WO2001052854A1 - Antagonistes du recepteur nk1 utilises pour le traitement du syndrome des jambes sans repos - Google Patents

Antagonistes du recepteur nk1 utilises pour le traitement du syndrome des jambes sans repos Download PDF

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Publication number
WO2001052854A1
WO2001052854A1 PCT/EP2001/000263 EP0100263W WO0152854A1 WO 2001052854 A1 WO2001052854 A1 WO 2001052854A1 EP 0100263 W EP0100263 W EP 0100263W WO 0152854 A1 WO0152854 A1 WO 0152854A1
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receptor antagonists
treatment
use according
men
rls
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PCT/EP2001/000263
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German (de)
English (en)
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Hans-Michael Brecht
Birgit Jung
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Boehringer Ingelheim Pharma Kg
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Publication of WO2001052854A1 publication Critical patent/WO2001052854A1/fr

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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4747—Quinolines; Isoquinolines spiro-condensed
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the invention relates to the use of NK-j receptor antagonists for the manufacture of a medicament for the treatment of restless legs syndrome (RLS).
  • RLS restless legs syndrome
  • Restless Legs Syndrome is a neurological disorder which manifests itself mainly in leg disorders such as tingling, pulling, tearing, itching, burning, cramps or pain and which triggers the irresistible urge to move. These disorders frequently occur when the person concerned is resting. Especially at night when sleeping, these emotional disorders and the consequent urge to move lead to restlessness and sleep disorders.
  • RLS occurs at all ages, with the frequency increasing in older age. The prevalence in the general population is around 5%. Because of the characteristics of the symptoms, RLS is one of the most common causes of sleep disorders. In 20-40 year olds, RLS is the cause of sleep-wax disorders in 7%, in 40-60 year olds in 18% and in over 60 year olds in 33%.
  • the indication for therapy is given.
  • a need for therapy usually occurs at the age of 40-50 years.
  • L-DOPA levodopa
  • dopamine agonists Short-term therapy studies have been carried out for individual dopamine agonists.
  • the dopamine agonists examined include: bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole and ropinirole. All of these dopamine agonists were found to be effective. There are no study results on long-term therapy with dopamine agonists, so that the question of the loss of effectiveness after long-term use (tachyphylaxis) cannot yet be answered.
  • the disadvantage of dopamine agonists is the occurrence of side effects such as nausea, vomiting, dizziness, hypotension, constipation, insomnia, which usually occur initially and depending on the dose.
  • clonidine 2- (2,6-dichloroanilino) -4,5-dihydroimidazole
  • the daily doses were between 0.1 and 0.9 mg.
  • the patients reported a decrease (statistically significant) in sensitive symptoms such as paresthesia, the urge to move and tiredness during the day.
  • the sleep latency was shortened, but the sleep quality, frequency of waking up or the periodic leg movements during sleep (PLMS) were not affected. Since more effective substances are available as monotherapy, clonidine is currently only conditionally recommended as an alternative form of therapy.
  • the present invention relates to the use of NK-
  • receptor antagonists selected from the group consisting of BIIf 1149, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968 (Saredutant), SR 140333 (Nolpitantium besilate / chloride) , LY 303 870 (Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, SR-144190, YM-49244, YM-44778, ZM -274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974, TAK - 637 and GR 205171, for
  • BIIF1149 it is particularly preferred to use an NK « receptor antagonist selected from the group consisting of BIIF 1149, CGP 60829, MK-869, CJ-11974 and GR 205171, for the manufacture of a medicament for the treatment of restless legs syndrome (RLS), the use of BIIF1149 can be regarded as highly preferred.
  • the active ingredient can likewise be a pharmacologically acceptable salt or an ester or a prodrug form, for example an ester, of the compounds mentioned above.
  • receptor antagonists in the therapy of restless legs syndrome can also take place in combination with other active substances in order to achieve a synergistic therapeutic effect.
  • a further aspect of the present invention thus aims at the use of a combination of active substances for the production of a pharmaceutical or pharmaceutical kits for the treatment of restless legs syndrome, characterized in that at least one of the active ingredients contained in the pharmaceutical or the pharmaceutical kit represents an NK-
  • the active ingredient can likewise be a pharmacologically acceptable salt or an ester or a prodrug form, for example an ester, of the abovementioned compounds.
  • L-DOPA plus benserazide and L-DOPA plus carbidopa are particularly preferred from the active ingredient components levodopa (L-DOPA) plus decarboxylase inhibitor, which can also be used to prepare the active ingredient combinations according to the invention containing at least one NK1 receptor antagonist.
  • buprenorphine from the group of opioids, buprenorphine, codeine, dextropropoxyphene, dihydrocodeine, fentanyl, hydromorphone, levomethadone, morphine, oxycodone, pethidine, tilidine, tramadol or their pharmacologically acceptable salts are preferred.
  • Codeine, dihydrocodeine, tramadol sufentanil and morphine are particularly preferred.
  • clonazepam and breadizolam are preferred.
  • SR-142801 (Osanetant) can preferably be used as NK3 receptor antagonist in the context of the above-mentioned active ingredient combinations.
