WO2001052854A1 - Nk1-receptor antagonists for treatment of restless legs syndrome - Google Patents

Nk1-receptor antagonists for treatment of restless legs syndrome 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)
French (fr)
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Hans-Michael Brecht
Birgit Jung
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Boehringer Ingelheim Pharma Kg
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    • 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.

Abstract

The invention relates to the use of NK1-receptor antagonists for production of a medicament for treatment of restless legs syndrome (RLS).

Description

NK-|-Rezeptor-Antagonisten zur Behandlung des Restless Legs Syndroms NK- | Receptor antagonists for the treatment of restless legs syndrome
Die Erfindung betrifft die Verwendung von NK-j-Rezeptor-Antagonisten zur Herstellung eines Arzneimittels zur Behandlung des Restless Legs Syndroms (RLS).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).
Hintergrund der Erfindung Das Restless Legs Syndrom ist eine neurologische Erkrankung, welche sich hauptsächlich durch Gefühlsstörungen der Beine, wie Kribbeln, Ziehen, Reißen, Jucken, Brennen, Krämpfe oder Schmerzen äußert und bei dem Betroffenen den unwiderstehlichen Drang auslöst, sich zu bewegen. Gehäuft treten diese Störungen auf, wenn sich der Betroffene ausruht. Besonders nachts beim Schlafen führen diese Gefühlsstörungen und der in Folge auftretende Bewegungsdrang zu Ruhelosigkeit und Schlafstörungen.Background of the Invention 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.
Das RLS tritt in allen Altersstufen auf, wobei die Häufigkeit im höheren Lebensalter zunimmt. Die Prävalenz in der Allgemein-Bevölkerung liegt bei ca. 5%. Aufgrund der Charakteristik der Symptome ist das RLS eine der häufigsten Ursachen von Schlafstörungen. Bei 20-40jährigen ist das RLS in 7%, bei 40-60jährigen in 18% und bei über 60-jährigen in 33% Ursache für Schlaf-Wachstörungen.The 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%.
Wenn die Schlaf- bzw. Lebensgualität des Patienten zunehmend durch RLS eingeschränkt ist oder die Patienten an Tagesmüdigkeit leiden, ist die Indikation zur Therapie gegeben. Eine Therapiebedürftigkeit tritt in der Regel im Alter von 40-50 Jahren ein.If the quality of sleep or quality of life of the patient is increasingly restricted by RLS or if the patient suffers from daytime fatigue, the indication for therapy is given. A need for therapy usually occurs at the age of 40-50 years.
Bisher steht eine zugelassene medikamentöse Behandlung nicht zur Verfügung. In Therapiestudien zeigten Monotherapien mit Dopaminagonisten, Opiaten, Benzodiazepinen, Carbamazepin, Clonidin oder die Kombinationsgabe von Levodopa (L-DOPA) in Kombination mit einem Dopadecarboxylasehemmer unterschiedliche Erfolge. Über Anwendungen von L-DOPA bei RLS liegen die meisten Arbeiten vor. Bei dessen Langzeittherapie kommt es zu einer deutlichen Beschwerdeabnahme mit Verbesserung der Lebens- und Schlafqualität. Der Nachteil der L-DOPA-Therapie besteht jedoch darin, daß bei manchen Patienten die Wirkung nachläßt und/oder eine Zunahme der RLS-Beschwerden am Tage (Reboundphänomen oder Augmentation) auftritt.Approved drug treatment has not been available to date. In therapy studies, monotherapy with dopamine agonists, opiates, benzodiazepines, carbamazepine, clonidine or the combination of levodopa (L-DOPA) in combination with a dopadecarboxylase inhibitor showed different successes. Most of the work is available on applications of L-DOPA at RLS. With its long-term therapy, there is a significant decrease in complaints with improvement in quality of life and sleep. The disadvantage of L-DOPA therapy is, however, that in some patients the effect wears off and / or an increase in RLS symptoms during the day (rebound phenomenon or augmentation) occurs.
