EP1545531A1 - Use of 5-ht2 receptor antagonists for the treatment of sleep disorders - Google Patents

Use of 5-ht2 receptor antagonists for the treatment of sleep disorders

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Publication number
EP1545531A1
EP1545531A1 EP03775144A EP03775144A EP1545531A1 EP 1545531 A1 EP1545531 A1 EP 1545531A1 EP 03775144 A EP03775144 A EP 03775144A EP 03775144 A EP03775144 A EP 03775144A EP 1545531 A1 EP1545531 A1 EP 1545531A1
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EP
European Patent Office
Prior art keywords
sleep
methanone
indol
piperazin
fluorophenethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP03775144A
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German (de)
French (fr)
Inventor
Gerd Bartoszyk
Christoph Van Amsterdam
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Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1545531A1 publication Critical patent/EP1545531A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to the use of 5-HT 2 receptor antagonists for the manufacture of a medicament for prolonging both nonREM sleep and REM sleep.
  • Novel N- (indolecarbonyl) piperazine derivatives and processes for their preparation are known from WO 01/07435.
  • the substances show, among other things, effects on the central nervous system with good tolerability and thereby has valuable pharmacological properties. They have a strong affinity for 5-HT 2 receptors, possessing 5-HT 2A receptor antagonist properties.
  • Indolcarbonyl piperazine derivatives are useful in both veterinary and human medicine for the treatment of central nervous system dysfunction and inflammation. They can be used for the prophylaxis and control of the consequences of cerebral infarct events (apoplexia cerebri) such as stroke (here trauma) and cerebral ischaemias and for the treatment of extrapyramidal motor side effects of neuroleptics (eg dystonic syndromes, neuroleptics induced muscle stiffness, tremor (including substance-induced tremor forms) or Parkinson's disease, including dopaminomimetic side effects of conventional Parkinson's drugs, for the acute and symptomatic treatment of Alzheimer's disease and for the treatment of amyotrophic lateral sclerosis.
  • apoplexia cerebri such as stroke (here trauma) and cerebral ischaemias
  • neuroleptics eg dystonic syndromes, neuroleptics induced muscle stiffness, tremor (including substance-induced tremor forms) or Parkinson's disease, including dopaminomimetic side effects
  • the substances are suitable as therapeutic agents for the treatment of brain trauma (eg after head injuries) or spinal cord trauma.
  • they are suitable as active pharmaceutical ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics, antihypertensives and / or for positively influencing compulsive behavior (obsessive-compulsive disorder, OCD), including obsessive-compulsive spectrum disorders (OCSD), anxiety, panic attacks, psychosis, schizophrenia, anorexia, delusional obsessions, agoraphobia, migraine, sleep disorders as well as sleep apnea, tardive dyskinesias, learning disabilities, age-related Memory disorders, eating disorders such as bulimia, substance abuse (including substance abuse-induced disorders) and / or sexual dysfunction.
  • endocrine disorders such as hyperprolactinaemia, in vasospasm, hypertension, gastrointestinal disorders, cardiovascular diseases and extrapyramidal symptoms as described in WO 99/11641 on page 2, lines 24-30.
  • N- (indolocarbonyl) piperazine derivatives are suitable for reducing intraocular pressure and for glaucoma treatment.
  • N- (indolocarbonyl) piperazine derivatives are described in WO 03/045392:
  • the substances are also suitable for the treatment of obesity, subtypes of anxiety, subtypes of schizophrenia and types of dementia of different origin and for the treatment of aggression disorders, the Parkinson's disease, attention deficit disorders with hyperactivity and behavioral disorders.
  • they can be used in the adjunctive treatment of low-dose neuro leptics treatment.
  • the object of the present invention was to find further valuable pharmaceutical uses for the abovementioned N- (indolocarbonyl) piperazine derivatives.
  • insomnia can be a symptom of a disease on the one hand, but also represent an independent clinical picture on the other hand. Thirty percent of adults suffer
  • Sleep disorders can manifest themselves in different ways: Sleep disorders are characterized by the length of time a person needs to fall asleep. If this time is more than thirty minutes, one can speak of falling asleep. The person concerned is then often awake for a long time, which in extreme cases can even last for hours.
  • sleep disturbance If a patient suffers from premature awakening, it is referred to as sleep disturbance. But that is only the case when the waking up happens six times a week before the end of six hours. Often, sleep is described as superficial and not very relaxing. A premature awakening is when the person often wakes up too early, and then can not fall asleep.
  • REM rapid eye movement
  • non-REM non-REM
  • the compounds of the invention While common sleep aids only prolong the nonREM sleep duration, with the REM sleep duration remaining unchanged or even decreased, the compounds of the invention also increase REM sleep duration, resulting in an improved sleep architecture. On the market, however, such as triazolam, zolpidem or Zoplicon - even shorten the REM sleep.
  • a selective antagonist of the receptor 5-HT 2A , R - (+) - alpha- (2,3-dimethoxyphenyl) -1 - (2- (4-fluorophenyl) ethyl) -4-piperidinemethanol disclosed, inter alia, is suitable for the treatment of sleep disorders, in particular, causes an extension of the slow-wave phases 3 and 4 of the nonREM sleep.
  • non-selective 5-HT 2A antagonists such as nefazodone
  • nefazodone have been reported to prolong REM sleep, slow wave
  • shares of nonREM sleep remain unchanged (Sharpley and Cowen, Biol. Psychiatry 37, 85-98, 1995).
  • 5 thalidomide is a sleep aid known to prolong both sleep periods; however, this substance is not a 5-HT 2 receptor antagonist.
  • the present invention therefore provides the use of 5-HT 2 receptor antagonists, in particular 5-HT 2A receptor antagonists, for the manufacture of a medicament for the prolongation of both nonREM sleep and REM sleep.
  • N- (indolecarbonyl) -piperazine derivatives according to the invention are particularly useful for the treatment of sleep disorders, as well as premature awakening in the morning.
  • Another object of the present invention is therefore the use of 5-HT 2 receptor antagonists, in particular ⁇ -HT ⁇ - receptor antagonists, for the manufacture of a medicament for the treatment of sleep disorders and drowsiness as well as premature morning awakening.
  • the invention further relates to the use of 5-HT 2 - receptor antagonists for the preparation of a pharmaceutical preparation containing the active ingredient according to the invention and optionally i excipients and / or adjuvants and optionally other active ingredients.
  • the medicaments can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or adjuvant and optionally in combination with one or more further active ingredient (s).
  • the 5-HT 2 - receptor antagonists are usually administered in analogy to known preparations, preferably in dosages between about 0.1 and 500 mg, 5 in particular between 5 and 300 mg per dosage unit.
  • the daily dosage is preferably between about 0.01 and 250 mg / kg, in particular between 0.02 and 100 mg / kg of body weight.
  • the 5-HT 2 receptor antagonists are administered in dosages of between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each particular patient depends on the most diverse 5
  • Factors such as the efficacy of the particular compound used, age, body weight, general health status, sex, diet, time and route of administration, excretion rate, drug combination and severity of the particular disease to which the therapy applies. Oral administration is preferred.
