CA2563687A1 - 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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CA2563687A1
CA2563687A1 CA002563687A CA2563687A CA2563687A1 CA 2563687 A1 CA2563687 A1 CA 2563687A1 CA 002563687 A CA002563687 A CA 002563687A CA 2563687 A CA2563687 A CA 2563687A CA 2563687 A1 CA2563687 A1 CA 2563687A1
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piperidinyl
carbonyl
dihydro
dibromo
amino
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Henri Doods
Klaus Rudolf
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International Gmbh
Henri Doods
Klaus Rudolf
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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
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    • 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
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    • 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
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    • 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
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    • 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
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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

' CA 02563687 2006-10-19 87543pct Use of a CGRP-antagonist combined with a serotonin-reuptake inhibitor in order to treat migraines Background to the invention Migraine is one of the most common neurological disorders and comprises periodic attacks of headache and nausea and a variety of other symptoms. Although considerable progress has been made, the pathophysiology of migraine is far from understood. A number of observations have pointed to the involvement of the "calcitonin gene related peptide" (CGRP). Migraine headaches involve the activation of the trigeminal system and the dilation of cranial blood vessels. CGRP is located in the neurons in trigeminal ganglia, and the CGRP levels are raised during a migraine attack, which is presumably what causes the vasodilatation observed.
It is therefore conceivable that inhibiting the dilation of the cranial blood vessels caused by CGRP might possibly give rise to a new treatment for migraine headaches.
Medicaments widely used for treating migraine are the so-called "triptans", e.g. suma-triptan and zolmitriptan. These compounds derive their activity against migraine from their vasoconstrictor properties and presumably their inhibition of the release of the 2o neuropeptide "calcitonin gene related peptide" (CGRP) (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: Theories, animal models and emerging therapies, Progress in Drug Research, vol. 51, 220-244), assuming that the levels thereof are raised during a migraine attack (Edvinsson, L., Goadsby, P. J. (1994), Neuropeptides in migraine and cluster headache, Cephalgia, 14(5), 320-327). A completely new approach for the treatment of migraine 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
3o antagonist, Br. J. Pharmacol., 129, 420-423).

' CA 02563687 2006-10-19 Background to the invention US Patent No. 5,023,269 describes how 3-aryloxy-3-substituted propanamines, such as for example duloxetine, are suitable for the treatment of pain. In particular, the serotonin reuptake inhibitor duloxetine may be used to treat migraine, as disclosed in International Patent Application PCT/US95/13289.
WO 98/11128 discloses modified amino acids with CGRP-antagonistic properties, the use thereof and processes for the preparation thereof as well as the use thereof for the preparation and purification of antibodies and as labelled 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, particularly migraine and cluster headaches. Other compounds with CGRP-antagonistic properties are described in International Applications PCT/EP03/02417, PCT/EP03/11762, ~ 5 PCT/EP03/11763, PCT/EP04/00087, PCT/EP00/02004, PCT/EP00/10463, PCT/EP00/10391 and PCT/EP00/13236.
Summary of the invention Surprisingly it was found that in a model assumed to predict the anti-migraine 2o activities of pharmaceutical compositions, the combination of two pharmaceutical compositions with completely different modes of activity, namely a CGRP-antagonist (A) and a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof leads to an improved activity compared with the activity of only one pharmaceutical composition.
Detailed description of the invention In a first aspect the present invention relates to a process for the treatment or prevention of indications which are selected from among the group comprising headaches, migraine and cluster headaches, this process comprising the joint so administration of 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.

~ ~ CA 02563687 2006-10-19 For the purposes of the present invention the active substance (A) used may be any pharmaceutically acceptable active substances which antagonise the known effects of CGRP or inhibit the release of CGRP from sensory nerve endings.
CGRP-antagonists (A) which may be used include for example the amino acid derivatives described in WO 98/11128 or DE 199 11 039, and the non-peptidic active substances described in WO 98/56779, WO 98/09630 and WO 97/09046.