Für einzelne Dopaminagonisten wurden Kurzzeittherapie-Studien durchgeführt. Zu den untersuchten Dopaminagonisten zählen: Bromocriptin, Cabergolin, Alpha- Dihydroergocryptin, Lisurid, Pergolid, Pramipexol und Ropinirol. Es zeigte sich, daß alle diese Dopaminagonisten wirksam sind. Studienergebnisse zur Langzeittherapie mit Dopaminagonisten liegen bisher nicht vor, so daß die Frage des Wirkverlustes nach Langzeiteinnahme (Tachyphylaxie) noch nicht beantwortet werden kann. Nachteil der Dopaminagonisten ist das Auftreten von Nebenwirkungen wie Übelkeit, Erbrechen, Schwindel, Hypotonie, Obstipation, Schlaflosigkeit, die in der Regel initial und dosisabhängig auftreten.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.
Die Verwendung des Antiparkinsonmittels Pramipexol, (S)-4,5,6,7-Tetrahydro-N6- propyl-2,6-benzothiazoldiamin, einem D2/D3 Agonisten (Dopaminagonist), zur Behandlung des RLS wird in der WO 98/31362 beschrieben. Benzodiazepine und Opiate sind ebenfalls wirksam bei RLS. Wegen der Gefahr der Abhängigkeit und der Toleranzentwicklung stehen diese Substanzen jedoch nur eingeschränkt für eine Therapie zur Verfügung. Carbamazepin wurde nur in wenigen teils offenen Studien in der Indikation RLS geprüft. Es führt nur zur partiellen Beschwerdefreiheit und gilt derzeit nicht als geeignetes Mittel zur Behandlung des RLS. Die Wirkung von Clonidin, 2-(2,6-Dichloranilino)-4,5-dihydroimidazol, das ursprünglich als Antihypertonikum und Miotikum entwickelt wurde, bei der Behandlung von RLS wurde in 4 offenen Studien, 2 doppelblinden, placebo-kontrollierten Studien und in einer Single case study untersucht. Die Tagesdosen lagen zwischen 0,1 - 0,9 mg. Die Patienten berichteten über eine Abnahme (statistisch signifikant) sensibler Symptome wie Pararsthesien, des Bewegungsdrangs und einer Müdigkeit während des Tages. Bei den objektiven polysomnographischen Meßparametern wurde zwar die Einschlaflatenz verkürzt, die Schlafqualität, Häufigkeit des Aufwachens oder die periodischen Beinbewegungen im Schlaf (PLMS) wurden dagegen nicht beeinflußt. Da als Monotherapie wirksamere Substanzen zur Verfügung stehen, wird derzeit Clonidin als alternative Therapieform nur bedingt empfohlen.The use of the anti-Parkinson agent pramipexole, (S) -4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole diamine, a D2 / D3 agonist (dopamine agonist), for the treatment of RLS is described in WO 98/31362 described. Benzodiazepines and opiates are also effective in RLS. However, due to the risk of dependency and the development of tolerance, these substances are only available for therapy to a limited extent. Carbamazepine has only been tested in a few partially open studies in the indication RLS. It only leads to partial freedom from symptoms and is currently not considered a suitable means of treating the RLS. The effect of clonidine, 2- (2,6-dichloroanilino) -4,5-dihydroimidazole, which was originally developed as an antihypertensive and miotic, in the treatment of RLS has been demonstrated in 4 open-label studies, 2 double-blind, placebo-controlled studies and in a single case study. 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. With the objective polysomnographic measurement parameters, 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.
Überraschenderweise wurde gefunden, daß durch die Gabe von NK-i-Rezeptor- Antagonisten die Suppression der RLS-Symptomatik bewirkt werden kann. Beschreibung der Erfindung Die vorliegende Erfindung betrifft die Verwendung von NK-|-Rezeptor-Antagonisten zur Herstellung eines Arzneimittels zur Behandlung des Restless Legs Syndroms (RLS).Surprisingly, it was found that the suppression of the RLS symptoms can be brought about by the administration of NK-i receptor antagonists. Description of the Invention The present invention relates to the use of NK- | receptor antagonists for the manufacture of a medicament for the treatment of restless legs syndrome (RLS).
Er indungsgemäß bevorzugt ist die Verwendung eines NK«|-Rezeptor-Antagonisten ausgewählt aus der Gruppe bestehend aus 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 und GR 205171 , zur Herstellung eines Arzneimittels zur Behandlung des Restless Legs Syndroms (RLS).It is preferred to use a indungsgemäß 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 the manufacture of a medicinal product for the treatment of restless legs syndrome (RLS).
