WO2005102322A1 - Use of a cgrp-antagonist combined with a serotonin-reuptake inhibitor in order to treat migraines - Google Patents

Use of a cgrp-antagonist combined with a serotonin-reuptake inhibitor in order to treat migraines Download PDF

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Publication number
WO2005102322A1
WO2005102322A1 PCT/EP2005/004076 EP2005004076W WO2005102322A1 WO 2005102322 A1 WO2005102322 A1 WO 2005102322A1 EP 2005004076 W EP2005004076 W EP 2005004076W WO 2005102322 A1 WO2005102322 A1 WO 2005102322A1
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Prior art keywords
piperidinyl
dihydro
carbonyl
dibromo
amino
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PCT/EP2005/004076
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German (de)
French (fr)
Inventor
Henri Doods
Klaus Rudolf
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Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Priority claimed from DE102004019736A external-priority patent/DE102004019736A1/en
Priority claimed from DE102004063754A external-priority patent/DE102004063754A1/en
Application filed by Boehringer Ingelheim International Gmbh, Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim International Gmbh
Priority to CA002563687A priority Critical patent/CA2563687A1/en
Priority to JP2007508808A priority patent/JP2007533685A/en
Priority to EP05735425A priority patent/EP1740175A1/en
Publication of WO2005102322A1 publication Critical patent/WO2005102322A1/en

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • 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

Definitions

  • Migraine is one of the most common neurological disorders and includes periodic bouts of headache and nausea, as well as a variety of other symptoms. Although significant progress has been made, the pathophysiology of migraines is still not understood. However, several observations indicate involvement of the calcitonin gene-related peptide (CGRP). Migraine headaches include activation of the trigeminal system and enlargement of the cranial vessels. CGRP is localized to neurons in trigeminal ganglia, and CGRP levels are elevated during a migraine attack, which is thought to cause the observed vasodilation. Accordingly, it is conceivable that the inhibition of the enlargement of the cranial vessels caused by CGRP may allow a new treatment for migraine headaches.
  • CGRP calcitonin gene-related peptide
  • migraines Medicines for migraines that are widely used are so-called “triptans”, for example sumatriptan and zolmitriptan. These compounds elicit their effects against migraines because of their vasoconstrictive properties and presumably their inhibition of the release of the neuropeptide calcitonin gene-related peptide (CGRP) (Ferrari, MD, Saxena, PR (1995), 5-HT1 receptors in migraine pathophysiology and treatment , Eur. J. Neurology, 2, 5-21; Johnson, KW, Phebus, LA, Cohen, ML (1998), Serotonin in migraine: Theiroes, animal modeis and emerging therapies, Progress in Drug Research, Vol.
  • CGRP neuropeptide calcitonin gene-related peptide
  • WO 98/11128 discloses modified amino acids with CGRP-antagonistic properties, their use and methods for their production as well as their use for the production and purification of antibodies and as labeled compounds in RIA and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.
  • the modified amino acids are therefore suitable for the acute and prophylactic treatment of headaches, in particular migraines and cluster headache.
  • the present invention provides a method of treating or preventing indications selected from the group consisting of headache, migraine and cluster headache, the method comprising co-administering a therapeutically effective amount of a CGRP antagonist ( A) or a physiologically acceptable salt thereof and a therapeutically effective amount of a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof to a person in need of such treatment.
  • a CGRP antagonist A
  • B serotonin reuptake inhibitor
  • active ingredient (A) all pharmaceutically acceptable active ingredients which antagonize the known effects of CGRP or which inhibit the release of CGRP from sensory nerve endings can be used as the active ingredient (A).
  • Possible CGRP antagonists (A) are, for example, the amino acid derivatives described in WO 98/11128 or DE 199 11 039, and also the non-peptide active ingredients described in WO 98/56779, WO 98/09630 and WO 97/09046.
  • the CGRP antagonist (A) is preferably selected from the group consisting of
  • Citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone or the physiologically tolerable salts thereof can be used as serotonin reuptake inhibitors (B).
  • Duloxetine is preferably used.
  • the dose for the serotonin reuptake inhibitor (B) is about 1/50 of the lowest normally recommended dose up to 1/1 of the normally recommended dose, by oral, nasal, inhalation, subcutaneous or intravenous routes.
  • the CGRP antagonist (A) or a physiologically tolerable salt thereof can be administered intravenously or subcutaneously in a dosage of 0.0001 to 3 mg / kg body weight, orally in a dosage of 0.1 to 20 mg / kg body weight or on nasalem or inhalation route in a dosage of 0.1 to 10 mg / kg body weight once, twice or three times a day in combination with
  • a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof administered orally at a dose of 0.03 to 1.43 mg / kg body weight once, twice or three times a day or
  • the present invention provides a pharmaceutical composition for the treatment or prevention of headache, migraine or cluster headache, which contains a therapeutically effective amount of a CGRP antagonist (A) or a physiologically tolerable salt thereof and a serotonin reuptake inhibitor (B ) or a physiologically tolerable salt thereof, as a combined preparation for simultaneous or sequential administration.
  • a CGRP antagonist A
  • a physiologically tolerable salt thereof a physiologically tolerable salt thereof
  • B serotonin reuptake inhibitor
  • a pharmaceutical composition according to the invention can have a single dosage unit of 0.1 to 1500 mg, preferably 0.3 to 1000 mg, particularly preferably 5 to 750 mg, of the CGRP antagonist (A) or an equivalent amount of a physiologically tolerable salt thereof and
  • All doses or dosage units of a physiologically compatible salt of one of the above-mentioned active compounds are to be understood as the dose or dosage of the active compound itself.
  • a pharmaceutical composition according to the invention can be a kit of parts for the treatment or prevention of headache, migraine or cluster headache, the kit comprising:
  • a first enclosure containing a pharmaceutical composition comprising a therapeutically effective amount of the CGRP antagonist (A) or a physiologically acceptable salt thereof and one or more physiologically acceptable diluents and / or carriers;
  • a second enclosure containing a pharmaceutical composition comprising a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof and one or more physiologically acceptable diluents and / or carriers.
  • a third aspect of the present invention is the use of the CGRP antagonist (A) or a physiologically acceptable salt thereof in combination with a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treatment or prevention of headache, migraine or cluster headache.
  • the CGRP antagonist (A) or a physiologically tolerable salt thereof can be administered, for example, using one of the pharmaceutical formulations described in the examples.
  • the examples that follow describe pharmaceutical compositions containing the CGRP antagonist (A) or a physiologically acceptable salt thereof and a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof.
  • Example 1a
  • composition / tablet Composition / tablet:
  • CGRP antagonist (A), serotonin reuptake inhibitor (B) and lactose (fine) are mixed homogeneously in a suitable mixer (e.g. Diosna P2); then the mixture is granulated with an aqueous povidone solution.
  • the granules are sieved with a Kressner sieve with 1.6 mm and dried at 40 ° C for 2 hours.
  • the granulate is then passed through a suitable mill, e.g. a Comill sieved at 3000 rpm with a mesh size of 1.1 mm.
  • the granules are then mixed with grospovidone for 5 minutes and then with magnesium stearate for 1 minute.
  • the mixture thus obtained is pressed in a tablet press into tablets with a suitable diameter.
  • CGRP antagonist (A), serotonin reuptake inhibitor (B), lactose (fine) and microcrystalline cellulose are mixed homogeneously in a suitable mixer (e.g. Diosna P2); the mixture is then granulated with water.
  • the granules are sieved with a Kressner sieve with 1.6 mm and dried at 40 ° C for 2 hours.
  • the granules are then passed in a suitable mill, e.g. a Comill sieved at 3000 rpm with a mesh size of 1.1 mm.
  • the granules are then mixed with croscarmellose for 5 minutes and then with magnesium stearate for 1 minute.
  • the mixture thus obtained is pressed in a tablet press into tablets with a suitable diameter.
  • the active ingredient is dissolved / suspended in water with stirring and optionally heating.
  • the isotonans mannitol is added and the solution is made up to the final volume with water.
  • Aqueous solution for intranasal use containing 40% CGRP antagonist (A) or an equivalent amount of a physiologically acceptable salt thereof and 10% serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof and 1.5% Labrasol
  • the active ingredients are dissolved / suspended in water with stirring and optionally heating.
  • the isotonans mannitol and Labrasol are added and the solution is made up to the final volume with water.
  • the pharmaceutical substances according to the invention can also be in the form of small particles such as e.g.
  • Pellets are made.
  • the active ingredient can be based on neutral pellets
  • Sucrose and starch or microcrystalline cellulose exist.
  • the production takes place in the following steps:
  • Serotonin Reuptake Inhibitor (B) 40 parts by weight
  • Hydroxypropyl cellulose is dissolved in 250 parts by weight of 2-propanol with stirring and then the active ingredients and talc are dispersed in this solution with stirring.
  • the active ingredient-containing pellets are sieved using a sieve with a nominal mesh size of 1.25 mm.
  • the good fraction (grain size ⁇ 1.25 mm) is processed further.
  • the active substance layer is generally built up in the same way, but the type of active substance and the amount, type of binder and quantity, amount of talc and water, isopropanol or amount of ethanol are varied.
  • the medicinal substances according to the invention can also be produced in the form of extrudates which, after cutting / spheronization, are filled directly into capsules or processed into tablets after grinding.
  • the production takes place in the following steps:
  • Serotonin Reuptake Inhibitor (B) 80 parts by weight
  • the extrusion strands are rounded off to form pellets in a spheronizer, rounding for approx. 3 minutes at approx. 850 RPM.
  • the pellets are dried in a fluidized bed dryer at 80 ° C. for about 1.5 hours.
  • the core material is fractionated using a tumbler screening machine with different screening trays with nominal mesh sizes from 0.71 to 1.25 mm. The appropriate good fractions between 0.71 and 0.90 or 0.90 and 1.12 mm are used.
  • Serotonin Reuptake Inhibitor (B) 60 parts by weight 200 parts by weight of the CGRP antagonist (A), 60 parts by weight of the Serotonin reuptake inhibitor (B), 40 parts by weight of the poloxamer and 6 parts by weight of the Povidon K25 are mixed in a wheel mixer for 15 minutes. The powder mixture is then introduced into a twin-screw extruder at a rate of approx. 1 kg / h. The temperature is controlled so that a target torque of approx. 19% is generated in the extruder. The extrusion is carried out via a die plate with 0.8 mm diameter holes.
  • the emerging extrusion strands are cut with a head tee, the extrusion strands are rounded off to pellets in a spheronizer, rounding for approx. 3 minutes at approx. 850 RPM at approx. 40 ° C. Drying of the pellets at 80 ° C approximately "1.5 h in a fluidized bed dryer.
  • the core material is fractionated using a tumbler screening machine with different screening trays with nominal mesh sizes from 0.71 to 1.25 mm.
  • the appropriate good fractions between 0.71 and 0.90 or 0.90 and 1.12 mm are used in the further processes.
  • compositions can vary and are shown below in tabular form.
  • Granules are further processed into tablets using conventional tableting aids as in Example 1.
  • X50 particle size / drop size, below which 50% of the particle quantity is in the range of 1.5 to 8 ⁇ m with respect to the volume distribution of the individual particles / drops
  • Q (5.8) corresponds to the quantity of particles which is below 5.8 ⁇ m in relation to the volume distribution of the droplets
  • the spray thus obtained is dried with the aid of a drying gas with an inlet temperature between 130 ° C and 200 ° C and an outlet temperature of 40 ° C to 120 ° C Spray gas 1 Nm 3 / h to 15 Nm 3 / h and the volume flow of the drying gas 15 Nm 3 / h to 150 Nm 3 / h.
  • the dried solid content is collected by means of a gravity separator and / or filter unit.
  • 1 capsule for powder inhalation contains:
  • the active substance is produced as a spherically nanostructured active substance particle and mixed homogeneously with lactose. The mixture is packed in hard gelatin capsules.
  • the active ingredient is dissolved in physiological saline.
  • the hard wax is melted and the active ingredients are suspended in the mass.
  • the mass is then poured into suitable suppository molds.
  • the dose amounts can vary and are shown in the table below.

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Abstract

The invention relates to a method for treating or preventing headaches, migraines or cluster headaches. Said method involves the common administration of a therapeutically active amount of a CGRP-antagonist (A) or a physiologically compatible salt thereof, and a therapeutically active amount of a serotonin-reuptake inhibitor (B) or a physiologically compatible salt thereof. The invention also relates to the corresponding pharmaceutical compositions and to the production thereof.

Description

Verwendung eines CGRP-Antagonisten in Kombination mit einem Serotonin- Wiederaufnahme-Hemmer zur Behandlung von Migräne Use of a CGRP antagonist in combination with a serotonin reuptake inhibitor to treat migraines
Hintergrund der ErfindungBackground of the Invention
Migräne ist eine der häufigsten neurologischen Störungen und beinhaltet periodische Anfälle von Kopfschmerzen und Übelkeit sowie eine Vielzahl weiterer Symptome. Obwohl erhebliche Fortschritte gemacht worden sind, wird die Pathophysiologie von Migräne weiterhin nicht verstanden. Mehrere Beobachtungen deuten jedoch auf eine Beteiligung des Calcitonin-Gen-bezogenen Peptids (CGRP) hin. Migränekopfschmerzen beinhalten die Aktivierung des trigeminalen Systems und die Erweiterung von kranialen Gefäßen. CGRP ist an Neuronen in trigeminalen Ganglia lokalisiert, und CGRP-Spiegel sind während eines Migräneanfalls erhöht, was vermutlich die beobachtete Vasodilation bewirkt. Dementsprechend ist denkbar, dass die Inhibition der von CGRP hervorgerufenen Erweiterung der kranialen Gefäße möglicherweise eine neue Behandlung von Migränekopfschmerzen erlaubt.Migraine is one of the most common neurological disorders and includes periodic bouts of headache and nausea, as well as a variety of other symptoms. Although significant progress has been made, the pathophysiology of migraines is still not understood. However, several observations indicate involvement of the calcitonin gene-related peptide (CGRP). Migraine headaches include activation of the trigeminal system and enlargement of the cranial vessels. CGRP is localized to neurons in trigeminal ganglia, and CGRP levels are elevated during a migraine attack, which is thought to cause the observed vasodilation. Accordingly, it is conceivable that the inhibition of the enlargement of the cranial vessels caused by CGRP may allow a new treatment for migraine headaches.
Breite Verwendung findende Arzneistoffe gegen Migräne sind sogenannte "Triptane", z.B. Sumatriptan und Zolmitriptan. Diese Verbindungen rufen ihre Wirkungen gegen Migräne aufgrund ihrer vasokonstriktiven Eigenschaften und vermutlich ihrer Inhibition der Freisetzung des Neuropeptids Calcitonin-Gen-bezogenes Peptid (CGRP) hervor (Ferrari, M. D., Saxena, P. R. (1995), 5-HT1 receptors in migraine pathophysiology and treatment, Eur. J. Neurology, 2, 5-21 ; Johnson, K. W., Phebus, L. A., Cohen, M. L. (1998), Serotonin in migraine: Theiroes, animal modeis and emerging therapies, Progress in Drug Research, Bd. 51, 220-244), wobei man annimmt, dass dessen Spiegel während eines Migräneanfalls erhöht sind (Edvinsson, L, Goadsby, P. J. (1994), Neuropeptides in migraine and cluster headache, Cephalgia, 14(5), 320-327). Ein völlig neuer Ansatz zur Behandlung von Migräne ist die Verwendung von CGRP-Antagonisten (Doods, H., Hallermayer, G., Wu, D., Entzeroth, M., Rudolf, K., Engel, W., Eberlein, W. (2000), Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist, Br. J. Pharma- col., 129, 420-423). Hintergrund der ErfindungMedicines for migraines that are widely used are so-called "triptans", for example sumatriptan and zolmitriptan. These compounds elicit their effects against migraines because of their vasoconstrictive properties and presumably their inhibition of the release of the neuropeptide calcitonin gene-related peptide (CGRP) (Ferrari, MD, Saxena, PR (1995), 5-HT1 receptors in migraine pathophysiology and treatment , Eur. J. Neurology, 2, 5-21; Johnson, KW, Phebus, LA, Cohen, ML (1998), Serotonin in migraine: Theiroes, animal modeis and emerging therapies, Progress in Drug Research, Vol. 51, 220 -244), assuming that its levels are elevated during a migraine attack (Edvinsson, L, Goadsby, PJ (1994), Neuropeptides in migraine and cluster headache, Cephalgia, 14 (5), 320-327). A completely new approach to treating migraines is the use of CGRP antagonists (Doods, H., Hallermayer, G., Wu, D., Entzeroth, M., Rudolf, K., Engel, W., Eberlein, W. (2000), Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist, Br. J. Pharmacol., 129, 420-423). Background of the Invention
Im US Patent Nr. 5,023,269 wird beschrieben, dass sich 3-Aryloxy-3-substituierte Propanamine, wie beispielsweise Duloxetin, zur Behandlung von Schmerzen eignen. Insbesondere der Serotonin-Wiederaufnahme-Hemmer Duloxetin kann zur Behandlung von Migräne verwendet werden, was in der internationalen Patentanmeldung PCT/US95/13289 offenbart wird.US Pat. No. 5,023,269 describes that 3-aryloxy-3-substituted propanamines, such as duloxetine, are suitable for the treatment of pain. In particular, the serotonin reuptake inhibitor duloxetine can be used to treat migraines, which is disclosed in the international patent application PCT / US95 / 13289.
