-CS-N(CH₃)₂, -NH-CS-N(C₂Hs)₂, -NH-CS-N(C₃H₇J₂, -NH-CS-N(cyclo-C₃H₅)₂, -NH-CS-N[CH(CH₃)₂]₂, -NH-CS-N[C(CH₃)₃]₂,

-NH-C(=NH)-NH2, -NH-C(=NH)-NHCH3, -NH-C(=NH)-NHC₂H₅,

-NH-C(=NH)-NHC₃H_7l -NH-C(=NH)-NH-cyclo-C₃H₅₎

-NH-C(=NH)-NH[CH(CH₃)₂], -NH-C(=NH)-NH[C(CH₃)₃],

-NH-C(=NH)-N(CH₃)₂, -NH-C(=NH)-N(C₂H₅)₂, -NH-C(=NH)-N(C₃H₇)₂, -NH-C(=NH)-N(cyclo-C₃H₅)₂₎ -NH-C(=NH>-N[CH(CH₃)₂]₂,

-NH-C(=NH)-N[C(CH₃)₃]₂, -0-CO-NH₂, -0-CO-NHCH₃, -0-CO-NHC₂H₅, -0-CO-NHC₃H₇, -O-CO-NH-cyclo-C₃H_5l -O-CO-NH[CH(CH₃)₂],

-O-CO-NH[C(CH₃)₃], -O-CO-N(CH₃)₂, -O-CO-N(C₂H₅)₂, -O-CO-N(C₃H₇)₂, -O-CO-N(cyclo-C₃H₅)₂, -O-CO-N[CH(CH₃)₂]_2l -O-CO-N[C(CH₃)₃]₂, -0-CO-OCH₃, -0-CO-OC₂H₅, -0-CO-OC₃H₇, -0-CO-O-CyCIo-C₃H₅, -O-CO-OCH(CH₃)₂, -O-CO-OC(CH₃)₃, -CH₂F₁ -CHF₂, -CF₃, -CH₂CI₁ -CH₂Br, -CH₂I₁ -CH₂-CH₂F, -CH₂-CHF₂, -CH₂-CF₃, -CH₂-CH₂CI, -CH₂-CH₂Br, -CH₂-CH₂I, -CH₃, -C₂H₅, -C₃H₇, -CH(CH₃)₂, -C(CH₃J₃, -C₄Hg, -CH₂-CH(CH₃)₂, -CH(CH₃)-C₂H₅, -C₅Hn, -CeHi₃, -C₇Hi₅, -CsHi₇, -cyclo-C₃H₅, -CyCb-C₄H₇, -cyclo-C₅H₉, -CyCIo-C₆Hn, -Ph, -CH₂-Ph, -CPh₃, -CH=CH₂, -CH₂-CH=CH₂, -C(CH₃)=CH₂, -CH=CH-CH₃,

-C₂H₄-CH=CH₂, -CH=C(CH₃)₂, -C≡CH, -C=C-CH₃, -CH₂-C≡CH;

X represents a single bond or a double bond;

n represents an integer from 1 to 10; as well as

salts, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, hydrates, solvates and racemates of the afore-mentioned compounds for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of brain disorders wherein the brain disorder is characterized by increased cranial pressure, or epileptic seizures, or neural edema. Said brain disorders are selected from acute traumatic brain injury, severe acute traumatic brain injury, epileptic seizures, symptomatic epilepsy and neural edema.

Preferred is the indication epileptic seizures and symptomatic epilepsy and especially preferred is the use of the 8-α-ergoline compounds and first of all lisuride for the treatment and prophylaxis of epileptic seizures which occur as a consequence of a brain injury event as well as epileptic seizures which occur during the acute phase or during rehabilitation phase after traumatic brain injury or after stroke. Furthermore, the use of the 8-α-ergoline compounds for the treatment of a brain injury event associated with increased cranial pressure occurring during the acute phase of the brain injury is especially preferred. Still especially preferred is the use of the 8-α- ergoline compounds for the treatment of a brain injury event associated with a brain edema occurring during the acute phase of a brain injury event.

Especially preferred for the treatment and where applicable the prophylaxis of the brain disorders disclosed herein are lisuride, terguride and proterguride as well as salts and combinations of these compounds. The compounds of the general formula (I) are basic and acidic addition-salts can be obtained by addition of organic or inorganic acids. As acids, which build an acidic addition-salt of the compound of formula (I)₁ the following can be mentioned: sulfuric acid, sulfonic acid, phosphoric acid, nitric acid, nitrous acid, perchloric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, succinic acid, oxalic acid, gluconic acid (glyconic acid, dextronic acid), lactic acid, malic acid, tartaric acid, tartronic acid (hydroxymalonic acid, hydroxypropionic diacid), fumaric acid, citric acid, ascorbic acid, maleic acid, malonic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, (o-, m-, p-) toluylic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid, p-aminosalicylic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluolsulfonic acid, naphthylsulfonic acid, naphthylaminesulfonic acid, sufanilic acid, camphorsulfonic acid, quinic acid (quinine acid), o-methyl-mandelic acid, hydrogenbenzenesulfonic acid, picric acid (2,4,6-trinitrophenol), adipic acid, d-o-tolyltartaric acid, amino acids such as methionine, tryptophan, arginine and especially acidic amino acids such as glutamic acid or aspartic acid.

With the presence of acidic groups also basic addition-salts may be formed, such as alkaline metal-salts as well as salts with amines. Thus, alkaline metal-salts, such as the sodium salt, the potassium salt, the lithium salt or the magnesium salt, the calcium salt, alkylamino salts or amino acid salts, such as with basic amino acids, e.g. lysine, can be formed. The general formula (I) also comprises stereoisomers, enantiomers, mixtures of enantiomers, diastereomers and mixtures of diastereomers, wherein chiral compounds of the following formulas (II) - (NE) are preferred, for example:

Further it is preferred, if R³ represents hydrogen. Moreover, it is preferred in all of the formulas disclosed herein, if R³ has the configuration shown in formula (II), (HA) and (HB)₁ i.e. protrudes out of the plane and accordingly R² lies behind the plane. Thus, the 8-α- ergolines are preferred. In the case, that X represents a single bond, the trans position of the two hydrogen atoms at C-5 and C-10 is preferred, as shown in the general formulas (IH) - (IIIE).

wherein

the residues R¹ - R⁴⁵ represent the above given denotation.

R¹ and/or R⁴ preferably represent hydrogen or an alkyl residue with 1 to 8 carbon atoms. R³ preferably represents a carbonyl group, to which a mono-, bi- or tricyclic heterocyclus is bound.