Besonders bevorzugt ist die Verwendung eines NK«|-Rezeptor-Antagonisten ausgewählt aus der Gruppe bestehend aus BIIF 1149, CGP 60829, MK-869, CJ- 11974 und GR 205171 , zur Herstellung eines Arzneimittels zur Behandlung des Restless Legs Syndroms (RLS), wobei die Verwendung von BIIF1149 als höchst bevorzugt angesehen werden kann.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.
Als Wirkstoff kann in allen Fällen gleichfalls ein pharmakologisch verträgliches Salz oder ein Ester oder eine Prodrugform, beispielsweise ein Ester, der vorstehend genannten Verbindungen eingesetzt werden.In all cases, 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.
Gegebenenfalls kann die erfindungsgemäße Verwendung von NK-|-Rezeptor- Antagonisten in der Therapie des Restless Legs Syndroms auch in Kombination mit anderen Wirstoffen erfolgen, um einen synergistischen Therapieeffekt zu erzielen. Ein weiterer Aspekt der vorliegenden Erfindung zielt somit auf die Verwendung einer Wirkstoffkombination zur Herstellung eines Arzneimittels oder Arzneimittelkits zur Behandlung des Restless Legs Syndroms, dadurch gekennzeichnet, daß wenigstens einer der in dem Arzneimittel oder dem Arzneimittelkit enthaltenen Wirkstoffe einen NK-|-Rezeptor-Antagonisten darstellt und ferner wenigstens ein Wirkstoff ausgewählt aus der Gruppe bestehend aus α2-Agonisten, Opioiden, Benzodiazepinen, Antiparkinsonmitteln, bevorzugt Dopaminagonisten, Levodopa (L-DOPA) plus Decarboxylasehemmern und NK3-Rezeptor-Antagonisten enthalten ist.If appropriate, the use of NK- | receptor antagonists according to the invention 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- | receptor antagonist and furthermore at least one active ingredient selected from the group consisting of α2 agonists, opioids, benzodiazepines, antiparkinson agents, preferably dopamine agonists, levodopa (L-DOPA) plus decarboxylase inhibitors and NK3 receptor antagonists.
Im Rahmen der vorstehend genannten Wirkstoffkombinationen können als α2- Agonisten bevorzugt Imidazolrezeptor-Agonisten eingesetzt werden, besonders bevorzugt sind Agmatin, Apraclonidin, Azepexol, Clonidin, Dexmedetomidin, Guanfacinel, Guanabenz, Lofexidin, Medetomidin, Naphazolin, Oxymetazolin, Para- Amino-Clonidin, Rilmenidin, Romifidin, Talipexol, Teryzolin, Tiamenidin, Tinabinol, Tizanidin, Tolonidin, Xylometazolin, Xylazin, AGN-190837, AGN-192836, BAM-1125, CP-18534-1 , DJ-741 , ICI-106270, IDPH-791 , MPV-295, MPV-2426, RWJ-52807, S- 18616, ST-91 , U-47476A, UK-1403, UK-14304, 6-(5-Methyl-chinoxalinyl)-imino- imidazolidin. Davon sind zur Herstellung der erfindungsgemäßen Wirkstoffkombination von besonderem Interesse Agmatin, Apraclonidin, Azepexol, Clonidin, Dexmedetomidin, Guanfacinel, Guanabenz, Lofexidin, Naphazolin, Oxymetazolin, Para-Amino-Clonidin, Rilmenidin, Romifidin Talipexol, Teryzolin, Tiamenidin, Tinabinol, Tizanidin, Tolonidin, Xylometazolin, Xylazin, S-18616, wobei Clonidin höchst bevorzugt ist. Als Wirkstoff kann in allen Fällen gleichfalls ein pharmakologisch verträgliches Salz oder ein Ester oder eine Prodrugform, beispielsweise ein Ester, der vorstehend genannten Verbindungen eingesetzt werden.Within the framework of the active ingredient combinations mentioned above, imidazole receptor agonists can preferably be used as α2 agonists, particularly preferred are agmatine, apraclonidine, azepexol, clonidine, dexmedetomidine, guanfacinel, guanabenz, lofexidine, medetomidine, naphazoline, oxymetazoline, para-amino-clonidine, rilmenidine, romifidine, talipexol, teryzoline, xamenizine, tolinidinzine, tolinidinzine AGN-190837, AGN-192836, BAM-1125, CP-18534-1, DJ-741, ICI-106270, IDPH-791, MPV-295, MPV-2426, RWJ-52807, S- 18616, ST-91, U-47476A, UK-1403, UK-14304, 6- (5-methyl-quinoxalinyl) imino imidazolidine. Of these, agmatine, apraclonidine, azepexol, clonidine, dexmedetomidine, guanfacinel, guanabenz, lofexidine, naphazoline, oxymetazoline, para-amino-clonidine, rilmenidine, romifidine talipexolamide, teryanidine, tolizidine, tolizidine, tolizidine, tolizidine, tolizidine, tolizidine, tolizidine, tolizidine, tolizidine, tolizidine, tolizidine, tolizidine, and tilanidine , Xylometazoline, xylazine, S-18616, with clonidine being most preferred. In all cases, 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.