Preferably, the CGRP antagonist (A) is selected from the group comprising (1 ) 1-[N2-[3,5-dibromo-N-[[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-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (3) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (4) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(11-~-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine, (5) 1-[N2-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (6) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(21-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (7) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine, (8) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3hn-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine, (9) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (10) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3hn-oxo-1,2,4-triazol 2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl) piperazine, (11 ) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxothieno[3,2-d]pyrimidin-3 yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1-piperidinyl)-piperid ine, ~5 (12) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1-ethyl-4-piperi-dinyl)-piperidine, (13) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-2o dinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine, (14) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi dinyl]carbonyl]-D-phenylala-nyl]-4-(1-cyclopropylmethyl-4-piperidinyl) piperidine, (15) 1-[N-[[4-[3,4-dihydro-2(11~-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(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-so hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine, (17) 1-[4-amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-( 1-piperidinyl)-piperid ine, (18) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine, (19) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-[2(1h~-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (21 ) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(11~-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl)-4-[3-(dimethylamino)propyl]-piperazine, (22) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine, (23) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[( 1-methyl-4-piperid inyl)carbonyl]-piperazine, (24) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[( 1-methyl-4-piperazinyl)carbonyl]-piperazine, (25) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(11--~-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine, (26) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(11~-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine, (27) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N'-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine, (28) 1-[N2-[[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(1H)-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(1H)-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(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-di-bromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine, ~5 (32) 1-[N2-[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-dibromo-N-[[4-(1,3-dihydro-6-hydroxy-2(2H)-oxobenzimidazol 1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1-piperidinyl)-piperid ine, (34) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-IV6,N~-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (35) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N ~,IVs-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (36) (R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxo-3o quinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine, (37) 1-[4-amino-3,5-dibromo-N-[[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-N-([4-[1,3-dihydro-2(2H)-oxoimidazo[4,5-c)quinolin-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1-piperid inyl)carbonyl]-piperidine, (39) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (40) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-N ~,IV6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (41) 1-[4-amino-N-[[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-dibromo-N-([4-[1,3-dihydro-4-phenyl-2(21-n-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine, (43) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(21~-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-2o piperidine, (44) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo(3.2.1 ]oct-3-yl)-piperazine, (45) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine, (46) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperi-dinyl)-piperazine, - $ -(47) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1 H-1,4 diazepin-1-yl)piperidine, (48) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]
carbonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine, (49) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(21-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine, (50) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(21-oxo-imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine, (51) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-4-( 1-methyl-4-piperidinyl)-piperidine, (52) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3.2.1 ]oct-3-yl)-2o piperazine, (53) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2h~-oxoimidazol-1-yl)-1-piperid inyl]carbonyl]-D-phenylalanyl]-4-( 1-methyl-4-piperid inyl)-piperazine, (54) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(21-~-oxo-imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-( 1-piperidinyl)-piperidine, (55) 1-[N6-acetyl-N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl) 1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (56) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine, _g_ (57) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperid inyl]carbonyl]-D-phenylalanyl]-4-( 1-methyl-4-piperidinyl )-piperidine, (58) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenylJ-2(2H)-oxoimidazol-1-yl]-1-piperid inyl]carbonyl]-D-phenylalanyl]-4-( 1-methyl-4-piperi-dinyl)-piperidine, (59) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-1o piperidinylJcarbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine, (60) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine, (61 ) 1-[3,5-dibromo-N-[[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-dibromo-N-[[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-dibromo-N-[[4-(1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxo-imidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1-methyl-4-piperi-dinyl)-piperidine, (64) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine, (65) 1-[4-amino-3,5-dibromo-N-[(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-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxo-imidazol-1-yl]-1-piperid inyl]carbonylJ-D-phenylalanyl]-4-(exo-8-methyl-8-aza-bicyclo[3.2.1 ]oct-3-yl)-piperazine, (67) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(11~-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-( 1-ethyl-4-piperidinyl)-piperid ine, (68) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine, (69) 1-[4-amino-3,5-dibromo-N-[[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 Joct-3-yl)-piperazine, (70) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1f~-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosylJ-4-[1-(cyclopropylmethyl)-4-piperidinyl]-piperidine, (71 ) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(11-~-oxoquinazolin-3-yl)-1-piperi-2o dinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (72) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine, (73) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine, (74) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(21-x-oxo-imidazol-1-yl]-1-piperid inyl]carbonyl]-D-tyrosyl]-4-( 1-methyl-4-piperid inyl)-3o piperazine, (75) 1-[N2-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl) piperazine, (76) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2h!)-oxoimidazol-1-yl)-piperidinyl]carbonyl]-D-tyrosyl]-4-( 1-piperidinyl)-piperid ine, (77) 1-[4-amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2f-I)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-1o piperidine, (78) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2f-I)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine, (79) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(21-I)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperi-dinyl)-piperazine, (80) 1-[4-amino-N-[[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-azepi-nyl)-piperidine, (81) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine, (82) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine, (83) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(21-n-oxoimidazol-1-yl]-1-piperid inyl]carbonyl]-D-phenylalanyl]-4-[4-( 1-oxoethyl)phenyl]-piperazine, (84) 1-[3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-( 1-methyl-4-piperidinyl)-piperazine, (85) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-nitrophenyl)-2(21-~-s oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine, (86) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-pyrrolidinyl)-piperidine, (87) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(21-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine and (88) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(21-oxoimidazol-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1-methyl-4-piperid inyl)-piperazine, the physiologically acceptable salts thereof and the hydrates of the salts.
The serotonin reuptake inhibitor (B) used may be citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone or the physiologically acceptable salts thereof. Preferably, duloxetine is used.
2s The dosage for the serotonin reuptake inhibitor (B) is roughly 1/50 of the lowest normally recommended dose to 1/1 of the normally recommended dose, by oral, nasal, inhalative, subcutaneous or intravenous route.
According to the invention the CGRP antagonist (A) or a physiologically acceptable 3o salt thereof may be administered by intravenous or subcutaneous route in a dosage of 0.0001 to 3 mg/kg of body weight, by oral route in a dosage of 0.1 to 20 mg/kg body weight or by nasal or inhalative 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, which may be administered by oral route in a dosage of 0.03 to 1.43 mg/kg body weight once, twice or three times a day or by intravenous or subcutaneous route in a dosage of 0.002 to 0.09 mg/kg body weight once or twice a day or by rectal route in a dosage of 0.007 to 0.36 mg/kg body weight once or twice a day or by nasal route in a dosage of 0.006 to 0.29 mg/kg body weight once or twice a day.
