USE OF A CGRP-ANTAGONIST COMBINED WITH A SEROTONIN-REUPTAKE INHIBITOR IN ORDER TO TREAT MIGRAINES

UTILISATION D'UN ANTAGONISTE DE CGRP EN COMBINAISON AVEC UN INHIBITEUR DE RECAPTAGE DE LA SEROTONINE POUR LE TRAITEMENT DES MIGRAINES

English 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.

French Abstract

La présente invention concerne un procédé de traitement ou de prévention de céphalées, de migraines ou de céphalées vasculaires de Horton. Ledit procédé consiste à administrer conjointement une quantité thérapeutique efficace d'un antagoniste de CGRP (A) ou d'un sel physiologiquement acceptable de celui-ci, et une quantité thérapeutique efficace d'un inhibiteur de recapatage de la sérotonine (B) ou d'un sel physiologiquement acceptable de celui-ci. L'invention concerne également les compositions pharmaceutiques correspondantes et leur fabrication.

Claims

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Claims
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,

<IMG>

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(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,

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(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,

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(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-
3-
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,

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(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,

-39-
(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,

-40-
(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,

-41-
(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,

-42-
(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-
1-
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

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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

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(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,

-45-
(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-
3
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,

-46-
(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,

-47-
(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,

-48-
(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-
3-
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,

-49-
(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,

-50-
(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,

-51-
(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,

-52-
(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,

-53-
(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-
1-
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.

-54-
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.

Description

' CA 02563687 2006-10-19
WO 2005/102322 PCT/EP2005/004076
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).

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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.

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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,

CA 02563687 2006-10-19
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(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,

CA 02563687 2006-10-19
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(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,

CA 02563687 2006-10-19
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(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,

CA 02563687 2006-10-19
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(38) 1-[4-amino-3,5-dibromo-N-([4-[1,3-dihydro-2(2H)-oxoimidazo[4,5-c)quinolin-
3-
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,

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(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,

CA 02563687 2006-10-19
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(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,

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(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,

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(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)-
1-
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,

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(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-
1-
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

CA 02563687 2006-10-19
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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.

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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
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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.

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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

CA 02563687 2006-10-19
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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.

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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
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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

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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:

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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.

CA 02563687 2006-10-19
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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

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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.

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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

CA 02563687 2006-10-19
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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.

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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

CA 02563687 2006-10-19
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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

CA 02563687 2006-10-19
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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

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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.

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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

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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

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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