USE OF CGRP ANTAGONISTS AND CGRP RELEASE INHIBITORS FOR COMBATING MENOPAUSAL HOT FLUSHES

UTILISATION D'ANTAGONISTES DE CGRP ET D'INHIBITEURS DE SECRETION CGRP SERVANT A LUTTER CONTRE LES BOUFFEES DE CHALEUR DE LA MENOPAUSE

English Abstract

The invention relates to the use of CGRP antagonists and CGRP
release inhibitors for treating menopausal hot flushes as well
as corresponding pharmaceutical compositions containing as
active substance one or more CGRP antagonists and/or CGRP
release inhibitors, and the preparation thereof.

French Abstract

La présente invention concerne l'utilisation d'antagonistes de CGRP et d'inhibiteurs de sécrétion CGRP servant à lutter contre les bouffées de chaleur de la ménopause. Cette invention concerne également les produits pharmaceutiques correspondants contenant comme substance active un ou plusieurs antagonistes de CGRP et/ou inhibiteurs de sécrétion CGRP, ainsi que leur production.

Claims

-30-
CLAIMS:
1. Use of the active substance selected from
calcitonin gene-related peptide (CGRP) antagonists and CGRP
release inhibitors for treating menopausal hot flushes,
wherein the CGRP release inhibitors are selected from the
group of serotonin 5-HT1D-agonists selected from avitriptan,
eletriptan, naratriptan, rizatriptan, sumatriptan and
zolmitriptan.
2. Use according to claim 1, wherein the active
substance is a CGRP antagonist.
3. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
4. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
5. Use according to claim 2, wherein the CGRP
antagonist is 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
6. Use according to claim 2, wherein the CGRP
antagonist is 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-

-31-
2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
7. Use according to claim 2, wherein the CGRP
antagonist is 1-[N2-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-
2(2H)-oxo-imidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-
L-lysyl]-4-(4-pyridinyl)-piperazine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
8. Use according to claim 2, wherein the CGRP
antagonist is 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, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
9. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
10. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
11. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-

-32-
phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
12. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
13. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxo-thieno[3,2-d]pyrimidin-3-yl)-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
14. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-
[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-l-yl]-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-
piperidinyl)-piperidine, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
15. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-
2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
16. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-

-33-
2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-
piperidine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
17. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
18. Use according to claim 2, wherein the CGRP
antagonist is (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-
oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-hydroxy-3,5-
dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-
piperidine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
19. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[N-
(aminocarbonyl)-N-phenyl-amino]-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(1-piperidinyl)-piperidine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
20. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
21. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(1,1-dioxido-

-34-
3(4H)-oxo-1,2,4-benzothiadiazin-2-yl)-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
22. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[2(1H)-
oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-piperidinyl)-piperidine, or a tautomer, a diastereomer,
an enantiomer, or a physiologically acceptable salt thereof.
23. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-
2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
24. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-
2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
25. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-
2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-
piperazine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
26. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-
2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-

-35-
phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-
piperazine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
27. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-
piperazine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
28. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-
piperidine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
29. Use according to claim 2, wherein the CGRP
antagonist is 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, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
30. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
31. Use according to claim 2, wherein the CGRP
antagonist is (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-
oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-

-36-
methylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-
piperazinyl)-piperidine, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
32. Use according to claim 2, wherein the CGRP
antagonist is (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-
oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-
methoxyphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-
piperidinyl)-piperidine, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
33. Use according to claim 2, wherein the CGRP
antagonist is (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-
oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-
dibromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-
piperazinyl)-piperidine, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
34. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer,
a diastereomer, an enantiomer, or a physiologically
acceptable salt thereof.
35. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer,
a diastereomer, an enantiomer, or a physiologically
acceptable salt thereof.
36. Use according to claim 2, wherein the CGRP
antagonist is 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-
2(2H)-oxo-benzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-

-37-
phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-
piperazine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
37. Use according to claim 2, wherein the CGRP
antagonist is 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-
piperazine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
38. Use according to claim 2, wherein the CGRP
antagonist is (R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-
(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-
oxobutyl]-4-(1-piperidinyl)-piperidine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
39. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer,
a diastereomer, an enantiomer, or a physiologically
acceptable salt thereof.
40. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
41. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-

-38-
2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(1-piperidinyl)-piperidine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
42. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer,
a diastereomer, an enantiomer, or a physiologically
acceptable salt thereof.
43. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
44. Use according to claim 2, wherein the CGRP
antagonist is 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, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
45. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
46. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-