Die WO 98/11128 offenbart modifizierte Aminosäuren mit CGRP-antagonistischen Eigenschaften, deren Verwendung und Verfahren zu deren Herstellung sowie deren Verwendung für die Herstellung und Reinigung von Antikörpern und als markierte Verbindungen in RIA- und ELISA-Assays und als diagnostische oder analytische Hilfsmittel in der Neurotransmitterforschung. Angesichts ihrer pharmakologischen Eigenschaften sind die modifizierten Aminosäuren also geeignet für die akute und prophylaktische Behandlung von Kopfschmerzen, insbesondere Migräne und Cluster headache. Weitere Verbindungen mit CGRP-antagonistischen Eigenschaften werden in den internationalen Anmeldungen PCT/EP03/02417, PCT/EP03/11762, PCT/EP03/11763, PCT/EP04/00087, PCT/EP00/02004, PCT/EP00/ 0463, PCT/EP00/10391 und PCT/EP00/13236 beschrieben.WO 98/11128 discloses modified amino acids with CGRP-antagonistic properties, their use and methods for their production as well as their use for the production and purification of antibodies and as labeled compounds in RIA and ELISA assays and as diagnostic or analytical aids in neurotransmitter research. In view of their pharmacological properties, the modified amino acids are therefore suitable for the acute and prophylactic treatment of headaches, in particular migraines and cluster headache. Further compounds with CGRP-antagonistic properties are described in the international applications PCT / EP03 / 02417, PCT / EP03 / 11762, PCT / EP03 / 11763, PCT / EP04 / 00087, PCT / EP00 / 02004, PCT / EP00 / 0463, PCT / EP00 / 10391 and PCT / EP00 / 13236.
Zusammenfassende Darstellung der ErfindungSummary of the invention
Überraschenderweise ist festgestellt worden, dass in einem Modell, von dem angenommen wird, dass es die Antimigränewirkungen von Arzneistoffen vorhersagt, die Kombination von zwei Arzneistoffen mit völlig verschiedener Wirkungsweise, nämlich einem CGRP-Antagonisten (A) und einem Serotonin-Wiederaufnahme-Hemmer (B) oder einem physiologisch verträglichen Salz davon zu einer besseren Wirkung im Vergleich mit der Wirkung nur eines Arzneistoffs führt.Surprisingly, it has been found that in a model believed to predict the anti-migraine effects of drugs, the combination of two drugs with completely different modes of action, namely a CGRP antagonist (A) and a serotonin reuptake inhibitor (B ) or a physiologically acceptable salt thereof leads to a better effect compared to the action of only one drug.
Ausführliche Darstellung der ErfindungDetailed description of the invention
Gemäß einem ersten Aspekt stellt die vorliegende Erfindung ein Verfahren zur Behandlung oder Prävention von Indikationen bereit, die aus der Gruppe ausgewählt sind, die aus Kopfschmerzen, Migräne und Cluster headache besteht, wobei das Verfahren die gemeinsame Verabreichung einer therapeutisch wirksamen Menge eines CGRP-Antagonisten (A) oder eines physiologisch verträglichen Salzes davon und einer therapeutisch wirksamen Menge eines Serotonin-Wiederaufnahme- Hemmers (B) oder ein physiologisch verträgliches Salz davon an eine Person, die einer derartigen Behandlung bedarf, umfasst.In a first aspect, the present invention provides a method of treating or preventing indications selected from the group consisting of headache, migraine and cluster headache, the method comprising co-administering a therapeutically effective amount of a CGRP antagonist ( A) or a physiologically acceptable salt thereof and a therapeutically effective amount of a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof to a person in need of such treatment.
Im Sinne der vorliegenden Erfindung können als Wirkstoff (A) alle pharmazeutisch verträglichen Wirkstoffe Verwendung finden, die die bekannten Wirkungen von CGRP antagonisieren oder die Freisetzung von CGRP aus sensorischen Nerven- endigungen hemmen.For the purposes of the present invention, all pharmaceutically acceptable active ingredients which antagonize the known effects of CGRP or which inhibit the release of CGRP from sensory nerve endings can be used as the active ingredient (A).
Als CGRP-Antagonisten (A) kommen beispielsweise die in der WO 98/11128 oder DE 199 11 039 beschriebenen Aminosäurederivate, ferner die in der WO 98/56779, WO 98/09630 und WO 97/09046 beschriebenen nichtpeptidischen Wirkstoffe in Betracht.Possible CGRP antagonists (A) are, for example, the amino acid derivatives described in WO 98/11128 or DE 199 11 039, and also the non-peptide active ingredients described in WO 98/56779, WO 98/09630 and WO 97/09046.
Erfindungsgemäß bevorzugt wird der CGRP-Antagonist (A) ausgewählt aus der Gruppe, bestehend ausAccording to the invention, the CGRP antagonist (A) is preferably selected from the group consisting of
(1 ) 1 -[/V2-[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]- carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(1) 1 - [/ V 2 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(2) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(2,3,4,5~tetrahydro-2(1 H)-oxo-1 ,3-benzodiazepin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(2) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (2,3,4,5 ~ tetrahydro-2 (1 H) -oxo-1,3-benzodiazepine-3- yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(3) 1 -[/V2-[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(3) 1 - [/ V 2 - [4-amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) - 1- piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(4) 1 -[Λ^-[4-Amino-3,5-dibrom- A/-[[4-(3,4-dihydro-2(1 H)-oxochinazoIin-3-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidin,(4) 1 - [Λ ^ - [4-Amino-3,5-dibromo-A / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazoline-3-yl) - 1-piperidinyl ] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) -piperidine,
(5) 1 -[/V2-[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin, (6) 1 -[/V2-[4-Amino-3,5-dibrom-/V-[[4-(1 ,3-dihydro-4-phenyl-2(2Aτ)-oxoimidazol- 1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(5) 1 - [/ V 2 - [3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl ] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine, (6) 1 - [/ V 2 - [4-amino-3,5-dibromo- / V - [[4- (1,3-dihydro-4-phenyl-2 (2Aτ) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(7) 1 -[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxothieno[3,4-d]pyrimidin-3-yl)- 1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidin,(7) 1 - [3,5-Dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxothieno [3,4-d] pyrimidin-3-yl) -1-piperidinyl ] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine,
(8) 1 -[4-Amino-3,5-dibrom-/V-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1 ,2,4-triazol- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidin,(8) 1 - [4-Amino-3,5-dibromo- / V - [[4- (2,4-dihydro-5-phenyl-3 (3H) -oxo-1, 2,4-triazole-2 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(9) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(2,4-dihydro-5-phenyl-3(3/-/)-oxo-1 ,2,4-triazol- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(9) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (2,4-dihydro-5-phenyl-3 (3 / - /) - oxo-1, 2,4- triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine,
(10) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1 ,2,4-triazol- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperazin,(10) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (2,4-dihydro-5-phenyl-3 (3H) -oxo-1, 2,4-triazole-2 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
(11) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxothieno[3,2-d]pyrimidin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(11) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxothieno [3,2-d] pyrimidin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(12) 1 -[4-Amino-3,5-dibrom-/V-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidin-yl]carbonyl]-D-phenylalanyl]-4-(1 -ethyl-4-piperi- dinyl)-piperidin,(12) 1 - [4-Amino-3,5-dibromo- / V - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1 - yl] -1-piperidin-yl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) piperidine,
(13) 1 -[4-Amino-3,5-dibrom-/V-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidin,(13) 1 - [4-Amino-3,5-dibromo- / V - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-hexyl-4-piperidinyl) -piperidine,
(14) 1 ~[4-Amino-3,5-dibrom-/V-[[4-[3,4-dihydro-2(1 /τ)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-piperidin,(14) 1 ~ [4-amino-3,5-dibromo- / V - [[4- [3,4-dihydro-2 (1 / τ) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-cyclopropylmethyl-4-piperidinyl) -piperidine,
(15) 1 -[Λ/-[[4-[3,4-Dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperidinyl]carbonyl]- 3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1 H-1-azepinyl)-piperidin, (16) (f?,S)-1-[4-[4-(3,4-Dihydro-2(1 /^)-oxochinazolin-3-yl)-1 -piperidinyl]-2-[(4-hy- droxy-3,5-dimethylphenyl)methyl]-1 ,4-dioxobutyl]-4-(1-piperidinyl)-piperidin,(15) 1 - [Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl] - 3-ethenyl-D, L-phenylalanyl] -4- (hexahydro-1 H-1-azepinyl) piperidine, (16) (f?, S) -1- [4- [4- (3,4-Dihydro-2 (1 / ^) - oxoquinazolin-3-yl) -1 -piperidinyl] -2 - [(4- hydroxy-3,5-dimethylphenyl) methyl] -1, 4-dioxobutyl] -4- (1-piperidinyl) piperidine,
(17) 1 -[4-Amino-3,5-dibrom-/V-[[4-[/V-(aminocarbonyl)-/V-phenylamino]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(17) 1 - [4-Amino-3,5-dibromo- / V - [[4 - [/ V- (aminocarbonyl) - / V-phenylamino] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(18) 1 -[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazin,(18) 1 - [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (5-methoxy-4-pyrimidinyl) piperazine,
(19) 1-[4-Amino-3,5-dibrom-/V-[[4-(1 ,1-dioxido-3(4/^-oxo-1 ,2,4-benzothiadiazin- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(19) 1- [4-Amino-3,5-dibromo- / V - [[4- (1, 1-dioxido-3 (4 / ^ - oxo-1, 2,4-benzothiadiazin- 2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(20) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[2(1 H)-oxochinolin-3-yl]-1 -piperidinyl]carbonyl]- D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(20) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [2 (1 H) -oxoquinolin-3-yl] -1 -piperidinyl] carbonyl] - D-phenylalanyl] -4 - (1-piperidinyl) -piperidine,
(21 ) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazin,(21) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- [3- (dimethylamino) propyl] piperazine,
(22) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidin,(22) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (4-methyl-1-piperazinyl) piperidine,
(23) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-piperazin,(23) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4 - [(1-methyl-4-piperidinyl) carbonyl] piperazine,
(24) 1 -[4-Amino-3,5ldibrom-/V-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazin,(24) 1 - [4-Amino-3.5 L dibromo / V - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4 - [(1-methyl-4-piperazinyl) carbonyl] -piperazine,
(25) 1-[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazin,(25) 1- [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [4- [4- (dimethylamino) butyl] phenyl] -piperazine,
(26) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidin, . .(26) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- [4- (dimethylamino) -1-piperidinyl] -piperidine, , ,
(27) 1 -[Λ -[[4-(1 ,3-Dihydro-4-phenyl-2(2/-/)-oxoimidazol-1 -yl)-1 -piperidinyl]carbonyl]- /V-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidin,(27) 1 - [Λ - [[4- (1,3-dihydro-4-phenyl-2 (2 / - /) - oxoimidazol-1 -yl) -1 -piperidinyl] carbonyl] - / V-methyl- D-tryptyl] -4- (4-methyl-1-piperazinyl) piperidine,
(28) 1-[/V2-[[4-(1 ,3-Dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]- N'-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidin,(28) 1 - [/ V 2 - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] - N '- (1, 1-dimethylethoxycarbonyl) -D-tryptyl] -4- (1-methyl-4-piperidinyl) -piperidine,
(29) (R,S)A -[4-[4-(3,4-Dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]-2-[(3,5-di- brom-4-methylphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)- piperidin,(29) (R, S) A - [4- [4- (3,4-Dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] -2 - [(3,5-di bromo-4-methylphenyl) methyl] -1, 4-dioxobutyl] -4- (4-methyl-1-piperazinyl) - piperidine,
(30) (ß,S)-1-[4-[4-(3,4-Dihydro-2(1 /-/)-oxochinazolin-3-yl)-1-piperidinyl]-2-[(3)5-di- brom-4-methoxyphenyl)methyl]-1 ,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)- piperidin,(30) (ß, S) -1- [4- [4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1-piperidinyl] -2 - [(3 ) 5-di-bromo-4-methoxyphenyl) methyl] -1, 4-dioxobutyl] -4- (1-methyl-4-piperidinyl) piperidine,
(31 ) (R,S)-1 -[4-[4-(3,4-Dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]-2-[(3,4-di- bromphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidin,(31) (R, S) -1 - [4- [4- (3,4-Dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] -2 - [(3,4- di-bromophenyl) methyl] -1, 4-dioxobutyl] -4- (4-methyl-1-piperazinyl) piperidine,
(32) 1 -[Λ/2-[N-[[4-(1 ,3-Dihydro-2(2H)-oxobenzimidazol-1 -yl)-1 -piperidinyljcarbonyl]- 3,5-dibrom-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(32) 1 - [Λ / 2 - [N - [[4- (1,3-dihydro-2 (2H) -oxobenzimidazol-1-yl) -1 -piperidinyljcarbonyl] - 3,5-dibromo-D-tyrosyl ] -L-lysyl] -4- (4-pyridinyl) piperazine,
(33) 1 -[4-Amino-3,5-dibrom-/V-[[4-(1 ,3-dihydro-6-hydroxy-2(2H)-oxobenzimidazol- 1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(33) 1 - [4-Amino-3,5-dibromo- / V - [[4- (1,3-dihydro-6-hydroxy-2 (2H) -oxobenzimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(34) 1 -[/V2-[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-2(2H)-oxobenzimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-Λ/6,Λ/6-dimethyl-L-lysyl]-4-(4-pyridinyl)- piperazin,(34) 1 - [/ V 2 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-2 (2H) -oxobenzimidazol-1-yl) -1-piperidinyl ] carbonyl] -D-phenylalanyl] -Λ / 6 , Λ / 6 -dimethyl-L-lysyl] -4- (4-pyridinyl) - piperazine,
(35) 1 -[/V2-[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-Λ/6,/V3-dimethyl-L-lysyl]-4-(4-pyridinyl)- piperazin,(35) 1 - [/ V 2 - [4-amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) - 1- piperidinyl] carbonyl] -D-phenylalanyl] -Λ / 6 , / V 3 -dimethyl-L-lysyl] -4- (4-pyridinyl) - piperazine,
(36) (R,S)A -[2-(4-Amino-3,5-dibrombenzoyl)-4-[4-(3,4-dihydro-2(1 H)-oxo- chinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidin, (37) 1-[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2,2-dioxido-2,1 ,3-benzothiadiazin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyI)-piperidin,(36) (R, S) A - [2- (4-amino-3,5-dibromobenzoyl) -4- [4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl ) -1-piperidinyl] -4-oxobutyl] -4- (1-piperidinyl) -piperidine, (37) 1- [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2,2-dioxido-2,1, 3-benzothiadiazin-3-yl) -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(38) 1-[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-2(2H)-oxoimidazo[4,5-c]chinolin- 3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)carbonyl]- piperidin,(38) 1- [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-2 (2H) -oxoimidazo [4,5-c] quinolin-3-yl] - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) carbonyl] piperidine,
(39) 1-[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1/ )-oxochinazolin-3-yl)-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(39) 1- [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 /) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(40) 1 -[N2-[3,5-Dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]- carbonyl]-D-tyrosyl]-Λ/6,Λ/6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazin,(40) 1 - [N 2 - [3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] - carbonyl] -D-tyrosyl] -Λ / 6 , Λ / 6 -dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine,
(41 ) 1-[4-Amino-/V-[[4-[4-(3-bromphenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1 -yl]- 1-piperidinyl]carbonyl]-3,5-dibrom-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidin,(41) 1- [4-Amino- / V - [[4- [4- (3-bromophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1 -yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(42) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-phenyl.2(2H)-oxoimidazol-1 -yl]- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidin,(42) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4-phenyl.2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-methyl-1-piperazinyl) piperidine,
(43) 1-[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)- piperidin,(43) 1- [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1- yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine,
(44) 1 -[4-Amino-3,5-dibrom-/V-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2/-/)- oxoimidazol-1-yl]-1 -piperidinyl] carbonyl]-D-phenylalanyl]-4-(exo-8-methyl- 8-azabicyclo[3.2.1]oct-3-yl)-piperazin,(44) 1 - [4-Amino-3,5-dibromo- / V - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 / - /) - oxoimidazole -1-yl] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) piperazine,
(45) 1-[3,5-Dibrom-/V-[[4-(1 ,3-dihydro-4-phenyl-2(2/- )-oxoimidazol-1-yl)-1-piperi- dinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidin, _ _(45) 1- [3,5-dibromo / V - [[4- (1,3-dihydro-4-phenyl-2 (2 / -) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine, _ _
(46) i -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -ethyl-4-piperi- dinyl)-piperazin,(46) i - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1 - yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) piperazine,