Aus der ebenfalls zur Herstellung der erfindungsgemäßen, wenigstens einen NK1- Rezeptor-Antagonisten enthaltenden Wirkstoffkombinationen einsetzbaren Wirkstoffkomponenten Levodopa (L-DOPA) plus Decarboxylasehemmer sind besonders die Kombinationen L-DOPA plus Benserazid und L-DOPA plus Carbidopa bevorzugt.The combinations 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.
Aus der Gruppe der Dopaminagonisten sind Bromocriptin, Cabergolin, α- Dihydroergocryptin, Lisurid, Pergolid, Pramipexol (HCI), Talipexol, Ropinirol, S(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxy-tetralin (z.B. als N-0923)oder (R)- 5,6-dihydro-5-(methylamino)-4H-imidazo(4,5,1-ij)chinolin-2(1 H)-on (R)-6 (PNU 95666) bzw. ein pharmakologisch verträgliches Salz davon bevorzugt.From the group of dopamine agonists are bromocriptine, cabergoline, α-dihydroergocryptine, lisuride, pergolide, pramipexole (HCI), talipexole, ropinirole, S (-) - 2- (N-propyl-N-2-thienylethylamino) -5-hydroxy- tetralin (e.g. as N-0923) or (R) - 5,6-dihydro-5- (methylamino) -4H-imidazo (4,5,1-ij) quinolin-2 (1 H) -one (R) - 6 (PNU 95666) or a pharmacologically acceptable salt thereof is preferred.
Aus der Gruppe der Opioide sind Buprenorphin, Codein, Dextropropoxyphen, Dihydrocodein, Fentanyl, Hydromorphon, Levomethadon, Morphin, Oxycodon, Pethidin, Tilidin, Tramadol oder deren pharmakologisch verträglichen Salze bevorzugt. Besonders bevorzugt sind Codein, Dihydrocodein, Tramadol Sufentanil und Morphin.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.
Aus der Gruppe der Benzodiazepine sind Clonazepam und Brotizolam bevorzugt.From the group of benzodiazepines, clonazepam and breadizolam are preferred.
Im Rahmen der vorstehend genannten Wirkstoffkombinationen kann als NK3- Rezeptor-Antagonist bevorzugt SR-142801 (Osanetant) eingesetzt werden. Bevorzugt ist die Kombination der erfindingsgemäß einsetzbaren NK-|-Rezeptor- Antagonisten mit Clonidin, bzw. eines dessen pharmakologisch verträglichen Salzes oder mit einem Dopaminagonisten, bevorzugt mit Pramipexol bzw. einem pharmakologisch verträglichen Salz davon.SR-142801 (Osanetant) can preferably be used as NK3 receptor antagonist in the context of the above-mentioned active ingredient combinations. The combination of the NK- | 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.
Die erfindungsgemäß einsetzbaren NK-|-Rezeptor-Antagonisten können gemäß den gängigen aus dem Stand der Technik bekannten pharmazeutischen Verfahren so formuliert werden, daß sie oral, spinal, peridural, anal, intravenös, inhalativ, subcutan oder transdermal appliziert werden kann. Bevorzugt sind orale und transdermale Applikationsformen. Entsprechendes gilt für die gegebenenfalls zusätzlich zur Erzielung eines synergistischen Effekts enthaltenen weiteren Wirkstoffe, wie sie vorstehend genannt werden. Die zu applizierende Tagesdosis ist naturgemäß abhängig vom Ausmaß bzw. der Stärke der RLS-Symptomatik. Erfindungsgemäß liegt der anwendbare Dosisbereich in weiten Grenzen pro Tag bei ca. 20 - 500 mg des NK-|-Rezeptor-Antagonisten.The NK- | -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- | Receptor antagonists.