Further it is preferred, if R² represents a residue -NH-CO-NH₂, -NH-CO-NHCH₃, -NH-CO-NHC₂H₅, -NH-CO-NHC₃H₇, -NH-CO-NH-CyCIo-C₃H₅, - NH-CO-NH[CH(CH₃)₂], -NH-CO-NH[C(CH₃)₃], -NH-CO-N(CH₃)₂,

-NH-CO-N(C₂Hs)₂, -NH-CO-N(C₃H₇)₂, -NH-CO-N(cyclo-C₃H₅)₂,

-NH-CO-N[CH(CH₃)₂]₂, -NH-CO-N[C(CH₃)₃]₂, -NH-CS-NH₂, -NH-CS-NHCH₃, -

NH-CS-NHC₂H₅, -NH-CS-NHC₃H₇, -NH-CS-NH-CyCIo-C₃H₅,

-NH-CS-NH[CH(CH₃)₂], -NH-CS-NH[C(CH₃)₃], -NH-CS-N(CH₃)₂,

-NH-CS-N(C₂Hs)₂, -NH-CS-N(C₃H₇J₂, -NH-CS-N(cyclo-C₃H₅)₂,

-NH-CS-N[CH(CH₃)₂]₂, -NH-CS-N[C(CH₃)₃]₂, -NH-C(=NH)-NH₂,

-NH-C(=NH)-NHCH₃, -NH-C(=NH)-NHC₂H₅, -NH-C(=NH)-NHC₃H7,

-NH-C(=NH)-NH-cyclo-C₃H₅, -NH-C(=NH)-NH[CH(CH₃)₂],

_NH-C(=NH)-NH[C(CH₃)₃]_> -NH-C(=NH)-N(CH₃)₂, -NH-C(=NH)-N(C₂H5)₂,

-NH-C(=NH>-N(C₃H₇)₂, -NH-C(=NH)-N(cyclo-C₃H5)₂,

-NH-C(=NH)-N[CH(CH₃)₂]₂ or -NH-C(=NH)-N[C(CH₃)₃]₂ and especially a residue - NH-CO-N(CH₃)₂, -NH-CO-N(C₂Hs)₂, -NH-CO-N(C₃H₇)₂,

-NH-CO-N(cyclo-C₃H₅)₂ or -NH-CO-N[CH(CH₃)₂]₂. It is further preferred in this case, if R³ represents hydrogen.

In the formulas (HD) and (IHD) R^* represents one of the residues R⁶ - R⁴⁵, which may be bound to a nitrogen atom. R^* especially represents a linear or branched, saturated or unsaturated acyl group with 1 to 20 carbon atoms, which can also comprise carboncycles, heterocycles or aromatic rings in the carbon chain, and the carbon chain of which can be further substituted with one or more of the residues R⁶ - R⁴⁵.

R^** represents in the formulas (ME) and (HIE) one of the residues R⁶ - R⁴⁵ and preferably an amino group, alkylamino group or dialkylamino group, wherein the alkyl group or the alkyl groups comprise 1 to 20 carbon atoms, wherein the alkyl groups can comprise or contain also carboncycles, heterocycles and aromatic systems and the alkyl groups can be branched or linear as well as saturated or unsaturated and can be substituted with one or more of the residues R⁶ - R⁴⁵. Especially preferred for R^** are -CH₂F, -CH₂-CH₂F, -CH₂-CHF₂, -CH₂-CF₃, -CH₂-CH₂CI₁

-CH₂-CH₂Br, -CH₂-CH₂I₁ -CH₃, -C₂H₅, -C₃H₇, -CH(CH₃J₂, -C(CH₃J₃, -C₄Hg, -CH₂-CH(CH₃)₂, -CH(CH₃)-C₂H₅, -C₅H₁₁, -CeHi₃, -C₇Hi₅, -CeHi₇, -cyclo-C₃H₅, -cyclo-C₄H₇, -CyCIo-C₅H₉, -cyclo-CβHn, -Ph, -CH₂-Ph, -CPh₃, -CH=CH₂, -CH₂-CH=CH₂, -C(CH₃)=CH₂, -CH=CH-CH₃, -C₂H₄-CH=CH₂, -CH=C(CH₃)₂, -C≡CH, -C=C-CH₃ and -CH₂-C=CH.

Preferred are following compounds of the formula (I): 8-α-ergoline, 8-α-1 ,6- dimethylergoline, 8-α-1-methylergoline, 8-α-6-methylergoline, 8-α-10-methoxyergoline, lisuride (CAS-No.: 18016-80-3, 3-(9,10-didehydro-6-methylergolin-8alpha-yl)-1 ,1- diethylurea), d-isolysergic acid, d-isolysergic acid amide, d-isolysergic acid diethylamide, proterguride and terguride ((+)-1 ,1-diethyl-3-(6-methyl-8α-ergolinyl)-urea). Particularly preferred is the use of terguride (trans-dihydrolisuride) and lisuride.

The pharmaceutical composition comprising the 8-α-ergoline derived compounds of the present invention is suitable for the treatment and/or prophylaxis of aspects of acute phase traumatic brain injury. The acute phase of traumatic brain injury begins immediately after the primary brain injury and has a duration of up to four weeks.

Particularly preferred is the treatment and/or prophylaxis of epileptic seizures in the acute phase of traumatic brain injury.

The ergoline derived compounds of the invention offer pharmacokinetic advantages over oral formulations as they can be administered as an intravenous or subcutaneous infusion or via a transdermal route, e.g. via a transdermal patch. This allows for stable and easily controllable plasma drug levels in a patient population that frequently has resorption and bioavailability problems. The possibility to administer lisuride via the intravenous or subcutaneous route is especially advantageous and preferred if the patient is hospitalized in an intensive care unit. As disclosed above, the ergoline derived compounds and especially lisuride, terguride and proterguride are useful for treatment and prophylaxis of epileptic seizures. Especially lisuride can be used to prevent seizures during acute brain injury or in the rehabilitation phase. This effect is linked to the molecular structure of lisuride. To those skilled in the art it is obvious that molecules that derive from a parent structure by chemical modification will exhibit similar activities in in vitro, in vivo and clinical studies. Indeed the lisuride derivatives terguride and proterguride which have been modified in the N-6 position by alkylation and the 9-10 position by hydrogenation have been demonstrated to exhibit a similar receptor profile.

The particular invention described here demonstrates (Example 1 ) the use of lisuride 6 months after a brain injury has occurred. To those skilled in the art there is no reason to not use lisuride earlier in the rehabilitation phase after a brain injury, since the molecule has an established and well understood safety profile.

Further, the preferred pharmaceutical composition for administration is subcutaneous or intravenous application. Controlled drug delivery systems provide maintenance of drug plasma levels within a desired range for an extended period of time. Parenteral administration can be achieved by means of continuous infusion by a perfusor system or a programmable minipump. Infusion pumps or perfusors are used to infuse pharmaceutical compositions into the circulatory system at the required dosage rate. The pharmaceutical composition can be continuously infused intravenously or subcutaneously.

Transdermal administration can be achieved by means of transdermal patch, such as a matrix plaster or a membrane plaster. Transdermal patch delivery systems control the rate and duration of drug input and are used to continuously infuse pharmaceutical compositions into the circulatory system.

Preferred is a pharmaceutical composition suitable for oral, low dose intravenous, subcutaneous or intramuscular injection, continuous intravenous infusion or continuous subcutaneous infusion, and transdermal administration. Particularly preferred is a pharmaceutical composition suitable for continuous intravenous infusion or continuous subcutaneous infusion administered by a perfusor system or a programmable minipump. Particularly preferred is a pharmaceutical composition suitable for administration via a transdermal patch.

Particularly preferred is a pharmaceutical composition suitable for oral administration.

The pharmaceutical composition comprising the ergoline derived compounds of the present invention is administered in a dosage corresponding to an effective concentration in the range of 0.5 - 25 microgram/kg body weight. Particularly preferred is that the dosage is infused continuously over a period of 24 hours to several years.

Another aspect of the invention is directed to pharmaceutical compositions comprising the 8-α-ergoline derived compounds as active ingredient prepared in a conventional liquid carrier or diluent and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way. The preferred pharmaceutical composition is suitable for parenteral administration or transdermal administration.