(47) 1 -[4-Amino-3,5-dibrom-Λ/~[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl]- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1 HA ,4-di- azepin-1 -yl)piperidin,(47) 1 - [4-amino-3,5-dibromo-Λ / ~ [[4- [1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-4-methyl-1 HA, 4-di-azepin-1 -yl) piperidine,
(48) 1 -[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]- carbonyl]-D-tyrosyl]-4-[1-(methylsulfonyl)-4-piperidinyl]-piperidin,(48) 1 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl] -D-tyrosyl ] -4- [1- (methylsulfonyl) -4-piperidinyl] -piperidine,
(49) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2/-/)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidin,(49) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2 / - /) - oxoimidazol-1-yl) - 1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine,
(50) 1 -[3,5-Dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)-oxo- . imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1/-/-1-azepinyl)- piperidin,(50) 1 - [3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxo-. imidazol-1-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro-1 / - / - 1-azepinyl) piperidine,
(51 ) 1 -[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolin-3-yl)-1 -piperidinyl]- carbonyl]-D-tyrosyl]-4-(1 -methyl-4-piperidinyl)-piperidin,(51) 1 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1 -piperidinyl] - carbonyl] -D -tyrosyl] -4- (1-methyl-4-piperidinyl) piperidine,
(52) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)- piperazin,(52) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) piperazine,
(53) 1 -[4-Amino-3,5-dibrom-/V-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazin,(53) 1 - [4-Amino-3,5-dibromo- / V - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
(54) 1 ~[3,5-Dibrom-Λ.-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)-oxo- imidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-tyrosyl]-4-(1 -piperidinyl)-piperidin,(54) 1 ~ [3,5-dibromo-Λ .- [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1 -piperidinyl] carbonyl] -D-tyrosyl] -4- (1 -piperidinyl) -piperidine,
(55) 1 -[N6-Acetyl-N2-[3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin, _ _(55) 1 - [N 6 -acetyl-N 2 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) - 1- piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine, _ _
(56) 1-[3,5-Dibrom-/V-[[4-(1 ,3-dihydro-4-phenyl-2(2/-/)-oxoimidazol-1-yl)-1-piperi- dinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 /--1-azepinyl)-piperidin,(56) 1- [3,5-dibromo / V - [[4- (1,3-dihydro-4-phenyl-2 (2 / - /) - oxoimidazol-1-yl) -1-piperidinyl ] carbonyl] -D-tyrosyl] -4- (hexahydro-1 / - 1-azepinyl) piperidine,
(57) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol- 1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidin,(57) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4- (3-thienyl) -2 (2H) -oxoimidazol-1-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(58) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2/-/)- oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperi- dinyl)-piperidin,(58) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 / - /) - oxoimidazole -1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(59) 1 -[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]carbo- nyl]-D-tyrosyl3-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidin,(59) 1 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl] -D- tyrosyl3-4- [1- (hydroxycarbonylmethyl) -4-piperidinyl] -piperidine,
(60) 1-[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1H)-oxochinazolin-3-yl]-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulfonyl-4-piperidinyl)-piperidin,(60) 1- [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1H) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methylsulfonyl-4-piperidinyl) -piperidine,
(61) 1-[3,5-Dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1-piperidinyl]carbo- nyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidin,(61) 1- [3,5-dibromo / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D- tyrosyl] -4- (4-piperidinyl) -piperidine,
(62) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidin,(62) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperidine,
(63) 1 -[4-Amino-3,5-dibrom-/V-[[4-(1 ,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxo- imidazol-1 -yl)-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperi- dinyl)-piperidin,(63) 1 - [4-Amino-3,5-dibromo- / V - [[4- (1,3-dihydro-4- (3-hydroxyphenyl) -2 (2H) -oxoimidazol-1-yl ) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(64) 1 -[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]carbo- nyl]-D-tyrosyl]-4-(hexahydro-1 H-1 -azepinyl)-piperidin,(64) 1 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl] -D- tyrosyl] -4- (hexahydro-1 H-1 azepinyl) piperidine,
(65) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl3-D-phenylalanyl]-4-(1 -piperidinyl)-piperidin, (66) 1-[4-Amino-3,5-dibrom-/V-[[4-[4-(3-bromphenyl)-1 ,3-dihydro-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-aza- bicyclo[3.2.1]oct-3-yl)-piperazin,(65) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl3-D-phenylalanyl] -4- (1-piperidinyl) piperidine, (66) 1- [4-Amino-3,5-dibromo- / V - [[4- [4- (3-bromophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1-yl ] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) piperazine,
(67) 1-[4-Amino-3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidin,(67) 1- [4-amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperidine,
(68) 1 -[4-Amino-3,5-Dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazin,(68) 1 - [4-Amino-3,5-dibromo / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) piperazine,
(69) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-aza- bicyclo[3.2.1]oct-3-yl)-piperazin,(69) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- (3-methoxyphenyl) -2 (2H) -oxoimidazol-1-yl ] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) piperazine,
(70) 1 -[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyljcarbo- nyl]-D-tyrosyl]-4-[1-(cyclopropylmethyl)-4-piperidinyl]-piperidin,(70) 1 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyljcarbonyl] -D-tyrosyl] -4- [1- (cyclopropylmethyl) -4-piperidinyl] -piperidine,
(71 ) 1 -[4-Amino-3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 /- )-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidin,(71) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 / -) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1H-1-azepinyl) -piperidine,
(72) 1-[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidin,(72) 1- [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-piperidinyl) -piperidine,
(73) 1-[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi- dinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidin,(73) 1- [3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (4-pyridinyl) -piperidine,
(74) 1-[3,5-Dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2W)-oxo- imidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-tyrosyl]-4-(1 -methyl-4-piperidinyl)- piperazin, (75) 1 -[/V2-[3,5-Dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)-oxo- imidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)- piperazin,(74) 1- [3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2W) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-methyl-4-piperidinyl) piperazine, (75) 1 - [/ V 2 - [3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazole -1 -yl] -1 -piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) - piperazine,
(76) 1 -[3,5-Dibrom-/V-[[4-(1 ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1 -yl)-1 -piperi- dinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidin,(76) 1 - [3,5-dibromo / V - [[4- (1,3-dihydro-4- (3-thienyl) -2 (2H) -oxoimidazol-1-yl) -1 -piperi- dinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine,
(77) 1-[4-Amino-/V-[[4-[4-(3-chlorphenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1-yl]- 1-piperidinyl]carbonyl]-3,5-dibrom-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidin,(77) 1- [4-amino- / V - [[4- [4- (3-chlorophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(78) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2/-/)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 H- 1 -azepinyl)-piperidin,(78) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 / - /) - oxoimidazole -1 -yl] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1H-1-azepinyl) -piperidine,
(79) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperi- dinyl)-piperazin,(79) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1 - yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
(80) 1 -[4-Amino-/V-[[4-[4-(3-chlorphenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1 -yl]- 1 -piperidinyl]carbonyl]-3,5-dibrom-D-phenylalanyl]-4-(hexahydro-1 H-1 -azepi- nyl)-piperidin,(80) 1 - [4-Amino- / V - [[4- [4- (3-chlorophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1 -yl] -1 -piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (hexahydro-1 H-1-azepinyl) piperidine,
(81) 1-[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazin,(81) 1- [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-pyridinyl) piperazine,
(82) 1 -[3,5-Dibrom-/V-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)-1 -piperi- dinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidin,(82) 1 - [3,5-dibromo / V - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-methyl-4-piperidinyl) -piperidine,
(83) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl]- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazin, (84) 1 -[3,5-Dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperidinyl]carbo- nyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazin,(83) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [4- (1-oxoethyl) phenyl] piperazine, (84) 1 - [3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl] -D- tyrosyl] -4- (1-methyl-4-piperidinyl) piperazine,
(85) 1 -[4-Amino-3,5-dibrom-/V-[[4-[1 ,3-dihydro-4-(3-nitrophenyl)-2(2/-/)-oxoimidazol- 1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperidinyl)- piperidin,(85) 1 - [4-Amino-3,5-dibromo- / V - [[4- [1,3-dihydro-4- (3-nitrophenyl) -2 (2 / - /) - oxoimidazole- 1 - yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(86) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 τ)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-pyrrolidinyl)-piperidin,(86) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 τ) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-pyrrolidinyl) -piperidine,
(87) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 HA -azepinyl)-piperidin und(87) 1 - [4-amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1 HA-azepinyl) piperidine and
(88) 1-[4-Amino-3,5-dibrom-N-[[4-(1 ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1- yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazin,(88) 1- [4-Amino-3,5-dibromo-N - [[4- (1,3-dihydro-4- (3-thienyl) -2 (2H) -oxoimidazol-1-yl) -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
deren physiologisch verträglichen Salzen und den Hydraten der Salze.their physiologically compatible salts and the hydrates of the salts.
Als Serotonin-Wiederaufnahme-Hemmer (B) können Citalopram, Duloxetin, Escitalopram, Fluoxetin, Fluvoxamin, Paroxetin, Sertralin, Trazodon oder die physiologisch verträglichen Salze davon verwendet werden. Vorzugsweise wird Duloxetin verwendet.Citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone or the physiologically tolerable salts thereof can be used as serotonin reuptake inhibitors (B). Duloxetine is preferably used.
Die Dosierung für den Serotonin-Wiederaufnahme-Hemmer (B) ist ungefähr 1/50 der niedrigsten normalerweise empfohlenen Dosis bis zu 1/1 der normalerweise empfohlenen Dosis, und zwar auf oralem, nasalem, inhalativem, subkutanem oder intravenösem Weg.The dose for the serotonin reuptake inhibitor (B) is about 1/50 of the lowest normally recommended dose up to 1/1 of the normally recommended dose, by oral, nasal, inhalation, subcutaneous or intravenous routes.
Erfindungsgemäß kann der CGRP-Antagonist (A) oder ein physiologisch verträglichen Salzes davon auf intravenösem oder subkutanem Weg in einer Dosierung von 0.0001 bis 3 mg/kg Körpergewicht verabreicht werden, auf oralem Weg in einer Dosierung von 0.1 bis 20 mg/kg Körpergewicht oder auf nasalem oder inhalativem Weg in einer Dosierung von 0.1 bis 10 mg/kg Körpergewicht einmal, zweimal oder dreimal täglich in Kombination mitAccording to the invention, the CGRP antagonist (A) or a physiologically tolerable salt thereof can be administered intravenously or subcutaneously in a dosage of 0.0001 to 3 mg / kg body weight, orally in a dosage of 0.1 to 20 mg / kg body weight or on nasalem or inhalation route in a dosage of 0.1 to 10 mg / kg body weight once, twice or three times a day in combination with
einem Serotonin-Wiederaufnahme-Hemmer (B) oder einem physiologisch verträglichen Salz davon, das auf oralem Weg in einer Dosierung von 0.03 bis 1.43 mg/kg Körpergewicht einmal, zweimal oder dreimal täglich odera serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof, administered orally at a dose of 0.03 to 1.43 mg / kg body weight once, twice or three times a day or
auf intravenösem oder subkutanem Weg in einer Dosierung von 0.002 bis 0.09 mg/kg Körpergewicht einmal oder zweimal täglich oderintravenously or subcutaneously at a dose of 0.002 to 0.09 mg / kg body weight once or twice a day or
auf rektalem Weg in einer Dosierung von 0.007 bis 0.36 mg/kg Körpergewicht einmal oder zweimal täglich oderrectally in a dose of 0.007 to 0.36 mg / kg body weight once or twice a day or
auf nasalem Weg in einer Dosierung von 0.006 bis 0.29 mg/kg Körpergewicht einmal oder zweimal täglich verabreicht werden kann.can be administered nasally at a dose of 0.006 to 0.29 mg / kg body weight once or twice a day.
Die vorliegende Erfindung stellt gemäß einem zweiten Aspekt eine pharmazeutische Zusammensetzung zur Behandlung oder Prävention von Kopfschmerzen, Migräne oder Cluster headache, die eine therapeutisch wirksame Menge eines CGRP- Antagonisten (A) oder eines physiologisch verträglichen Salzes davon und einem Serotonin-Wiederaufnahme-Hemmer (B) oder einem physiologisch verträglichen Salz davon besteht, als kombinierte Zubereitung für die gleichzeitige oder zeitlich aufeinander folgende Verabreichung bereit.According to a second aspect, the present invention provides a pharmaceutical composition for the treatment or prevention of headache, migraine or cluster headache, which contains a therapeutically effective amount of a CGRP antagonist (A) or a physiologically tolerable salt thereof and a serotonin reuptake inhibitor (B ) or a physiologically tolerable salt thereof, as a combined preparation for simultaneous or sequential administration.
Eine erfindungsgemäße pharmazeutische Zusammensetzung kann eine einzelne Dosierungseinheit von 0.1 bis 1500 mg, vorzugsweise 0.3 bis 1000 mg, besonders bevorzugt 5 bis 750 mg, des CGRP-Antagonisten (A) oder einer äquivalenten Menge eines physiologisch verträglichen Salzes davon undA pharmaceutical composition according to the invention can have a single dosage unit of 0.1 to 1500 mg, preferably 0.3 to 1000 mg, particularly preferably 5 to 750 mg, of the CGRP antagonist (A) or an equivalent amount of a physiologically tolerable salt thereof and
eine einzelne Dosierungseinheit von 0.1 bis 150 mg, vorzugsweise 0.2 bis 100 mg, beispielsweise 10 bis 100 mg, besonders bevorzugt 10 bis 80 mg, insbesondere 40 bis 80 mg, des Serotonin-Wiederaufnahme-Hemmers (B) oder einer äquivalenten Menge eines physiologisch verträglichen Salzes davon enthalten. Alle Dosen oder Dosierungseinheiten eines physiologisch verträglichen Salzes einer der vorstehend genannten aktiven Verbindungen sind als Dosis oder Dosierung der aktiven Verbindung selbst zu verstehen.a single dosage unit of 0.1 to 150 mg, preferably 0.2 to 100 mg, for example 10 to 100 mg, particularly preferably 10 to 80 mg, in particular 40 to 80 mg, of the serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically tolerable one Contain salt of it. All doses or dosage units of a physiologically compatible salt of one of the above-mentioned active compounds are to be understood as the dose or dosage of the active compound itself.
Ferner kann eine erfindungsgemäße pharmazeutische Zusammensetzung ein Kit von Teilen für die Behandlung oder Prävention von Kopfschmerzen, Migräne oder Cluster headache sein, wobei das Kit umfasst:Furthermore, a pharmaceutical composition according to the invention can be a kit of parts for the treatment or prevention of headache, migraine or cluster headache, the kit comprising:
(a) eine erste Umschließung enthaltend eine pharmazeutische Zusammensetzung umfassend eine therapeutisch wirksame Menge des CGRP-Antagonisten (A) oder eines physiologisch verträglichen Salzes davon und ein oder mehrere physiologisch verträgliche Verdünnungsmittel und/oder Trägerstoffe; und(a) a first enclosure containing a pharmaceutical composition comprising a therapeutically effective amount of the CGRP antagonist (A) or a physiologically acceptable salt thereof and one or more physiologically acceptable diluents and / or carriers; and
(b) eine zweite Umschließung enthaltend eine pharmazeutische Zusammensetzung umfassend einen Serotonin-Wiederaufnahme-Hemmer (B) oder ein physiologisch verträgliches Salz davon und einen oder mehrere physiologisch verträgliche Verdünnungsmittel und/oder Trägerstoffe.(b) a second enclosure containing a pharmaceutical composition comprising a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof and one or more physiologically acceptable diluents and / or carriers.