Die orale Gabe kann in Form einer Tablette, als Pulver, als Pulver in einer Kapsel (z.B. Hartgelatinekapsel), als Lösung oder Suspension erfolgen. Bei spinalen, intravenösen und subcutanen Applikationen wird die erfindungsgemäße Wirkstoffkombination als Lösung gegeben. Die anale Applikation erfolgt über Suppositorien. Im Fall einer inhalativen Gabe kann die Wirkstoffkombination als Pulver, als wäßrige oder wässrig-ethanolische Lösung oder mittels einer Treibgasformulierung erfolgen. Bei der transdermalen Applikation kann der Wirkstoff entweder als Salbe oder Creme auf die Haut aufgetragen werden, bevorzugt wird er jedoch über ein Pflaster verabreicht.Oral administration can take the form of a tablet, powder, powder in a capsule (e.g. hard gelatin capsule), solution or suspension. In spinal, intravenous and subcutaneous applications, the active substance combination according to the invention is given as a solution. The anal application takes place via suppositories. In the case of inhalation administration, 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. In the case of transdermal application, the active ingredient can be applied to the skin either as an ointment or cream, but is preferably administered via a plaster.
Im Fall der Pflaster kann der Wirkstoff bzw. die Wirkstoffkombination entweder direkt an die äußere Hautschicht abgegeben werden oder er wird mittels eines transdermalen Pflasters als Lösung oder als Gel, z.B. in einer Polymermatrix eingebettet, über Mikronadeln oder Mikroschneiden, die das Stratum Corneum der Haut durchdringen direkt in die tiefer liegenden Hautschichten abgegeben. Solch ein transdermales Pflaster mit Mikroschneiden oder Mikrostacheln ist beispielsweise in der Patentanmeldung WO 97/03718 offenbart. Die Patentanmeldung WO 91/07998 beschreibt ein Verfahren mittels dessen Wirkstoffe durch Einstellen eines bestimmten pH-Werts der Haut verbessert transdermal appliziert werden können. Die US 5,112, 842, bzw. deren europäisches Pendant EP 0428038, offenbaren ein transdermales Pflaster zur Applikation von Pramipexol. Auf alle drei Patentschriften wird hiermit ausdrücklich inhaltlich Bezug genommen, um zu verdeutlichen, wie die erfindungsgemäße Wirkstoffkombination mittels eines transdermalen Pflasters appliziert werden kann.In the case of the plasters, 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. Such 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. US 5,112,842, or their European counterpart EP 0428038, disclose a transdermal patch for the application of pramipexole. The content of all three patents is hereby expressly referred to in order to clarify how the Active ingredient combination according to the invention can be applied by means of a transdermal patch.
Beide Arten der oben beschriebenen Pflaster (mit und ohne Mikroschneiden oder Mikrostacheln) geben den Wirkstoff kontinuierlich an bzw. in die Haut ab, so daß Konzentrationsspitzen und die damit verbundenen möglichen Nebenwirkungen vermieden werden. Die Abgabe des Wirkstoffs bzw. der Wirkstoffkombination kann passiv oder aktiv erfolgen. Ein aktiver Transport kann rein mechanisch, elektrisch, osmotisch oder über lontophorese erfolgen. Gegebenenfalls wird die Abgabe elektronisch gesteuert, gegebenenfalls unter Kontrolle des Blutplasmaspiegels durch Sensoren oder Mikrosensoren, die in das Pflaster integriert sind oder mit ihm in kommunikativer Verbindung stehen, wodurch der Blutplasmaspiegel je nach individueller Bedürftigkeit gezielt eingestellt werden kann und demzufolge eine stetige Abgabe nicht zwingend erforderlich ist.Both types of the plasters described above (with and without microcuts or microsticks) 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.
In den Fällen, in denen NKi-Rezeptor-Antagonisten im Rahmen einer Kombinationstherapie mit den vorstehend genannten anderen Wirkstoffen eingesetzt werden soll, können die Wirkstoffkombinationen in einer jeweils eigenständigen Formulierung vorliegen (z.B. je in einer Kapsel oder jeweils als Tablette), in einer einzigen Formulierung, darin jedoch voneinander getrennt (z.B. in einer Kapsel mit zwei oder mehr Kammern) oder sie liegen in einer einzigen Formulierung vermischt vor (z.B. in Form einer Tablette oder in einer Kapsel mit nur einer Kammer). Im dem Fall, in dem die Wirkstoffe jeweils unabhängig voneinander eigenständig formuliert sind, ist es nicht zwingend, daß die beiden Stoffe über den gleichen Applikationsweg gegeben werden, sondern es können auch Kombinationen von Formulierungen eingesetzt werden, bei denen die beiden Wirkstoffe über getrennte Applikationswege verabreicht werden. Bevorzugt sind jedoch solche Formulierungen, bei denen die beiden Wirkstoffe über den gleichen Applikationsweg gegeben werden. Vorteilhafter Weise werden die beiden Wirkstoffe gemeinsam in einer Applikationsform formuliert.In cases in which NKi receptor antagonists are to be used as part of a combination therapy with the other active substances mentioned above, 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). In the case in which 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. However, 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.