Further, the preferred pharmaceutical composition is suitable for controlled administration via parenteral administration or transdermal administration. Controlled drug delivery systems provide maintenance of drug plasma levels within a desired range for an extended period of time. Depending on the formulation and the application this time may be, for example, anywhere from 24 hours to 4 weeks or without a predefined limit as a longterm chronic therapy.

Parenteral administration can be achieved by means of continuous infusion by a perfusor system or a programmable minipump. Infusion pumps or perfusors are used to infuse pharmaceutical compositions into the circulatory system at the required dosage rate. The pharmaceutical composition can be continuously infused intravenously or subcutaneously. Transdermal administration can be achieved by means of transdermal patch, such as a matrix plaster or a membrane plaster. Transdermal patch delivery systems control the rate and duration of drug input and are used to continuously infuse pharmaceutical compositions into the circulatory system. Preferred is a pharmaceutical composition suitable for low dose intravenous, subcutaneous or intramuscular injection, continuous intravenous infusion or continuous subcutaneous infusion, and transdermal administration. Particularly preferred is a pharmaceutical composition suitable for continuous intravenous infusion or continuous subcutaneous infusion administered by a perfusor system or a programmable minipump. Particularly preferred is a pharmaceutical composition suitable for administration via a transdermal patch.

The pharmaceutical composition comprising the 8-α-ergoline derived compounds of the present invention is administered in a dosage corresponding to an effective concentration in the range of 0.5 - 25 μg/kg body weight.

Particularly preferred is that the dosage is infused continuously over a period of 24 hours to 4 weeks. Another aspect of the present invention is directed to a method of treatment and/or prophylaxis of aspects of traumatic brain injury comprising administering an effective amount of a compound according to general formula (I) to a patient in need thereof.

Preferred are compounds of the general formula (I) which are selected from the group comprising: 8-α-ergoline, 8-α-1 ,6-dimethylergoline, 8-α-1-methylergoline, 8-α-6- methylergoline, 8-α-10-methoxyergoline, lisuride, d-isolysergic acid, d-isolysergic acid amide, d-isolysergic acid di-ethylamide, proterguride and terguride or pharmaceutically acceptable salts thereof. Particularly preferred are lisuride and terguride or pharmaceutically acceptable salts thereof.

The 8-α-ergoline derived compounds of the present invention are also suitable for a method of treatment and/or prophylaxis of aspects of acute phase traumatic brain injury.

Particularly preferred is a method of treatment and/or prophylaxis of aspects of acute phase traumatic brain injury.

Another aspect of the present invention is directed to a method of treatment and/or prophylaxis of aspects of traumatic brain injury, wherein the compound according to general formula (I) is administered parenterally or transdermal^ to a patient in need thereof. Preferred is administration by low dose intravenous, subcutaneous or intramuscular injection, continuous intravenous infusion or continuous subcutaneous infusion and transdermal administration. Particularly preferred is administration of the continuous intravenous infusion or continuous subcutaneous infusion by a perfusor system or a programmable minipump.

Particularly preferred is administration via a transdermal patch. Another aspect of the present invention is directed to a method of treatment and/or prophylaxis of aspects of traumatic brain injury, wherein the compound of the general formula (I) is administered in a dosage corresponding to an effective concentration in the range of 0.5 - 50 μg/kg preferably 5 - 25 μg/kg body weight. Preferred is a method of treatment and/or prophylaxis wherein the dosage is infused continuously over a period of from 24 hours to 4 weeks.

Description of figures:

Figure 1 Diagram showing the intracranial pressure (ICP) measured at different time-points before and after trauma. Bolus administration of 0.3 mg/kg at 30 minutes following CCII. Mean values and standard error.

Figure 2 Structure of lisuride,

Figure 3 Structure of terguride.

The following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Examples

EXAMPLE 1

A double blind placebo controlled study to evaluate the therapeutic effect of lisuride after brain injury by stroke.

MATERIALS AND METHODS In a double blind placebo controlled study, 160 patients with a diagnosis of sequelae of focal cerebrovascular disease were included. Following the experimental protocol these admission criteria were adopted: 1. Diagnosis of focal hemisphere lesion (haemorrhage, thrombosis, softening, etc)

2. Patients should be able to walk with or without support.

3. A time interval from the stroke between 2 and 24 months

4. First discharge from the hospital

5. Age between 40 and 80 years

6. Absence of severe speech derangements

7. Absence of senile dementia or severe symptoms of mental or physical deterioration

8. Absence of severe metabolic, cardiocirculatory, renal or liver disorders. The order of treatments, i.e. Lisuride (0.05 mg tablets) or placebo was established according to a computerized randomization schedule in double blind conditions. The two types of tablets and tablet bottles were indistinguishable as far as size, shape, color or any other aspect and only the randomization number printed on the bottles allowed identification. Every patient received a bottle containing 40 tablets for the treatment in the Hospital and four bottles of 140 tablets each for home treatment. The total duration of treatment was six months followed by another three months without therapy. The recommended dose was three tablets per day, which was gradually reached in order to avoid the appearance of side effects, according to the following scheme: - one tablet in the evening during the first two days;

- one tablet in the morning and one in the evening in the two subsequent days,

- one tablet in the morning plus one at noon and one in the evening starting from the fifth day of therapy. In order to assess the treatment effectiveness, its activity on clinical symptoms, and the drug tolerability all the patients were submitted to a follow-up examination in the hospital after 12 weeks of treatment or from hospital discharge (when this date was different from the beginning of treatment) and four home or hospital examinations at 6, 18, 24 and 36 weeks from the beginning of treatment or discharge. All the patients who started the treatment were considered in order to evaluate effectiveness and tolerability with the exception of those patients who dropped out for unknown reasons before the 12^th week. For the effects assessed by psychodiagnostic inventories only patients who had completed at least 12 weeks of treatment were included. The following effectiveness parameters have been taken into account: 1. Frequency of rehospitalisation

2. Death rate

3. Deterioration rate

4. Frequency and kind of occurring diseases

5. Frequency and kind of accompanying symptoms

6. Frequency of drop out due to death, recurrence, occurring diseases or accompanying symptoms

7. Duration of treatment.

For a further evaluation of treatment effects a series of 12 psychodiagnostic inventories (including both rating scales and psychometric tests) was adopted. They were administered according to the following schedule: all the tests hereunder reported were repeated at time 0 and after 12 weeks of treatment, whereas only the NUDS, SCAG, and Bf-S were administered at the 6th, 18th, 24th, and 36th weeks.

1. NUDS (North Western University Disability Scale

2. SCAG (Sandoz Clinical Assessment Geriatric Rating Scale)

3. Albert Scale (Rating scale for the assessment of hemiplegic patients)

4. Bf-S by Zerssen ("Befindlichkeits" Scale for self-evaluation of well-being)

5. Number connection (ordered connection of a series of numbered circles by means of a pencil)

6. Circle Tapping (to touch with the tip of the pencil a series of small circles)

7. Association of symbols with numbers (the reproduction of fixed symbols instead of numbers)

8. Square tapping (to touch with the tip of the pencil a series of small squares)

9. Labyrinth (to be followed with the pencil)

10. Peg board test (stake transposition)

11. Corsi test (for the assessment of spatial memory)

12. Syndrom-Kurztest by Hellmut Erzigkeit (for the assessment of severity of psychorganic function)

The tolerability of the treatment was assessed by means of a retrospective evaluation of side effects (or accompanying symptoms) recorded during the various follow-up examinations. To this purpose it is to be noted that many symptoms recorded during the study had to be reinterpreted after the opening of randomization key as accompanying symptoms probably related to the lack of a protective action against their appearance. The tolerability was also evaluated by repeating after 12 weeks of treatment the physical examination including the determination of blood pressure and various hematochemical tests (hemoglobin, hematocrit, RBC, WBC with formula, platelets, glucose, BUN, creatinine, electrolytes, bilirubin, alkaline phosphatase, SGOT, SGPT, gamma-GT, serum protein levels) and urinalysis. All the results of the present study were submitted to codification and statistical analysis. The data were then gathered in Tables according to the treatment and the time of observation. Means and standard deviations at each time interval have been calculated for parametric data, as well as the difference at 12 weeks vs basal conditions. The Square Chi test and multivariate analysis were adopted for the comparisons of data. The statistical significance for all the calculations has been set at alpha = 0.05.