In a second aspect the present invention provides a pharmaceutical composition for the treatment or prevention of headaches, migraine or cluster headache, which consists of 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 thereof, as a combined preparation for simultaneous or sequential administration.
2o A pharmaceutical composition according to the invention may contain 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 acceptable salt thereof and 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, particularly 40 to 80 mg, of the serotonin reuptake inhibitor (B) or an equivalent amount of a physiologically acceptable salt thereof.
3o All the doses or dosage units of a physiologically acceptable salt of one of the above-mentioned active compounds should be understood as being doses or dosages of the active compound itself.
Moreover a pharmaceutical composition according to the invention may be a kit of parts for the treatment or prevention of headache, migraine or cluster headaches, the kit comprising:
(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) 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.
In a third aspect the present invention relates to 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 preparing a pharmaceutical composition for the treatment or prevention of headaches, migraine or cluster headache.
The CGRP antagonist (A) or a physiologically acceptable salt thereof may be administered e.g. using one of the pharmaceutical formulations described in the Examples. The Examples that follow describe pharmaceutical compositions which contain the CGRP antagonist (A) or a physiologically acceptable salt thereof and a serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof.

' CA 02563687 2006-10-19 Example 1a Tablets containing 100 mg CGRP antagonist (A) or an eguivalent amount of a physiologically acceptable salt thereof and 50 ma serotonin reuptake inhibitor (B) or an eguivalent amount of a physioloaical~ acceptable salt thereof Composition/Tablet:
CGRP antagonist (A) 100 mg serotonin reuptake inhibitor (B) 50 mg lactose 375 mg magnesium stearate 3.0 mg povidone 8.5 mg crospovidone 14.4 mg volatile component: water Method of preparation:
CGRP antagonist (A), serotonin reuptake inhibitor (B) and lactose (fine) are homogeneously mixed in a suitable mixer (e.g. Diosna P2); then the mixture is granulated with an aqueous povidone solution. The granulated material is screened 2o through a 1.6 mm Kressner screen and dried for 2 hours at 40°C. Then the granules are screened in a suitable mill, e.g. a Comill, at 3000 rpm with a mesh size of 1.1 mm. The granules are then mixed with crospovidone for 5 minutes and then with magnesium stearate for 1 minute. The mixture thus obtained is compressed in a tablet press to produce tablets of suitable diameter.
This method is the basis for other examples listed in the Table that follows.
Table 1 CGRP serotonin Exampleantagonistreuptake inhibitormg mg mg mg Mg-(A) [mg](B) [mg] lactosepovidonecrospovidonestearate 1.1 570 10 1160.0 26.1 44.2 9.1 1.2 430 50 960.0 21.6 36.5 7.5 1.3 560 20 470.0 26.1 44.2 9.1 1.4 560 50 630.0 18.6 31.5 6.5 1.5 480 50 820.0 20.3 34.3 7.0 1.6 430 70 645.0 17.2 29.1 6.0 1.7 250 40 580.0 13.1 22.1 4.5 1.8 510 20 870.0 21.0 35.5 7.3 1.9 240 70 620.0 14.0 23.6 4.8 1.10 310 60 740.0 16.7 28.2 5.8 1.11 190 70 520.0 11.7 19.8 4.1 1.12 10 10 140.0 2.4 4.1 0.8 1.13 540 70 790.0 21.0 35.5 7.3 1.14 1000 10 40.0 15.8 26.6 5.5 1.15 390 40 860.0 19.4 32.7 6.7 1.16 350 70 840.0 18.9 32.0 6.6 1.17 240 40 560.0 12.6 21.3 4.4 1.18 250 40 580.0 13.1 22.1 4.5 1.19 40 40 160.0 3.6 6.1 1.2 1.20 270 50 640.0 14.4 24.4 5.0 1.21 460 60 660.0 17.7 29.9 6.1 1.22 490 70 540.0 16.5 27.9 5.7 1.23 150 60 420.0 9.5 16.0 3.3 1.24 20 20 80.0 1.8 3.0 0.6 1.25 40 10 100.0 2.3 3.8 0.8 Example 2 Tablets containing 100 mg CGRP antagonist (A~ or an eauivalent amount of a physiologically acceptable salt thereof and 50 ma serotonin reuptake inhibitor (B) or an eauivalent amount of a physiologically acceptable salt thereof Composition:
CGRP antagonist (A) 100 mg serotonin reuptake inhibitor (B) 50 mg lactose 284 mg microcrystalline cellulose 89.5 mg magnesium stearate 7.2 mg croscarmellose 7.3 mg volatile component: water Method of preparation:
CGRP antagonist (A), serotonin reuptake inhibitor (B), lactose (fine) and microcrystalline cellulose are homogeneously mixed in a suitable mixer (e.g.
Diosna P2); then the mixture is granulated with water. The granulated material is screened 2o through a 1.6 mm Kressner screen and dried for 2 hours at 40°C. Then the granules are screened in a suitable mill, e.g. a Comill, 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 compressed in a tablet press to produce tablets of suitable diameter.
This method is the basis for other examples listed in the Table that follows.