Ein dritter Aspekt der vorliegenden Erfindung ist die Verwendung des CGRP-Antagonisten (A) oder eines physiologisch verträglichen Salzes davon in Kombination mit einem Serotonin-Wiederaufnahme-Hemmer (B) oder einem physiologisch verträglichen Salz davon für die Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung oder Prävention von Kopfschmerzen, Migräne oder Cluster headache.A third aspect of the present invention is the use of the CGRP antagonist (A) or a physiologically acceptable salt thereof in combination with a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treatment or prevention of headache, migraine or cluster headache.
Der CGRP-Antagonist (A) oder ein physiologisch verträgliches Salz hiervon kann z.B. unter Verwendung einer der in den Beispielen beschriebenen pharmazeutischen Formulierungen verabreicht werden. Die Beispiele, die folgen, beschreiben pharmazeutische Zusammensetzungen, die den CGRP-Antagonisten (A) oder ein physiologisch verträgliches Salz davon und einen Serotonin-Wiederaufnahme-Hemmer (B) oder ein physiologisch verträgliches Salz davon enthalten. Beispiel 1aThe CGRP antagonist (A) or a physiologically tolerable salt thereof can be administered, for example, using one of the pharmaceutical formulations described in the examples. The examples that follow describe pharmaceutical compositions containing the CGRP antagonist (A) or a physiologically acceptable salt thereof and a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof. Example 1a
Tabletten enthaltend 100 mα CGRP-Antagonist (A) oder eine äquivalente Menge eines physiologisch verträglichen Salzes davon und 50 mg Serotoni n-Wiederaufnah- me-Hemmer (B) oder eine äquivalente Menge eines physiologisch verträglichen Salzes davonTablets containing 100 mα of CGRP antagonist (A) or an equivalent amount of a physiologically acceptable salt thereof and 50 mg of Serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof
Zusammensetzung/Tablette:Composition / tablet:
CGRP-Antagonist (A) 100 mgCGRP antagonist (A) 100 mg
Serotonin-Wiederaufnahme-Hemmer (B) 50 mgSerotonin reuptake inhibitor (B) 50 mg
Lactose 375 mgLactose 375 mg
Magnesiumstearat 3.0 mgMagnesium stearate 3.0 mg
Povidon 8.5 mgPovidone 8.5 mg
Grospovidon 14.4 mg Flüchtiger Bestandteil: WasserGrospovidone 14.4 mg Volatile component: water
Herstellung:production:
CGRP-Antagonist (A), Serotonin-Wiederaufnahme-Hemmer (B) und Lactose (fein) werden in einem geeigneten Mischer (z.B. Diosna P2) homogen gemischt; anschließend granuliert man die Mischung mit einer wässrigen Povidon-Lösung. Das Granulat wird mit einem Kressner-Sieb mit 1.6 mm gesiebt und 2 Stunden bei 40°C getrocknet. Im Anschluss wird das Granulat in einer geeigneten Mühle, z.B. einer Comill bei 3000 U/Minute mit Maschenweite 1.1 mm gesiebt. Daraufhin wird das Granulat 5 Minuten mit Grospovidon gemischt und anschließend noch 1 Minute mit Magnesiumstearat. Die so erhaltene Mischung wird in einer Tablettenpresse zu Tabletten mit einem geeigneten Durchmesser gepresst.CGRP antagonist (A), serotonin reuptake inhibitor (B) and lactose (fine) are mixed homogeneously in a suitable mixer (e.g. Diosna P2); then the mixture is granulated with an aqueous povidone solution. The granules are sieved with a Kressner sieve with 1.6 mm and dried at 40 ° C for 2 hours. The granulate is then passed through a suitable mill, e.g. a Comill sieved at 3000 rpm with a mesh size of 1.1 mm. The granules are then mixed with grospovidone for 5 minutes and then with magnesium stearate for 1 minute. The mixture thus obtained is pressed in a tablet press into tablets with a suitable diameter.
Dieses Herstellungsverfahren ist die Grundlage weiterer Beispiele, die in der folgenden Tabelle aufgelistet sind. Tabelle 1This manufacturing process is the basis of further examples, which are listed in the following table. Table 1
Figure imgf000017_0001
Figure imgf000017_0001
Beispiel 2Example 2
Tabletten enthaltend 100 mg CGRP-Antagonist (A) oder eine äguivalente Menge eines physiologisch verträglichen Salzes davon und 50 mg Serotonin-Wiederaufnah- me-Hemmer (B) oder eine äquivalente Menge eines physiologisch verträglichen Salzes davonTablets containing 100 mg of CGRP antagonist (A) or an equivalent amount of a physiologically acceptable salt thereof and 50 mg of serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof
Zusammensetzung:Composition:
CGRP-Antagonist (A) 100 mgCGRP antagonist (A) 100 mg
Serotonin-Wiederaufnahme-Hemmer (B) 50 mgSerotonin reuptake inhibitor (B) 50 mg
Lactose 284 mg mikrokristalline Cellulose 89.5 mg Magnesiumstearat 7.2 mgLactose 284 mg microcrystalline cellulose 89.5 mg Magnesium stearate 7.2 mg
Croscarmellose 7.3 mgCroscarmellose 7.3 mg
Flüchtiger Bestandteil: WasserVolatile component: water
Herstellung:production:
CGRP-Antagonist (A), Serotonin-Wiederaufnahme-Hemmer (B), Lactose (fein) und mikrokristalline Cellulose werden in einem geeigneten Mischer (z.B. Diosna P2) homogen gemischt; anschließend wird die Mischung mit Wasser granuliert. Das Granulat wird mit einem Kressner-Sieb mit 1.6 mm gesiebt und 2 Stunden bei 40°C getrocknet. Im Anschluss wird das Granulat in einer geeigneten Mühle, z.B. einer Comill bei 3000 U/Minute mit Maschenweite 1.1 mm gesiebt. Daraufhin wird das Granulat 5 Minuten mit Croscarmellose und anschließend noch 1 Minute mit Magnesiumstearat gemischt. Die so erhaltene Mischung wird in einer Tablettenpresse zu Tabletten mit einem geeigneten Durchmesser gepresst.CGRP antagonist (A), serotonin reuptake inhibitor (B), lactose (fine) and microcrystalline cellulose are mixed homogeneously in a suitable mixer (e.g. Diosna P2); the mixture is then granulated with water. The granules are sieved with a Kressner sieve with 1.6 mm and dried at 40 ° C for 2 hours. The granules are then passed in a suitable mill, e.g. a Comill sieved at 3000 rpm with a mesh size of 1.1 mm. The granules are then mixed with croscarmellose for 5 minutes and then with magnesium stearate for 1 minute. The mixture thus obtained is pressed in a tablet press into tablets with a suitable diameter.
Dieses Herstellungsverfahren ist die Grundlage weiterer Beispiele, die in der folgenden Tabelle aufgelistet sind.This manufacturing process is the basis of further examples, which are listed in the following table.
Tabelle 2Table 2
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000018_0001
Figure imgf000019_0001
Beispiel 3aExample 3a
Wässrige Lösung zur intranasalen Anwendung enthaltend 20% CGRP-Antagonist (A) oder eine äquivalente Menge eines physiologisch verträglichen Salzes davon und 5% Serotonin-Wiederaufnahme-Hemmer (B) oder eine äquivalente Menge eines physiologisch verträglichen Salzes davonAqueous solution for intranasal use containing 20% CGRP antagonist (A) or an equivalent amount of a physiologically acceptable salt thereof and 5% serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof
Zusammensetzung:Composition:
CGRP-Antagonist (A) 20 mg Serotonin-Wiederaufnahme-Hemmer (B) 5 mgCGRP antagonist (A) 20 mg serotonin reuptake inhibitor (B) 5 mg
Mannitol 5 mgMannitol 5 mg
Wasser ad 0.1 mlWater ad 0.1 ml
Durchführung:Execution:
Der Wirkstoff wird in Wasser unter Rühren und gegebenenfalls Erwärmen gelöst/suspendiert. Das Isotonans Mannitol wird zugegeben und die Lösung wird mit Wasser auf das Endvolumen aufgefüllt.The active ingredient is dissolved / suspended in water with stirring and optionally heating. The isotonans mannitol is added and the solution is made up to the final volume with water.
Beispiel 3bExample 3b
Wässrige Lösung zur intranasalen Anwendung enthaltend 40% CGRP-Antagonist (A) oder eine äguivalente Menge eines physiologisch verträglichen Salzes davon und 10% Serotonin-Wiederaufnahme-Hemmer (B) oder eine äquivalente Menge eines physiologisch verträglichen Salzes davon und 1.5% LabrasolAqueous solution for intranasal use containing 40% CGRP antagonist (A) or an equivalent amount of a physiologically acceptable salt thereof and 10% serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof and 1.5% Labrasol
Zusammensetzung:Composition:
CGRP-Antagonist (A) 40 mgCGRP antagonist (A) 40 mg
Serotonin-Wiederaufnahme-Hemmer (B) 10 mg Labrasol 1.5 mgSerotonin reuptake inhibitor (B) 10 mg Labrasol 1.5 mg
Mannitol 5 mg Wasser ad 0.1 mlMannitol 5 mg Water ad 0.1 ml
Durchführung:Execution:
Die Wirkstoffe werden in Wasser unter Rühren und gegebenenfalls Erwärmen gelöst/suspendiert. Das Isotonans Mannitol und Labrasol werden zugegeben und die Lösung wird mit Wasser auf das Endvolumen aufgefüllt.The active ingredients are dissolved / suspended in water with stirring and optionally heating. The isotonans mannitol and Labrasol are added and the solution is made up to the final volume with water.
Dieses Herstellungsverfahren ist die Grundlage weiterer Beispiele, die in der folgenden Tabelle aufgelistet sind.This manufacturing process is the basis of further examples, which are listed in the following table.
Tabelle zu 3a und bTable 3a and b
Figure imgf000020_0001
Figure imgf000020_0001
Pelletspellets
Die erfindungsgemäßen Arzneistoffe können auch in Form kleiner Partikeln wie z.B.The pharmaceutical substances according to the invention can also be in the form of small particles such as e.g.
Pellets hergestellt werden. Hierbei kann der Wirkstoff auf Neutralpellets, die ausPellets are made. The active ingredient can be based on neutral pellets
Saccharose und Stärke oder mikrokristalliner Cellulose bestehen, aufgetragen werden.Sucrose and starch or microcrystalline cellulose exist.
Die Herstellung erfolgt in folgenden Schritten:The production takes place in the following steps:
1. Auswahl bzw. Herstellung von Starterpellets1. Selection or production of starter pellets
2. Aufbau der Wirkstoffschicht Fakultativ: Überziehen von Pellets zur Stabilitätsverbesserung oder Geschmackskorrektur oder - falls gewünscht - zur Retardierung einer oder mehrerer Wirkstoffe.2. Structure of the active substance layer Optional: coating of pellets to improve stability or to correct taste or - if desired - to retard one or more active ingredients.
Beispiel 4Example 4
Herstellung einer Wirkstoffauftragung mit 100 Gewichtsteilen CGRP-Antagonist (A) oder einer äquivalenten Menge eines physiologisch verträglichen Salzes davon und 40 Gewichtsteilen Serotonin-Wiederaufnahme-Hemmer (B) oder einer äguivalenten Menge eines physiologisch verträglichen Salzes davonPreparation of an active ingredient application with 100 parts by weight of CGRP antagonist (A) or an equivalent amount of a physiologically acceptable salt thereof and 40 parts by weight of serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof
Zusammensetzung:Composition:
Kernmaterial 200 GewichtsteileCore material 200 parts by weight
Hydroxypropylcellulose 38 GewichtsteileHydroxypropyl cellulose 38 parts by weight
Talkum 20 GewichtsteileTalc 20 parts by weight
CG RP-Antagonist (A) 100 GewichtsteileCG RP antagonist (A) 100 parts by weight
Serotonin-Wiederaufnahme-Hemmer (B) 40 GewichtsteileSerotonin Reuptake Inhibitor (B) 40 parts by weight
In 250 Gewichtsteilen 2-Propanol wird Hydroxypropylcellulose unter Rühren gelöst und anschließend werden in dieser Lösung die Wirkstoffe und Talkum unter Rühren dispergiert.Hydroxypropyl cellulose is dissolved in 250 parts by weight of 2-propanol with stirring and then the active ingredients and talc are dispersed in this solution with stirring.
In einer Wirbelschichtprozessanlage werden 200 Gewichtsteile Kernmaterial bei einer Zulufttemperatur von 20°C bis 30°C mit der wirkstoffhaltigen Dispersion imIn a fluidized bed process plant, 200 parts by weight of core material are mixed with the active ingredient-containing dispersion at a supply air temperature of 20 ° C to 30 ° C
Unterbettsprühverfahren besprüht. Die wirkstoffhaltigen Pellets werden anschließend im Umlufttrockenschrank bei 35°C über 8 Stunden nachgetrocknet.Sprayed under bed spraying process. The active ingredient-containing pellets are then dried in a forced-air drying cabinet at 35 ° C. for 8 hours.
Zur Entfernung von Agglomeraten werden die wirkstoffhaltigen Pellets mit einem Sieb mit der nominalen Maschenweite 1.25 mm gesiebt. Die Gutfraktion (Korngröße < 1.25 mm) wird weiterverarbeitet.To remove agglomerates, the active ingredient-containing pellets are sieved using a sieve with a nominal mesh size of 1.25 mm. The good fraction (grain size <1.25 mm) is processed further.
Der Aufbau der Wirkstoffschicht erfolgt generell in immer gleicher Weise, wobei aber Wirkstoffart und Menge, Bindemittelart und Menge, Talkummenge und Wasser, Isopropanol bzw. Ethanolmenge variiert werden.The active substance layer is generally built up in the same way, but the type of active substance and the amount, type of binder and quantity, amount of talc and water, isopropanol or amount of ethanol are varied.
Weitere Beispiele sind in Tabelle 4 gezeigt. Tabelle 4Further examples are shown in Table 4. Table 4
Figure imgf000022_0001
Figure imgf000022_0001
Extrudateextrudates
Die erfindungsgemäßen Arzneistoffe können auch in Form von Extrudaten hergestellt werden, die nach Schneiden/Spheronisieren direkt in Kapseln abgefüllt oder nach Mahlen zu Tabletten verarbeitet werden.The medicinal substances according to the invention can also be produced in the form of extrudates which, after cutting / spheronization, are filled directly into capsules or processed into tablets after grinding.
Die Herstellung erfolgt in folgenden Schritten:The production takes place in the following steps:
1. Extrusion1. extrusion
2a. Schneiden/Spheronisieren2a. Cutting / spheronising
2b. Mahlen und anschließendes Verarbeiten zu Tabletten Beispiel 5a2 B. Grinding and subsequent processing into tablets Example 5a
Herstellung von Feuchtextrudaten mit 300 Gewichtsteilen CGRP-Antagonist (A) oder einer äguivalenten Menge eines physiologisch verträglichen Salzes davon und 80 Gewichtsteilen Serotonin-Wiederaufnahme-Hemmer (B) oder einer äguivalenten Menge eines physiologisch verträglichen Salzes davonPreparation of moisture extrudates with 300 parts by weight of CGRP antagonist (A) or an equivalent amount of a physiologically acceptable salt thereof and 80 parts by weight of serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof
Zusammensetzung:Composition:
Povidon 6 GewichtsteilePovidon 6 parts by weight
Mikrokristalline Cellulose 40 GewichtsteileMicrocrystalline cellulose 40 parts by weight
CGRP-Antagonist (A) 300 GewichtsteileCGRP antagonist (A) 300 parts by weight
Serotonin-Wiederaufnahme-Hemmer (B) 80 GewichtsteileSerotonin Reuptake Inhibitor (B) 80 parts by weight
300 Gewichtsteile CGRP-Antagonist (A), 80 Gewichtsteile Serotonin-Wiederaufnah- me-Hemmer (B), 40 Gewichtsteile Mikrokristalline Cellulose (Avicel PH 101) und 6 Gewichtsteile Povidon (Kollidon K25) werden in einem Rhönradmischer 15 Minuten lang gemischt. Dann wird die Pulvermischung zusammen mit Wasser, mit einer Geschwindigkeit von ca. 1 kg/h, in einen Doppelschnecken-Extruder eingebracht. Die Wasserdosierung wird automatisch so geregelt, dass im Extruder ein Solldrehmoment von ca. 19% erzeugt wird. Die Extrusion erfolgt über eine Düsenplatte mit Bohrungen von 0.8 mm Durchmesser.300 parts by weight of the CGRP antagonist (A), 80 parts by weight of the serotonin reuptake inhibitor (B), 40 parts by weight of microcrystalline cellulose (Avicel PH 101) and 6 parts by weight of povidone (Kollidon K25) are mixed in a wheel mixer for 15 minutes. The powder mixture is then introduced into a twin-screw extruder together with water at a rate of approximately 1 kg / h. The water metering is automatically controlled so that a target torque of approx. 19% is generated in the extruder. The extrusion is carried out via a die plate with 0.8 mm diameter holes.