Im Fall der transdermalen Pflaster können beispielsweise die Wirkstoffe entweder je in einem separaten Pflaster gegeben werden, in einem gemeinsamen Pflaster, wobei die Wirkstoffe jedoch innerhalb des Pflasters getrennt gelagert sind, oder sie liegen als Gemisch in einem Pflaster vor. Analoges gilt für die anderen oben beschriebenen Applikationsformen.In the case of transdermal patches, for example, 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.
Die erfindungsgemäße Wirkstoffformulierung wird je nach Applikationsart gemäß den aus dem Stand der Technik bekannten Verfahren zubereitet und kann demgemäß die aus dem entsprechenden Fachgebiet einschlägig bekannten Formulierungsbestandteile beinhalten.Depending on the type of application, 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.
Daneben kann sie weitere pharmakologisch aktive Substanzen oder kosmetische Zusatzstoffe beinhalten.In addition, it can contain other pharmacologically active substances or cosmetic additives.
In allen Fällen können die NK-|-Rezeptor-Antagonisten, wie auch die gegebenenfalls zusätzlich zur Erzielung eines synergistischen Effekts enthaltenen weiteren Wirkstoffe sowohl als Neutralverbindung oder in Form eines ihrer pharmakologisch verträglichen Salzes verwendet werden. Die NK«|-Rezeptor-Antagonisten, wie auch die gegebenenfalls zusätzlich zur Erzielung eines synergistischen Effekts enthaltenen weiteren Wirkstoffe können gleichermaßen sowohl als neutrale Verbindungen, als jeweils gleiche oder jeweils unterschiedliche Salze oder als Kombination aus einem Salz eines Wirkstoffs und neutralen anderen Wirkstoffen verwendet werden. Die unterschiedlichen Varianten werden von der Applikationsart beeinflußt. In Fällen, in denen die NK-|-Rezeptor-Antagonisten, wie auch die gegebenenfalls zusätzlich zur Erzielung eines synergistischen Effekts enthaltenen weiteren Wirkstoffe in einer gemeinsamen Formulierung vorliegen, handelt es sich bevorzugt jeweils um die Neutralverbindung oder jeweils um das gleiche Salz (z.B. Hydrochlorid). Das gleiche gilt bevorzugt auch in dem Fall, wenn die NK-|-Rezeptor- Antagonisten, wie auch die gegebenenfalls zusätzlich zur Erzielung eines synergistischen Effekts enthaltenen weiteren Wirkstoffe je als Tablette oder Kapsel oral eingenommen werden.In all cases, the NK- | -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. The NK « | -receptor antagonists, as well as the additional active ingredients which may additionally be used to achieve a synergistic effect, can equally be used both as neutral compounds, as the same or different salts in each case or as a combination of a salt of an active ingredient and neutral other active ingredients , The different variants are influenced by the type of application. In cases in which the NK- | -receptor antagonists, as well as the further active ingredients which may additionally be present in order to achieve a synergistic effect, are preferably present in a common formulation, it is preferably in each case the neutral compound or in each case the same salt (for example hydrochloride ). The same applies preferably also in the case when the NK- | 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.
Unabhängig von der Applikationsart werden die NK-|-Rezeptor-Antagonisten, wie auch die gegebenenfalls zusätzlich zur Erzielung eines synergistischen Effekts enthaltenen weiteren Wirkstoffe bevorzugt in einem zeitlichen Zusammenhang innerhalb von bevorzugt 24 Stunden, besonders bevorzugt innerhalb von 12 Stunden, und insbesondere bevorzugt innerhalb von 1 Stunde verabreicht. Am stärksten bevorzugt ist eine gleichzeitige Applikation innerhalb von maximal 15 Minuten. Regardless of the type of application, the NK- | -receptor antagonists, as well as the further active ingredients optionally additionally to achieve a synergistic effect, 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.