  • receptor antagonists which can be used according to the invention is preferred with clonidine, or one of its pharmacologically acceptable salts or with a dopamine agonist, preferably with pramipexole or a pharmacologically acceptable salt thereof.
  • -receptor antagonists which can be used according to the invention can be formulated in accordance with the conventional pharmaceutical processes known from the prior art in such a way that they can be administered orally, spinally, epidurally, anal, intravenously, by inhalation, subcutaneously or transdermally. Oral and transdermal application forms are preferred. The same applies to the additional active ingredients, as mentioned above, which may additionally be used to achieve a synergistic effect.
  • the daily dose to be applied is naturally dependent on the extent or strength of the RLS symptoms. According to the invention, the dose range that can be used per day is approximately 20-500 mg of NK-
  • Oral administration can take the form of a tablet, powder, powder in a capsule (e.g. hard gelatin capsule), solution or suspension.
  • the active substance combination according to the invention is given as a solution.
  • the anal application takes place via suppositories.
  • the active ingredient combination can be in the form of a powder, as an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation.
  • the active ingredient can be applied to the skin either as an ointment or cream, but is preferably administered via a plaster.
  • the active ingredient or combination of active ingredients can either be delivered directly to the outer skin layer or it can be embedded as a solution or as a gel, e.g. in a polymer matrix, using a transdermal patch, via microneedles or microcuts that penetrate the stratum corneum of the skin released directly into the deeper layers of skin.
  • a transdermal patch with micro-cutting edges or micro-spikes is disclosed, for example, in patent application WO 97/03718.
  • Patent application WO 91/07998 describes a method by means of which active ingredients can be applied transdermally in an improved manner by adjusting a certain pH of the skin.
  • Both types of the plasters described above continuously release the active ingredient into or into the skin, so that concentration peaks and the possible side effects associated therewith are avoided.
  • the active ingredient or combination of active ingredients can be delivered passively or actively. Active transport can take place purely mechanically, electrically, osmotically or via iontophoresis. If necessary, the delivery is controlled electronically, if necessary under the control of the blood plasma level by sensors or microsensors which are integrated in the plaster or are in communication with it, so that the blood plasma level can be specifically adjusted according to the individual need and consequently a constant delivery is not absolutely necessary is.
  • the active substance combinations can be in a separate formulation (for example in a capsule or as a tablet), in a single formulation , but separated from one another (eg in a capsule with two or more chambers) or they are mixed in a single formulation (eg in the form of a tablet or in a capsule with only one chamber).
  • the active ingredients are each formulated independently of one another, it is not imperative that the two substances be administered via the same route of administration, but combinations of formulations in which the two active ingredients are administered via separate routes of administration can also be used become.
  • preferred formulations are those in which the two active compounds are administered via the same route of administration.
  • the two active ingredients are advantageously formulated together in one application form.
  • the active ingredients can either be given in a separate patch, in a common patch, but the active ingredients are stored separately within the patch, or they are present as a mixture in a patch.
  • the active ingredients can either be given in a separate patch, in a common patch, but the active ingredients are stored separately within the patch, or they are present as a mixture in a patch. The same applies to the other application forms described above.
  • the active substance formulation according to the invention is prepared and can be prepared using the methods known from the prior art accordingly contain the formulation constituents known from the corresponding specialist field.
  • it can contain other pharmacologically active substances or cosmetic additives.
  • -receptor antagonists as well as the further active ingredients which may additionally be used to achieve a synergistic effect, can be used both as a neutral compound or in the form of a pharmacologically acceptable salt.
  • -receptor antagonists as well as the further active ingredients which may additionally be present in order to achieve a synergistic effect
  • a common formulation it is preferably in each case the neutral compound or in each case the same salt (for example hydrochloride ).
  • receptor antagonists, as well as the further active ingredients optionally additionally contained to achieve a synergistic effect are each taken orally as tablets or capsules.
  • -receptor antagonists are preferably used in a time context within preferably 24 hours, particularly preferably within 12 hours, and particularly preferably within Administered 1 hour. Most preferred is simultaneous application within a maximum of 15 minutes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Psychology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'antagonistes du récepteur NK1 pour la production d'un médicament servant à traiter le syndrome des jambes sans repos (RLS).
PCT/EP2001/000263 2000-01-18 2001-01-11 Antagonistes du recepteur nk1 utilises pour le traitement du syndrome des jambes sans repos WO2001052854A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10001785.1 2000-01-18
DE10001785A DE10001785A1 (de) 2000-01-18 2000-01-18 NK¶1¶-Rezeptor-Antagonisten zur Behandlung des Restless Legs Syndroms