Das Ausrunden der Extrusionsstränge zu Pellets erfolgt in einem Spheronizer, wobei ca. 3 Minuten mit ca. 850 RPM gerundet wird. Die Pellets werden bei 80°C ca. 1.5 h in einem Wirbelschichttrockner getrocknet.The extrusion strands are rounded off to form pellets in a spheronizer, rounding for approx. 3 minutes at approx. 850 RPM. The pellets are dried in a fluidized bed dryer at 80 ° C. for about 1.5 hours.
Das Kernmaterial wird über eine Taumelsiebmaschine mit unterschiedlichen Siebböden mit nominalen Maschenweiten von 0.71 bis 1.25 mm fraktioniert. Die jeweils geeigneten Gutfraktionen zwischen 0.71 und 0.90 bzw. 0.90 und 1.12 mm werden verwendet.The core material is fractionated using a tumbler screening machine with different screening trays with nominal mesh sizes from 0.71 to 1.25 mm. The appropriate good fractions between 0.71 and 0.90 or 0.90 and 1.12 mm are used.
Weitere Beispiele sind in Tabelle 5 gezeigt. Tabelle 5Further examples are shown in Table 5. Table 5
Figure imgf000024_0001
Figure imgf000024_0001
*Gwt = Gewichtsteile * Gwt = parts by weight
Beispiel 6Example 6
Herstellung von Schmelzextrudaten mit 200 Gewichtsteilen CGRP-Antagonist (A. oder einer äguivalenten Menge eines physiologisch verträglichen Salzes davon und 60 Gewichtsteilen Serotonin-Wiederaufnahme-Hemmer (B) oder einer äguivalenten Menge eines physiologisch verträglichen Salzes davonPreparation of melt extrudates with 200 parts by weight of CGRP antagonist (A. or an equivalent amount of a physiologically acceptable salt thereof and 60 parts by weight of serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof
Zusammensetzung:Composition:
Povidon 6 GewichtsteilePovidon 6 parts by weight
Poloxamer 40 GewichtsteilePoloxamer 40 parts by weight
CGRP-Antagonist (A) 200 GewichtsteileCGRP antagonist (A) 200 parts by weight
Serotonin-Wiederaufnahme-Hemmer (B) 60 Gewichtsteile 200 Gewichtsteile CGRP-Antagonist (A), 60 Gewichtsteile Serotoni n-Wiederauf- nahme-Hemmer (B), 40 Gewichtsteile Poloxamer und 6 Gewichtsteile Povidon K25 werden in einem Rhönradmischer 15 Minuten lang gemischt. Daraufhin wird die Pulvermischung mit einer Geschwindigkeit von ca. 1 kg/h in einen Doppelschnecken- Extruder eingebracht. Die Temperatur wird so geregelt, dass im Extruder ein Solldrehmoment von ca. 19% erzeugt wird. Die Extrusion erfolgt über eine Düsenplatte mit Bohrungen von 0.8 mm Durchmesser.Serotonin Reuptake Inhibitor (B) 60 parts by weight 200 parts by weight of the CGRP antagonist (A), 60 parts by weight of the Serotonin reuptake inhibitor (B), 40 parts by weight of the poloxamer and 6 parts by weight of the Povidon K25 are mixed in a wheel mixer for 15 minutes. The powder mixture is then introduced into a twin-screw extruder at a rate of approx. 1 kg / h. The temperature is controlled so that a target torque of approx. 19% is generated in the extruder. The extrusion is carried out via a die plate with 0.8 mm diameter holes.
Die austretenden Extrusionstränge werden mit einem Kopfabschlag geschnitten, das Ausrunden der Extrusionsstränge zu Pellets erfolgt in einem Spheronizer, wobei ca. 3 Minuten mit ca. 850 RPM bei ca. 40°C gerundet wird. Trocknung der Pellets bei 80°C ca. "1.5 h in einem Wirbelschichttrockner.The emerging extrusion strands are cut with a head tee, the extrusion strands are rounded off to pellets in a spheronizer, rounding for approx. 3 minutes at approx. 850 RPM at approx. 40 ° C. Drying of the pellets at 80 ° C approximately "1.5 h in a fluidized bed dryer.
Das Kernmaterial wird über eine Taumelsiebmaschine mit unterschiedlichen Siebböden mit nominalen Maschenweiten von 0.71 bis 1.25 mm fraktioniert. Die jeweils geeigneten Gutfraktionen zwischen 0.71 und 0.90 bzw. 0.90 und 1.12 mm werden in den weiteren Prozessen verwendet.The core material is fractionated using a tumbler screening machine with different screening trays with nominal mesh sizes from 0.71 to 1.25 mm. The appropriate good fractions between 0.71 and 0.90 or 0.90 and 1.12 mm are used in the further processes.
Die jeweiligen Zusammensetzungen können variieren und werden im folgenden in Tabellenform dargestellt.The respective compositions can vary and are shown below in tabular form.
Tabelle 6Table 6
Figure imgf000025_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000026_0001
*Gwt = Gewichtsteile* Gwt = parts by weight
Beispiel 7Example 7
Weiterverarbeitung zu TablettenFurther processing into tablets
Die Extrudate werden in einer geeigneten Mühle gemahlen, das entstehendeThe extrudates are ground in a suitable mill, the resulting
Granulat wird mit üblichen Tablettierhilfsstoffen analog Beispiel 1 zu Tabletten weiterverarbeitet.Granules are further processed into tablets using conventional tableting aids as in Example 1.
PulveπnhalativumPulveπnhalativum
Herstellung sphärisch nanostrukturierter Mikropartikel der Wirkstoffe zur Herstellung eines PulverinhalativumsManufacture of spherically nanostructured microparticles of the active ingredients for the manufacture of a powder inhalant
Die Wirkstoffe werden zur Herstellung einer Wirkstofflösung von 4 Gew.-% entsprechend in einem Ethanol/Wasser (4:1)-Gemisch gelöst und die Wirkstofflösung so versprüht, dass ein Sprühnebel mit einer Tropfengröße mit dem Kennwert X50 (Medianwert = Teilchengröße/Tropfengröße, unterhalb derer 50% der Teilchenmenge liegt bezüglich der Volumenverteilung der einzelnen Teilchen/Tropfen) im Bereich von 1.5 bis 8 μm und Q(5.8) (Entspricht der Teilchenmenge, die bezogen auf die Volumenverteilung der Tröpfchen unterhalb von 5.8 μm liegt) zwischen 30 und 100% erzielt wird. Der so erhaltene Sprühnebel wird mit Hilfe eines Trocknungsgases mit einer Eingangstemperatur zwischen 130°C und 200°C und einer Ausgangstemperatur von 40°C bis 120°C getrocknet Dabei beträgt der Volumenstrom des Sprühgases 1 Nm3/h bis 15 Nm3/h und der Volumenstrom des Trocknungsgases 15 Nm3/h bis 150 Nm3/h. Der getrocknete Feststoffanteil wird mittels Massekraftabscheider und/oder Filtereinheit gesammelt.To produce an active ingredient solution of 4% by weight, the active ingredients are correspondingly dissolved in an ethanol / water (4: 1) mixture and the active ingredient solution is sprayed in such a way that a spray mist with a drop size with the characteristic value X50 (median value = particle size / drop size, below which 50% of the particle quantity is in the range of 1.5 to 8 μm with respect to the volume distribution of the individual particles / drops) and Q (5.8) (corresponds to the quantity of particles which is below 5.8 μm in relation to the volume distribution of the droplets) between 30 and 100 % is achieved. The spray thus obtained is dried with the aid of a drying gas with an inlet temperature between 130 ° C and 200 ° C and an outlet temperature of 40 ° C to 120 ° C Spray gas 1 Nm 3 / h to 15 Nm 3 / h and the volume flow of the drying gas 15 Nm 3 / h to 150 Nm 3 / h. The dried solid content is collected by means of a gravity separator and / or filter unit.
Beispiel 8Example 8
Kapseln für die Pulverinhalation mit 0.5 mg CGRP-Antagonist (A) oder einer äquivalenten Menge eines physiologisch verträglichen Salzes davon und 0.25 mg Serotonin-Wiederaufnahme-Hemmer (B) oder einer äguivalenten Menge eines physiologisch verträglichen Salzes davonCapsules for powder inhalation with 0.5 mg CGRP antagonist (A) or an equivalent amount of a physiologically acceptable salt thereof and 0.25 mg of serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof
Zusammensetzung:Composition:
1 Kapsel für die Pulverinhalation enthält:1 capsule for powder inhalation contains:
CGRP-Antagonist (A) 0.5 mgCGRP antagonist (A) 0.5 mg
Serotonin-Wiederaufnahme-Hemmer (B) 0.25 mgSerotonin reuptake inhibitor (B) 0.25 mg
Lactose 20 mgLactose 20 mg
Hartgelatinekapseln 50 mgHard gelatin capsules 50 mg
Herstellungsverfahren:Production method:
Der Wirkstoff wird als sphärisch nanostrukturierte Wirkstoff partikel hergestellt und homogen mit Lactose gemischt. Das Gemisch wird in Hartgelatinekapseln gepackt.The active substance is produced as a spherically nanostructured active substance particle and mixed homogeneously with lactose. The mixture is packed in hard gelatin capsules.
Weitere Beispiele sind in Tabelle 8 aufgelistet.Other examples are listed in Table 8.
Tabelle 8Table 8
Figure imgf000027_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000028_0001
Beispiel 9Example 9
Iniektionslösung mit 0.3 mg CGRP-Antagonist (A) oder einer äguivalenten Menge eines physiologisch verträglichen Salzes davon und 0.2 mg Serotonin-Wiederauf- nahme-Hemmer (B) oder einer äguivalenten Menge eines physiologisch verträglichen Salzes davonIniection solution with 0.3 mg CGRP antagonist (A) or an equivalent amount of a physiologically acceptable salt thereof and 0.2 mg serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof
Zusammensetzung:Composition:
CGRP-Antagonist (A) 0.3 mgCGRP antagonist (A) 0.3 mg
Serotonin-Wiederaufnahme-Hemmer (B) 0.2 mg physiologische KochsalzlösungSerotonin reuptake inhibitor (B) 0.2 mg saline
Der Wirkstoff wird in physiologischer Kochsalzlösung gelöst.The active ingredient is dissolved in physiological saline.
Die Dosismengen können variieren und werden im folgenden in Tabellenform dargestellt. Tabelle 9The dose amounts can vary and are shown in the table below. Table 9
Figure imgf000029_0001
Figure imgf000029_0001
Beispiel 10Example 10
Suppositorien mit 200 mg CGRP-Antagonist (A) oder einer äquivalenten Menge. eines physiologisch verträglichen Salzes davon und 150 mg Serotonin-Wiederauf- nahme-Hemmer (B) oder einer äguivalenten Menge eines physiologisch verträglichen Salzes davonSuppositories with 200 mg CGRP antagonist (A) or an equivalent amount. a physiologically acceptable salt thereof and 150 mg of serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof
Zusammensetzung:Composition:
CGRP-Antagonist (A) 200 mgCGRP antagonist (A) 200 mg
Serotonin-Wiederaufnahme-Hemmer (B) 150 mgSerotonin reuptake inhibitor (B) 150 mg
Hartwachs ad 2 gHard wax ad 2 g
Herstellung:production:
Das Hartwachs wird geschmolzen und die Wirkstoffe in der Masse suspendiert.The hard wax is melted and the active ingredients are suspended in the mass.
Anschließend wird die Masse in geeignete Zäpfchenformen ausgegossen. Die Dosismengen können variieren und werden im folgenden in Tabellenform dargestellt.The mass is then poured into suitable suppository molds. The dose amounts can vary and are shown in the table below.
Tabelle 10Table 10
Figure imgf000030_0001
Figure imgf000030_0001

Claims

_ .Patentansprüche _ .Patent claims
1. Verfahren zur Behandlung oder Prävention von Indikationen, die aus der Gruppe ausgewählt sind, die aus Kopfschmerzen, Migräne und Cluster headache besteht, wobei das Verfahren die gemeinsame Verabreichung einer therapeutisch wirksamen Menge eines CGRP-Antagonisten (A) oder eines physiologisch verträglichen Salz davon und einer therapeutisch wirksamen Menge eines Serotonin- Wiederaufnahme-Hemmers (B) oder eines physiologisch verträglichen Salzes davon gegen Migräne an eine Person, die einer derartigen Behandlung bedarf, umfasst.1. A method of treating or preventing indications selected from the group consisting of headache, migraine and cluster headache, the method comprising co-administering a therapeutically effective amount of a CGRP antagonist (A) or a physiologically acceptable salt thereof and a therapeutically effective amount of a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof against migraine to a person in need of such treatment.