  • the 5-HT 2 receptor antagonists can also be used together with other drugs, in particular other sleep aids, in the treatment of the mentioned diseases.
  • the invention therefore also relates to the use of 5-HT 2 receptor antagonists in combination with one or more further sleeping pills in the above-described sleep therapy.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the new compounds, for example
  • the preparations indicated may be sterilized and / or contain excipients such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavorings and / or flavorings. If desired, they may also contain one or more other active ingredients, for example one or more vitamins.
  • a solution of 100 g of an active ingredient according to the invention and 5 g of dihydrogen phosphate phosphate in 3 l of double distilled water is adjusted to pH 6.5 with 2 N 5 hydrochloric acid, filtered sterile, filled into injection jars, lyophilized and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • Example A2 Suppositories 0
  • a mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared according to the invention, 9:38 g NaH 2 PO 4 x 2 H 2 O, 28.48 g NaH 2 PO 4 x 12 H 2 0 and 0.1 g Benzalko- niumchlorid in 940 ml of double-distilled water. It is adjusted to pH 6.8 0, filled to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example A4 ointment
  • a mixture of 1 kg of an active ingredient according to the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a conventional manner into tablets, such that each tablet contains 10 mg of active ingredient.
  • Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
  • Example A7 Capsules 2 kg of a drug according to the invention are in the usual way in
  • a solution of 1 kg of an active ingredient according to the invention in 60 l of bidistilled water is filled into ampoules, lyophilized under aseptic conditions and closed under sterile conditions. Each vial contains 10 mg of active ingredient.
  • triazolam increases nonREM sleep by 2 min / h at a dose of 0.1 mg / kg and by 6.5 min / h at a dose of 0.4 mg / kg, which corresponds to the maximum effect of triazolam ,
  • zolpidem extends nonREM sleep by 5 min / h at 5 mg / kg and 7 min / h at 10 mg / kg.
  • Zoplicon (2.5 - 5 mg / kg) shows a comparable effect.
  • (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone is capable of prolonging nonREM sleep with the
  • Example B Treatment of rats with (3-cyan-1H-indol-7-yl) -f4- (4-fluorophenethyl) -piperazin-1-ylj-methanone, hydrochloride
  • rats are implanted into the brain under anesthetic EEG electrodes. After a 15-day recovery period, these electrodes are connected to an amplifier via a flexible cable and the brain waves of non-anesthetized animals are recorded for 12 hours.
  • Cyan-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone results in a significant extension of both nonREM and REM sleep, and that these extensions are significant .
  • Sleep Stage REM Latency Time from onset of sleep to
  • This trial is a crossover study. That is, one and the same animal is optionally first solvent (Vehicie), after a week waiting time then the test substance (3-cyano-1 H-indol-7-yl) - [4- (4-fluorophenethyl) piperazine-1 yl] -methanone (compound), or administration is in reverse order.
  • Table 2 Significances of the values from Table 1.
  • the measured values after vehicle or compound application are compared with each other using the statistical method of analysis of variance (ANOVA).
  • ANOVA statistical method of analysis of variance
  • the p-value is a statistical measure of the likelihood that a difference between the measurements will occur randomly or due to the substance application. According to international standards, a p-value of less than 0.05 is said to be "significant".

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Abstract

The invention relates to the use of 5-HT2 receptor antagonists for producing a medicament which extends non-REM sleep and REM sleep.

Description

VERWENDUNG VON 5-HT2 REZEPTORANTAGONISTEN ZUR BEHANDLUNG VON SCHLAFSTÖRUNGEN USE OF 5-HT2 RECEPTOR ANTAGONISTS FOR THE TREATMENT OF SLEEP DISORDERS
Die Erfindung betrifft die Verwendung von 5-HT2-Rezeptorantagonisten zur Herstellung eines Arzneimittels zur Verlängerung sowohl des nonREM- Schlafs als auch des REM-Schlafs.The invention relates to the use of 5-HT 2 receptor antagonists for the manufacture of a medicament for prolonging both nonREM sleep and REM sleep.
Neuartige N-(lndolcarbonyl-)piperazinderivate und Verfahren zu ihrer Herstellung sind aus der WO 01/07435 bekannt. Die Substanzen zeigen bei guter Verträglichkeit unter anderem Wirkungen auf das Zentralnervensystem und verfügt dabei über wertvolle pharmakologische Eigenschaften. Sie weisen eine starke Affinität zu 5-HT2 -Rezeptoren auf, wobei sie 5-HT2A- Rezeptor-antagonistische Eigenschaften besitzen.Novel N- (indolecarbonyl) piperazine derivatives and processes for their preparation are known from WO 01/07435. The substances show, among other things, effects on the central nervous system with good tolerability and thereby has valuable pharmacological properties. They have a strong affinity for 5-HT 2 receptors, possessing 5-HT 2A receptor antagonist properties.
Ferner ist aus der WO 01/07435 bekannt, daß sich besagte N-Furthermore, it is known from WO 01/07435 that said N
(lndolcarbonyl-)piperazinderivate sowohl in der Veterinär- als auch in der Humanmedizin zur Behandlung von Funktionsstörungen des Zentralnervensystems sowie von Entzündungen eignen. Sie können zur Prophylaxe und zur Bekämpfung der Folgen cerebraler Infarktgeschehen (apoplexia cerebri) wie Schlaganfall (hier beispielsweise Traumata) und cerebraler I- schämien sowie zur Behandlung extrapyramidal-motorischer Nebenwirkungen von Neuroleptika (z.B. dystone Syndrome, von durch Neuroleptika in- duzierte Muskelsteifheit, Tremor (inkl. substanzinduzierte Tremorformen) oder extrapyramidale Bewegungsstörungen) sowie des Morbus Parkinson, inkl. dopaminomimetischer Nebenwirkungen herkömmlicher Parkinson- Medikamente, zur akuten und symptomatischen Therapie der Alzheimer Krankheit sowie zur Behandlung der amyotrophen Lateralsklerose verwendet werden. Ebenso eignen sich die Substanzen als Therapeutika zur Behandlung von Hirntraumata (z.B. nach Kopfverletzungen) oder Rückenmarkstraumata. Insbesondere sind sie jedoch geeignet als Arzneimittelwirkstoff für Anxiolytika, Antidepressiva, Antipsychotika, Neuroleptika, Anti- hypertonika und/oder zur positiven Beeinflussung von Zwangsverhalten (obsessive-compulsive disorder, OCD), inklusive der anankastischen Spektrumsstörungen (obsessive-compulsive spectrum disorders OCSD), Angstzuständen, Panikattacken, Psychosen, Schizophrenie, Anorexie, wahnhaften Zwangsvorstellungen, Agoraphobie, Migräne, Schlafstörungen wie auch Schlafapnoe, tardiver Dyskinesien, Lernstörungen, altersabhängiger Erinnerungsstörungen, Essstörungen wie Bulimie, Drogenmissbrauch (inkl. von durch Substanzmissbrauch induzierten Störungen) und/oder Sexualfunktionsstörungen. Desweiteren sind sie geeignet zur Behandlung von endokrinen Erkrankungen wie Hyperprolactinaemie, ferner bei Vasospasmen, Hypertension, gastrointestinalen Erkrankungen, cardiovaskulären Erkrankungen sowie extrapyramidaler Symptome wie in der WO 99/11641 auf Seite 2, Zeile 24- 30 beschrieben.(Indolcarbonyl) piperazine derivatives are useful in both veterinary and human medicine for the treatment of central nervous system dysfunction and inflammation. They can be used for the prophylaxis and control of the consequences of cerebral infarct events (apoplexia cerebri) such as stroke (here trauma) and cerebral ischaemias and for the treatment of extrapyramidal motor side effects of neuroleptics (eg dystonic syndromes, neuroleptics induced muscle stiffness, tremor (including substance-induced tremor forms) or Parkinson's disease, including dopaminomimetic side effects of conventional Parkinson's drugs, for the acute and symptomatic treatment of Alzheimer's disease and for the treatment of amyotrophic lateral sclerosis. Likewise, the substances are suitable as therapeutic agents for the treatment of brain trauma (eg after head injuries) or spinal cord trauma. In particular, however, they are suitable as active pharmaceutical ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics, antihypertensives and / or for positively influencing compulsive behavior (obsessive-compulsive disorder, OCD), including obsessive-compulsive spectrum disorders (OCSD), anxiety, panic attacks, psychosis, schizophrenia, anorexia, delusional obsessions, agoraphobia, migraine, sleep disorders as well as sleep apnea, tardive dyskinesias, learning disabilities, age-related Memory disorders, eating disorders such as bulimia, substance abuse (including substance abuse-induced disorders) and / or sexual dysfunction. Furthermore, they are suitable for the treatment of endocrine disorders such as hyperprolactinaemia, in vasospasm, hypertension, gastrointestinal disorders, cardiovascular diseases and extrapyramidal symptoms as described in WO 99/11641 on page 2, lines 24-30.
