EP1545531A1 - Verwendung von 5-ht2-rezeptorantagonisten zur behandlung von schlafst rungen - Google Patents

Verwendung von 5-ht2-rezeptorantagonisten zur behandlung von schlafst rungen

Info

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
Authority
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.)
Withdrawn
Application number
EP03775144A
Other languages
German (de)
English (en)
French (fr)
Inventor
Gerd Bartoszyk
Christoph Van Amsterdam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=32010223&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1545531(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1545531A1 publication Critical patent/EP1545531A1/de
Withdrawn legal-status Critical Current

Links

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".

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychology (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Indole Compounds (AREA)
EP03775144A 2002-10-04 2003-09-03 Verwendung von 5-ht2-rezeptorantagonisten zur behandlung von schlafst rungen Withdrawn EP1545531A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10246357A DE10246357A1 (de) 2002-10-04 2002-10-04 Verwendung von 5-HT2Rezeptorantagonisten
DE10246357 2002-10-04
PCT/EP2003/009738 WO2004032932A1 (de) 2002-10-04 2003-09-03 Verwendung von 5-ht2-rezeptorantagonisten zur behandlung von schlafstörungen

Publications (1)

Publication Number Publication Date
EP1545531A1 true EP1545531A1 (de) 2005-06-29

Family

ID=32010223

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03775144A Withdrawn EP1545531A1 (de) 2002-10-04 2003-09-03 Verwendung von 5-ht2-rezeptorantagonisten zur behandlung von schlafst rungen

Country Status (18)

Country Link
US (1) US20060040951A1 (pl)
EP (1) EP1545531A1 (pl)
JP (1) JP2006503870A (pl)
KR (1) KR20050054996A (pl)
CN (1) CN1688309A (pl)
AR (1) AR041476A1 (pl)
AU (1) AU2003283237A1 (pl)
BR (1) BR0314945A (pl)
CA (1) CA2501082A1 (pl)
DE (1) DE10246357A1 (pl)
MX (1) MXPA05003437A (pl)
PE (1) PE20040569A1 (pl)
PL (1) PL374077A1 (pl)
RU (1) RU2005113712A (pl)
TW (1) TW200410691A (pl)
UA (1) UA79993C2 (pl)
WO (1) WO2004032932A1 (pl)
ZA (1) ZA200503520B (pl)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004047517A1 (de) * 2004-09-28 2006-03-30 Merck Patent Gmbh Neuartige Kristallform von (3-Cyan-1H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon, Hydrochlorid

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3865939A (en) * 1973-02-23 1975-02-11 Procter & Gamble Edible oils having hypocholesterolemic properties
DE3119383A1 (de) * 1981-05-15 1982-12-02 Basf Ag, 6700 Ludwigshafen Verfahren zur herstellung von feinverteilten, pulverfoermigen carotinodpraeparaten
US5244887A (en) * 1992-02-14 1993-09-14 Straub Carl D Stanols to reduce cholesterol absorption from foods and methods of preparation and use thereof
DE60004479T2 (de) * 1999-02-03 2004-06-24 Forbes Medi-Tech Inc., Vancouver Verfahren zur herstellung von phytosterol- oder phytostanol-mikropartikeln
DE19934433A1 (de) * 1999-07-22 2001-01-25 Merck Patent Gmbh N-(Indolcarbonyl-)piperazinderivate
US6391370B1 (en) * 1999-11-12 2002-05-21 Kraft Foods, Inc. Micromilling plant sterols and emulsifiers
US6576285B1 (en) * 2000-11-14 2003-06-10 Sunpure Ltd. Cholesterol lowering beverage
DE10102944A1 (de) * 2001-01-23 2002-07-25 Merck Patent Gmbh Verfahren zur Herstellung von (3-Cyan-1H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon und dessen Salzen
DE10157673A1 (de) * 2001-11-24 2003-06-05 Merck Patent Gmbh Verwendung von N-(Indolcarbonyl-)piperazinderivaten

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004032932A1 *

Also Published As

Publication number Publication date
ZA200503520B (en) 2006-02-22
PL374077A1 (pl) 2005-09-19
JP2006503870A (ja) 2006-02-02
AU2003283237A1 (en) 2004-05-04
TW200410691A (en) 2004-07-01
DE10246357A1 (de) 2004-04-15
US20060040951A1 (en) 2006-02-23
BR0314945A (pt) 2005-08-02
MXPA05003437A (es) 2005-07-05
WO2004032932A1 (de) 2004-04-22
CN1688309A (zh) 2005-10-26
RU2005113712A (ru) 2005-11-20
PE20040569A1 (es) 2004-08-30
AR041476A1 (es) 2005-05-18
KR20050054996A (ko) 2005-06-10
UA79993C2 (en) 2007-08-10
CA2501082A1 (en) 2004-04-22

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