-39-
[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, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
47. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-
2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-
4-(1-piperidinyl)-piperidine, or a tautomer, a diastereomer,
an enantiomer, or a physiologically acceptable salt thereof.
48. Use according to claim 2, wherein the CGRP
antagonist is 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-
piperidinyl)-piperazine, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
49. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a diastereomer, an enantiomer,
or a physiologically acceptable salt thereof.
50. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer,
a diastereomer, an enantiomer, or a physiologically
acceptable salt thereof.
51. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-

-40-
phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
52. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-
(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl]-1-
piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-
azepinyl)-piperidine, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
53. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
54. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-
piperazine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
55. Use according to claim 2, wherein the CGRP
antagonist is 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, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
56. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-

-41-
(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl]-1-
piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-
piperidine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
57. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer,
a diastereomer, an enantiomer, or a physiologically
acceptable salt thereof.
58. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-
2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-
4-(hexahydro-1H-1-azepinyl)-piperidine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
59. Use according to claim 2, wherein the CGRP
antagonist is 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, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
60. Use according to claim 2, wherein the CGRP
antagonist is 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-
piperidinyl)-piperidine, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
61. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-

-42-
oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-
(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
62. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-
2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-
piperidine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
63. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-
oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-
piperidinyl)-piperidine, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
64. Use according to claim 2, wherein the CGRP
antagonist is 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, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
65. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-
(3-hydroxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-
piperidinyl)-piperidine, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
66. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-
oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-

-43-
(hexahydro-1H-1-azepinyl)-piperidine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
67. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
68. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[4-(3-
bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-
azabicyclo[3,2,1]oct-3-yl)-piperazine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
69. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
70. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
71. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-

-44-
(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-
azabicyclo[3,2,1]oct-3-yl)-piperazine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
72. Use according to claim 2, wherein the CGRP
antagonist is 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, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
73. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
74. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-
2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(4-piperidinyl)-piperidine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
75. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-
2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-
4-(4-pyridinyl)-piperidine, or a tautomer, a diastereomer,
an enantiomer, or a physiologically acceptable salt thereof.
76. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-

-45-
(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl]-1-
piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-
piperazine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
77. Use according to claim 2, wherein the CGRP
antagonist is 1-[N2-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-
(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-
piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-
piperazine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
78. Use according to claim 2, wherein the CGRP
antagonist is 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)-piperidine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
79. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
80. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
81. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-

-46-
[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-
piperidinyl)-piperazine, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
82. Use according to claim 2, wherein the CGRP
antagonist is 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-azepinyl)-
piperidine, or a tautomer, a diastereomer, an enantiomer, or
a physiologically acceptable salt thereof.
83. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
84. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-
2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-
4-(1-methyl-4-piperidinyl)-piperidine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
85. Use according to claim 2, wherein the CGRP
antagonist is 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, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
86. Use according to claim 2, wherein the CGRP
antagonist is 1-[3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-

-47-
oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-
methyl-4-piperidinyl)-piperazine, or a tautomer, a
diastereomer, an enantiomer, or a physiologically acceptable
salt thereof.
87. Use according to claim 2, wherein the CGRP
antagonist is 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, or a tautomer, a diastereomer, an
enantiomer, or a physiologically acceptable salt thereof.
88. Use according to claim 2, wherein the CGRP
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-
2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(1-pyrrolidinyl)-piperidine, or a tautomer,
a diastereomer, an enantiomer, or a physiologically
acceptable salt thereof.
89. Use according to claim 2, wherein the CGRP
antagonist is 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, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
90. Use according to claim 2, wherein the CGRP
antagonist is 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, or a
tautomer, a diastereomer, an enantiomer, or a
physiologically acceptable salt thereof.
91. Use of the active substance selected from CGRP
antagonists and CGRP release inhibitors in preparation of a