RESULTS

According to the randomization sequence 190 patients have been selected, but only 183 of them regularly entered the trial (Table 1 ). TABLE 1 : PATIENT SELECTION

At the statistical evaluation 23 other patients had to be excluded from this group; 17 because they had used drugs not allowed during the trial and 6 did not return for the examination scheduled 12 weeks after hospital discharge.

A total of 160 patients were then considered (Table 2): 81 received Lisuride and 79 placebo, 2/3 were males and the side of the hemisphere vascular lesion was without differences. In both treatment groups six months on average had elapsed from stroke (Table 2). TABLE 2: PATIENT CHARACTERISTICS (standard deviation in parenthesis)

A large majority of the patients (about 90%) were also affected by other diseases (Table 3). Hypertension was the most frequent concurrent disease, as it was observed in the 50% of the patients. The 40% of patients had only one concurrent, and the 30% had two diseases (Table 3)

TABLE 3: CONCOMITANT DISEASES AT THE BEGINNING OF THE STUDY (% values in parenthesis)

No significant differences were observed between the two treatment groups as far as concurrent diseases are concerned. The physical examination performed in basal conditions and after 12 weeks did not disclose any severe signs or symptoms. The most frequent signs are related to limb conditions and deep reflexes and are directly interpreted as consequences of the cerebrovascular lesion.

Duration of compliance to the trial

Out of the 160 patients enrolled in the trial, 138 (86.2%) returned to the hospital for the scheduled examination after 12 weeks (Table 4). Other 15 patients failed to return for the subsequent examination (18th week) in the Lisuride group (8 drop outs and 7 for lack of follow-up examination). In the placebo group 30 patients did not return (18 drop outs and 12 for lack of follow-up examination). This difference between groups is statistically significant (p < 0.01 ). The mean duration of trial continuation, reported in months at the scheduled controls (Table 4) is about two months longer in Lisuride group, however the difference vs placebo is not significant (Lisuride: 24.84 months; placebo: 22.61 months).

TABLE 4a: DURATION OF STAYING IN THE STUDY: LISURIDE (N=81 )

TABLE 4b: DURATION OF STAYING IN THE STUDY: PLACEBO (N=79)

Statistical test: Chi square

^* = Lisuride vs Placebo: p < 0,05

^** = Lisuride vs Placebo: p < 0,01

Drop-outs

A total of 90 drop-outs (56%) were observed during the 9 months of the trial; 43 (53%) in the Lisuride group and 47 (59%) in the placebo group. During the first six months, i.e. during the treatment phase of the study, 66 of these drop-outs were recorded (29 in Lisuride and 37 in placebo group). These differences between placebo and Lisuride groups are not statistically significant, are attributed to the occurrence of cardiocirculatory diseases and to side effects No difference was observed as far as the number of patients with early drop-out due to deterioration, lack of cooperation, new hospitalization, and other reasons,

Side Effects

Forty patients (25%; 13 in the Lisuride group and 27 in the placebo group) reported side effects (Table 5). The difference between the two groups is statistically significant (p <

0.01 ). A close examination of these side effects indicates that all the symptoms were equally distributed in the two treatment groups, with the exception of epileptic fits (real or suspected) that appeared in 11 patients in placebo group and in one patient of the

Lisuride group. In half of them these fits prompted the doctor to stop treatment (Table 5). These differences between groups are significant.

TABLE 5: SIDE EFFECTS AND/OR CONCOMITANT SYMPTOMS AND THEIR INFLUENCE ON THE STAYING IN THE STUDY

KIND OF SIDE EFFECT LISURIDE PLACEBO

Epileptic attacks O ^* 7

Suspected epileptic attacks 1 5

Hypertensive crisis 1 3

Various heart and Vascular diseases 0 1 Vertigo/faint 1

Flushes 1 0

Headache 2 0

Nausea 0 2

Vomiting 0 1

Diarrhoea 0 2

Other g.i. disturbances 1 1

Asthenia 1 0

General malaise 1 0

Mvo/arthralαia 0 1

Skin diseases 1 1

Enzymatic and metabolic disorders 2 2

Halitosis 0 1

Sleep disturbances 0 3

Psychomotor unrest 1 2

Mental confusion 2 0

Hallucinations 1 0

Total Side Effects ^**17 ^*33

Total cases with side effects **13 ^**27

^CJN

Statistical test: Chi Square

* = Lisuride-Placebo p < 0,05

** = Lisuride-Placebo p < 0,01 Concurring diseases

New diseases appeared in 36 cases (22.5%; 18 in Lisuride group and 18 in the placebo group) during the study period . In 20 of them (9 in Lisuride and 11 in placebo group) the treatment under study had to be withdrawn: in 9 cases (2 in Lisuride and 7 in placebo group) because the disease could be related to treatment itself (cardiovascular, gastrointestinal diseases or changes in glucose metabolism) and in 11 cases (7 in Lisuride and 4 in placebo group) because the treatment for these disorders (frequently requiring hospitalization) hindered the prosecution of the treatment under study. The differences between the two groups were not statistically significant. It is however to be noted the greater incidence of cardiac and cerebrovascular diseases in placebo group (5 cases) vs. Lisuride group (1 case).

Deterioration and recurrences

In twelve patients (7.5%; 6 cases for each group) general conditions worsened during the trial. In two other patients (one for each group) thrombosis or brain ischemia recurred. No difference between groups was found.

Deaths

Two deaths occurred during the trial, both in the placebo group: patient no. 51 died from heart attack 10 weeks after the beginning of treatment and patient no. 76 died from a recurrence of thrombosis 6 months after hospital discharge. New hospitalizations

During the 9 months of the trial 18 patients (18.7%) had to be rehospitalized in the same or other institutions: 9 patients due to worsening or recurrence (5 in Lisuride and 4 in placebo group), two patients (in placebo) for heart disease, three patients (in placebo) for epileptic fits, and the remaining 16 patients for various disorders.

Unknown events as drop-out cause

In 39 patients the trial was interrupted before the 9 months for unknown reasons. About half of them (18 cases) left between the 6th and the 9th month (wash out period), while the remaining 21 patients (54%) left between the 3rd and the 6th month of treatment. The differences between the two treatment groups (23 in Lisuride and 16 in placebo) are not statistically significant

Global evaluation of negative events

Table 6 reports the total adverse events that occurred during the trial and the total number of cases with adverse events (each patient is counted only once). A significant difference (p < 0.01 ) was found between the two therapeutic groups. In the Lisuride group fewer side effects occurred, patients under Lisuride therapy developed also fewer newly diagnosed conditions.