Zudem eignen sich die N-(lndolcarbonyl-)piperazinderivate zur Verminderung des Augeninnendruckes und zur Glaucombehandlung.In addition, the N- (indolocarbonyl) piperazine derivatives are suitable for reducing intraocular pressure and for glaucoma treatment.
Weitere Verwendungen dieser N-(lndolcarbonyl-)piperazinderivate sind in der WO 03/045392 beschrieben: So eignen sich die Substanzen auch zur Behandlung von Fettsucht, Subtypen der Angst, Subtypen der Schizophrenie und Typen von Demenz unterschiedlichen Ursprungs sowie zur Therapie von Aggressionsstörungen, der Parkinson-Krankheit, Aufmerksam- keitsdefizitstörungen mit Hyperaktivität und Verhaltensstörungen. Schließlich können sie in der Zusatzbehandlung bei einer niedrigdosierten Neuro- leptika-Behandlung eingesetzt werden.Further uses of these N- (indolocarbonyl) piperazine derivatives are described in WO 03/045392: Thus, the substances are also suitable for the treatment of obesity, subtypes of anxiety, subtypes of schizophrenia and types of dementia of different origin and for the treatment of aggression disorders, the Parkinson's disease, attention deficit disorders with hyperactivity and behavioral disorders. Finally, they can be used in the adjunctive treatment of low-dose neuro leptics treatment.
Der vorliegenden Erfindung lag nun die Aufgabe zugrunde, weitere wertvolle pharmazeutische Verwendungen für die vorgenannten N-(lndolcarbonyl- )piperazinderivate zu finden.The object of the present invention was to find further valuable pharmaceutical uses for the abovementioned N- (indolocarbonyl) piperazine derivatives.
Zwar ist die Verwendung dieser Verbindungen zur Behandlung von Schlafstörungen sowie Schlafapnoe aus der WO 01/07435 bekannt; überra- schenderweise wurde jedoch nun gefunden, daß sie - im Unterschied zu herkömmlichen Schlafmitteln - die pharmakologisch bedeutsame Fähigkeit besitzen, beide Schlafanteile, das heißt den nonREM-Schlaf (einschließlich dessen Slow-Wave-Anteile) und den REM-Schlaf zu verlängern.Although the use of these compounds for the treatment of sleep disorders and sleep apnea is known from WO 01/07435; sur- Unfortunately, however, it has now been found, unlike conventional sleep aids, that they have the pharmacologically significant ability to prolong both sleep components, ie nonREM sleep (including its slow wave components) and REM sleep.
Viele Personen leiden unter Schlafstörungen, die zum einen Symptom einer Erkrankung sein können, zum anderen aber auch ein eigenständiges Krankheitsbild darstellen. Dreißig Prozent der Erwachsenen leiden unterMany people suffer from insomnia, which can be a symptom of a disease on the one hand, but also represent an independent clinical picture on the other hand. Thirty percent of adults suffer
Schlafstörungen.Sleep disorders.
Schlafstörungen können sich auf unterschiedliche Weise äußern: Einschlafstörungen sind charakterisiert durch die Länge des Zeitraumes, den ein Mensch zum Einschlafen braucht. Liegt diese Zeit über dreißig Minuten, so kann man von Einschlafstörungen sprechen. Der Betroffene liegt dann oft lange wach, was in extremen Fällen sogar stundenlang andauern kann.Sleep disorders can manifest themselves in different ways: Sleep disorders are characterized by the length of time a person needs to fall asleep. If this time is more than thirty minutes, one can speak of falling asleep. The person concerned is then often awake for a long time, which in extreme cases can even last for hours.
Leidet ein Patient unter vorzeitigem Aufwachen, so spricht man von Durchschlafstörungen. Das ist aber nur dann der Fall, wenn das Aufwachen vor Ablauf von sechs Stunden drei mal pro Woche geschieht. Oft wird der Schlaf dann als oberflächlich und wenig erholsam beschrieben. Von vorzeitigem Erwachen spricht man, wenn der Betroffenen häufig viel zu früh aufwacht, und dann nicht mehr einschlafen kann.If a patient suffers from premature awakening, it is referred to as sleep disturbance. But that is only the case when the waking up happens six times a week before the end of six hours. Often, sleep is described as superficial and not very relaxing. A premature awakening is when the person often wakes up too early, and then can not fall asleep.