-48-
pharmaceutical composition for treating menopausal hot
flushes, wherein the CGRP release inhibitors are selected
from the group of serotonin 5-HT1D-agonists selected from,
avitriptan, eletriptan, naratriptan, rizatriptan,
sumatriptan and zolmitriptan.
92. Use according to claim 91, wherein the active
substance is a CGRP antagonist.
93. Use according to claim 92, wherein the CGRP
antagonist is one of the CGRP antagonists, tautomers,
diastereomers, enantiomers and salts defined in any one of
claims 3 to 90.
94. A pharmaceutical composition for treating
menopausal hot flushes, comprising the active substance
selected from CGRP antagonists and CGRP release inhibitors
and one or more inert carrier or diluent, wherein the CGRP
release inhibitors are selected from the group of serotonin
5-HT1D-agonists selected from avitriptan, eletriptan,
naratriptan, rizatriptan, sumatriptan and zolmitriptan.
95. A pharmaceutical composition according to claim
94, wherein the active substance is a CGRP antagonist.
96. A pharmaceutical composition for treating
menopausal hot flushes, comprising the active substance
selected from CGRP antagonists and CGRP release inhibitors
and one or more inert carrier or diluent, wherein the CGRP
release inhibitors are selected from the group of serotonin
5-HT1D-agonists selected from avitriptan, eletriptan,
naratriptan, rizatriptan, sumatriptan and zolmitriptan and
wherein the CGRP antagonist is one or more of the CGRP
antagonists, tautomers, diastereomers, enantiomers and salts
defined in any one of claims 3 to 90.

-49-
97. A commercial package comprising the active
substance selected from CGRP antagonists and CGRP release
inhibitors, together with printed matter comprising
instructions for use thereof for treating menopausal hot
flushes, wherein the CGRP release inhibitors are selected
from the group of serotonin 5-HT1D-agonists selected from
avitriptan, eletriptan, naratriptan, rizatriptan,
sumatriptan and zolmitriptan.
98. A commercial package according to claim 97,
wherein the active substance is a CGRP antagonist.
99. A commercial package comprising the active
substance selected from CGRP antagonists and CGRP release
inhibitors, together with printed matter comprising
instructions for use thereof for treating menopausal hot
flushes, wherein the CGRP release inhibitors are selected
from the group of serotonin 5-HT1D-agonists selected from
avitriptan, eletriptan, naratriptan, rizatriptan,
sumatriptan and zolmitriptan and wherein the CGRP antagonist
is the CGRP antagonist or the tautomer, diastereomer,
enantiomer or salt thereof defined in any one of claims 3
to 90.

Description

CA 02378428 2002-02-08
' 72625pri
Boehringer Ingelheim Pharma KG Case 5/1268-Ro
D-55216 Ingelheim/Rhein foreign filing
Use of CGRP antagonists and CGRP release inhibitors for
combating menopausal hot flushes
Hot flushes are a common symptom of peri/post-menopausal
syndrome the physiology of which is still not fully
understood. Apart from hormone replacement therapy, which is a
complex intervention and frequently cannot be used long-term
owing to its side effects, there has up until now been no
simple therapy largely free from side effects for this
generally troublesome condition.
Hot flushes are caused by vasodilatation and increased blood
flow. A number of publications have mentioned the possibility
that CGRP (calcitonin gene-related peptide) plays a part in
the occurrence of menopausal hot flushes in oestrogen-
deficient women owing to the vasodilatory properties of this
neuropeptide ([1]: J. Endocrinol. (1995), 146(3), 431-437;
[2]: Acta Physiol. Scand. (1998), 162(4), 517-522; [3]: Am. J.
Obstet. Gynecol. (1996), 175(3, Pt. 1), 638-642). The
therapeutic use of CGRP antagonists for treating menopausal
syndrome has not previously been proposed in the literature.
It has now been found that the symptoms of menopausal hot
flushes can be effectively prevented or their distressing
effects substantially alleviated by substances which
antagonise the effects of CGRP (CGRP antagonists) or inhibit
or reduce the release of CGRP from sensory nerve endings (CGRP
release inhibitors), this therapeutic approach being superior
to hormone replacement therapy in particular because of its
lack of side effects.
The present invention thus relates to the use of CGRP
antagonists and/or CGRP release inhibitors for combating