TABLE 6: FREQUENCY OF ADVERSE EVENTS DURING THE STUDY

Statistical test: Chi Square

* = Lisuride-Placebo p < 0,05

*^* = Lisuride-Placebo p < 0,01

Psvchodiagnostic Inventories

No statistically significant differences between Lisuride and placebo were found with the rating scales and psychometric tests. Blood Pressure

In basal conditions and at 12th week systolic and diastolic blood pressures were determined in lying position and in orthostatic position, immediately after standing up and one minute later. Only slight changes were observed that were not significantly different within or between groups.

CONCLUSIONS

Treatment with Lisuride prevented the occurrence of seizures after brain injury

Treatment with Lisuride did not lead to a worsening of cognitive performance or motor symptoms.

Patients under Lisuride enjoyed a reduced morbidity compared to patients under placebo treatment.

EXAMPLE 2

Preparation of a sterile lyophilisate with lisuride hydrogenmaleate for injection after dissolving.

2.0 mg of lisuride hydrogenmaleate are dissolved together with 20.0 g of lactose- monohydrate, 0.4 g of citric acid monohydrate and 1.0 g of sodium citrate dihydrate in 976.6 g of water for injection purposes.

The obtained colorless to light yellow solution has a pH value between 4.5 and 5.4. This solution is pre-filtered over a membrane filter and then sterile filtered over another membrane filter (0.2 urn) under aseptic conditions. Each 1.0 g of the obtained sterile solution is transferred into sterilized vials with an inner volume of 6 ml, provided with a rubber plug suitable for the subsequent lyophilization and cooled to -40 to -50 ⁰C in a lyophilizator. Then it is dried and post-dried, respectively, under vacuum obtaining a dry substance bulk. The vials are sealed and crimped under aseptic conditions. In this way 1000 vials (theoretical yield) each with 2 mg of lyophilized lisuride hydogenmaleate are obtained. The lyophilisate is reconstituted by dissolving with sterile, physiological saline solution and yields a sterile solution ready to use for injection and infusion. EXAMPLE 3

Preparation of a matrix plaster with lisuride for transdermal application.

2.5 g of lisuride are mixed with 2.13 g of acetone and 51.54 g of a solution of basic butylmethacrylate copolymer (eudragit 100 solution). 5.0 g of polyvinylpyrrolidone 5 (povidone 25), 2.5 g of tocopherol, 5.0 g of dodecyl-N, N-dimethylaminoacetate (alternatively 5.0 g of 1-dodecanol), 1.0 g of Foral E 105 and 0.65 g of an antioxidant (e.g. butylhydroxyanisol) are added to the solution. The obtained coating solution is continuously spread, under appropriate process conditions in a coater, onto a polymer film of polyethylene and then dried to an area weight of 50 mg/10 cm2 (± 5%) of coated area. The obtained sticky matrix is laminated with a polymer film which is siliconised on one side and in a further step stamped into plasters of a a size for the therapeutic utilisation (e.g. 20 cm²) and packaged in bags. After application on intact hairless skin, the prepared Lisuride plaster continuously releases the active agent at a rate of between 0,1 to 0,5 μg/ cm²/h over several days into the systemic circulation. The dosage can be adjusted through the use of different plaster sizes.

EXAMPLE 4

Preparation of a membrane plaster with lisuride for transdermal application.

By means of a laboratory coater a membrane of microporous polyethylene (Solupor® 10P05A) is coated as a control membrane (or alternatively of ethylenevinylacetate copolymer (EVA, Cotran® 3M 9728)) with a skin-acceptable silicon adhesive (BioPSA®7-4202) (alternatively polyisobutylene adhesive, Oppanol®) and dried with an area weight of about 10 to 25 mg/cm2 and then laminated with a liner (polyethylene) which is siliconized on one side.

The obtained laminate is annularly sealed in a suitable sealing apparatus with heat sealable polyethylene except for a small opening and stamped. Into the cavity formed about 0,5 ml of a 1 % solution of Lisuride in 2-propanol, hydroxypropylcellulose 30 (Klucel® LF) and tocopherol are filled via the remaining opening by means of a suitable injection device and then completely sealed. After equilibration and removal of the release liner the membrane plaster can be adhered on the intact hairless skin and releases Lisuride continuously and with a constant rate. The dosage can be adjusted through the use of different plaster sizes. EXAMPLE 5: Controlled Cortical Impact Injury (CCII) Rat model for treatment of TBI

Fifty male Sprague-Dawly rats (350-40Og) were anesthetized with isofluoran gas/N2O. A cortical controlled impact injury was performed as followed: A trauma was applied directly on the intact meninx through a pneumatically driven 5 mm bolt with convex end. Rate (7 m/s) Penetration depth (1.5 mm), contact time (300 ms) and localization (stereotactic fastener, impedance controlled positioning) are controlled, so that always the same deflection of the meninx takes place, resulting in a focal, mechanical cortex injury.

30 minutes after the CCII the therapy group (n=18) received randomized 0.3 mg/kg body weight Lisuride s.c, the placebo group received an equivalent amount of sterile common salt solution. In the group of 18 rats anesthesia was maintained for 3h after Drug/Placebo application and the EEG was recorded continuously. Intracranial pressure was measured through an implanted pressure transducer. In a second group of 32 rats directly after the CCII application osmotic pumps (Alzet 2ML1 , 10 μl/h, 0.5 mg/kg/d) were implanted to continuously deliver Lisuride (or Placebo). Animals of this group were sacrificed 24hrs after CCII and 30 min after application of 2ml/kg 2% Evans Blue. Wet weight, dry weight of brain hemispheres and extravasation of Evans Blue were determined subsequently.

RESULTS

Cardiovascular effects

There were no baseline differences in cardiovascular parameters, such as mean arterial pressure (MAP) and heart rate, between treatment groups. Following CCII, MAP was significantly reduced, but within normal limits in both groups (p<0.01 ). After drug application a more severe hypotensive effect was observed in lisuride-treated animals (85±15 mmHg vs. 68±8 mmHg at 60 minutes after trauma; p<0.01 ). This was sustained over 3 hours after drug treatment and lead to a significant lisuride effect on MAP p<0.05.

At the same time a bradycardic response was observed in both groups following drug application (p<0.01 ; Fig. 3). This was mostly treatment-related (p<0.01 ) and only sustained in lisuride treated animals (342±50 vs. 286±23 bpm and 382±50 vs. 309±32 bpm at 60 and 210 minutes after trauma, respectively; p<0.05). Intracranial pressure and cerebral perfusion pressure

Before trauma intracranial pressure (ICP) was similar in both groups (11±1 immHg) and increased significantly after trauma (15±1 mmHg at 30 minutes after CCII; p<0.01 ). After drug-application, measured post-traumatic ICP was lower in lisuride treated animals.11 mmHg vs 15 mmHg (Fig. 1 ).

Resulting cerebral perfusion pressures (CPP) were significantly reduced after trauma (p<0.01 ). Lisuride 56±10 vs. controls 70±14 mmHg at 60 minutes after CCII) and was sustained over the entire observation period of 3 hours (p<0.01 ).

Electroencephalography (EEG)

Two animals in the treatment group displayed epileptiform discharges after trauma but before drug application. After treatment 6 animals (67%) presented with transient epileptiform discharges in both groups each. The total number of seizures was lower in the treatment group (10 vs 19) and the average duration was shorter (106±61 vs. 301±102, p<0.1 ).

The cumulative duration of seizures in both groups over time indicated, that the majority of seizures terminated within 30 minutes of drug-application in lisuride-treated animals, whereas control animals continued to display epileptiform discharges thereafter.