Table 2 serotonin mg mg Example CGRP antagonistreuptake inhibitormg microcryst.Mg- mg cros-(A) [mg] (B) [mg] lactosecellulosestearatecarmellose 2.1 210 80 435.0 145.0 13.1 13.2 2.2 10 100 165.0 55.0 5.0 5.0 2.3 80 10 135.0 45.0 4.1 4.1 2.4 210 70 420.0 140.0 12.6 12.8 2.5 260 20 420.0 140.0 12.6 12.8 2.6 140 20 240.0 80.0 7.2 7.3 2.7 10 60 105.0 35.0 3.2 3.2 2.8 10 30 60.0 20.0 1.8 1.8 2.9 280 60 380.0 144.0 13.0 13.2 2.10 120 60 270.0 90.0 8.1 8.2 2.11 80 20 150.0 50.0 4.5 4.6 2.12 240 60 450.0 150.0 13.5 13.7 2.13 290 30 480.0 160.0 14.4 14.6 2.14 320 100 360.0 156.0 14.0 14.3 2.15 80 60 210.0 70.0 6.3 6.4 2.16 190 50 360.0 120.0 10.8 11.0 2.17 60 40 150.0 50.0 4.5 4.6 2.18 10 10 30.0 10.0 0.9 0.9 2.19 20 10 45.0 15.0 1.4 1.4 2.20 360 50 370.0 156.0 14.0 14.3 ' CA 02563687 2006-10-19 Example 3a Agueous solution for intranasal application containing 20% CGRP antagonist (A) or an eguivalent amount of a physiologically acceptable salt thereof and 5%
serotonin reuptake inhibitor (B) or an eguivalent amount of a physiologically acceptable salt thereof Composition:
CGRP antagonist (A) 20 mg serotonin reuptake inhibitor (B) 5 mg mannitol 5 mg water ad 0.1 ml Method:
~5 The active substance is dissolved/suspended in water with stirring and optionally heating. The isotonic agent mannitol is added and the solution is made up to the final volume with water.
Example 3b Agueous solution for intranasal application containing 40% CGRP antagonist (A) or an eguivalent amount of a physiologically acceptable salt thereof and 10%
serotonin reuptake inhibitor (B) or an eguivalent amount of a physiologically acceptable salt thereof and 1.5% Labrasol Composition:
CGRP antagonist (A) 40 mg serotonin reuptake inhibitor (B) 10 mg Labrasol 1.5 mg 3o mannitol 5 mg water ad 0.1 ml Method:
The active substances are dissolved/suspended in water with stirring and optionally heating. The isotonic agent mannitol and Labrasol are added and the solution is made up to the final volume with water.
This method is the basis for other Examples which are listed in the following Table.
Table relating to 3a and b CGRP
Example antagonistserotonin reuptakemg mg mg water (A) [mg] inhibitor (B) Mannitol Labrasol [mg]

3.1 20 3.5 5 3.00 68.50 3.2 70 4.8 5 3.00 17.16 3.3 50 2.5 5 1.50 41.00 3.4 40 2.8 5 0.00 52.22 3.5 30 5.0 5 0.00 60.00 3.6 60 2.0 5 3.00 30.00 3.7 20 10.0 5 1.50 63.50 3.8 30 5.0 5 1.50 58.50 3.9 10 4.0 5 0.00 81.00 3.10 70 10.0 5 0.00 15.00 3.11 70 4.0 5 3.00 18.00 3.12 60 2.5 5 3.00 29.50 3.13 5 4.0 5 3.00 83.00 3.14 30 20.0 5 3.00 42.00 3.15 70 5.0 5 1.50 18.50 Pellets The medicaments according to the invention may also be prepared in the form of small particles such as e.g. pellets. The active substance may be applied to neutral pellets consisting of sucrose and starch or microcrystalline cellulose.
The preparation comprises the following steps:
1. selection or preparation of starter pellets 2. build-up of the layer of active substance Optional: coating the pellets to improve their stability or correct the flavour or - if desired - to delay the release of one or more active substances.
Example 4 Preparation of an licationof active substance comprising100 partsby weight app CGRP anta gonist or an guivalent amount of a ically ptable (A) e physiolog acce salt thereof and 40 partsby weight serotonin reuptake (B) or eguivalent inhibitor an amount of a physioloaically acceptable salt thereof Composition:
core material 200 parts by weight ~5 hydroxypropylcellulose 38 parts by weight talc 20 parts by weight CGRP antagonist (A) 100 parts by weight serotonin reuptake inhibitor (B) 40 parts by weight 2o Hydroxypropylcellulose is dissolved in 250 parts by weight of 2-propanol with stirring and then the active substances and talc are dispersed in this solution with stirring.
In a fluidised bed processor 200 parts by weight of core material are sprayed with the dispersion containing the active substance at an air inlet temperature of 20°C to 30°C
using the under-bed spraying method. The pellets containing the active substance 25 are then dried in the circulating air dryer at 35°C for 8 hours.
To remove lumps the pellets containing the active substance are screened through a screen with a nominal mesh size of 1.25 mm. The product fraction (particle size <
1.25 mm) is processed further.
3o The layer of active substance is generally always produced in the same way, but the nature and amount of active substance, the nature and amount of binder and the amount of talc and water, isopropanol or ethanol vary.
Other Examples are shown in Table 4.