CA 02378428 2002-02-08
- 2 -
menopausal hot flushes, including both prevention and acute
treatment. The use according to the invention preferably
comprises monotherapy with a single substance, but also
includes combined therapy with a number of substances from the
specified groups of active substances. Moreover, the treatment
according to the invention may be carried out in addition to
conventional hormone replacement therapy.
The invention also relates to the use of CGRP antagonists
and/or CGRP release inhibitors for preparing a pharmaceutical
composition for treating menopausal hot flushes as well as the
corresponding pharmaceutical compositions containing as active
substance one or more CGRP antagonists and/or CGRP release
inhibitors.
Any pharmaceutically acceptable active substances which
antagonise the known effects of CGRP or inhibit the release of
CGRP from sensory nerve endings may be used for the purposes
of the present invention.
Examples of CGRP antagonists include the amino acid
derivatives described in WO 98/11128 or DE 199 11 039, as well
as the non-peptidic active substances described in WO
98/56779, WO 98/09630 and WO 97/09046.
Examples of CGRP release inhibitors include serotonin 5-HT1D-
agonists such as avitriptan, eletriptan, naratriptan,
rizatriptan, sumatriptan or zolmitriptan, as well as 5-HT1F-
agonists or NPY-agonists.
Of the CGRP antagonists described in WO 98/11128, the
following compounds, for example, may be used for the
treatment of menopausal hot flushes, for the preparation of a
corresponding pharmaceutical composition and as an ingredient
of a corresponding pharmaceutical composition:

CA 02378428 2002-02-08
- 3 -
(A) 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,
(B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-
oxo-1,3-benzodiazepin-3-yl)-i-piperidinyl]carbonyl]-D-phenyl-
alanyl]-4-(1-piperidinyl)-piperidine,
(C) 1- [N2- [4-amino-3, 5-dibromo-N- [ [4- (3, 4-dihydro-2 (1H) -oxo-
quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-
lysyl]-4-(4-pyridinyl)-piperazine,
(D) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo-
quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-
lysyl]-4-(4-pyridinyl)-piperidine,
(E) 1- [N2- [3, 5-dibromo-N- [ [4- (1, 3-dihydro-4-phenyl-2 (2H) -oxo-
imidazol-1-yl)-i-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-
4-(4-pyridinyl)-piperazine,
(F) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-
2(2H)-oxoimidazol-l-yl)-1-piperidinyl]carbonyl]-D-phenyl-
alanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(G) 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,
(H) 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-phenyl-
alanyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(I) 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-phenyl-
alanyl]-4-(1-piperidinyl)-piperidine,

CA 02378428 2002-02-08
4 -
(J) 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-phenyl-
alanyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(K) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo-
thieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenyl-
alanyl]-4-(1-piperidinyl)-piperidine,
(L) 1- [4-amino-3, 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3- (tri-
fluoromethyl)phenyl] -2 (2H) -oxoimidazol-l-yl] -1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-
piperidinyl)-piperidine,
(M) 1- [4-amino-3, 5-dibromo-N- [ [4- [3,4-dihydro-2 (1H) -
oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-hexyl-4-piperidinyl)-piperidine,
(N) 1- [4-amino-3, 5-dibromo-N- [ [4- [3, 4-dihydro-2 (1H) -
oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-cyclopropylmethyl-4-piperidinyl)-piperidine,
(0) 1- [N- [ [4- [3, 4-dihydro-2 (1H) -oxoquinazolin-3-yl] -1-pipe-
ridinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-lH-
1-azepinyl)-piperidine,
(P) (R, S) -1- [4- [4- (3, 4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-
piperidinyl]-2-[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-di-
oxobutyl]-4-(1-piperidinyl)-piperidine,
(Q) 1-[4-amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenyl-
amino] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-
piperidinyl)-piperidine,
(R) 1- [4-amino-3, 5-dibromo-N- [ [4- (3,4-dihydro-2 (1H) -
oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(5-methoxy-4-pyrimidinyl)-piperazine,

CA 02378428 2002-02-08
-
(S) 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,
(T) 1- [4-amino-3, 5-dibromo-N- [ [4- [2 (1H) -oxoquinolin-3-yl] -1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine,
(U) 1- [4-amino-3, 5-dibromo-N- [ [4- [3, 4-dihydro-2 (1H) -
oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
[3-(dimethylamino)propyl]-piperazine,
(V) 1- [4-amino-3, 5-dibromo-N- [ [4- [3, 4-dihydro-2 (1H) -
oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(4-methyl-l-piperazinyl)-piperidine,
(W) 1- [4-amino-3, 5-dibromo-N- [ [4- [3, 4-dihydro-2 (1H) -
oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
[(1-methyl-4-piperidinyl)carbonyl]-piperazine,
(X) 1- [4-amino-3, 5-dibromo-N- [ [4- [3, 4-dihydro-2 (1H) -
oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
[(1-methyl-4-piperazinyl)carbonyl]-piperazine,
(Y) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo-
quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-
4- [4- [4- (dimethylamino)butyl]phenyl] -piperazine,
(Z) 1- [4-amino-3, 5-dibromo-N- [ [4- (3, 4-dihydro-2 (1H) -oxo-
quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-
4-[4-(dimethylamino)-1-piperidinyl]-piperidine,
(AA) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-
1-piperidinyl]carbonyl]-N'-methyl-D-tryptyl]-4-(4-methyl-l-
piperazinyl)-piperidine,