Effects of lisuride maleate on brain edema and blood brain barrier damage

Gravimetrical analysis of brain edema

Brain water content of traumatized hemispheres increased to 80.2±1.2% in control animals as opposed to the contralateral, non-traumatized side (78.7±0.5%). Brain water content was reduced in animals treated with lisuride (79.0±0.9 and 78.5±0.5%) resulting in a decrease of brain edema from 12±3% to 8±4%.

Extravasation of Evans Blue

Evans Blue extravasation was reduced in rats treated lisuride, although this effect was significant in the non-traumatized hemisphere (p<0.05) and less obvious on the traumatized side (p<0.1 ).

Claims

1. Use of the compounds of the general formula (I)

wherein

R¹ and R⁴ represent independently from each other -H, -CHO, -COCH₃,

-COC₂H₅, -COC₃H₇, -CO-CyCIo-C₃H₅, -COCH(CH₃)₂, -COC(CH₃)₃, -COOH, -COOCH₃, -COOC₂H₅, -COOC₃H₇, -COO-cyclo-C₃H₅,

-COOCH(CH₃)₂, -COOC(CH₃)₃, -CONH₂, -CONHCH₃, -CONHC₂H₅, -CONHC₃H₇, -CONH-cyclo-C₃H₅, -CONH[CH(CH₃)₂], -CONH[C(CH₃)₃], -CON(CH₃)₂, -CON(C₂Hs)₂, -CON(C₃H₇)₂, -CON(cyclo-C₃H₅)₂,

-CON[CH(CH₃)₂]₂, -CON[C(CH₃)₃]₂, -NH₂, -NHCH₃, -NHC₂H₅, -NHC₃H₇, -NH-CyClO-C₃H₅, -NHCH(CH₃)₂, -NHC(CH₃)₃, -N(CH₃J₂, -N(C₂H₅)₂,

-N(C₃H₇),, -N(cyclo-C₃H₅)₂, -N[CH(CH₃)₂]₂, -N[C(CH₃)₃]₂₎ -SOCH₃, -SOC₂H₅, -SOC₃H₇, -SO-cyclo-C₃H₅, -SOCH(CH₃)₂, -SOC(CH₃)₃₎ -SO₂CH₃, -SO₂C₂H₅, -SO₂C₃H₇, -SO₂-CyCIo-C₃H₅, -SO₂CH(CH₃)₂, -SO₂C(CHa)₃, -SO₃H, -SO₃CH₃, -SO₃C₂H₅, -SO₃C₃H₇, -SO₃-CyCIo-C₃H₅, -SO₃CH(CH₃)₂, -SO₃C(CH₃)₃, -CH₂F, -CHF₂, -CF₃, -CH₂CI₁ -CH₂Br₁

-CH₂I, -CH₂-CH₂F, -CH₂-CHF₂, -CH₂-CF₃, -CH₂-CH₂CI, -CH₂-CH₂Br₁ -CH₂-CH₂I₁ -CH₃, -C₂H₅, -C₃H₇, -CH(CH₃)_2l -C(CH₃)₃₎ -C₄H₉, -CH₂-CH(CH₃)₂, -CH(CH₃)- C₂H₅, -C₅Hn, -CeHi₃, -C₇Hi₅, -CeHi₇, -cyclo-C₃H_5l -cyclo-C₄H₇, -CyCIo-C₅H₉, -CyCIo-C₆H₁₁, -Ph₁ -CH₂-Ph₁ -CPh₃, -CH=CH₂, -CH₂-CH=CH₂, -C(CH₃)=CH_2l -CH=CH-CH₃,

-C₂H₄-CH=CH₂, -CH=C(CH₃)_2l -C≡CH, -C≡C-CH₃, -CH₂-C≡CH;

R⁵ represents one of the residues -H, -F, -Cl, -Br, -I, -CN or -NO₂;

R⁶ - R⁴⁵ represent independently from each other -H, -OH, -OCH₃, -OC₂H₅, -OC₃H₇, -O-cyclo-C₃H₅, -OCH(CH₃)₂, -OC(CH₃)_3l -OC₄H₉, -OPh, -OCH₂-Ph, -OCPh₃, -SH, -SCH₃, -SC₂H₅, -SC₃H₇, -S-CyClO-C₃H₅, -SCH(CH₃)₂, -SC(CH₃J₃, -NO₂, -F, -Cl, -Br, -I, -N₃, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH₃, -COC₂H₅,

-COC₃H₇, -CO-CyCIo-C₃H₅, -COCH(CH₃)₂, -COC(CH₃)₃, -COOH, -COCN, -COOCH₃, -COOC₂H₅, -COOC₃H₇, -COO-CyCIo-C₃H₅, -COOCH(CH₃)₂, -COOC(CH₃)₃, -0OC-CH₃, -0OC-C₂H₅, -0OC-C₃H₇, -0OC-CyCb-C₃H₅, -OOC-CH(CH₃)₂, -OOC-C(CH₃)₃, -CONH₂, -CONHCH₃, -CONHC₂H₅, -CONHCsH₇, -CONH-CyClO-C₃H₅, -CONH[CH(CH₃)₂], -CONH[C(CH₃)₃],

-CON(CH₃)₂, -CON(C₂H₅)₂, -CON(C₃H₇)₂, -CON(cyclo-C₃H₅)₂,

-CON[CH(CH₃)₂]₂, -CON[C(CH₃)₃]₂, -NH₂, -NHCH₃, -NHC₂H₅, -NHC₃H₇, -NH-CyClO-C₃H₅, -NHCH(CHs)₂, -NHC(CH₃)₃, -N(CH₃)₂, -N(C₂H₅)₂, -N(C₃H₇J₂, -N(cyclo-C₃H₅)₂, -N[CH(CH₃)₂]₂, -N[C(CH₃)₃]_2> -SOCH₃, -SOC₂H₅, -SOC₃H₇, -SO-CyCIo-C₃H₅, -SOCH(CHs)₂, -SOC(CH₃)₃, -SO₂CH₃, -SO₂C₂H₅,

-SO₂C₃H₇, -SO₂-CyClO-C₃H₅, -SO₂CH(CH₃)₂, -SO₂C(CHs)₃, -SO₃H₁ -SO₃CH₃, -SO₃C₂H₅, -SO₃C₃H₇, -SO₃-cyclo-C₃H₅, -SO₃CH(CH₃)₂, -SO₃C(CH₃)₃, -OCF₃, -OC₂F₅, -0-COOCH₃, -0-COOC₂H₅,

-0-COOC₃H₇, -O-COO-cyclo-C₃H₅, -O-COOCH(CH₃)₂, -O-COOC(CH₃)₃, -NH-CO-NH₂, -NH-CO-NHCH₃, -NH-CO-NHC₂H₅, -NH-CO-NHC₃H₇,

-NH-CO-NH-CyClO-C₃H₅, -NH-CO-NH[CH(CH₃)₂], -NH-CO-NH[C(CHs)₃], -NH-CO-N(CH₃)₂, -NH-CO-N(C₂H₅)_2l -N H-CO-N(C₃H₇J₂,

-NH-CO-N(cyclo-C₃H₅)₂, -NH-CO-N[CH(CH₃)₂]₂, -N H-CO-N [C(CH₃)₃]₂, -NH-CS-NH₂, -NH-CS-NHCH₃, -NH-CS-NHC₂H₅, -NH-CS-NHC₃H₇, -NH-CS-NH-CyCIo-C₃H₅, -NH-CS-NH[CH(CH₃)₂], -NH-CS-NH[C(CHs)₃],