Der Schlaf des Menschen und vieler Säuger, wie bspw. auch Nagetieren läßt sich grob in die beiden Stadien REM (=rapid eye movement) und non- REM unterteilen, die während des Schlafs mehrmals im Wechsel auftreten. Wie der Name schon sagt, bewegen sich in der REM-Phase die Augen heftig in den Augenhöhlen unter den geschlossenen Lidern. Diese Phase ist die intensivste Traumphase beim Menschen. Beim nonREM-Schlaf werden 4 Stadien unterschieden, von denen die Stadien 3 und 4 als "Slow-The sleep of humans and many mammals, such as rodents, can be roughly subdivided into the two stages REM (= rapid eye movement) and non-REM, which occur several times alternately during sleep. As the name implies, in the REM phase the eyes move violently in the eye sockets under the closed eyelids. This phase is the most intense dream phase in humans. NonREM sleep distinguishes 4 stages, of which stages 3 and 4 are
Wave-Schlaf" bezeichnet werden. Zur Erzielung einer maximalen Erholungswirkung beim Schlaf kommt es auf eine optimale Schlafarchitektur, das heißt auf ein ausgewogenes Verhältnis beider Schlafphasen zueinander an. Dabei sollte sich die Gesamtschlafdauer wie folgt auf die einzelnen Schlafstadien verteilen: nonREM Stadium 1 : 5% nonREM Stadium 2: 50 % nonREM Stadium 3 und 4: 20% REM: 25%Wave sleep ". In order to achieve maximum recovery during sleep, optimum sleep architecture is important, ie a balanced relationship between the two sleep phases. The total sleep time should be distributed among the individual sleep stages as follows: nonREM stage 1: 5% nonREM stage 2: 50% nonREM stage 3 and 4: 20% REM: 25%
Während gängige Schlafmittel lediglich die nonREM-Schlafdauer verlängern, wobei die REM-Schlafdauer unverändert bleibt oder sogar verringert wird, erhöhen die erfindungsgemäßen Verbindungen auch die REM-Schlaf- Dauer, was zu einer verbesserten Schlafarchitektur führt. Auf dem Markt befindliche Mittel - wie etwa Triazolam, Zolpidem oder Zoplicon - dagegen verkürzen sogar den REM-Schlaf.While common sleep aids only prolong the nonREM sleep duration, with the REM sleep duration remaining unchanged or even decreased, the compounds of the invention also increase REM sleep duration, resulting in an improved sleep architecture. On the market, however, such as triazolam, zolpidem or Zoplicon - even shorten the REM sleep.
Es war bereits seit längerem bekannt, daß die Verlängerung des nonREM- Schlafs (insbesondere des Slow-Wave-Anteile) bei der Ratte (Dugovic und Wauquier, Eur. J. Pharmacol. 137, 145-6, 1987) und auch beim Menschen (van Laar et al., Psychopharmacology (Berlin). 154, 189-97, 2001 ) durch 5- HT2-Rezeptorantagonisten bewirkt wird. Es war aber unklar, welcher Re- zeptor-Subtyp für diesen Effekt verantwortlich ist. Zunächst wurde der 5- HT2C-Rezeptor favorisiert (Sharpley et al., Neuropharmacology 33, 467-71 , 1994). Später wurde in der WO 00/12090 ein selektiver Antagonist des Rezeptors 5-HT2A, R-(+)-alpha-(2,3-dimethoxyphenyl)-1 -(2-(4-fluorophenyl)ethyl)-4- piperidinmethanol, offenbart, der unter anderem zur Behandlung von Schlafstörungen geeignet ist, wobei er insbesondere eine Verlängerung der Slow-Wave-Phasen 3 und 4 des nonREM-Schlafs bewirkt.It has long been known that the prolongation of nonREM sleep (especially the slow wave content) in the rat (Dugovic and Wauquier, Eur. J. Pharmacol. 137, 145-6, 1987) and also in humans ( van Laar et al., Psychopharmacology (Berlin). 154, 189-97, 2001) by 5-HT 2 receptor antagonists. However, it was unclear which type of receptor subtype was responsible for this effect. First, the 5-HT 2C receptor was favored (Sharpley et al., Neuropharmacology 33, 467-71, 1994). Later, in WO 00/12090, a selective antagonist of the receptor 5-HT 2A , R - (+) - alpha- (2,3-dimethoxyphenyl) -1 - (2- (4-fluorophenyl) ethyl) -4-piperidinemethanol disclosed, inter alia, is suitable for the treatment of sleep disorders, in particular, causes an extension of the slow-wave phases 3 and 4 of the nonREM sleep.
Von nicht-selektiven 5-HT2A-Antagonisten, wie Nefazodone, wurde hingegen berichtet , daß sie zwar den REM-Schlaf verlängern, die Slow-Wave- Anteile des nonREM-Schlafs jedoch unverändert lassen (Sharpley und Cowen, Biol. Psychiatry 37, 85-98, 1995).However, non-selective 5-HT 2A antagonists, such as nefazodone, have been reported to prolong REM sleep, slow wave However, shares of nonREM sleep remain unchanged (Sharpley and Cowen, Biol. Psychiatry 37, 85-98, 1995).
Zwar ist mit dem früher einmal unter dem Namen Contergan vermarktetenAlthough is marketed with the former once under the name Contergan
5 Thalidomid ein Schlafmittel bekannt, das ebenfalls beide Schlafphasen verlängert; jedoch ist diese Substanz kein 5-HT2-Rezeptorantagonist.5 thalidomide is a sleep aid known to prolong both sleep periods; however, this substance is not a 5-HT 2 receptor antagonist.
Bis zum gegenwärtigen Zeitpunkt ist kein Antagonist der 5-HT2-Rezeptoren 10 bekannt, der in der Lage ist, sowohl den nonREM- als auch den REM-To date, no antagonist of 5-HT 2 receptors 10 is known which is capable of producing both the nonREM and REM neurons.
Schlaf zu verlängern. Mit der vorliegenden Erfindung wurde somit ein neuartiges Wirkprinzip aufgefunden, welches neue Möglichkeiten der Schlafverlängerung und damit neue Formen der Therapie von Schlafstörungen i eröffnet.To extend sleep. With the present invention, a novel mode of action was thus found, which opens up new possibilities of sleep extension and thus new forms of therapy for sleep disorders.