Claims

Patentansprüche claims
1 ) Verwendung von NK-|-Rezeptor-Antagonisten zur Herstellung eines Arzneimittels zur Behandlung des Restless Legs Syndroms (RLS).1) Use of NK- | receptor antagonists in the manufacture of a medicament for the treatment of restless legs syndrome (RLS).
2) Verwendung nach Anspruch 1 , dadurch gekennzeichnet, daß die NK-|- Rezeptor-Antagonisten ausgewählt sind aus der Gruppe bestehend aus BIIF2) Use according to claim 1, characterized in that the NK- | - receptor antagonists are 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-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 und GR 205171.11467, 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.
3) Verwendung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß die NK-i- Rezeptor-Antagonisten ausgewählt sind aus der Gruppe bestehend aus BIIF 1149, CGP 60829, MK-869, CJ-11974 und GR 205171.3) Use according to claim 1 or 2, characterized in that the NK-i receptor antagonists are selected from the group consisting of BIIF 1149, CGP 60829, MK-869, CJ-11974 and GR 205171.
4) Verwendung nach einem der Ansprüche 1 , 2 oder 3 dadurch gekennzeichnet, daß die NK-|-Rezeptor-Antagonisten gegebenenfalls in Form ihrer pharmakologisch verträglichen Salze, Ester oder Prodrugform vorliegen.4) Use according to one of claims 1, 2 or 3, characterized in that the NK- | receptor antagonists are optionally in the form of their pharmacologically acceptable salts, esters or prodrug form.
5) Verwendung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet daß neben wenigstens einem NK-|-Rezeptor-Antagonisten weitere Wirstoffe zur Erzielung eines synergistischen Therapieeffekts verwendet werden.5) Use according to one of claims 1 to 4, characterized in that in addition to at least one NK- | receptor antagonist, further active ingredients are used to achieve a synergistic therapeutic effect.
6) Verwendung nach Anspruch 5, dadurch gekennzeichnet, daß die weiteren Wirkstoffe ausgewählt sind aus der Gruppe bestehend aus α2-Agonisten, Opioiden, Benzodiazepinee, Antiparkinsonmitteln, Levodopa (L-DOPA) plus Decarboxylasehmmer und NK3-Rezeptor-Antagonisten. 6) Use according to claim 5, characterized in that the further active ingredients are selected from the group consisting of α2-agonists, opioids, benzodiazepines, antiparkinson agents, levodopa (L-DOPA) plus decarboxylase inhibitor and NK3 receptor antagonists.
PCT/EP2001/000263 2000-01-18 2001-01-11 Nk1-receptor antagonists for treatment of restless legs syndrome WO2001052854A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002103A2 (en) * 2001-06-29 2003-01-09 Pharmacia Corporation Hydrophobic dopamine agonists administered to the dermis

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005013726A1 (en) * 2005-03-22 2006-09-28 Grünenthal GmbH Transdermal therapeutic system for transdermal application of opioid containing analgesics, especially using a plaster for application to permit long-term, pain-free application

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011368A1 (en) * 1992-11-12 1994-05-26 Pfizer Inc. Quinuclidine derivative as substance p antagonist
WO1998001450A1 (en) * 1996-07-03 1998-01-15 Merck Sharp & Dohme Limited Spiro-piperidine derivatives and their use as therapeutic agents
WO1998002158A1 (en) * 1996-07-17 1998-01-22 Merck & Co., Inc. Alteration of circadian rhythmicity with a tachykinin antagonist
US5985874A (en) * 1998-05-11 1999-11-16 Merck Sharp & Dohme Ltd. Substituted morpholine derivative and its use as a therapeutic agent
WO2000047562A1 (en) * 1999-02-09 2000-08-17 Merck Sharp & Dohme Limited Spirocyclic ketones and their use as tachykinin antagonists
WO2000056727A1 (en) * 1999-03-19 2000-09-28 Merck Sharp & Dohme Limited Tetrahydropyran derivatives and their use as therapeutic agents
WO2000071107A2 (en) * 1999-05-21 2000-11-30 Pfizer Products Inc. New pharmaceutical combinations for nos inhibitors