-NH-CS-N(CHs)₂, -NH-CS-N(C₂Hs)₂, -NH-CS-N(C₃H₇J₂,

-NH-CS-N(cyc!o-C₃H₅)₂, -NH-CS-N[CH(CH₃)₂]_2> -NH-CS-N[C(CH₃)₃]₂, -NH-C(=NH)-NH₂, -NH-C(=NH)-NHCH₃, -NH-C(=NH>-NHC₂H₅,

-NH-C(=NH)-NHC₃H₇, -NH-C(=NH)-NH-cyclo-C₃H5, -NH-C(=NH)-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3],

_NH-C(=NH)-N(CH3)2, -NH-C(=NH)-N(C2H5)₂, -NH-C(=NH)-N(C3H7)2, _NH-C(=NH)-N(cyclo-C3H5)2, -NH-C(=NH)-N[CH(CH3)2]2,

-NH-C(=NH)-N[C(CH3)3]2, -0-CO-NH₂, -0-CO-NHCH₃, -0-CO-NHC₂H₅, -0-CO-NHC₃H₇, -0-CO-NH-CyClO-C₃H₅, -O-CO-NH[CH(CH₃)₂],

-O-CO-NH[C(CH₃)₃], -O-CO-N(CH₃)₂, -O-CO-N(C₂H₅)₂, -O-CO-N(C₃H₇)₂, -O-CO-N(cyclo-C₃H₅)₂, -O-CO-N[CH(CH₃)₂]₂, -O-CO-N[C(CH₃)₃]₂,

-0-CO-OCH₃, -0-CO-OC₂H₅, -0-CO-OC₃H₇, -0-CO-O-CyCIo-C₃H₅, -O-CO-OCH(CH₃)₂, -O-CO-OC(CH₃)₃, -CH₂F, -CHF₂, -CF₃, -CH₂CI, -CH₂Br, -CH₂I, -CH₂-CH₂F, -CH₂-CHF₂, -CH₂-CF₃, -CH₂-CH₂CI,

-CH₂-CH₂Br, -CH₂-CH₂I₁ -CH₃, -C₂H₅, -C₃H₇, -CH(CH₃)₂, -C(CH₃)₃, -C₄Hg₁ -CH₂-CH(CH₃)₂, -CH(CH₃)-C₂H₅, -C₅Hn, -CeHi₃, -C₇Hi₅, -CsHi₇, -cyclo-C₃H₅, -cydo-C₄H₇, -cyclo-C₅H₉, -CyCIo-C₆Hn, -Ph, -CH₂-Ph, -CPh₃, -CH=CH₂, -CH₂-CH=CH₂, -C(CH₃)=CH₂, -CH=CH-CH₃, -C₂H₄-CH=CH₂, -CH=C(CH₃)₂, -C≡CH, -C=C-CH₃, -CH₂-C=CH;

X represents a single bond or a double bond;

n represents an integer from 1 to 10; as well as

salts, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, hydrates, solvates and racemates of the afore-mentioned compounds for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of brain disorder wherein the brain disorder is characterized by increased cranial pressure or epileptic seizures or neural edema.

2. Use of the compounds of the general formula (I) wherein

R¹ and R⁴ represent independently from each other -H, -CHO₁ -COCH₃,

-COC₂H₅, -COC₃H₇, -CO-cyclo-C₃H₅, -COCH(CH₃)_2l -COC(CH₃)₃, -COOH, -COOCH₃, -COOC₂H₅, -COOC₃H₇, -COO-cyclo-C₃H_5l -COOCH(CH₃)₂, -COOC(CH₃)₃, -CONH₂, -CONHCH₃, -CONHC₂H₅, -CONHC₃H₇, -CONH-cyclo-C₃H₅, -CONH[CH(CH₃)₂], -CONH[C(CH₃)₃], -CON(CHa)₂, -CON(C₂H₅)₂, -CON(C₃H₇)₂, -CON(cyclo-C₃H₅)₂,

-CON[CH(CH₃)₂]₂, -CON[C(CH₃)₃]2, -SO₃C₂H₅, -SO₃C₃H₇, -SO₃-CyCIo-C₃H₅, -SO₃CH(CH₃)_2l -SO₃C(CH₃)₃, -CH₂F, -CHF₂, -CF₃, -CH₂CI, -CH₂Br, -CH₂I, -CH₂-CH₂F, -CH₂-CHF₂, -CH₂-CF₃, -CH₂-CH₂CI, -CH₂-CH₂Br, -CH₂-CH₂I, -CH₃, -C₂H₅, -C₃H₇, -CH(CH₃J₂, -C(CH₃J₃, -C₄H₉, -CH₂-CH(CH₃)_2l -CH(CHa)-C₂H₅, -C₅Hn, -C₆H₁₃, -C₇Hi₅, -C₈Hi₇,

-cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-CeHn, -Ph, -CH₂-Ph, -CPh₃, -CH=CH₂, -CH₂-CH=CH₂, -C(CH₃)=CH₂, -CH=CH-CH₃, -C₂H₄-CH=CH₂, -CH=C(CH₃)₂, -C≡CH, -C=C-CH₃, -CH₂-C=CH; R² and R³ represent independently from each other -H, -R⁶, -NH-CO— NH- alkyl residue or -NH-CO— N(dialkyl residue);

alkyl and dialkyl represent independently of each other -CH2F, -CH₂-CH₂F₁ -CH₂-CHF₂, -CH₂-CF₃, -CH₂-CH₂CI, -CH₂-CH₂Br, -CH₂-CH₂I, -CH₃, - C₂H₅, -C₃H₇, -CH(CH₃)₂, -C(CH₃)₃, -C₄H₉, -CH₂-CH(CH₃)₂, -CH(CH₃)-C₂H5,

-C₅H₁₁, -C₆H₁₃, -C₇H₁₅, -C₈H₁₇, -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, - CyCIo-C₆H₁₁, -Ph, -CH₂-Ph, -CPh₃, -CH=CH₂, -CH₂-CH=CH₂, - C(CHa)=CH₂, -CH=CH-CH₃, -C₂H₄-CH=CH₂, -CH=C(CH₃)₂, -C≡CH, -C≡C- CH₃ and -CH₂-O=CH;

R⁵ represents one of the residues -H or -Br;

R⁶ - R⁴⁵ represent independently from each other -H₁ -OH, -OCH₃, -OC₂H₅, -OC₃H₇, -O-cyclo-C₃H₅, -OCH(CH₃)₂, -OC(CH₃)₃, -OC₄H₉, -OPh, -OCH₂-Ph, -OCPh₃, -SH, -SCH₃, -SC₂H₅, -SC₃H₇, -S-cyclo-C₃H₅, -SCH(CH₃)₂, -SC(CH₃)₃, -NO₂, -F, -Cl, -Br, -I, -N₃, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH₃, -COC₂H₅,

-COC₃H₇, -CO-cyclo-C₃H₅, -COCH(CH₃)₂, -COC(CH₃)_3l -COOH, -COCN, -COOCH₃, -COOC₂H₅, -COOC₃H₇, -COO-cyclo-C₃H₅, -COOCH(CH₃)₂, -COOC(CHa)₃, -0OC-CH₃, -0OC-C₂H₅, -0OC-C₃H₇, -OOC-cyclo-C₃H₅, -OOC-CH(CH₃)₂, -OOC-C(CH₃)₃, -CONH₂, -CONHCH₃, -CONHC₂H₅, -CONHC₃H₇, -CONH-CyClO-C₃H₅, -CONH[CH(CH₃)₂], -CONH[C(CH₃)₃],