CA 02378428 2002-02-08
6 -
(AB) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-i-yl)-
1-piperidinyl]carbonyl]-N'-(1,1-dimethylethoxycarbonyl)-D-
tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(AC) (R,S) -1- [4- [4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-
piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxo-
butyl]-4-(4-methyl-l-piperazinyl)-piperidine,
(AD) (R, S) -1- [4- [4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-
piperidinyl]-2-[(3,5-dibromo-4-methoxyphenyl)methyl]-1,4-
dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(AE) (R, S) -1- [4- [4- (3, 4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-
piperidinyl]-2-[(3,4-dibromphenyl)methyl]-1,4-dioxobutyl]-4-
(4-methyl-l-piperazinyl)-piperidine,
(AF) 1- [N2- [N- [ [4- (1, 3-dihydro-2 (2H) -oxobenzimidazol-l-yl) -
1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-
4-(4-pyridinyl)-piperazine,
(AG) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-6-hydroxy-
2 (2H) -oxobenzimidazol-l-yl) -1-piperidinyl] carbonyl] -D-
phenylalanyl]-4-(1-piperidinyl)-piperidine,
(AH) 1- [N2- [4-amino-3, 5-dibromo-N- [ [4- (1, 3-dihydro-2 (2H) -oxo-
benzimidazol-l-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-
N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine,
(AI) 1- [N2- [4-amino-3, 5-dibromo-N- [ [4- (3, 4-dihydro-2 (1H) -oxo-
quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-
N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine,
(AJ) (R, S) -1- [2- (4-amino-3, 5-dibromobenzoyl) -4- [4- (3, 4-
dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-
4-(1-piperidinyl)-piperidine,

CA 02378428 2002-02-08
- 7 -
(AK) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-
2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]carbonyl]-D-phenyl-
alanyl]-4-(1-piperidinyl)-piperidine,
(AL) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-2(2H)-oxoimi-
dazo[4,5-c]quinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenyl-
alanyl]-4-(1-piperidinyl)carbonyl]-piperidine
(AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-
oxoquinazolin-3-yl)-i-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-piperidinyl)-piperidine,
(AN) 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,
(AO) 1- [4-amino-N- [ [4- [4- (3-bromophenyl) -1, 3-dihydro-2 (2H) -
oxoimidazol-l-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-
phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(AP) 1- [4-amino-3, 5-dibromo-N- [ [4- [1, 3-dihydro-4-phenyl-2 (2H) -
oxoimidazol-l-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(4-methyl-l-piperazinyl)-piperidine,
(AQ) 1- [4-amino-3, 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3- (tri-
fluoromethyl)phenyl] -2 (2H) -oxoimidazol-l-yl] -1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine,
(AR) 1- [4-amino-3, 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3- (tri-
fluoromethyl)phenyl] -2 (2H) -oxoimidazol-1-yl] -1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-
azabicyclo[3,2,1]oct-3-yl)-piperazine,
(AS) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxo-
imidazol-i-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-
piperidinyl)-piperidine,

CA 02378428 2002-02-08
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(AT) 1- [4-amino-3, 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3-
(trifluoromethyl)phenyl] -2 (2H) -oxoimidazol-l-yl] -1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-
piperidinyl)-piperazine,
(AU) 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-lH-1,4-diazepin-l-yl)piperidine,
(AV) 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,
(AW) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-
oxoimidazol-l-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-methyl-4-piperidinyl)-piperidine,
(AX) 1- [3, 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3- (trifluoromethyl) -
phenyl]-2(2H)-oxoimidazol-l-yl]-1-piperidinyl]carbonyl]-D-
tyrosyl]-4-(hexahydro-lH-1-azepinyl)-piperidine,
(AY) 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,
(AZ) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo-
quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine,
(BA) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-
oxoimidazol-l-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-methyl-4-piperidinyl)-piperazine,
(BB) 1- [3, 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3- (trifluoromethyl) -
phenyl]-2(2H)-oxoimidazol-l-yl]-1-piperidinyl]carbonyl]-D-
tyrosyl]-4-(1-piperidinyl)-piperidine,