Table 4 CGRP
Ex. antagonist(B) *pbw *pbw *pbw *pbw *pbw *pbw *pbw (A) [*pbw][mg] povidoneHPC pelletstalc iso- EtOH H20 propanol 4.1 150 25.0 28.8 0.0 144.0 31.7 1890 0 0 4.2 210 2.5 24.3 0.0 121.5 26.7 1600 0 1600 4.3 250 2.8 24.4 0.0 121.8 26.8 0 1610 0 4.4 560 14.5 0.0 26.7 133.5 29.4 0 0 1760 4.5 450 2.5 0.0 24.3 121.5 26.7 0 1600 0 4.6 430 5.0 0.0 24.8 124.0 27.3 0 1640 0 4.7 70 10.0 25.8 0.0 129.0 28.4 1700 0 0 4.8 360 80.0 39.8 0.0 199.0 43.8 2630 0 0 4.9 530 100.00.0 43.8 219.0 48.2 0 2890 0 4.105 25.0 28.8 0.0 144.0 31.7 1900 0 0 4.11230 50.0 33.8 0.0 169.0 37.2 2230 0 0 4.1220 100.00.0 43.8 219.0 48.2 0 0 2890 4.13230 90.0 0.0 41.8 209.0 46.0 4210 0 0 4.14540 25.0 0.0 28.8 144.0 31.7 1900 0 0 4.15500 50.0 0.0 33.8 169.0 37.2 2230 0 0 4.1640 15.0 0.0 26.8 134.0 29.5 0 1800 0 4.17150 85.0 0.0 40.8 204.0 44.9 0 0 4950 4.1810 75.0 38.8 0.0 194.0 42.7 2600 0 0 4.19140 100.043.8 0.0 219.0 48.2 3610 0 0 4.20430 80.0 0.0 39.8 199.0 43.8 0 0 2670 4.21250 20.0 0.0 27.8 139.0 30.6 1870 0 0 4.22120 80.0 0.0 39.8 199.0 43.8 2670 0 0 4.23260 12.7 0.0 26.3 131.7 29.0 0 0 1770 4.24500 25.0 28.8 0.0 144.0 31.7 0 0 1930 4.251000 5.9 25.0 0.0 124.9 27.5 0 1680 0 4.26400 60.0 35.8 0.0 179.0 39.4 0 2400 0 4.27440 75.0 38.8 0.0 194.0 42.7 0 3210 0 4.28350 25.0 0.0 28.8 144.0 31.7 0 0 1930 4.29210 100.00.0 43.8 219.0 48.2 0 0 2940 *pbw = parts by weight; EtOH= ethanol Fxtri mlatpc The medicaments according to the invention may also be prepared in the form of extrudates which after cutting/spheronising are packed directly into capsules or s ground up and processed to form tablets.
The preparation method comprises the following steps:
1. Extrusion 2a. Cutting/Spheronising 2b. Grinding and subsequent processing into tablets Example 5a Preparation of moist extrudates with 300 parts by weight of CGRP antagonist (A) or an eguivalent amount of a physiologically acceptable salt thereof and 80 parts by 1 s weight of serotonin reuptake inhibitor (B) or an eguivalent amount of a physiologically acceptable salt thereof Composition:
povidone 6 parts by weight 2o microcrystalline cellulose 40 parts by weight CGRP antagonist (A) 300 parts by weight serotonin reuptake inhibitor (B) 80 parts by weight 300 parts by weight CGRP antagonist (A), 80 parts by weight serotonin reuptake 25 inhibitor (B), 40 parts by weight microcrystalline cellulose (Avicel PH 101 ) and 6 parts by weight povidone (collidone K25) are mixed for 15 minutes in a gyrowheel mixer.
Then the powder mixture is placed in a twin-screw extruder together with water, at a speed of approx. 1 kg/h. The addition of water is automatically regulated to produce a torque of approx. 19% in the extruder. Extrusion is carried out through a nozzle plate 3o with bores 0.8 mm in diameter.
The extruded strips are formed into rounded pellets in a Spheronizer, taking approx.
3 minutes at approx. 850 RPM.
The pellets are dried at 80°C for approx. 1.5 h in a fluidised bed dryer.
The core material is fractionated through a tumbler screening machine with different sieve plates with nominal mesh sizes of from 0.71 to 1.25 mm. The appropriate product fractions between 0.71 and 0.90 and between 0.90 and 1.12 mm are used.
Other Examples are shown in Table 5.
Table 5 CGRP *pbw *pbw Example antagonist serotonin reuptakemicrocryst.*pbw polyethylene-(A) inhibitor (B) cellulosepovidoneglycol 4000 [*pbw] [*pbw]

5.1 20 10 6.0 0.9 50 5.2 370 25 79.0 11.9 5.3 160 20 36.0 5.4 144 5.4 110 2.5 22.5 3.4 90 5.5 110 50 32.0 4.8 128 5.6 370 20 78.0 11.7 312 5.7 250 50 60.0 9.0 5.8 370 50 84.0 12.6 5.9 390 22.1 82.4 12.4 5.10 40 200 48.0 7.2 192 5.11 200 10 42.0 6.3 5.12 30 7.5 7.5 1.1 30 5.13 380 20 80.0 12.0 5.14 360 20 76.0 11.4 5.15 250 25 55.0 8.3 5.16 160 22.1 36.4 5.5 5.17 10 80 18.0 2.7 72 5.18 380 60 88.0 13.2 5.19 160 60 44.0 6.6 5.20 260 50 62.0 9.3 *pbw = parts by weight Example 6 Preparation of molten extrudates containinc~200 parts by weight CGRP
antagonist (A) or an eauivalent amount of a physiologically acceptable salt thereof and 60 parts by weight serotonin reuptake inhibitor (B) or an eauivalent amount of a physiologically acceptable salt thereof Composition:
povidone 6 parts by weight Poloxamer 40 parts by weight CGRP antagonist (A) 200 parts by weight serotonin reuptake inhibitor (B) 60 parts by weight 200 parts by weight CGRP antagonist (A), 60 parts by weight serotonin reuptake ~ 5 inhibitor (B), 40 parts by weight poloxamer and 6 parts by weight povidone K25 are mixed for 15 minutes in a gyrowheel mixer. Then the powder mixture is placed in a twin-screw extruder at a speed of approx. 1 kg/h. The temperature is regulated to produce a torque of approx. 19% in the extruder. Extrusion is carried out through a nozzle plate with bores 0.8 mm in diameter.