Dabei werden vorzugsweise die folgenden Verbindungen verwendet, die in der WO 01/07435 - gegebenenfalls in der Form eines ihrer Salze - näher charakterisiert sind: 0The following compounds are preferably used, which are more closely characterized in WO 01/07435 - optionally in the form of one of their salts:
(1 H-lndol-4-yl)-(4-phenethyl-piperazin-1-yl)-methanon,(1H-indol-4-yl) - (4-phenethyl-piperazin-1-yl) -methanone,
(1 H-lndol-4-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,(1H-indol-4-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone,
(1 H-lndol-4-yl)-[4-(2,5-dichlor-thiophen-3-ylethyl)-piperazin-1-yl]-methanon,(1H-indol-4-yl) - [4- (2,5-dichloro-thiophen-3-yl-ethyl) -piperazin-1-yl] -methanone,
(3-Formyl-1 H-indol-5-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon, 5 (1 H-lndol-6-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,(3-Formyl-1H-indol-5-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone, 5 (1H-indol-6-yl) - [4- (4 -fluorphenethyl) piperazin-1-yl] -methanone,
(1 H-lndol-6-yl)-[4-(thiophen-2-ylethyl)-piperazin-1 -yl]-methanon, Hydrochlo- rid, F. (1 H-lndol-6-yl)-[4-(2,5-dichlor-thiophen-3-ylethyl)-piperazin-1-yl]- methanon, 0 (3-Cyan-1 H-indol-6-yl)-[4-(4-fluorphenethyl)-piperazin-1 -yl]-methanon,(1H-indol-6-yl) - [4- (thiophen-2-yl-ethyl) -piperazine-1-yl] -methanone, hydrochloride, F. (1H-indol-6-yl) - [4 - (2,5-dichloro-thiophen-3-yl-ethyl) -piperazin-1-yl] -methanone, 0 (3-cyano-1H-indol-6-yl) - [4- (4-fluorophenethyl) -piperazine -1 -yl] -methanone,
(1 H-lndol-7-yl)-(4-phenethyl-piperazin-1-yl)-methanon, (1 H-lndol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon, (1 H-lndol-7-yl)-[4-(5-chlor-thiophen-2-ylethyl)-piperazin-1-yl]-methanon, (3-Formyl-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon, 5 (3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon, (2,3-Dimethyl-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon, (6,7,8,9-Tetrahydro-5H-carbazol-3-yl)-(4-phenethyl-piperazin-1-yl)- methanon,(1H-indol-7-yl) - (4-phenethyl-piperazin-1-yl) -methanone, (1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl ] -methanone, (1H-indol-7-yl) - [4- (5-chloro-thiophen-2-yl-ethyl) -piperazin-1-yl] -methanone, (3-formyl-1H-indole-7 -yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone, 5 (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazine-1 -yl] -methanone, (2,3-dimethyl-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone, (6,7,8,9-tetrahydro-5H-carbazol-3-yl) - (4-phenethyl-piperazin-1-yl) -methanone,
(3-Formyl-1 H-indol-6-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,(3-formyl-1H-indol-6-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone,
(1 H-lndol-6-yl)-[4-(5-chlor-thiophen-2-ylethyl)-piperazin-1-yl]-methanon,(1H-indol-6-yl) - [4- (5-chloro-thiophen-2-yl-ethyl) -piperazin-1-yl] -methanone,
(1 H-lndol-4-yl)-[4-(5-chlor-thiophen-2-ylethyl)-piperazin-1-yl]-methanon,(1H-indol-4-yl) - [4- (5-chloro-thiophen-2-yl-ethyl) -piperazin-1-yl] -methanone,
(3-Cyan-1 H-indol-5-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,(3-cyano-1H-indol-5-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone,
(3-Cyan-1 H-indol-7-yl)-[4-(naphth-2-ylethyl)-piperazin-1-yl]-methanon,(3-cyano-1H-indol-7-yl) - [4- (naphth-2-yl-ethyl) -piperazin-1-yl] -methanone,
(3-Cyan-1 H-indol-4-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,(3-cyano-1H-indol-4-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone,
10 (3-Cyan-1 H-indol-4-yl)-[4-(2-fluorphenethyl)-piperazin-1 -yl]-methanon,10 (3-cyano-1H-indol-4-yl) - [4- (2-fluorophenethyl) -piperazin-1-yl] -methanone,
(3-Cyan-1H-indol-7-yl)-[4-(2-fluorphenethyl)-piperazin-1-yl]-methanon, (3-Aminocarbonyl-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]- methanon,(3-cyano-1H-indol-7-yl) - [4- (2-fluorophenethyl) -piperazin-1-yl] -methanone, (3-aminocarbonyl-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone,
Λ Γ (3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,Λ Γ (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone,
(3-Cyan-1 H-lndol-7-yl)-[4-(5-chlor-thiophen-2-ylethyl)-piperazin-1-yl]- methanon, (3-Cyan-1 H-indol-7-yl)-(4-phenethyl-piperazin-1-yl)-methanon, (3-Cyan-1 H-indol-7-yl)-[4-(2,4-difluorphenethyl)-piperazin-1-yl]-methanon.(3-cyano-1H-indol-7-yl) - [4- (5-chloro-thiophen-2-yl-ethyl) -piperazin-1-yl] -methanone, (3-cyano-1H-indole-7 -yl) - (4-phenethyl-piperazin-1-yl) -methanone, (3-cyano-1H-indol-7-yl) - [4- (2,4-difluorophenethyl) -piperazin-1-yl] -methanone.
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Erfindungsgemäß besonders bevorzugt ist die Verwendung von (3-Cyan-Particularly preferred according to the invention is the use of (3-cyano)
1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon und (3-1 H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone and (3
Amiπocarbonyl-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]- methanon. 5 Ganz besonders bevorzugt ist (3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)- piperazin-1-yl]-methanon.Aminocarbonyl-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone. 5 Very particular preference is given to (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone.
Gegenstand der vorliegenden Erfindung ist daher die Verwendung von 5- 0 HT2-Rezeptorantagonisten, insbesondere 5-HT2A-Rezeptorantagonisten, zur Herstellung eines Medikaments zur Verlängerung sowohl des nonREM- Schlafs als auch des REM-Schlafs.The present invention therefore provides the use of 5-HT 2 receptor antagonists, in particular 5-HT 2A receptor antagonists, for the manufacture of a medicament for the prolongation of both nonREM sleep and REM sleep.
In diesem Zusammenhang stellte sich heraus, daß sich die erfindungsge5 mäßen N-(lndolcarbonyl-)piperazinderivate dabei besonders zur Behand- lung von Ein- und Durchschlafstörungen sowie vorzeitigem Erwachen am Morgen eignen.In this connection, it has been found that the N- (indolecarbonyl) -piperazine derivatives according to the invention are particularly useful for the treatment of sleep disorders, as well as premature awakening in the morning.
Ein weiterer Gegenstand der vorliegenden Erfindung ist daher die Verwendung von 5-HT2-Rezeptorantagonisten, insbesondere δ-HT^- Rezeptorantagonisten, zur Herstellung eines Medikaments zur Behandlung von Ein- und Durchschlafstörungen sowie vorzeitigem Erwachen am Morgen.Another object of the present invention is therefore the use of 5-HT 2 receptor antagonists, in particular δ-HT ^ - receptor antagonists, for the manufacture of a medicament for the treatment of sleep disorders and drowsiness as well as premature morning awakening.
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Die Erfindung betrifft weiterhin die Verwendung von 5-HT2- Rezeptorantagonisten zur Herstellung einer pharmazeutischen Zubereitung, enthaltend den erfindungsgemäßen Wirkstoff sowie gegebenenfalls i Träger- und/oder Hilfsstoffe und gegebenenfalls weitere Wirkstoffe.The invention further relates to the use of 5-HT 2 - receptor antagonists for the preparation of a pharmaceutical preparation containing the active ingredient according to the invention and optionally i excipients and / or adjuvants and optionally other active ingredients.
Hierbei können die Arzneimittel zusammen mit mindestens einem festen, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoff(en) in eine geeignete Dosierungsform gebracht werden. 0In this case, the medicaments can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or adjuvant and optionally in combination with one or more further active ingredient (s). 0
In der erfindungsgemäßen Schlaftherapie werden die 5-HT2- Rezeptorantagonisten in der Regel in Analogie zu bekannten Präparaten verabreicht, vorzugsweise in Dosierungen zwischen etwa 0,1 und 500 mg, 5 insbesondere zwischen 5 und 300 mg pro Dosierungseinheit. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,01 und 250 mg/kg, insbesondere zwischen 0,02 und 100 mg/kg Körpergewicht.In the sleep therapy according to the invention, the 5-HT 2 - receptor antagonists are usually administered in analogy to known preparations, preferably in dosages between about 0.1 and 500 mg, 5 in particular between 5 and 300 mg per dosage unit. The daily dosage is preferably between about 0.01 and 250 mg / kg, in particular between 0.02 and 100 mg / kg of body weight.