CA 02378428 2002-02-08
- 9 -
(BC) 1- [N6-acetyl-N2- [3, 5-dibromo-N- [ [4- (3, 4-dihydro-2 (1H) -
oxoquinazolin-3-yl)-i-piperidinyl]carbonyl]-D-tyrosyl]-L-
lysyl]-4-(4-pyridinyl)-piperazine,
(BD) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimi-
dazol-l-yl)-i-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-
1H-1-azepinyl)-piperidine,
(BE) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-
2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenyl-
alanyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(BF) 1- [4-amino-3, 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3-
(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-l-yl]-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-
piperidinyl)-piperidine,
(BG) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-
yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonyl-
methyl)-4-piperidinyl]-piperidine,
(BH) 1- [4-amino-3, 5-dibromo-N- [ [4- [3, 4-dihydro-2 (1H) -oxo-
quinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-
methylsulphonyl-4-piperidinyl)-piperidine,
(BI) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-
yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (4-piperidinyl) -
piperidine,
(BJ) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-
oxoimidazol-l-yl)-i-piperidinyl]carbonyl]-D-phenylalanyl]-
4-(l-ethyl-4-piperidinyl)-piperidine,
(BK) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-hydroxy-
phenyl)-2(2H)-oxoimidazol-l-yl)-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine,

CA 02378428 2002-02-08
- 10 -
(BL) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-
yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-lH-1-
azepinyl)-piperidine,
(BM) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-
oxoimidazol-l-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-piperidinyl)-piperidine,
(BN) 1-[4-amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-1,3-dihy-
dro-2(2H)-oxoimidazol-l-yl]-1-piperidinyl]carbonyl]-D-phenyl-
alanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-
piperazine,
(BO) 1- [4-amino-3, 5-dibromo-N- [ [4- (3,4-dihydro-2 (1H) -oxo-
quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-
4-(1-ethyl-4-piperidinyl)-piperidine,
(BP) 1- [4-amino-3, 5-dibromo-N- [ [4- (3, 4-dihydro-2 (1H) -oxo-
quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-
4-(1-ethyl-4-piperidinyl)-piperazine,
(BQ) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxy-
phenyl)-2(2H)-oxoimidazol-l-yl]-1-piperidinyl]carbonyl]-D-
phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-
piperazine,
(BR) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-
yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- [1- (cyclopropyl-
methyl)-4-piperidinyl]-piperidine,
(BS) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-
oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(hexahydro-lH-l-azepinyl)-piperidine,

CA 02378428 2002-02-08
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(BT) 1- [4-amino-3, 5-dibromo-N- [ [4- (3, 4-dihydro-2 (1H) -oxo-
quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(4-piperidinyl)-piperidine,
(BU) 1- [3, 5-dibromo-N- [ [4- (1, 3-dihydro-4-phenyl-2 (2H) -oxo-
imidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-
pyridinyl)-piperidine,
(BV) 1- [3, 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3- (trifluoromethyl) -
phenyl] -2 (2H) -oxoimidazol-i-yl] -1-piperidinyl] carbonyl] -D-
tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(BW) 1- [N2- [3, 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3- (trifluorome-
thyl)phenyl]-2(2H)-oxoimidazol-l-yl]-1-piperidinyl]carbonyl]-
D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(BX) 1- [3, 5-dibromo-N- [ [4- (1, 3-dihydro-4- (3-thienyl) -2 (2H) -
oxoimidazol-l-yl)-i-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-
piperidinyl)-piperidine,
(BY) 1- [4-amino-N- [ [4- [4- (3-chlorophenyl) -1, 3-dihydro-2 (2H) -
oxoimidazol-l-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-
phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(BZ) 1- [4-amino-3, 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3-
(trifluoromethyl)phenyl] -2 (2H) -oxoimidazol-l-yl] -1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-lH-1-
azepinyl)-piperidine,
(CA) 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-
piperidinyl)-piperazine,
(CB) 1- [4-amino-N- [ [4- [4- (3-chlorophenyl) -1, 3-dihydro-2 (2H) -
oxoimidazol-l-yl]-i-piperidinyl]carbonyl]-3,5-dibromo-D-
phenylalanyl]-4-(hexahydro-lH-1-azepinyl)-piperidine,