2. Verfahren nach Anspruch 1 , dadurch gekennzeichnet, dass der CGRP- Antagonist ausgewählt ist aus der Gruppe, bestehend aus2. The method according to claim 1, characterized in that the CGRP antagonist is selected from the group consisting of
(1 ) 1 -[/V2-[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]- carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(1) 1 - [/ V 2 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(2) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1 ,3-benzodiazepin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(2) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (2,3,4,5-tetrahydro-2 (1 H) -oxo-1,3-benzodiazepine-3- yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(3) 1-[Λ^-[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(3) 1- [Λ ^ - [4-amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) - 1 piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(4) 1 -[/V2-[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidin,(4) 1 - [/ V 2 - [4-amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) - 1- piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) -piperidine,
(5) 1 -[/V2-[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(5) 1 - [/ V 2 - [3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl ] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(6) 1 -[Λf -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2/-/)-oxoimidazoI- 1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(6) 1 - [Λf - [4-amino-3,5-dibromo-Λ / - [[4- (1, 3-dihydro-4-phenyl-2 (2 / - /) - oxoimidazoI-1-yl ) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(7) 1 -[3,5-Dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxothieno[3,4-d]pyrimidin-3-yl)- 1-piperidiny!]carbonyl]-D-tyrosyi]-4-(1-piperidinyl)-piperidin, _(7) 1 - [3,5-Dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxothieno [3,4-d] pyrimidin-3-yl) -1-piperidiny !] carbonyl] -D-tyrosyi] -4- (1-piperidinyl) -piperidine, _
(8) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(2,4-dihydro-5-phenyl-3(3/-/)-oxo-1 ,2,4-triazol- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidin,(8) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (2,4-dihydro-5-phenyl-3 (3 / - /) - oxo-1, 2,4- triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(9) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1 ,2,4-triazol- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(9) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (2,4-dihydro-5-phenyl-3 (3H) -oxo-1, 2,4-triazole-2 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(10) 1 -[4-Amino-3,5-dibrom-Λ-[[4-(2,4-dihydro-5-phenyl-3(3/-/)-oxo-1 ,2,4-triazol- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperazin,(10) 1 - [4-Amino-3,5-dibromo-Λ - [[4- (2,4-dihydro-5-phenyl-3 (3 / - /) - oxo-1, 2,4-triazole - 2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) - piperazine,
(11) 1 -[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxothieno[3,2-d]pyrimidin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(11) 1 - [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxothieno [3,2-d] pyrimidin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(12) 1 -[4-Amino-3,5-dibrom-Λ-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidin-yl]carbonyl]-D-phenylalanyl]-4-(1 -ethyl-4-piperi- dinyl)-piperidin,(12) 1 - [4-Amino-3,5-dibromo-Λ - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl ] -1-piperidin-yl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) piperidine,
(13) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 ^)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidin,(13) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 ^) - oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-hexyl-4-piperidinyl) -piperidine,
(14) 1 -[4-Amino-3,5-dibrom-/V-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-piperidin,(14) 1 - [4-Amino-3,5-dibromo / V - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-cyclopropylmethyl-4-piperidinyl) -piperidine,
(15) 1 -[Λ/-[[4-[3,4-Dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperidinyl]carbonyl]- 3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1 H-1 -azepinyl)-piperidin,(15) 1 - [Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl] - 3-ethenyl-D, L-phenylalanyl] -4- (hexahydro-1 H-1 azepinyl) piperidine,
(16) (R,S)-1-[4-[4-(3,4-Dihydro-2(1 /-/)-oxochinazolin-3-yl)-1-piperidinyl]-2-[(4-hy- droxy-3,5-dimethylphenyl)methyl]-1 ,4-dioxobutyl]-4-(1-piperidinyl)-piperidin,(16) (R, S) -1- [4- [4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1-piperidinyl] -2 - [(4- hydroxy-3,5-dimethylphenyl) methyl] -1, 4-dioxobutyl] -4- (1-piperidinyl) piperidine,
(17) 1 -[4-Amino-3,5-dibrom- V-[[4-[Λ/-(aminocarbonyl)-Λ/-phenylamino]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin, (18) 1 -[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazin,(17) 1 - [4-Amino-3,5-dibromo-V - [[4- [Λ / - (aminocarbonyl) -Λ / -phenylamino] -1 -piperidinyl] carbonyl] -D-phenylalanyl] - 4- (1-piperidinyl) -piperidine, (18) 1 - [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (5-methoxy-4-pyrimidinyl) piperazine,
(19) 1-[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,1 -dioxido-3(4H)-oxo-1 ,2(4-benzothiadiazin- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(19) 1- [4-Amino-3,5-dibromo-Λ / - [[4- (1, 1 -dioxido-3 (4H) -oxo-1, 2 ( 4-benzothiadiazin- 2-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(20) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[2(1 H)-oxochinolin-3-yl]-1 -piperidinyljcarbonyl]- D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(20) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [2 (1 H) -oxoquinolin-3-yl] -1 -piperidinyljcarbonyl] - D-phenylalanyl] -4- ( 1-piperidinyl) -piperidine,
(21) 1-[4-Amino-3,5-dibrom-/V-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1-piperi- dinyi]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazin,(21) 1- [4-Amino-3,5-dibromo- / V - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1-piperidinyi] carbonyl ] -D-phenylalanyl] -4- [3- (dimethylamino) propyl] piperazine,
(22) 1-[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidin,(22) 1- [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (4-methyl-1-piperazinyl) piperidine,
(23) 1 -[4-Amino-3,5-dibrom-/V-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[(1 -methyl-4-piperidinyl)carbonyl]-piperazin,(23) 1 - [4-Amino-3,5-dibromo- / V - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4 - [(1-methyl-4-piperidinyl) carbonyl] piperazine,
(24) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyI]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazin,(24) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyI] -4 - [(1-methyl-4-piperazinyl) carbonyl] -piperazine,
(25) 1-[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazin,(25) 1- [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [4- [4- (dimethylamino) butyl] phenyl] -piperazine,
(26) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidin,(26) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- [4- (dimethylamino) -1-piperidinyl] -piperidine,
(27) 1 -[Λ^-[[4-(1 ,3-Dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)-1 -piperidinyljcarbonyl]- Λ/,-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidin,(27) 1 - [Λ ^ - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1 -piperidinyljcarbonyl] - - / , -methyl-D-tryptyl ] -4- (4-methyl-1-piperazinyl) piperidine,
(28) 1 -[Λ -[[4-(1 ,3-Dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)-1 -piperidinyl]carbonyl]- N'-(1 ,1 -dimethylethoxycarbonyl)-D-tryptyl]-4-(1 -methyl-4-piperidinyl)-piperidin, _(28) 1 - [Λ - [[4- (1, 3-Dihydro-4-phenyl-2 (2H) -oxoimidazol-1 -yl) -1 -piperidinyl] carbonyl] - N '- (1, 1 - dimethylethoxycarbonyl) -D-tryptyl] -4- (1-methyl-4-piperidinyl) piperidine, _
(29) (R,S)-1-[4-[4-(3,4-Dihydro-2(1 /^-oxochinazolin-3-yl)-1-piperidinyl]-2-[(3,5-di- brom-4-methylphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)- piperidin,(29) (R, S) -1- [4- [4- (3,4-Dihydro-2 (1 / ^ - oxoquinazolin-3-yl) -1-piperidinyl] -2 - [(3,5- di-bromo-4-methylphenyl) methyl] -1, 4-dioxobutyl] -4- (4-methyl-1-piperazinyl) piperidine,
(30) (R,S)-1 -[4-[4-(3,4-Dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]-2-[(3,5-di- brom-4-methoxyphenyl)methyl]-1 ,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)- piperidin,(30) (R, S) -1 - [4- [4- (3,4-Dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] -2 - [(3,5- di-bromo-4-methoxyphenyl) methyl] -1, 4-dioxobutyl] -4- (1-methyl-4-piperidinyl) piperidine,
(31 ) ( ?,S)-1-[4-[4-(3,4-Dihydro-2(1 H)-oxochinazolin-3-yl)-1-piperidinyl]-2-[(3,4-di- bromphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidin,(31) (?, S) -1- [4- [4- (3,4-Dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] -2 - [(3,4- di-bromophenyl) methyl] -1, 4-dioxobutyl] -4- (4-methyl-1-piperazinyl) piperidine,
(32) 1 -[/v2-[N-[[4-(1 ,3-Dihydro-2(2/-/)-oxobenzimidazol-1 -yl)-1 -piperidinyl]carbonyl]- 3,5-dibrom-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(32) 1 - [/ v 2 - [N - [[4- (1,3-dihydro-2 (2 / - /) - oxobenzimidazol-1 -yl) -1 -piperidinyl] carbonyl] - 3,5- dibromo-D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(33) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-6-hydroxy-2(2H)-oxobenzimidazol- 1 -yl)-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -piperidinyl)-piperidin,(33) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-6-hydroxy-2 (2H) -oxobenzimidazole-1-yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine,
(34) 1 -[Λi2-[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-2(2H)-oxobenzimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-Λ/6,Λ/s-dimethyl-L-lysyl]-4-(4-pyridinyl)- piperazin,(34) 1 - [Λi 2 - [4-amino-3,5-dibromo-Λ / - [[4- (1, 3-dihydro-2 (2H) -oxobenzimidazol-1-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -Λ / 6 , Λ / s -dimethyl-L-lysyl] -4- (4-pyridinyl) - piperazine,
(35) 1 -[Λ/2-[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 -/)-oxochinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-Λ/6,Λ/6-dimethyl-L-lysyl]-4-(4-pyridinyl)- piperazin,(35) 1 - [Λ / 2 - [4-amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 - /) - oxoquinazolin-3-yl) - 1 -piperidinyl] carbonyl] -D-phenylalanyl] -Λ / 6 , Λ / 6 -dimethyl-L-lysyl] -4- (4-pyridinyl) - piperazine,
(36) (f.,S)-1-[2-(4-Amino-3,5-dibrombenzoyl)-4-[4-(3,4-dihydro-2(1 H)-oxo- chinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1 -piperidinyl)-piperidin,(36) (f., S) -1- [2- (4-Amino-3,5-dibromobenzoyl) -4- [4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3 -yl) -1-piperidinyl] -4-oxobutyl] -4- (1-piperidinyl) piperidine,
(37) 1-[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2,2-dioxido-2,1 ,3-benzothiadiazin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin, (38) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-2(2H)-oxoimidazo[4,5-c]chinolin- 3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)carbonyl]- piperidin,(37) 1- [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2,2-dioxido-2,1, 3-benzothiadiazin-3-yl) -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (38) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-2 (2H) -oxoimidazo [4,5-c] quinolin-3-yl] - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) carbonyl] piperidine,
(39) 1 -[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1 -piperidinyl )-piperidin,(39) 1 - [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-piperidinyl) piperidine,
(40) 1 -[N2-[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolin-3-yl)-1 -piperidinyl]- carbony -D-tyrosyll-Λ^.Λ^-dimethyl-L-lysylj^ ^-pyridiny -piperazin,(40) 1 - [N 2 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1 -piperidinyl] - carbony -D-tyrosyll-Λ ^ .Λ ^ -dimethyl-L-lysylj ^ ^ -pyridiny -piperazine,
(41 ) 1-[4-Amino-Λ/-[[4-[4-(3-bromphenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1-yl]- 1-piperidinyl]carbonyl]-3,5-dibrom-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidin,(41) 1- [4-Amino-Λ / - [[4- [4- (3-bromophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(42) 1-[4-Amino-3)5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidin,(42) 1- [4-Amino-3 ) 5-dibromo-Λ / - [[4- [1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-methyl-1-piperazinyl) piperidine,
(43) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -piperidinyl)-- piperidin,(43) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1- yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine,
(44) i-[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2/-/)- oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl- 8-azabicyclo[3.2.1]oct-3-yl)-piperazin,(44) i- [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 / - /) - oxoimidazole -1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) piperazine,
(45) 1 -[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)-1 -piperi- dinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidin,(45) 1 - [3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine,
(46) 1-[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -ethyl-4-piperi- dinyl)-piperazin, (47) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -ylj- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1 HA ,4-di- azepin-1 -yl)piperidin,(46) 1- [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1 - yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) piperazine, (47) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4-phenyl-2 (2H) -oxoimidazole-1-yl-1-piperidinyl] carbonyl ] -D-phenylalanyl] -4- (hexahydro-4-methyl-1 HA, 4-di-azepin-1-yl) piperidine,
(48) 1 -[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]- carbonyl]-D-tyrosyl]-4-[1-(methylsulfonyl)-4-piperidinyl]-piperidin,(48) 1 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl] -D-tyrosyl ] -4- [1- (methylsulfonyl) -4-piperidinyl] -piperidine,
(49) 1-[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2/-/)-oxoimidazol-1-yl)- 1-piperidinyljcarbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidin,(49) 1- [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2 / - /) - oxoimidazol-1-yl) - 1 -piperidinyljcarbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine,
(50) 1 -[3,5-Dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)-oxo- ,imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1/-/-1-azepinyl)- piperidin,(50) 1 - [3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxo-, imidazol-1-yl ] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro-1 / - / - 1-azepinyl) - piperidine,
(51 ) 1-[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1/-/)-oxochinazolin-3-yl)-1-piperidinyl]- carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidin,(51) 1- [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D -tyrosyl] -4- (1-methyl-4-piperidinyl) -piperidine,
(52) 1 -[4-Amino-3,5-dibrom-A/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)- piperazin,(52) 1 - [4-Amino-3,5-dibromo-A / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) piperazine,
(53) 1-[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazin,(53) 1- [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
(54) 1-[3,5-Dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2/-/)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidin,(54) 1- [3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 / - /) - oxo-imidazole-1 -yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine,
(55) 1 -[N6-Acetyl-N2-[3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(55) 1 - [N 6 -acetyl-N 2 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) - 1- piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(56) 1-[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi- dinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1/--1-azepinyl)-piperidin, _(56) 1- [3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro-1 / - 1-azepinyl) -piperidine, _
(57) 1-[4-Amino-3,5-dibrom-Λ/-t[4-(1 ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol- 1 -yl)- -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperidinyl)- piperidin,(57) 1- [4-Amino-3,5-dibromo-Λ / -t [4- (1,3-dihydro-4- (3-thienyl) -2 (2H) -oxoimidazole-1-yl) - -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(58) 1-[4-Amino-3,5-dibrom-/V-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperi- dinyl)-piperidin,(58) 1- [4-Amino-3,5-dibromo- / V - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1 - yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(59) 1-[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl]carbo- nyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidin,(59) 1- [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl ] -4- [1- (hydroxycarbonylmethyl) -4-piperidinyl] -piperidine,
(60) 1-[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1H)-oxochinazolin-3-yl]-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsuifonyl-4-piperidinyl)-piperidin,(60) 1- [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1H) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methylsuifonyl-4-piperidinyl) -piperidine,
(61 ) 1-[3,5-Dibrom-Λ.-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl]carbo- nyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidin,(61) 1- [3,5-dibromo-Λ .- [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl ] -4- (4-piperidinyl) -piperidine,
(62) 1-[4-Amino-3,5-dibrom-A/-[[4-(1 ,3-dihydro-4-phenyl-2(2/-/)-oxoimidazol-1-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidin,(62) 1- [4-Amino-3,5-dibromo-A / - [[4- (1,3-dihydro-4-phenyl-2 (2 / - /) - oxoimidazol-1-yl) - 1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperidine,
(63) 1 -[4-Amino-3,5-dibrom-/V-[[4-(1 ,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxo- imidazol-1 -yl)-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperi- dinyl)-piperidin,(63) 1 - [4-Amino-3,5-dibromo- / V - [[4- (1,3-dihydro-4- (3-hydroxyphenyl) -2 (2H) -oxoimidazol-1-yl ) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(64) 1-[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl]carbo- nyl]-D-tyrosyl]-4-(hexahydro-1 HA -azepinyl)-piperidin,(64) 1- [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl ] -4- (hexahydro-1 HA-azepinyl) piperidine,
(65) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(65) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(66) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[4-(3-bromphenyl)-1 ,3-dihydro-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]r4-(exo-8-methyl-8-aza- bicyclo[3.2.1]oct-3-yl)-piperazin, (67) 1-[4-Amino-3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidin,(66) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [4- (3-bromophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1-yl ] -1-piperidinyl] carbonyl] -D-phenylalanyl] r4- (exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) piperazine, (67) 1- [4-amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperidine,
(68) 1-[4-Amino-3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazin,(68) 1- [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) piperazine,
(69) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-aza- bicyclo[3.2.1]oct-3-yl)-piperazin,(69) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- (3-methoxyphenyl) -2 (2H) -oxoimidazol-1-yl ] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) piperazine,
(70) 1-[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl]carbo- nyl]-D-tyrosyl]-4-[1-(cyclopropylmethyl)-4-piperidinyl]-piperidin,(70) 1- [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl ] -4- [1- (cyclopropylmethyl) -4-piperidinyl] -piperidine,
(71) 1-[4-Amino-3,5-Dibrom-A/-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1/- -1-azepinyl)-piperidin,(71) 1- [4-Amino-3,5-dibromo-A / - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1 / - -1-azepinyl) piperidine,
(72) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidin,(72) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1 -piperidinyl ] carbonyl] -D-phenylalanyl] -4- (4-piperidinyl) -piperidine,
(73) 1 -[3,5-Dibrom-/V-[[4-(1 ,3-dihydro-4-phenyl-2(2/- )-oxoimidazol-1 -yl)-1 -piperi- dinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidin,(73) 1 - [3,5-dibromo / V - [[4- (1,3-dihydro-4-phenyl-2 (2 / -) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (4-pyridinyl) -piperidine,
(74) 1 -[3,5-Dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2/-/)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(f-methyl-4-piperidinyl)- piperazin,(74) 1 - [3,5-Dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 / - /) - oxo-imidazole-1 -yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (f-methyl-4-piperidinyl) - piperazine,
(75) 1 -[Λ/2-[3,5-Dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2/-/)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)- piperazin,(75) 1 - [Λ / 2 - [3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 / - /) - oxo-imidazol-1-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) - piperazine,
(76) 1 -[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1 -yl)-1 -piperi- dinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidin, _ _(76) 1 - [3,5-dibromo-Λ / - [[4- (1,3-dihydro-4- (3-thienyl) -2 (2H) -oxoimidazol-1-yl) -1 -piperi- dinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine, _ _
(77) 1 -[4-Amino-/V-[[4-[4-(3-chlorphenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1-yl]- 1 -piperidinyl]carbonyl]-3,5-dibrom-D-phenylalanyl]-4-(1 -methyl-4-piperidinyl)- piperidin,(77) 1 - [4-Amino- / V - [[4- [4- (3-chlorophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1-yl] -1 -piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(78) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1-yl]-1τpiperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 H- 1 -azepinyl)-piperidin,(78) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1- yl] -1τpiperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1 H-1-azepinyl) piperidine,
(79) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperi- dinyl)-piperazin,(79) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1 - yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
(80) 1 -[4-Amino-Λ/-[[4-[4-(3-chlorphenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1 -yl]- 1-piperidinyl]carbonyl]-3,5-dibrom-D-phenylalanyl]-4-(hexahydro-1 H-1-azepi- nyl)-piperidin,(80) 1 - [4-Amino-Λ / - [[4- [4- (3-chlorophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (hexahydro-1 H-1-azepinyl) piperidine,
(81) 1-[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2/-/)-oxoimidazol-1-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazin,(81) 1- [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2 / - /) - oxoimidazol-1-yl) - 1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-pyridinyl) piperazine,
(82) 1-[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2 τ)-oxoimidazol-1-yl)-1-piperi- dinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidin,(82) 1- [3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2τ) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl ] -D-tyrosyl] -4- (1-methyl-4-piperidinyl) -piperidine,
(83) 1 -[4-Amino-3,5-dibrom-Λ-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl]- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazin,(83) 1 - [4-Amino-3,5-dibromo-Λ - [[4- [1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl ] -D-phenylalanyl] -4- [4- (1-oxoethyl) phenyl] piperazine,
(84) 1 -[3,5-Dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperidinyljcarbo- nyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazin,(84) 1 - [3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyljcarbonyl] -D-tyrosyl] -4- (1-methyl-4-piperidinyl) piperazine,
(85) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-(3-nitrophenyl)-2(2W)-oxoimidazol- 1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperidinyl)- piperidin, _ _(85) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- (3-nitrophenyl) -2 (2W) -oxoimidazole-1-yl] - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine, _ _
(86) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-pyrrolidinyl)-piperidin,(86) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-pyrrolidinyl) -piperidine,
(87) 1-[4-Amino-3,5-dibrom-/v-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 HA -azepinyl)-piperidin und .(87) 1- [4-Amino-3,5-dibromo- / v - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1 HA-azepinyl) piperidine and.