Vorzugsweise werden die 5-HT2-Rezeptorantagonisten dabei in Dosierungen zwischen etwa 1 und 500 mg, insbesondere zwischen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,02 und 10 mg/kg Körpergewicht. Die spezielle Dosis für jeden bestimmten Patienten hängt jedoch von den verschiedensten 5Preferably, the 5-HT 2 receptor antagonists are administered in dosages of between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. However, the specific dose for each particular patient depends on the most diverse 5
Faktoren ab, beispielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszu- stand, Geschlecht, von der Kost, vom Verabfolgungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.Factors such as the efficacy of the particular compound used, age, body weight, general health status, sex, diet, time and route of administration, excretion rate, drug combination and severity of the particular disease to which the therapy applies. Oral administration is preferred.
Die 5-HT2-Rezeptorantagonisten können auch zusammen mit anderen Wirkstoffen, insbesondere anderen Schlafmitteln, in der Behandlung der erwähnten Krankheiten eingesetzt werden.The 5-HT 2 receptor antagonists can also be used together with other drugs, in particular other sleep aids, in the treatment of the mentioned diseases.
Gegenstand der Erfindung ist daher auch die Verwendung von 5-HT2- Rezeptorantagonisten in Kombination mit einem oder mehreren weiteren Schlafmitteln in der zuvor beschriebenen Schlaftherapie.The invention therefore also relates to the use of 5-HT 2 receptor antagonists in combination with one or more further sleeping pills in the above-described sleep therapy.
Eine konkrete Anleitung zur Synthese der hier beschriebenen 5-HT- Rezeptor-antagonistischen N-(lndolcarbonyl-)piperazinderivate kann der WO 01/07435 entnommen werden.Specific instructions for the synthesis of the 5-HT receptor-antagonistic N- (indolecarbonyl) -piperazine derivatives described herein can be found in WO 01/07435.
Die erfindungsgemäßen pharmazeutischen Zubereitungen können als Arzneimittel in der Human- und Veterinärmedizin eingesetzt werden. Als Trägersubstanzen kommen organische oder anorganische Stoffe in Frage, die sich für die enterale (z.B. orale), parenterale oder topische Applikation eig- nen und mit den neuen Verbindungen nicht reagieren, beispielsweiseThe pharmaceutical preparations according to the invention can be used as medicaments in human and veterinary medicine. Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the new compounds, for example
Wasser, pflanzliche Öle, Benzylalkohole, Polyethylenglykole, Gelatine, Kohlehydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur enteralen Applikation dienen insbesondere Tabletten, Dragees, Kap- sein, Sirupe, Säfte, Tropfen oder Suppositoren, zur parenteralen Applikation Lösungen, vorzugsweise ölige oder wässrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenden Lyophilisate z.B. zur Herstellung von Injektionspräparaten verwendet werden. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Färb-, Geschmacks- und/oder Aromastoffe enthalten. Sie können, falls erwünscht, auch einen oder mehrere weitere Wirkstoffe enthalten, z.B. ein oder mehrere Vitamine.Water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, vaseline. Tablets, dragees, capsules, syrups, juices, drops or suppositories are used for enteral administration, solutions for parenteral administration, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use ointments, creams or powders. The new compounds can also be lyophilized and the obtained lyophilisates be used for example for the preparation of injection preparations. The preparations indicated may be sterilized and / or contain excipients such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavorings and / or flavorings. If desired, they may also contain one or more other active ingredients, for example one or more vitamins.
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
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Beispiel A1 : InjektionsgläserExample A1: Injection glasses
Eine Lösung von 100 g eines erfindungsgemäßen Wirkstoffs und 5 g Di- nathumhydrogenphosphat in 3 I zweifach destilliertem Wasser wird mit 2 n ^5 Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.A solution of 100 g of an active ingredient according to the invention and 5 g of dihydrogen phosphate phosphate in 3 l of double distilled water is adjusted to pH 6.5 with 2 N 5 hydrochloric acid, filtered sterile, filled into injection jars, lyophilized and sealed sterile. Each injection jar contains 5 mg of active ingredient.
Beispiel A2: Suppositorien 0Example A2: Suppositories 0
Man schmilzt ein Gemisch von 20 g eines erfindungsgemäßen Wirkstoffs mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.A mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
5 Beispiel A3: Lösung5 Example A3: Solution
Man bereitet eine Lösung aus 1 g eines erfindungsgemäßen Wirkstoffs, 9.38 g NaH2PO4 x 2 H2O, 28.48 g NaH2PO4 x 12 H20 und 0.1 g Benzalko- niumchlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 0 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.A solution of 1 g of an active ingredient is prepared according to the invention, 9:38 g NaH 2 PO 4 x 2 H 2 O, 28.48 g NaH 2 PO 4 x 12 H 2 0 and 0.1 g Benzalko- niumchlorid in 940 ml of double-distilled water. It is adjusted to pH 6.8 0, filled to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.
Beispiel A4: SalbeExample A4: ointment
Man mischt 500 mg eines erfindungsgemäßen Wirkstoffs mit 99,5 g Vase5 line unter aseptischen Bedingungen. Beispiel A5: Tabletten500 mg of an active ingredient according to the invention are mixed with 99.5 g of vase 5 line under aseptic conditions. Example A5: Tablets
Ein Gemisch von 1 kg eines erfindungsgemäßen Wirkstoffs, 4 kg Lactose, 1.2 kg Kartoffelstärke, 0.2 kg Talk und 0.1 kg Magnesiumstearat wird in üblicher weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.A mixture of 1 kg of an active ingredient according to the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a conventional manner into tablets, such that each tablet contains 10 mg of active ingredient.
Beispiel A6: DrageesExample A6: dragees
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
Beispiel A7: Kapseln 2 kg eines erfindungsgemäßen Wirkstoffs werden in üblicher Weise inExample A7: Capsules 2 kg of a drug according to the invention are in the usual way in
Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.Filled hard gelatin capsules, so that each capsule contains 20 mg of the active ingredient.
Beispiel A8: AmpullenExample A8: Ampoules
Eine Lösung von 1 kg eines erfindungsgemäßen Wirkstoffs in 60 I zweifach destilliertem Wasser wird in Ampullen abgefüllt, unter aseptischen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff.A solution of 1 kg of an active ingredient according to the invention in 60 l of bidistilled water is filled into ampoules, lyophilized under aseptic conditions and closed under sterile conditions. Each vial contains 10 mg of active ingredient.
Die Wirkung der erfindungsgemäßen 5-HT2-Rezeptor-antagonistischen N- (lndolcarbonyl-)piperazinderivate stellt sich, wie am Beispiel von (3-Cyan- 1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon beschrieben, wie folgt dar:The effect of the 5-HT 2 receptor antagonistic N- (indolecarbonyl) piperazine derivatives according to the invention arises, as shown by the example of (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) - piperazin-1-yl] -methanone, as follows:
In Versuchen, bei denen die Hirnströme der Ratte über 6 Stunden während der Dunkelphase aufgezeichnet wurden, haben die Erfinder der vorliegenden Patentanmeldung herausgefunden, daß (3-Cyan-1 H-indol-7-yl)-[4-(4- fluorphenethyl)-piperazin-1-yl]-methanon bei einer Dosis von 3 mg/kg per os einen maximalen Anstieg des nonREM-Schlafs um ca. 5 Minuten pro Stunde bewirkt, wogegen der durchschnittliche Anstieg bei ca. 4 min/h liegt.In experiments in which the rat brain waves were recorded for 6 hours during the dark phase, the inventors of the present patent application found that (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone at a dose of 3 mg / kg per os causes a maximum increase in nonREM sleep by about 5 minutes per hour, whereas the average increase is about 4 min / h.