CA 02378428 2002-02-08
- 12 -
(CC) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-
oxoimidazol-l-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(4-pyridinyl)-piperazine,
(CD) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimi-
dazol-i-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-
piperidinyl)-piperidine,
(CE) 1- [4-amino-3, 5-dibromo-N- [ [4- [1, 3-dihydro-4-phenyl-2 (2H) -
oxoimidazol-l-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
[4- (1-oxoethyl) phenyl] -piperazine,
(CF) 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,
(CG) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-nitrophe-
nyl) -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenyl-
alanyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(CH) 1- [4-amino-3, 5-dibromo-N- [ [4- [3,4-dihydro-2 (1H) -oxo-
quinazolin-3-yl]-i-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-pyrrolidinyl)-piperidine,
(CI) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-
oxoimidazol-l-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(hexahydro-lH-1-azepinyl)-piperidine and
(CJ) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-
2(2H)-oxoimidazol-l-yl)-i-piperidinyl]carbonyl]-D-phenyl-
alanyl]-4-(1-methyl-4-piperidinyl)-piperazine,
the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the physiologically acceptable salts
thereof, while the compounds

CA 02378428 2002-02-08
- 13 -
(A) 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,
(3) 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-phenyl-
alanyl]-4-(1-piperidinyl)-piperidine,
(I) 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-phenyl-
alanyl]-4-(1-piperidinyl)-piperidine,
(J) 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-phenyl-
alanyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(AC) (R, S) -1- [4- [4- (3, 4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-
piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxo-
butyl]-4-(4-methyl-i-piperazinyl)-piperidine,
(AF) 1- [N2- [N- [ [4- (1, 3-dihydro-2 (2H) -oxobenzimidazol-l-yl) -
1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-
4-(4-pyridinyl)-piperazine and
(AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-
oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-piperidinyl)-piperidine,
the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the physiologically acceptable salts
thereof, and especially the compounds
(A) 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 and

CA 02378428 2003-12-16
27400-235
-14-
(B) 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,
the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the physiologically acceptable salts
thereof are particularly preferred.
The dosage required to produce the desired effect
is appropriately 0.0001 to 3 mg/kg of body weight,
preferably 0.01 to 1 mg/kg of body weight for intravenous or
subcutaneous administration and 0.01 to 10 mg/kg of body
weight, preferably 0.1 to 10 mg/kg of body weight for
administration by oral or nasal route or by inhalation, 1 to
3 times a day in each case.
If the treatment with CGRP antagonists and/or CGRP
release inhibitors is given as a supplement to conventional
hormone replacement therapy, it is advisable to reduce the
doses given above, and in this case the dosage may range
from 1/5 of the lower limits specified above up to 1/1 of
the upper limits specified above.
For this purpose, the CGRP antagonists and/or CGRP
release inhibitors may be formulated with one or more
conventional inert carriers and/or diluents, e.g. with corn
starch, lactose, glucose, microcrystalline cellulose,
magnesium stearate, polyvinylpyrrolidone, citric acid,
tartaric acid, water, water/ethanol, water/glycerol,
water/sorbitol, water/polyethyleneglycol, propylene glycol,
cetylstearyl alcohol, carboxymethylcellulose or fatty
substances such as hard fat or suitable mixtures thereof in
conventional galenic preparations such as plain or coated
tablets, capsules, powders, suspensions, solutions,

CA 02378428 2003-12-16
27400-235
-14a-
metering aerosols or suppositories. The formulation may be
part of a commercial package comprising written material
with instructions for use of the formulation in treating
post-menopausal hot flushes.

CA 02378428 2002-02-08
- 15 -
Preparations which are particularly suitable for treating
menopausal hot flushes are those which contain one of the
active substances
(A) 1- [N2- [3, 5-dibromo-N- [ [4- (3,4-dihydro-2 (1H) -
oxoquinazolin-3-yl)-i-piperidinyl]carbonyl]-D-tyrosyl]-L-
lysyl]-4-(4-pyridinyl)-piperazine,
(B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-
oxo-1,3-benzodiazepin-3-yl)-i-piperidinyl]carbonyl]-D-phenyl-
alanyl]-4-(1-piperidinyl)-piperidine,
(I) 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-phenyl-
alanyl]-4-(1-piperidinyl)-piperidine,
(J) 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-phenyl-
alanyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(AC) (R, S) -1- [4- [4- (3, 4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-
piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxo-
butyl]-4-(4-methyl-l-piperazinyl)-piperidine,
(AF) 1- [N2- [N- [ [4- (1, 3-dihydro-2 (2H) -oxobenzimidazol-l-yl) -
1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-
4-(4-pyridinyl)-piperazine or
(AM) 1- [4-amino-3, 5-dibromo-N- [ [4- (3, 4-dihydro-2 (1H) -
oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-piperidinyl)-piperidine,
in one of the following pharmaceutical formulations:
capsules for powder inhalation containing 1 mg of active
substance, preferably active substance (A) or (B),