2o The extruded strips are cut and formed into rounded pellets in a Spheronizer, taking approx. 3 minutes at approx. 850 RPM at about 40°C.
The pellets are dried at 80°C for approx. 1.5 h in a fluidised bed dryer.
The core material is fractionated through a tumbler screening machine with different 25 sieve plates with nominal mesh sizes of from 0.71 to 1.25 mm. The appropriate product fractions between 0.71 and 0.90 and between 0.90 and 1.12 mm are used in subsequent processes.
The compositions may vary and are shown in tabulated form below.
Table 6 CGRP *pbw Example antagonistserotonin reuptake*pbw *pbw polyethylene-(A) [*pbw]inhibitor (B) povidonepoloxamer glycol 4000 [*pbw]

6.1 140 60 3.0 50.8 6.2 200 22.1 3.3 56.4 6.3 330 25 5.3 90.1 6.4 160 15 2.6 44.4 6.5 10 50 0.9 15.2 45.7 6.6 230 2.5 3.5 59.0 6.7 140 12.5 2.3 38.7 6.8 70 60 2.0 33.0 99.0 6.9 390 10 6.0 101.5 6.10 330 10 5.1 86.3 6.11 380 2.5 5.7 97.1 6.12 360 40 6.0 101.5 6.13 270 25 4.4 74.9 6.14 400 60 6.9 116.7 6.15 280 75 5.3 90.1 6.16 230 40 4.1 68.5 6.17 120 60 2.7 45.7 6.18 150 5 2.3 39.3 6.19 180 100 4.2 71.1 6.20 30 150 2.7 45.7 137.0 6.21 190 10 3.0 50.8 6.22 390 50 6.6 111.7 6.23 210 15 3.4 57.1 6.24 60 10 1.1 17.8 53.3 *pbw = parts by weight Example 7 Further processing into tablets The extrudates are ground in a suitable mill, the resulting granules are further processed with conventional tabletting excipients analogously to Example 1 to form tablets.
Inhalable powder Preparation of spherically nanostructured microparticles of the active substances for preparing an inhalable powder In order to prepare an active substance solution of 4 wt.% the active substances are dissolved accordingly in an ethanol/water (4:1 ) mixture and the active substance ~5 solution is sprayed so as to obtain a spray mist with a droplet size having the characteristic X50 (median value = particle size/droplet size, below which 50%
of the quantity of particles falls relative to the distribution by volume of the individual particles/drops) in the range from 1.5 to 8 pm and Q(5.8) (corresponds to the quantity of particles, based on the distribution by volume of the droplets below 5.8 pm) of 2o between 30 and 100% is obtained. The spray mist thus obtained is dried using a drying gas with an entry temperature of between 130°C and 200°C
and an exit temperature of 40°C to 120°C. The current by volume of the spray gas is 1 Nm3/h to 15 Nm3/h and the current by volume of the drying gas is 15 Nm3/h to 150 Nm3/h.
The dried solid content is collected using a gravity precipitator and/or a filter unit.
Example 8 Capsules for powder inhalation containing 0.5 mp CGRP antagonist (A) or an eauivalent amount of a physiologically acceptable salt thereof and 0.25 ma serotonin 3o reuptake inhibitor (B) or an eauivalent amount of a physiologically acceptable salt thereof Composition:
1 capsule for powder inhalation contains:
CGRP antagonist (A) 0.5 mg serotonin reuptake inhibitor (B) 0.25 mg s lactose 20 mg hard gelatine capsules 50 mg Method of preparation:
The active substance is prepared as spherically nanostructured particles of active substance and homogeneously mixed with lactose. The mixture is packed into hard gelatine capsules.
Other Examples are listed in Table 8.