-CON(CH₃)₂, -CON(C₂Hs)₂, -CON(C₃H₇)₂, -CON(cyclo-C₃H₅)₂,

-CON[CH(CH₃)₂]₂, -CON[C(CH₃)₃]₂, -NH₂, -NHCH₃, -NHC₂H₅, -NHC₃H₇, -NH-CyClO-C₃H₅, -NHCH(CH₃)₂, -NHC(CHa)₃, -N(CH₃)₂, -N(C₂H₅)₂, -N(C₃H₇)_2l -N(cyclo-C₃H₅)₂, -N[CH(CH₃)₂]₂, -N[C(CH₃)₃]₂, -SOCH₃, -SOC₂H₅, -SOC₃H₇, -SO-CyCIo-C₃H₅, -SOCH(CH₃)₂, -SOC(CH₃)₃, -SO₂CH₃, -SO₂C₂H₅,

-SO₂C₃H₇, -SO₂-CyClO-C₃H₅, -SO₂CH(CH₃)₂, -SO₂C(CH₃)₃, -SO₃H, -SO₃CH₃, -SO₃C₂H₅, -SO₃C₃H₇, -SO₃-cyclo-C₃H₅, -SO₃CH(CH₃)₂, -SO₃C(CH₃)₃, -OCF₃, -OC₂F₅, -0-COOCH₃, -0-COOC₂H₅,

-0-COOC₃H₇, -O-COO-cyclo-C₃H₅, -O-COOCH(CH₃)₂, -O-COOC(CH₃)_3l -NH-CO-NH₂, -NH-CO-NHCH₃, -NH-CO-NHC₂H₅, -NH-CO-NHC₃H₇,

-NH-CO-NH-CyClO-C₃H₅, -NH-CO-NH[CH(CHa)₂], -NH-CO-NH[C(CHa)₃], -NH-CO-N(CH₃)₂, -NH-CO-N(C₂Hs)₂, -NH-CO-N(C₃H₇)₂,

-NH-CO-N(cyclo-C₃Hs)₂, -NH-CO-N[CH(CH₃)₂]₂, -NH-CO-N[C(CH₃)₃]₂, -NH-CS-NH₂, -NH-CS-NHCH₃, -NH-CS-NHC₂H₅, -NH-CS-NHC₃H₇, -NH-CS-NH-CyClO-C₃H₅, -NH-CS-NH[CH(CH₃)₂], -NH-CS-NH[C(CH₃)₃],

-NH-CS-N(CH₃)₂, -NH-CS-N(C₂Hs)₂, -NH-CS-N(C₃H₇)₂,

-NH-CS-N(cyclo-C₃H₅)₂, -NH-CS-N[CH(CH₃)₂]₂, -NH-CS-N[C(CH₃)a]2, -NH-C(=NH)-NH₂, -NH-C(=NH)-NHCH₃, -NH-C(=NH>-NHC₂H₅,

-NH-C(=NH>-NHC₃H₇, -NH-C(=NH)-NH-cyclo-C₃H₅, -NH-C(=NH)-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH₃)3],

-NH-C(=NH)-N(CH3)2, -NH-C(=NH)-N(C2H5)2, -NH-C(=NH>-N(C3H7)2, -NH-C(=NH)-N(cyclo-C3H₅)2, -NH-C(=NH)-N[CH(CH3)2]2,

-O-CO-N H [C(CH₃)₃], -O-CO-N(CH₃)₂, -O-CO-N(C₂H₅)₂, -O-CO-N(C₃H₇)_2l -O-CO-N(cyclo-C₃H₅)₂, -O-CO-N[CH(CH₃)₂]₂, -O-CO-N[C(CH₃)₃]2,

-0-CO-OCH₃, -0-CO-OC₂Hs, -0-CO-OC₃H₇, -0-CO-O-CyClO-C₃H₅, -O-CO-OCH(CH₃)₂₎ -O-CO-OC(CH₃)₃, -CH₂F, -CHF₂, -CF₃, -CH₂CI, -CH₂Br, -CH₂I, -CH₂-CH₂F, -CH₂-CHF₂, -CH₂-CF₃, -CH₂-CH₂CI,

-CH₂-CH₂Br, -CH₂-CH₂I, -CH₃, -C₂H₅, -C₃H₇, -CH(CH₃)₂, -C(CH₃J₃, -C4H₉, -CH₂-CH(CH₃)₂, -CH(CH₃)-C₂H₅, -C₅Hn, -CeHi₃, -C₇Hi₅, -CsHi₇, -cyclo-C₃H₅, -cyclo-C₄H₇, -CyCIo-C₅H₉, -cyclo-CeHn, -Ph, -CH₂-Ph, -CPh₃, -CH=CH₂, -CH₂-CH=CH₂, -C(CH₃)=CH₂, -CH=CH-CH₃, -C₂H₄-CH=CH₂, -CH=C(CH₃)₂, -C≡CH, -C≡C-CH₃, -CH₂-C≡CH;

X represents a single bond or a double bond;

n represents an integer from 1 to 10.

3. Use according to claim 1 , wherein the compound of the general formula (I) is selected from the group comprising: 8-α-ergoline, 8-α-1 ,6-dimethylergoline, 8-α-1- methylergoline, δ-α-6-methylergoline, δ-α-10-methoxyergoline, lisuride, d- isolysergic acid, d-isolysergic acid amide, d-isolysergic acid di-ethylamide, proterguride and terguride.

4. Use according to claim 1 , wherein the compound of the general formula (I) is selected from the group comprising: lisuride, terguride and proterguride.

5. Use according to one of claims 1 to 4, wherein the brain disorder is selected from acute traumatic brain injury, severe acute traumatic brain injury, epileptic seizures, symptomatic epilepsy, neural edema and increased cranial pressure associated with traumatic brain injury.

6. Use according to one of the preceding claims, wherein the epileptic seizures occur as a consequence of a brain injury event.

7. Use according to one of the preceding claims, wherein the epileptic seizures occur during the acute phase in traumatic brain injury or during the rehabilitation phase in traumatic brain injury or in the rehabilitation phase after stroke.

8. Use according to one of claims 1 to 5, wherein the brain edema occurs during the acute phase of a brain injury event.

9. Use according to one of claims 1 to 5, wherein the increased cranial pressure occurs during the acute phase of a brain injury event

10. Use according to one of claims 1 to 9, wherein the pharmaceutical composition is suitable for parenteral, transdermal, oral, low dose intravenous, or subcutaneous administration, or intramuscular injection, continuous intravenous infusion, or continuous subcutaneous infusion.

11. Use according to claim 10 wherein the continuous intravenous infusion or continuous subcutaneous infusion is administered by a perfusor system or a programmable minipump.

12. Use according to claim 10 wherein the pharmaceutical composition is suitable for transdermal administration via transdermal patch as a longterm chronic therapy.

13. Use according to any one of claims 10 to 12, wherein the compound of the general formula (I) is administered in a dosage corresponding to an effective concentration in the range of 0.5 - 25 μg/kg body weight.

14. Use according to claim 13, wherein the dosage is infused during acute brain injury continuously over a period from 24 hours to 4 weeks and in the case of epileptic seizures and symptomatic epilepsy as a chronic longterm therapy.