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011368A1 (en) * 1992-11-12 1994-05-26 Pfizer Inc. Quinuclidine derivative as substance p antagonist
WO1998001450A1 (en) * 1996-07-03 1998-01-15 Merck Sharp & Dohme Limited Spiro-piperidine derivatives and their use as therapeutic agents
WO1998002158A1 (en) * 1996-07-17 1998-01-22 Merck & Co., Inc. Alteration of circadian rhythmicity with a tachykinin antagonist
US5985874A (en) * 1998-05-11 1999-11-16 Merck Sharp & Dohme Ltd. Substituted morpholine derivative and its use as a therapeutic agent
WO2000047562A1 (en) * 1999-02-09 2000-08-17 Merck Sharp & Dohme Limited Spirocyclic ketones and their use as tachykinin antagonists
WO2000056727A1 (en) * 1999-03-19 2000-09-28 Merck Sharp & Dohme Limited Tetrahydropyran derivatives and their use as therapeutic agents
WO2000071107A2 (en) * 1999-05-21 2000-11-30 Pfizer Products Inc. New pharmaceutical combinations for nos inhibitors

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
ASTOLFI M ET AL: "Improved discriminatory properties between human and murine tachykinin NK-1 receptors of MEN 10930: A new potent and competitive antagonist.", NEUROPEPTIDES, vol. 31, no. 4, 1997, pages 373 - 379, XP001006033, ISSN: 0143-4179 *
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 *
DOI TAKAYUKI ET AL: "Effects of TAK-637, an NK1 antagonist, on functions of the lower urinary tract (2) Role of the NK1 receptors in the micturition reflex in guinea pigs.", JAPANESE JOURNAL OF PHARMACOLOGY, vol. 79, no. SUPPL. 1, 1999, 72nd Annual Meeting of the Japanese Pharmacological Society;Sapporo, Japan; March 22-25, 1999, pages 195P, XP001006277, ISSN: 0021-5198 *
EVANGELISTA STEFANO ET AL: "Effect of men 11467, a potent and selective pseudo-peptide tachykinin NK-1 antagonist, on colitis induced by acetic acid guinea-pigs.", GASTROENTEROLOGY, vol. 116, no. 4 PART 2, April 1999 (1999-04-01), Digestive Disease Week and the 100th Annual Meeting of the American Gastroenterological Association;Orlando, Florida, USA; May 16-19, 1999, pages A707, XP001006079, ISSN: 0016-5085 *
FAUCHÈRE J.L., KUCHARCZYK N., JACOBY E. ET AL.: "The dipeptide neurokinin-1- receptor antagonist S19752 is a potent and long-acting inhibitor of bronchoconstriction when administered by aerosol to the guinea pig in vivo.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 7, no. 2, 1997, pages 203 - 208, XP004135993 *
GOLDHILL JON ET AL: "Antisecretory and relaxatory effects of tachykinin antagonists in the guinea-pig intestinal tract.", JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 51, no. 9, 1999, pages 1041 - 1048, XP001006071, ISSN: 0022-3573 *
HUSKEY SU-ER W ET AL: "Substance P receptor antagonist I: Conversion of phosphoramidate prodrug after i.v. administration to rats and dogs.", DRUG METABOLISM AND DISPOSITION, vol. 27, no. 11, November 1999 (1999-11-01), pages 1367 - 1373, XP001006214, ISSN: 0090-9556 *
KUBOTA HIROKAZU ET AL: "Spiro-substituted piperidines as neurokinin receptor antagonist: III. Synthesis of (racemic)-N-(2-(3,4-dichlorophenyl)-4-(spiro-substituted piperidin-1'-yl)butyl)-N-methylbenzamides and evaluation of NK1-NK2 dual antagonistic activities.", CHEMICAL & PHARMACEUTICAL BULLETIN (TOKYO), vol. 46, no. 10, October 1998 (1998-10-01), pages 1538 - 1544, XP001002554, ISSN: 0009-2363 *
SANTICIOLI PAOLO ET AL: "MEN 11420, a potent and selective tachykinin NK2 receptor antagonist in the guinea-pig and human colon.", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, vol. 356, no. 5, November 1997 (1997-11-01), pages 678 - 688, XP001006389, ISSN: 0028-1298 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002103A2 (en) * 2001-06-29 2003-01-09 Pharmacia Corporation Hydrophobic dopamine agonists administered to the dermis
WO2003002103A3 (en) * 2001-06-29 2003-04-10 Pharmacia Corp Hydrophobic dopamine agonists administered to the dermis

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