Die Vergleichssubstanz Triazolam dagegen verlängert den nonREM-Schlaf bei einer Dosis von 0,1 mg/kg um 2 min/h und bei einer Dosis von 0,4 mg/kg um 6,5 min/h, was bei Triazolam dem maximalen Effekt entspricht.The reference substance triazolam, on the other hand, increases nonREM sleep by 2 min / h at a dose of 0.1 mg / kg and by 6.5 min / h at a dose of 0.4 mg / kg, which corresponds to the maximum effect of triazolam ,
Unter den gleichen Bedingungen verlängert Zolpidem den nonREM-Schlaf um 5 min/h bei 5 mg/kg und 7 min/h bei 10 mg/kg. Zoplicon (2,5 - 5 mg/kg) zeigt einen vergleichbaren Effekt.Under the same conditions, zolpidem extends nonREM sleep by 5 min / h at 5 mg / kg and 7 min / h at 10 mg / kg. Zoplicon (2.5 - 5 mg / kg) shows a comparable effect.
Damit ist (3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1 -yl]- methanon in seiner Fähigkeit den nonREM-Schlaf zu verlängern mit denThus, (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone is capable of prolonging nonREM sleep with the
Referenzschlafmitteln vergleichbar.Reference sleepers comparable.
Es gibt jedoch einen wichtigen Unterschied zwischen der erfindungsgemäßen Verbindung und den Referenzschlafmitteln hinsichtlich ihrer Wirkung auf den REM-Schlaf. Die gängigen Schlafmittel verkürzen dieses Schlafstadium: Triazolam (0,1-1 ,6 mg/kg) um 0,3 bis 2,1 min/h, Zolpidem (5 -10 mg/kg) und Zopiclon (2,5 - 5 mg/kg) um 0,3 bis 1 ,6 min/h (die Werte beziehen sich auf eine δstündige Aufzeichnung während der Dunkelphase an der Ratte). Diese Unterschiede rühren von einer Verringerung der Dauer der einzelnen REM-Phasen (Triazolam) oder von einer Verringerung der Anzahl dieser Phasen her (Zolpidem / Zopiclon). (3-Cyan-1 H-indol-7-yl)-[4- (4-fluorphenethyl)-piperazin-1-yl]-methanon hingegen verlängert den REM- Schlaf durchschnittlich um 0,8 min/h und mit einem Maximum von 2 min/h.However, there is an important difference between the compound of the invention and the reference sleep aids in their effect on REM sleep. The usual sleep medications shorten this sleep stage: triazolam (0.1-1, 6 mg / kg) by 0.3 to 2.1 min / h, zolpidem (5 -10 mg / kg) and zopiclone (2.5 - 5 mg / kg) by 0.3 to 1.6 minutes / h (the values refer to a δ-hour recording during the dark phase on the rat). These differences are due to a reduction in the duration of the individual REM phases (triazolam) or a reduction in the number of these phases (zolpidem / zopiclone). (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone, on the other hand, increases REM sleep by an average of 0.8 min / h and a maximum from 2 min / h.
Dies folgt im wesentlichen aus der Erhöhung der Anzahl der REM- Episoden.This essentially follows from the increase in the number of REM episodes.
Diese Eigenschaft von (3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)- piperazin-1-yl]-methanon ist somit einzigartig und eröffnet neuartige Mög- lichkeiten der Schlafverlängerung, insbesondere bei der Behandlung von Ein- und Durchschlafstörungen und vorzeitigem Erwachen am Morgen.This property of (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone is thus unique and opens up novel possibilities. sleep extension, especially in the treatment of falling asleep and staying awake in the morning and premature awakening in the morning.
Die zuvor beschriebene Wirksamkeit von (3-Cyan-1 H-indol-7-yl)-[4-(4- fluorphenethyl)-piperazin-1-yl]-methanon bei der Behandlung der erfindungsgemäßen Schlafstörungen kann in vivo wie folgt ermittelt werden.The above-described activity of (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone in the treatment of the sleep disorders according to the invention can be determined in vivo as follows ,
Beispiel B: Behandlung von Ratten mit (3-Cvan-1H-indol-7-yl)-f4-(4- fluorphenethyl)-piperazin-1-ylj-methanon, HvdrochloridExample B: Treatment of rats with (3-cyan-1H-indol-7-yl) -f4- (4-fluorophenethyl) -piperazin-1-ylj-methanone, hydrochloride
Zur Messung der Hirnströme werden Ratten unter Narkose EEG- Elektroden in das Gehirn implantiert. Nach einer 15-tägigen Erholungszeit werden diese Elektroden über ein flexibles Kabel an einen Verstärker angeschlossen und die Hirnströme der nicht narkotisierten Tiere über 12 Stunden aufgezeichnet.To measure the brain waves, rats are implanted into the brain under anesthetic EEG electrodes. After a 15-day recovery period, these electrodes are connected to an amplifier via a flexible cable and the brain waves of non-anesthetized animals are recorded for 12 hours.
Zuvor wird (3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1 -yl]- methanon in einer Konzentration von 0,1 ml/ 100 g Erdnußöl gelöst. Diese Lösung (compound) oder zum Vergleich lediglich das Lösungsmittel (vehic- le) wird den Versuchstieren in einer Dosis von 3 mg/kg oral verabreicht. Aus den gefilterten und verstärkten Hirnstromsignalen werden über eine Spektralanalyse nach Fourier unter Einschluß bestimmter Kriterien diePreviously, (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazine-1-yl] -methanone is dissolved in a concentration of 0.1 ml / 100 g of peanut oil. This solution (compound) or, for comparison, only the solvent (vehicle) is orally administered to the experimental animals at a dose of 3 mg / kg. The filtered and amplified cerebral current signals are analyzed using a Fourier spectral analysis, including certain criteria
Schlafstadien ausgewertet. Anhand der Muster sind die Schlafstadien REM und nonREM-Schlaf identifizierbar.Sleep stages evaluated. Based on the patterns, the sleep stages REM and nonREM sleep are identifiable.
Die Versuchsergebnisse sind in den Tabellen 1 (Wirkung der Substanz) und 2 (Signifikanzen der Meßwerte) dargestellt. Es wird deutlich, daß (3-The test results are shown in Tables 1 (Effect of the substance) and 2 (Significance of the measured values). It becomes clear that (3-
Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon zu einer deutlichen Verlängerung sowohl des nonREM- als auch des REM-Schlafs führt und daß diese Verlängerungen signifikant sind. Tabellel : Effekt von (3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin- 1-yl]-methanon auf verschiedene Schlafparameter der Ratte (Mittelwert ± Standardfehler).Cyan-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone results in a significant extension of both nonREM and REM sleep, and that these extensions are significant , Table: Effect of (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone on various sleep parameters of the rat (mean ± standard error).