(88) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-(3-thienyl)-2(2/-/)-oxoimidazol-1 - yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazin,(88) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4- (3-thienyl) -2 (2 / - /) - oxoimidazole-1 - yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
deren physiologisch verträglichen Salzen und den Hydraten der Salze.their physiologically compatible salts and the hydrates of the salts.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass der Serotonin-Wiederaufnahme-Hemmer (B) ausgewählt ist aus der Gruppe, bestehend aus Citalopram, Duloxetin, Escitalopram, Fluoxetin, Fluvoxamin, Paroxetin, Sertralin, Trazodon und deren physiologisch verträglichen Salzen.3. The method according to claim 1 or 2, characterized in that the serotonin reuptake inhibitor (B) is selected from the group consisting of citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone and their physiologically tolerable salts ,
4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, dass es sich bei dem Serotonin-Wiederaufnahme-Hemmer (B) um Duloxetin oder ein physiologisch verträgliches Salz davon handelt.4. The method according to claim 3, characterized in that the serotonin reuptake inhibitor (B) is duloxetine or a physiologically acceptable salt thereof.
5. Verfahren nach Anspruch 1 , dadurch gekennzeichnet, dass der ausgewählte CGRP-Antagonist (A) oder ein physiologisch verträgliches Salz davon auf intravenösem oder subkutanem Weg in einer Dosierung von 0.0001 bis 3 mg/kg Körpergewicht, auf oralem Weg in einer Dosierung von 0.1 bis 20 mg/kg Körpergewicht oder auf nasalem oder inhalativem Weg in einer Dosierung von 0.1 bis 10 mg/kg Körpergewicht einmal, zweimal oder dreimal täglich verabreicht wird und5. The method according to claim 1, characterized in that the selected CGRP antagonist (A) or a physiologically acceptable salt thereof by intravenous or subcutaneous route in a dosage of 0.0001 to 3 mg / kg body weight, orally in a dosage of 0.1 up to 20 mg / kg body weight or by nasal or inhalation in a dosage of 0.1 to 10 mg / kg body weight once, twice or three times a day and
der Serotonin-Wiederaufnahme-Hemmer (B) oder ein physiologisch verträgliches Salz davon, das auf oralem Weg in einer Dosierung von 0.03 bis 1.43 mg/kg Körpergewicht einmal, zweimal oder dreimal täglich oder auf intravenösem oder subkutanem Weg in einer Dosierung von 0.002 bis 0.09 mg/kg Körpergewicht einmal oder zweimal täglich oderthe serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof, which is taken orally at a dosage of 0.03 to 1.43 mg / kg body weight once, twice or three times a day or intravenously or subcutaneously at a dose of 0.002 to 0.09 mg / kg body weight once or twice a day or
auf rektalem Weg in einer Dosierung von 0.007 bis 0.36 mg/kg Körpergewicht einmal oder zweimal täglich oderrectally in a dose of 0.007 to 0.36 mg / kg body weight once or twice a day or
auf nasalem Weg in einer Dosierung von 0.006 bis 0.29 mg/kg Körpergewicht einmal oder zweimal täglich verabreicht werden kann.can be administered nasally at a dose of 0.006 to 0.29 mg / kg body weight once or twice a day.
6. Pharmazeutische Zusammensetzung für die Behandlung oder Prävention von Kopfschmerzen, Migräne oder Cluster headache, umfassend eine therapeutisch wirksame Menge eines CGRP-Antagonisten (A) oder eines physiologisch verträglichen Salzes davon und einen Serotonin-Wiederaufnahme-Hemmer (B) oder ein physiologisch verträgliches Salz davon als kombinierte Zubereitung für die gleichzeitige oder zeitlich aufeinander folgende Verabreichung.6. A pharmaceutical composition for the treatment or prevention of headache, migraine or cluster headache, comprising a therapeutically effective amount of a CGRP antagonist (A) or a physiologically acceptable salt thereof and a serotonin reuptake inhibitor (B) or a physiologically acceptable salt of which as a combined preparation for simultaneous or sequential administration.
7. Pharmazeutische Zusammensetzung nach Anspruch 6, umfassend eine einzelne Dosierungseinheit von 0.1 bis 1500 mg eines CGRP-Antagonisten (A) oder eines physiologisch verträglichen Salzes davon und eine einzelne Dosierungseinheit von 0.1 bis 150 mg eines Serotonin- Wiederaufnahme-Hemmers (B) oder eines physiologisch verträglichen Salzes davon.7. A pharmaceutical composition according to claim 6, comprising a single dosage unit of 0.1 to 1500 mg of a CGRP antagonist (A) or a physiologically acceptable salt thereof and a single dosage unit of 0.1 to 150 mg of a serotonin reuptake inhibitor (B) or one physiologically acceptable salt thereof.
8. Kit von Teilen für die Behandlung oder Prävention von Kopfschmerzen, Migräne oder Cluster headache, wobei das Kit umfasst:8. Kit of parts for the treatment or prevention of headache, migraine or cluster headache, the kit comprising:
(a) eine erste Umschließung enthaltend eine pharmazeutische Zusammensetzung umfassend eine therapeutisch wirksame Menge eines CGRP- Antagonisten (A) oder eines physiologisch verträglichen Salzes davon und ein oder mehrere physiologisch verträgliche Verdünnungsmittel und/oder Trägerstoffe; und - -(a) a first enclosure containing a pharmaceutical composition comprising a therapeutically effective amount of a CGRP antagonist (A) or a physiologically acceptable salt thereof and one or more physiologically acceptable diluents and / or carriers; and - -
(b) eine zweite Umschließung enthaltend eine pharmazeutische Zusammensetzung umfassend einen Serotonin-Wiederaufnahme-Hemmer (B) oder ein physiologisch verträgliches Salz davon und ein oder mehrere physiologisch verträgliche Verdünnungsmittel und/oder Trägerstoffe.(b) a second enclosure containing a pharmaceutical composition comprising a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof and one or more physiologically acceptable diluents and / or carriers.
9. Kit von Teilen nach Anspruch 8, wobei das Kit Duloxetin oder ein physiologisch verträgliches Salz davon in der zweiten Umschließung umfasst.9. The kit of parts of claim 8, wherein the kit comprises duloxetine or a physiologically acceptable salt thereof in the second enclosure.
10. Verwendung eines CGRP-Antagonisten (A) oder eines physiologisch verträglichen Salzes davon in Kombination mit einem Serotonin-Wiederaufnahme- Hemmer (B) oder einem physiologisch verträglichen Salz davon für die Herstellung einer pharmazeutischen Zusammensetzung für die Behandlung oder Prävention von Kopfschmerzen, Migräne oder Cluster headache.10. Use of a CGRP antagonist (A) or a physiologically acceptable salt thereof in combination with a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment or prevention of headache, migraine or Cluster headache.
11. Verwendung gemäß Anspruch 10, dadurch gekennzeichnet, dass der CGRP- Antagonist (A) ausgewählt ist aus der Gruppe bestehend aus11. Use according to claim 10, characterized in that the CGRP antagonist (A) is selected from the group consisting of
(1 ) 1 -[Λ -[3,5-Dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]- carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(1) 1 - [Λ - [3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] - carbonyl] - D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(2) 1 -[4-Amino-3,5-dibrom-/V-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1 ,3-benzodiazepin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(2) 1 - [4-Amino-3,5-dibromo- / V - [[4- (2,3,4,5-tetrahydro-2 (1 H) -oxo-1,3-benzodiazepine-3- yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(3) 1 -[Λi -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(3) 1 - [Λi - [4-amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(4) 1 -[Λf?-[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 W)-oxochinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidin,(4) 1 - [Λf ? - [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 W) -oxoquinazolin-3-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) -piperidine,
(5) 1 -[ΛA -[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin, (6) 1 -[/v2-[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2/-/)-oxoimidazol- 1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(5) 1 - [ΛA - [3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl ] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine, (6) 1 - [/ v 2 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2 / - /) - oxoimidazole-1 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(7) 1 -[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxothieno[3,4-d]pyrimidin-3-yl)- 1 -piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidin,(7) 1 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxothieno [3,4-d] pyrimidin-3-yl) -1 -piperidinyl ] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine,
(8) 1 -[4-Amino-3,5-dibrom-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1 ,2,4-triazol- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidin,(8) 1 - [4-Amino-3,5-dibromo-N - [[4- (2,4-dihydro-5-phenyl-3 (3H) -oxo-1, 2,4-triazole-2- yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(9) 1 -[4-Amino-3,5-dibrom-/V-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1 ,2,4-triazol- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(9) 1 - [4-Amino-3,5-dibromo- / V - [[4- (2,4-dihydro-5-phenyl-3 (3H) -oxo-1, 2,4-triazole-2 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(10) 1 -[4-Amino-3,5-dibrom-/V-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1 ,2,4-triazol- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperazin,(10) 1 - [4-Amino-3,5-dibromo- / V - [[4- (2,4-dihydro-5-phenyl-3 (3H) -oxo-1, 2,4-triazole-2 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
(11) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxothieno[3,2-d]pyrimidin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(11) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxothieno [3,2-d] pyrimidin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(12) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)- oxoimidazol-1-yl]-1-piperidin-yl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperi- dinyl)-piperidin,(12) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1- yl] -1-piperidin-yl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) piperidine,
(13) 1 -[4-Amino-3,5-dibrom-Λ.-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyi]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidin,(13) 1 - [4-Amino-3,5-dibromo-Λ .- [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyi ] -D-phenylalanyl] -4- (1-hexyl-4-piperidinyl) -piperidine,
(14) 1 -[4-Amino-3,5-dibrom-/V-[[4-[3,4-dihydro-2(1 /- )-oxochinazolin-3-yl]-1-piperi- dinyl]carbonyl]-D-phenylalanyI]-4-(1-cyclopropylmethyl-4-piperidinyl)-piperidin,(14) 1 - [4-Amino-3,5-dibromo- / V - [[4- [3,4-dihydro-2 (1 / -) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyI] -4- (1-cyclopropylmethyl-4-piperidinyl) -piperidine,
(15) 1 -[Λ/-[[4-[3,4-Dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperidinyljcarbonyl]- 3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1 H-1-azepinyl)-piperidin, _ _(15) 1 - [Λ / - [[4- [3,4-Dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyljcarbonyl] -3-ethenyl-D, L-phenylalanyl] -4 - (hexahydro-1 H-1-azepinyl) piperidine, _ _
(16) (R,S)-1-[4-[4-(3,4-Dihydro-2(1 H)-oxochinazolin-3-yl)-1-piperidinyl]-2-[(4-hy- droxy-3,5-dimethylphenyl)methyl]-1 ,4-dioxobutyl]-4-(1-piperidinyl)-piperidin,(16) (R, S) -1- [4- [4- (3,4-Dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] -2 - [(4-hy- droxy-3,5-dimethylphenyl) methyl] -1, 4-dioxobutyl] -4- (1-piperidinyl) piperidine,
(17) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[/V-(aminocarbonyl)-Λ/-phenylamino]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(17) 1 - [4-Amino-3,5-dibromo-Λ / - [[4 - [/ V- (aminocarbonyl) -Λ / -phenylamino] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(18) 1 -[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazin,(18) 1 - [4-Amino-3,5-dibromo / V - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1 -piperidinyl ] carbonyl] -D-phenylalanyl] -4- (5-methoxy-4-pyrimidinyl) piperazine,
(19) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,1-dioxido-3(4H)-oxo-1 ,2,4-benzothiadiazin- 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(19) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (1, 1-dioxido-3 (4H) -oxo-1, 2,4-benzothiadiazin-2-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(20) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[2(1 H)-oxochinolin-3-yl]-1 -piperidinyl]carbonyl]- D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(20) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [2 (1 H) -oxoquinolin-3-yl] -1 -piperidinyl] carbonyl] - D-phenylalanyl] -4 - (1-piperidinyl) -piperidine,
(21 ) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazin,(21) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- [3- (dimethylamino) propyl] piperazine,
(22) 1 -[4-Amino-3,5-dibrom-/V-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidin,(22) 1 - [4-Amino-3,5-dibromo- / V - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (4-methyl-1-piperazinyl) piperidine,
(23) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-piperazin,(23) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4 - [(1-methyl-4-piperidinyl) carbonyl] piperazine,
(24) 1 -[4-Amino-3,5-dibrom-/V-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazin,(24) 1 - [4-Amino-3,5-dibromo- / V - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4 - [(1-methyl-4-piperazinyl) carbonyl] -piperazine,
(25) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazin,(25) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- [4- [4- (dimethylamino) butyl] phenyl] -piperazine,
(26) 1 -[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidin, _ _(26) 1 - [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- [4- (dimethylamino) -1-piperidinyl] -piperidine, _ _
(27) 1 -[Λ^-[[4-(1 ,3-Dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)-1 -piperidinyl]carbonyl]- /V-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidin,(27) 1 - [Λ ^ - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1 -piperidinyl] carbonyl] - / V-methyl-D- tryptyl] -4- (4-methyl-1-piperazinyl) piperidine,
(28) 1 -[Λ^-[[4-(1 ,3-Dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)-1 -piperidinyl]carbonyl]- N'-(1 ,1 -dimethylethoxycarbonyl)-D-tryptyl]-4-(1 -methyl-4-piperidinyl)-piperidin,(28) 1 - [Λ ^ - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1 -piperidinyl] carbonyl] - N '- (1,1 -dimethylethoxycarbonyl) -D-tryptyl] -4- (1-methyl-4-piperidinyl) -piperidine,
(29) (R,S)-Λ -[4-[4-(3,4-Dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]-2-[(3,5-di- brom-4-methylphenyl)methyl]-1 ,4-dioxobutyi]-4-(4-methyl-1-piperazinyl)- piperidin,(29) (R, S) -Λ - [4- [4- (3,4-Dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] -2 - [(3,5- di-bromo-4-methylphenyl) methyl] -1, 4-dioxobutyi] -4- (4-methyl-1-piperazinyl) piperidine,
(30) (R,S)A -[4-[4-(3,4-Dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]-2-[(3,5-di- brom-4-methoxyphenyl)methyl]-1 ,4-dioxobutyl]-4-(1 -methyl-4-piperidinyl)- piperidin,(30) (R, S) A - [4- [4- (3,4-Dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] -2 - [(3,5-di bromo-4-methoxyphenyl) methyl] -1, 4-dioxobutyl] -4- (1-methyl-4-piperidinyl) - piperidine,
(31) (R,S)-1-[4-[4-(3,4-Dihydro-2(1 H)-oxochinazolin-3-yl)-1-piperidinyl]-2-[(3,4-di- bromphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidin,(31) (R, S) -1- [4- [4- (3,4-Dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] -2 - [(3,4- di-bromophenyl) methyl] -1, 4-dioxobutyl] -4- (4-methyl-1-piperazinyl) piperidine,
(32) 1 -[Λ/2-[N-[[4-(1 ,3-Dihydro-2(2H)-oxobenzimidazol-1 -yl)-1 -piperidinyl]carbonyl]- 3,5-dibrom-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin,(32) 1 - [Λ / 2 - [N - [[4- (1,3-dihydro-2 (2H) -oxobenzimidazol-1-yl) -1 -piperidinyl] carbonyl] - 3,5-dibromo-D -tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine,
(33) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-6-hydroxy-2(2H)-oxobenzimidazol- 1 -yl)-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -piperidinyl)-piperidin,(33) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-6-hydroxy-2 (2H) -oxobenzimidazole-1-yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine,
(34) 1 -[/v2-[4-Amino-3,5-dibrom-/V-[[4-(1 ,3-dihydro-2(2H)-oxobenzimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-Λ/6,Λ/6-dimethyl-L-lysyl]-4-(4-pyridinyl)- piperazin,(34) 1 - [/ v 2 - [4-Amino-3,5-dibromo- / V - [[4- (1,3-dihydro-2 (2H) -oxobenzimidazol-1-yl) - 1-piperidinyl ] carbonyl] -D-phenylalanyl] -Λ / 6 , Λ / 6 -dimethyl-L-lysyl] -4- (4-pyridinyl) - piperazine,