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Publication Number Publication Date
WO2001052854A1 true WO2001052854A1 (fr) 2001-07-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002103A2 (fr) * 2001-06-29 2003-01-09 Pharmacia Corporation Profil pharmacocinetique ameliore d'agonistes hydrophobes de la dopamine injectes dans le derme

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Publication number Priority date Publication date Assignee Title
DE102005013726A1 (de) * 2005-03-22 2006-09-28 Grünenthal GmbH Transdermale therapeutische Systeme mit verbesserter Verträglichkeit

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WO1998001450A1 (fr) * 1996-07-03 1998-01-15 Merck Sharp & Dohme Limited Derives de spiro-piperidine et leur utilisation en tant qu'agents therapeutiques
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WO2000047562A1 (fr) * 1999-02-09 2000-08-17 Merck Sharp & Dohme Limited Cetones spirocycliques et leurs utilisation comme antagonistes des tachykinines
WO2000056727A1 (fr) * 1999-03-19 2000-09-28 Merck Sharp & Dohme Limited Derives de tetrahydropyrane et leur utilisation comme agents therapeutiques
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Title
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ASTOLFI M ET AL: "MEN 11149, a potent antagonist of the tachykinin NK-1 receptor.", BRITISH JOURNAL OF PHARMACOLOGY, vol. 120, no. PROC. SUPPL., 1997, Meeting of the British Pharmacological Society;Glaxo, Scotland; December 18-20, 1996, pages 202P, XP001006075, ISSN: 0007-1188 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002103A2 (fr) * 2001-06-29 2003-01-09 Pharmacia Corporation Profil pharmacocinetique ameliore d'agonistes hydrophobes de la dopamine injectes dans le derme
WO2003002103A3 (fr) * 2001-06-29 2003-04-10 Pharmacia Corp Profil pharmacocinetique ameliore d'agonistes hydrophobes de la dopamine injectes dans le derme

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