Total Time: Zeit über den Messzeitraum, der in den jeweiligenTotal Time: Time over the measurement period, in the respective
Schlafstadien verbracht wird Episode Duration: Mittlere Dauer einer Episode des jeweiligenSleep stages is spent Episode Duration: Mean duration of an episode of each
Schlafstadiums REM Latency: Zeitraum vom Beginn des Schlafes bis zumSleep Stage REM Latency: Time from onset of sleep to
Eintreten der ersten REM-Phase Inter-REM interval: Mittlere Zeit zwischen den Intervallen im REM-Occurrence of the first REM phase Inter-REM interval: Mean time between the intervals in the REM
Stadium Compound: Bezeichnung für diejenigen Tiere, die dieStage Compound: term for those animals that the
Testsubstanz bekommen haben. Vehicie: Bezeichnung für diejenigen Tiere, die lediglich das Lösungsmittel bekommen haben. Wakefulness: WachzustandHave received test substance. Vehicie: name for those animals that have received only the solvent. Wakefulness: wakefulness
Bei diesem Versuch handelt es sich um eine Crossover-Studie. Das heißt, ein und dasselbe Tier bekommt wahlweise zuerst Lösungsmittel (Vehicie), nach einer Woche Wartezeit dann die Testsubstanz (3-Cyan-1 H-indol-7- yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon (Compound), oder die Verabreichung erfolgt in umgekehrter Reihenfolge. Tabelle 2: Signifikanzen der Werte aus Tabelle 1.This trial is a crossover study. That is, one and the same animal is optionally first solvent (Vehicie), after a week waiting time then the test substance (3-cyano-1 H-indol-7-yl) - [4- (4-fluorophenethyl) piperazine-1 yl] -methanone (compound), or administration is in reverse order. Table 2: Significances of the values from Table 1.
n.s.: die jeweiligen Meßwerte aus Tabelle 1 sind nicht signifikant ns: the respective measured values from Table 1 are not significant
Die gemessenen Werte nach Vehicie- bzw. nach Compound-Applikation werden mit dem statistischen Verfahren der Varianzanalyse (analysis of va- riance = ANOVA) miteinander verglichen. Der p-Wert ist ein statistisches Maß für die Wahrscheinlichkeit, dass ein Unterschied zwischen den Messwerten zufällig auftritt oder durch die Substanzapplikation bedingt ist. Internationalen Standards zufolge wird ein p-Wert von unter 0,05 als "signifikant" bezeichnet.The measured values after vehicle or compound application are compared with each other using the statistical method of analysis of variance (ANOVA). The p-value is a statistical measure of the likelihood that a difference between the measurements will occur randomly or due to the substance application. According to international standards, a p-value of less than 0.05 is said to be "significant".
Aus Abbildung 1 wird deutlich, daß beim nonREM-Schlaf insbesondere die als Slow-Wave-Sleep bezeichneten Stadien 3 und 4 verlängert werden. Die Kurve zeigt den Effekt von (3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)- piperazin-1-yl]-methanon auf die relative Deltapower im Ratten-EEG, ausgedrückt als Differenz vom Kontroll-Level (gestrichelte Null-Linie), in Abhängigkeit von der Uhrzeit. Als Deltapower oder Delta Waves werden die im EEG registrierten "langsamen" Wellen bezeichnet, die für die Slow- Wave-Sleep-Stadien kennzeichnend sind. Für jede Ratte wurde zunächst der Stunden-Mittelwert nach Lösemit- tel(Vehicle-)behandlung ermittelt und vom Wert nach Substanzbehandlung abgezogen. Die relative Deltapower ist insgesamt signifikant erhöht. From Figure 1 it becomes clear that in nonREM sleep especially stages 3 and 4, called slow wave sleep, are extended. The curve shows the effect of (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone on the relative delta power in the rat EEG, expressed as difference from the control level (dashed zero line), depending on the time of day. Deltapower or Delta Waves are the "slow" waves registered in the EEG that characterize the slow wave sleep stages. For each rat, the hourly mean value after solvent (vehicle) treatment was first determined and subtracted from the value after substance treatment. The relative delta power is significantly increased overall.

Claims

Patentansprüche claims
1. Verwendung von 5-HT2-Rezeptorantagonisten sowie deren physiologisch unbedenklichen Salzen und Solvaten zu Herstellung eines Medikaments zur Verlängerung sowohl des nonREM-Schlafs als auch des REM-Schlafs.1. Use of 5-HT 2 receptor antagonists and their physiologically acceptable salts and solvates for the manufacture of a medicament for prolonging both nonREM sleep and REM sleep.
2. Verwendung gemäß Anspruch 1 , dadurch gekennzeichnet, daß es2. Use according to claim 1, characterized in that it
10 sich um Antagonisten des 5-HT2-Rezeptorsubtyps 5-HT2a handelt.10 are antagonists of the 5-HT 2 receptor subtype 5-HT 2a .
3. Verwendung von 5-HT2a-Rezeptorantagonisten gemäß Anspruch 2, ausgewählt aus einer Gruppe bestehend aus 15 (a) (3-Aminocarbonyl-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1- yl]-methanon,3. Use of 5-HT 2a receptor antagonists according to claim 2, selected from a group consisting of 15 (a) (3-aminocarbonyl-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazine- 1- yl] -methanone,
(b) (3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1 -yl]- methanon sowie deren physiologisch unbedenklichen Salzen und Solvaten zur(b) (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone and their physiologically acceptable salts and solvates
20 Herstellung eines Medikaments zur Verlängerung sowohl des nonREM-Schlafs als auch des REM-Schlafs.20 Manufacture of a drug to prolong both nonREM sleep and REM sleep.
4. Verwendung von (3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-4. Use of (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -
9 «:9 «:
^J piperazin-1-yl]-methanon sowie dessen physiologisch unbedenklichen Salzen und Solvaten zur Herstellung eines Arzneimittels zur Verlängerung sowohl des nonREM-Schlafs als auch des REM- Schlafs.^ J piperazin-1-yl] -methanone and its physiologically acceptable salts and solvates for the manufacture of a medicament for prolonging both nonREM sleep and REM sleep.
3030
5. Verwendung von 5-HT2-Rezeptorantagonisten sowie deren physiologisch unbedenklichen Salzen und Solvaten gemäß einem oder mehreren der Ansprüche 1 bis 4 zur Herstellung eines Medikaments zur Behandlung von Ein- und Durchschlafstörungen sowie vorzeitigem5. Use of 5-HT 2 receptor antagonists and their physiologically acceptable salts and solvates according to one or more of claims 1 to 4 for the manufacture of a medicament for the treatment of sleep disorders and drowsiness as well as premature
35 Erwachen am Morgen.35 Awakening in the morning.
6. Verwendung von 5-HT2-Rezeptorantagonisten sowie deren physiologisch unbedenklichen Salzen und Solvaten gemäß einem oder mehreren der Ansprüche 1 bis 5 in Kombination mit einem oder mehreren weiteren Schlafmitteln. 6. Use of 5-HT 2 receptor antagonists and their physiologically acceptable salts and solvates according to one or more of claims 1 to 5 in combination with one or more further sleeping pills.
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