(35) 1 -[Λ^-[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-y[)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-Λ/s,Λ/6-dimethyl-L-lysyl]-4-(4-pyridinyl)- piperazin,(35) 1 - [Λ ^ - [4-amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-y [) - 1- piperidinyl] carbonyl] -D-phenylalanyl] -Λ / s , Λ / 6 -dimethyl-L-lysyl] -4- (4-pyridinyl) - piperazine,
(36) (R,S)A -[2-(4-Amino-3,5-dibrombenzoyl)-4-[4-(3,4-dihydro-2(1 H)-oxo- chinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidin, (37) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2,2-dioxido-2,1 ,3-benzothiadiazin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(36) (R, S) A - [2- (4-amino-3,5-dibromobenzoyl) -4- [4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl ) -1-piperidinyl] -4-oxobutyl] -4- (1-piperidinyl) -piperidine, (37) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2,2-dioxido-2,1, 3-benzothiadiazin-3-yl) -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(38) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-2(2H)-oxoimidazo[4,5-c]chinolin- 3-yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)carbonyl]- piperidin,(38) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-2 (2H) -oxoimidazo [4,5-c] quinolin-3-yl] - 1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) carbonyl] piperidine,
(39) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin,(39) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(40) 1 -[N2-[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]- carbonyl]-D-tyrosyl]-/V6,Λ/6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazin,(40) 1 - [N 2 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] - carbonyl] -D-tyrosyl] - / V 6 , Λ / 6 -dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine,
(41 ) 1 -[4-Amino-Λ/-[[4-[4-(3-bromphenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1 -yl]- 1 -piperidinyl]carbonyl]-3,5-dibrom-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidin,(41) 1 - [4-amino-Λ / - [[4- [4- (3-bromophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1 -yl] -1 -piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(42) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl]- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidin,(42) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-methyl-1-piperazinyl) piperidine,
(43) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)- piperidin,(43) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1- yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine,
(44) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl- 8-azabicyclo[3,2,1]oct-3-yl)-piperazin,(44) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1- yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3,2,1] oct-3-yl) piperazine,
(45) 1-[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi- dinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidin, _ _(45) 1- [3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine, _ _
(46) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2/-/)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -ethyl-4-piperi- dinyl)-piperazin,(46) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 / - /) - oxoimidazole -1 -yl] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) piperazine,
(47) 1 -[4-Amino-3,5-dibrom-/V-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl]- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1 H-1 ,4-di- azepin-1 -yl)piperidin,(47) 1 - [4-Amino-3,5-dibromo- / V - [[4- [1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-4-methyl-1 H-1, 4-di-azepin-1-yl) piperidine,
(48) 1 -[3,5-Dibrom-/V-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolin-3-yl)-1 -piperidinyl]- carbonyl]-D-tyrosyl]-4-[1-(methylsulfonyl)-4-piperidinyl]-piperidin,(48) 1 - [3,5-dibromo / V - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl] -D -tyrosyl] -4- [1- (methylsulfonyl) -4-piperidinyl] -piperidine,
(49) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidin,(49) 1 - [4-amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine,
(50) 1-[3,5-Dibrom-/V-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)-oxo- imidazol-1-yl]-1 -piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1 -azepinyl)- piperidin,(50) 1- [3,5-dibromo- / V - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro-1 H-1 azepinyl) piperidine,
(51 ) 1-[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1-piperidinyi]- carbonyl]-D-tyrosyl]-4-( 1 -methy l-4-pi peridi nyl)-piperidi n ,(51) 1- [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyi] carbonyl] -D-tyrosyl ] -4- (1-methyl-4-pi peridi nyl) -piperidi n,
(52) 1 -[4-Amino-3,5-dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)- piperazin,(52) 1 - [4-Amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3,2,1] oct-3-yl) piperazine,
(53) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazin,(53) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
(54) 1 -[3,5-Dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2/-/)-oxo- imidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-tyrosyl]-4-(1 -piperidinyl)-piperidin,(54) 1 - [3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 / - /) - oxo-imidazole-1 -yl] -1 -piperidinyl] carbonyl] -D-tyrosyl] -4- (1 -piperidinyl) -piperidine,
(55) 1 -[N6-Acetyl-N2-[3,5-dibrom-A.-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazin, _ _(55) 1 - [N 6 -acetyl-N 2 - [3,5-dibromo-A .- [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) - 1- piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine, _ _
(56) 1 -[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)-1 -piperi- dinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1-azepinyl)-piperidin,(56) 1 - [3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro-1 H-1-azepinyl) piperidine,
(57) 1 -[4-Amino-3,5-dibrom-/V-[[4-(1 ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol- 1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperidinyl)- piperidin,(57) 1 - [4-Amino-3,5-dibromo- / V - [[4- (1,3-dihydro-4- (3-thienyl) -2 (2H) -oxoimidazol-1-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(58) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperi- dinyl)-piperidin,(58) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1 - yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(59) 1 -[3,5-Dibrom-/V-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolin-3-yl)-1 -piperidinyl]carbo- nyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidin,(59) 1 - [3,5-dibromo / V - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl] - D-tyrosyl] -4- [1- (hydroxycarbonylmethyl) -4-piperidinyl] -piperidine,
(60) 1 -[4-Amino-3,5-dibrom-/V-[[4-[3,4-dihydro-2(1 /-/)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulfonyl-4-piperidinyl)-piperidin,(60) 1 - [4-Amino-3,5-dibromo / V - [[4- [3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl] -1 -piperidinyl ] carbonyl] -D-phenylalanyl] -4- (1-methylsulfonyl-4-piperidinyl) -piperidine,
(61 ) 1 -[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolin-3-yl)-1 -piperidinyljcarbo- nyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidin,(61) 1 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1 -piperidinyljcarbonyl] -D- tyrosyl] -4- (4-piperidinyl) -piperidine,
(62) 1 -[4-Amino-3,5-dibrom-/V-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidin,(62) 1 - [4-Amino-3,5-dibromo / V - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperidine,
(63) 1 -[4-Amino-3,5-dibrom- -[[4-(1 ,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxo- imidazol-1 -yl)-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperi- dinyl)-piperidin,(63) 1 - [4-Amino-3,5-dibromo - - [[4- (1,3-dihydro-4- (3-hydroxyphenyl) -2 (2H) -oxoimidazol-1-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(64) 1 -[3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]carbo- nyl]-D-tyrosyl]-4-(hexahydro-1 HA -azepinyl)-piperidin,(64) 1 - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl] -D- tyrosyl] -4- (hexahydro-1 HA-azepinyl) -piperidine,
(65) 1 -[4-Amino-3,5-dibrόm-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidin, (66) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[4-(3-bromphenyl)-1 ,3-dihydro-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyI]-4-(exo-8-methyI-8-aza- bicyclo[3,2,1]oct-3-yl)-piperazin,(65) 1 - [4-Amino-3,5-dibrm-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (66) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [4- (3-bromophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1-yl ] -1-piperidinyl] carbonyl] -D-phenylalanyI] -4- (exo-8-methyl-8-azabicyclo [3,2,1] oct-3-yl) piperazine,
(67) 1 -[4-Amino-3,5-Dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyI]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidin,(67) 1 - [4-Amino-3,5-dibromo / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyI ] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperidine,
(68) 1 -[4-Amino-3,5-Dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazin,(68) 1 - [4-Amino-3,5-dibromo / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) piperazine,
(69) 1 -[4-Amino-3,5-dibrom-/V-[[4-[1 ,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyI]-4-(exo-8-methyl-8-aza- bicyclo[3,2,1]oct-3-yl)-piperazin,(69) 1 - [4-Amino-3,5-dibromo- / V - [[4- [1,3-dihydro-4- (3-methoxyphenyl) -2 (2H) -oxoimidazol-1-yl ] -1-piperidinyl] carbonyl] -D-phenylalanyI] -4- (exo-8-methyl-8-azabicyclo [3,2,1] oct-3-yl) piperazine,
(70) 1 -[3,5-Dibrom-/V-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]carbo- nyl]-D-tyrosyI]-4-[1-(cyclopropylmethyl)-4-piperidinyl]-piperidin,(70) 1 - [3,5-dibromo / V - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl] -D- tyrosyI] -4- [1- (cyclopropylmethyl) -4-piperidinyl] -piperidine,
(71) 1-[4-Amino-3,5-Dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1-piperi- dinyl]carbonyI]-D-phenylalanyl]-4-(hexahydro-1 /-/-1-azepinyl)-piperidin,(71) 1- [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyI ] -D-phenylalanyl] -4- (hexahydro-1 / - / - 1-azepinyl) piperidine,
(72) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidin,(72) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (4-piperidinyl) -piperidine,
(73) 1 -[3,5-Dibrom-/V-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)-1 -pϊperi- dinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidin,(73) 1 - [3,5-dibromo / V - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1 -pperidinyl] carbonyl] -D-tyrosyl] -4- (4-pyridinyl) -piperidine,
(74) 1 -[3,5-Dibrom-/V-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)-oxo- imidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-tyrosyl]-4-(1 -methyl-4-piperidinyl)- piperazin, (75) 1 -[Λ^-[3,5-Dibrom-A/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2/-/)-oxo- imidazoI-1-yl]-1 -piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)- piperazin,(74) 1 - [3,5-dibromo / V - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-methyl-4-piperidinyl) piperazine, (75) 1 - [Λ ^ - [3,5-dibromo-A / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 / - /) - oxo imidazoI-1-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) - piperazine,
(76) 1 -[3,5-Dibrom-/V-[[4-(1 ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1 -yl)-1 -piperi- dinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidin,(76) 1 - [3,5-dibromo / V - [[4- (1,3-dihydro-4- (3-thienyl) -2 (2H) -oxoimidazol-1-yl) -1 -piperi- dinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine,
(77) 1-[4-Amino-Λ/-[[4-[4-(3-chlorphenyl)-1 ,3-dihydro-2(2/-/)-oxoimidazol-1-yl]- 1 -piperidinyl]carbonyl]-3,5-dibrom-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidin,(77) 1- [4-Amino-Λ / - [[4- [4- (3-chlorophenyl) -1, 3-dihydro-2 (2 / - /) - oxoimidazol-1-yl] -1 -piperidinyl ] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(78) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 H- 1 -azepinyl)-piperidin,(78) 1 - [4-Amino-3,5-dibromo-Λ / - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1 - yl] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1 H-1-azepinyl) -piperidine,
(79) 1 -[4-Amino-3,5-dibrom-/V-[[4-[1 ,3-dihydro-4-[3-(trifluormethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -methyl-4-piperi- dinyl)-piperazin,(79) 1 - [4-Amino-3,5-dibromo- / V - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) - oxoimidazole-1 - yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
(80) 1 -[4-Amino-Λ/-[[4-[4-(3-chlorphenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1-yl]- 1 -piperidinyl]carbonyl]-3,5-dibrom-D-phenylalanyl]-4-(hexahydro-1 H-1 -azepi- nyl)-piperidin,(80) 1 - [4-Amino-Λ / - [[4- [4- (3-chlorophenyl) -1, 3-dihydro-2 (2H) -oxoimidazol-1-yl] -1 -piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (hexahydro-1 H-1-azepinyl) piperidine,
(81 ) 1 -[4-Amino-3,5-dibrom-/V-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazin,(81) 1 - [4-Amino-3,5-dibromo- / V - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-pyridinyl) piperazine,
(82) 1 -[3,5-Dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2/-/)-oxoimidazol-1 -yl)-1 -piperi- dinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidin,(82) 1 - [3,5-Dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2 / - /) - oxoimidazol-1-yl) -1 -piperidinyl ] carbonyl] -D-tyrosyl] -4- (1-methyl-4-piperidinyl) -piperidine,
(83) 1 -[4-Amino-3,5-dibrom-/V-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl]- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazin, (84) 1 -[3,5-Dibrom-/V-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperidinyl]carbo- nyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazin,(83) 1 - [4-Amino-3,5-dibromo- / V - [[4- [1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- [4- (1-oxoethyl) phenyl] piperazine, (84) 1 - [3,5-dibromo- / V - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl] -D- tyrosyl] -4- (1-methyl-4-piperidinyl) piperazine,
(85) 1 -[4-Amino-3,5-dibrom-/V-[[4-[1 ,3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimidazol- 1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidin,(85) 1 - [4-Amino-3,5-dibromo- / V - [[4- [1,3-dihydro-4- (3-nitrophenyl) -2 (2H) -oxoimidazol-1-yl] - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine,
(86) 1-[4-Amino-3,5-dibrom-Λ/-[[4-[3,4-dihydro-2(1 H)-oxochinazolin-3-yl]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-pyrrolidinyl)-piperidin,(86) 1- [4-Amino-3,5-dibromo-Λ / - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1 -piperidinyl] carbonyl ] -D-phenylalanyl] -4- (1-pyrrolidinyl) -piperidine,
(87) 1 -[4-Amino-3,5-dibrom-Λ/-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 HA -azepinyl)-piperidin und(87) 1 - [4-amino-3,5-dibromo-Λ / - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1 HA-azepinyl) piperidine and
(88) 1 -[4-Amino-3,5-dibrom-/V-[[4-(1 ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1 - yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazin,(88) 1 - [4-Amino-3,5-dibromo- / V - [[4- (1,3-dihydro-4- (3-thienyl) -2 (2H) -oxoimidazol-1 - yl) - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine,
deren physiologisch verträglichen Salzen und den Hydraten der Salze.their physiologically compatible salts and the hydrates of the salts.
12. Verfahren nach Anspruch 10 oder 11 , dadurch gekennzeichnet, dass der Serotonin-Wiederaufnahme-Hemmer (B) ausgewählt ist aus der Gruppe, bestehend aus Citalopram, Duloxetin, Escitalopram, Fluoxetin, Fluvoxamin, Paroxetin, Sertralin, Trazodon und deren physiologisch verträglichen Salzen.12. The method according to claim 10 or 11, characterized in that the serotonin reuptake inhibitor (B) is selected from the group consisting of citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone and their physiologically tolerable salts ,
13. Verfahren nach Anspruch 12, dadurch gekennzeichnet, dass der Serotonin- Wiederaufnahme-Hemmer (B) Duloxetin oder ein physiologisch verträgliches Salz davon ist.13. The method according to claim 12, characterized in that the serotonin reuptake inhibitor (B) is duloxetine or a physiologically acceptable salt thereof.
14. Verwendung des CGRP-Antagonisten (A) oder eines physiologisch verträglichen Salzes davon für die Herstellung einer pharmazeutischen Zusammensetzung oder eines Kits von Teilen nach einem der Ansprüche 6 bis 9. 14. Use of the CGRP antagonist (A) or a physiologically tolerable salt thereof for the production of a pharmaceutical composition or a kit of parts according to one of claims 6 to 9.
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