15 Table 8 serotonin reuptake inhibitormg Example CGRP antagonist (A) (B) [mg] lactose [mg]

8.1 20.10 20.00 9.90 8.2 29.50 10.40 10.10 8.3 13.10 8.30 28.60 8.4 29.10 12.20 8.70 8.5 26.50 8.00 15.50 8.6 8.10 17.00 24.90 8.7 16.70 10.20 23.10 8.8 5.10 13.80 31.10 8.9 1.10 19.80 29.10 8.1 17.20 0.90 31.90 8.11 10.20 11.70 28.10 8.12 17.20 6.50 26.30 8.13 11.30 19.30 19.40 8.14 16.90 4.50 28.60 serotonin reuptake inhibitormg Example CGRP antagonist (A) (B) [mg] lactose [mg]

8.15 1.20 12.80 36.00 8.16 24.70 16.70 8.60 8.17 4.80 18.30 26.90 8.18 32.80 6.30 10.90 8.19 3.60 14.00 32.40 8.2 29.20 18.10 2.70 8.21 7.60 14.30 28.10 8.22 28.70 14.70 6.60 8.23 29.10 14.50 6.40 8.24 19.60 4.40 26.00 8.25 35.40 5.90 8.70 8.26 6.10 6.90 37.00 8.27 34.40 8.70 6.90 Example 9 Iniectable solution containing 0.3 ma CGRP antagonist (A) or an eguivalent amount of a physioloaically acceptable salt thereof and 0.2 ma serotonin reuptake inhibitor (B) or an eguivalent amount of a physiologically acceptable salt thereof Composition:
1o CGRP antagonist (A) 0.3 mg serotonin reuptake inhibitor (B) 0.2 mg physiological saline The active substance is dissolved in physiological saline.
The amounts may vary and are shown in tabular form below.
Table 9 CGRP antagonist serotonin reuptake Example (A) [pbw] inhibitor (B) [pbw]

9.1 0.20 0.07 9.2 14.30 4.77 9.3 4.40 1.47 9.4 10.30 3.43 9.5 1.80 0.60 9.6 50.00 16.67 9.7 4.40 1.47 9.8 9.40 3.13 9.9 2.60 0.87 9.10 8.20 2.73 9.11 4.30 1.43 9.12 25.50 8.50 9.13 14.20 4.73 9.14 13.40 4.47 9.15 5.40 1.80 9.16 6.90 2.30 9.17 7.70 2.57 9.18 30.00 10.00 9.19 8.30 2.77 9.20 13.10 4.37 Example 10 Suppositories containing 200 ma CGRP antagonist (A) or an eguivalent amount of a physiologically acceptable salt thereof and 150 mg serotonin reuptake inhibitor (B) or an eguivalent amount of a physiologically acceptable salt thereof ' ' CA 02563687 2006-10-19 Composition:
CGRP antagonist (A) 200 mg serotonin reuptake inhibitor (B) 150 mg hard wax ad 2 g Method of preparation:
The hard wax is melted and the active substances are suspended in the mass.
Then the mass is poured into suitable suppository moulds.
The amounts may vary and are shown in tabular form below.
Table 10 CGRP antagonist serotonin reuptake Example (A) inhibitor [mg] (B) [mg]

10.1 250 20 10.2 280 10 10.3 460 60 10.4 540 70 10.5 320 120 10.6 180 10 10.7 150 180 10.8 480 160 10.9 590 40 10.10 180 170 10.11 520 40 10.12 540 100 10.13 110 90 10.14 560 140 10.15 50 120 10.16 320 150 10.17 440 30 10.18 590 20 10.19 140 180 10.20 340 110 10.21 180 30 10.22 140 190 10.23 260 160 10.24 340 50

Claims (14)

1. Process for the treatment or prevention of indications which are selected from among the group comprising headaches, migraine and cluster headaches, this process comprising the joint administration of 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 for treating migraine to a person in need of such treatment.
2. Process according to claim 1, characterised in that the CGRP antagonist is selected from the group comprising (1) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (2) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (3) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (4) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine, (5) 1-[N2-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (6) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (17) 1-[4-amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (18) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine, (19) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (21) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi dinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine, (22) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine, (23) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-piperazine, (24) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine, (25) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine, (26) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine, (27) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N'-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine, (28) 1-[N2-[[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(1H)-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(1H)-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(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-di-bromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine, (32) 1-[N2-[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-dibromo-N-[[4-(1,3-dihydro-6-hydroxy-2(2H)-oxobenzimidazol 1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (34) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (35) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (36) (R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine, (37) 1-[4-amino-3,5-dibromo-N-[[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-N-[[4-[1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)carbonyl]-piperidine, (39) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (40) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (41) 1-[4-amino-N-[[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-dibromo-N-[[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-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (44) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-piperazine, (45) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine, (46) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperi-dinyl)-piperazine, (47) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine, (48) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]
carbonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine, (49) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (51) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine, (52) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-piperazine, (53) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine, (55) 1-[N6-acetyl-N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl) 1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (56) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (57) 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)-piperidine, (58) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperi-dinyl)-piperidine, (59) 1-[3,5-dibromo-N-[[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-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine, (61) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine, (62) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-(1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxo-imidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperi-dinyl)-piperidine, (64) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (65) 1-[4-amino-3,5-dibromo-N-[[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-N-[[4-[4-(3-bromophenyl)-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)-piperazine, (67) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine, (68) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine, (69) 1-[4-amino-3,5-dibromo-N-[[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)-piperazine, (70) 1-[3,5-dibromo-N-[[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-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi dinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (72) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine, (73) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine, (74) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine, (75) 1-[N2-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (76) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazo1-1-y1)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine, (77) 1-[4-amino-N-[[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-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (79) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperi-dinyl)-piperazine, (80) 1-[4-amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(hexahydro-1H-1-azepi-nyl)-piperidine, (81) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine, (82) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine, (83) 1-[4-amino-3,5-dibromo-N-[[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-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine, (85) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-pyrrolidinyl)-piperidine, (87) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine and (88) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine, the physiologically acceptable salts thereof and the hydrates of the salts.

3. Process according to claim 1 or 2, characterised in that the serotonin reuptake inhibitor (B) is selected from the group comprising citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone and the physiologically acceptable salts thereof.
4. Process according to claim 3, characterised in that the serotonin reuptake inhibitor (B) is duloxetine or a physiologically acceptable salt thereof.
5. Process according to claim 1, characterised in that the selected CGRP
antagonist (A) or a physiologically acceptable salt thereof is administered by intravenous or subcutaneous route in a dosage of 0.0001 to 3 mg/kg body weight, by oral route in a dosage of 0.1 to 20 mg/kg body weight or by nasal or inhalative route in a dosage of 0.1 to 10 mg/kg body weight once, twice or three times a day and the serotonin reuptake inhibitor (B) or a physiologically acceptable salt thereof, which may be administered by oral route in a dosage of 0.03 to 1.43 mg/kg body weight once, twice or three times a day or by intravenous or subcutaneous route in a dosage of 0.002 to 0.09 mg/kg body weight once or twice a day or by rectal route in a dosage of 0.007 to 0.36 mg/kg body weight once or twice a day or by nasal route in a dosage of 0.006 to 0.29 mg/kg body weight once or twice a day.
6. Pharmaceutical composition for the treatment or prevention of headaches, 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 thereof as a combined preparation for simultaneous or sequential administration.
7. 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 a physiologically acceptable salt thereof.
8. Kit of parts for the treatment or prevention of headaches, migraine or cluster headache, the kit comprising:
(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) 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 of parts according to claim 8, the kit containing duloxetine or a physiologically acceptable salt thereof in the second enclosure.
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 preparing a pharmaceutical composition for the treatment or prevention of headaches, migraine or cluster headache.
11. Use according to claim 10, characterised in that the CGRP antagonist (A) is selected from the group consisting of (1) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (2) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (3) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (4) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine, (5) 1-[N2-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (6) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (7) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine, (8) 1-[4-amino-3,5-dibromo-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) piperidine, (9) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (10) 1-[4-amino-3,5-dibromo-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) piperazine, (11) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (12) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperi-dinyl)-piperidine, (13) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine, (14) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl) piperidine, (15) 1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (16) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-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-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (18) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine, (19) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (21) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine, (22) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine, (23) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-piperazine, (24) 1-(4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-((1-methyl-4-piperazinyl)carbonyl]-piperazine, (25) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine, (26) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine, (27) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N'-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine, (28) 1-[N2-[[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(1H)-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(1H)-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(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-di-bromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine, (32) 1-[N2-[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-dibromo-N-[[4-(1,3-dihydro-6-hydroxy-2(2H)-oxobenzimidazol 1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (34) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (35) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (36) (R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine, (37) 1-[4-amino-3,5-dibromo-N-[[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-N-[[4-[1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)carbonyl]-piperidine, (39) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (40) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (41) 1-[4-amino-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazo1-1-y1]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine, (42) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine, (44) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-piperazine, (45) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine, (46) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperi-dinyl)-piperazine, (47) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1 H-1,4 diazepin-1-yl)piperidine, (48) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]
carbonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine, (49) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (51) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-4-( 1-methyl-4-piperidinyl)-piperidine, (52) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-piperazine, (53) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine, (55) 1-[N6-acetyl-N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (56) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine, (57) 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)-piperidine, (58) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperi-dinyl)-piperidine, (59) 1-[3,5-dibromo-N-[[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-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine, (61) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine, (62) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-(1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxo-imidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperi-dinyl)-piperidine, (64) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (65) 1-[4-amino-3,5-dibromo-N-[[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-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(21-oxo-imidazol-1-yl]-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazine, (67) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine, (68) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine, (69) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxo-imidazol-1-yl]-1-piperid inyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazine, (70) 1-[3,5-dibromo-N-[[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-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (72) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine, (73) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine, (74) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine, (75) 1-[N2-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (76) 1-[3,5-dibromo- N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazo1-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine, (77) 1-[4-amino-N-[[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-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (79) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperi-dinyl)-piperazine, (80) 1-[4-amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(hexahydro-1H-1-azepi-nyl)-piperidine, (81) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine, (82) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi-dinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine, (83) 1-[4-amino-3,5-dibromo-N-[[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-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine, (85) 1-[4-amino-3,5-dibromo-N-[[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-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperi-dinyl]carbonyl]-D-phenylalanyl]-4-(1-pyrrolidinyl)-piperidine, (87) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine and (88) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine, the physiologically acceptable salts thereof and the hydrates of the salts.
12. Process according to claim 10 or 11, characterised in that the serotonin reuptake inhibitor (B) is selected from the group consisting of citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone and the physiologically acceptable salts thereof.
13. Process according to claim 12, characterised in that the serotonin reuptake inhibitor (B) is duloxetine or a physiologically acceptable salt thereof.
14. Use of the CGRP antagonist (A) or a physiologically acceptable salt thereof for preparing a pharmaceutical composition or a kit of parts according to one of claims 6 to 9.
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