CA 02378428 2002-02-08
= - 16 -
inhalable solution for nebulisers containing 1 mg of active
substance, preferably active substance (A) or (B),
propellant gas-operated metering aerosol containing 1 mg of
active substance, preferably active substance (A) or (B),
nasal spray containing 1 mg of active substance, preferably
active substance (A) or (B),
tablets containing 20 mg of active substance, preferably
active substance (B),
capsules containing 20 mg of active substance, preferably
active substance (B),
aqueous solution for nasal application containing 10 mg of
active substance, preferably active substance (A) or (B),
aqueous solution for nasal application containing 5 mg of
active substance, preferably active substance (A) or (B), or
suspension for nasal application containing 20 mg of active
substance, preferably active substance (A) or (B).
CGRP is released by sensory nerves, e.g. the trigeminal nerve
which innervates part of the skin of the face. It has already
been shown that stimulation of the trigeminal ganglion in
humans leads to an increase in the CGRP plasma level and
causes reddening of the face ([41: P.J. Goadsby et al., Annals
of Neurology, Vol. 23, No. 2, 1988, 193-196,).
To demonstrate that hot flushes can be successfully treated
using CGRP antagonists and CGRP release inhibitors, an
increased release of endogenous CGRP was induced in marmosets
by stimulating the trigeminal ganglion, leading to increased
blood flow through the blood vessels of the skin. The efficacy

CA 02378428 2002-02-08
- 17 -
of the following test substances was characterised by
determining the dose administered i.v. which reduces by 5021;
the increased blood flow through the skin of the face which
has been brought about by endogenous CGRP:
(A) = 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,
(B) = 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-phenyl-
alanyl]-4-(1-piperidinyl)-piperidine,
(AC) = (R,S) -1- [4- [4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -i-
piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxo-
butyl]-4-(4-methyl-l-piperazinyl)-piperidine,
(AM) = 1- [4-amino-3, 5-dibromo-N- [ [4- (3, 4-dihydro-2 (1H) -
oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-
(1-piperidinyl)-piperidine,
(DA) = sumatriptan and
(DB) = zolmitriptan.
T~P~cri = t- i on of m--hod :
Marmosets of both sexes (300-400 g) are anaesthetised with
pentobarbital (initially with 30 mg/kg, i.p., followed by
infusion of 6mg/kg/h, i.m.). The body temperature is
maintained at 37 C using a heating plate. Pancurmium is
administered as a muscle relaxant (initially 1 mg/kg, 0.5 mg
after each hour thereafter). The animal's head is secured in a
stereotactical apparatus. After the skin on the head has been
opened using a lengthwise incision, a small hole is drilled in
the skull and a bipolar electrode (Rhodes SNES 100) is lowered
into the trigeminal ganglion.

CA 02378428 2002-02-08
- 18 -
Locating the ganglion is made easier by the use of an X-ray
which shows up the bone structure of the skull. The petrous
bone serves as a guide for placing the electrode (CCX-Digital
X-ray apparatus). The position of the electrode in the
ganglion is monitored at the end of each experiment. The
stimulation parameters are:
Hz, 2 mA, 2 msec, for 30 sec.
The blood flow in the micro-vessels of the facial skin is
determined by laser Doppler flow measurement using a PeriFlux
Laser Doppler System.
The animals are exposed to 2 to 3 stimulation periods at
intervals of 30 min in each case. The first stimulation serves
as a reference value for the other stimulations. The test
substances are administered i.v. 5 min before the 2nd and 3rd
stimulation periods.
Tah1P 1: "5001 dose" = i.v. dose which reduces by 50% the
increased blood flow through the facial skin caused by
endogenous CGRP
Substance 50o dose,
A 0.003 mg/kg
B 0.042 mg/kg
AC 0.018 mg/kg
AM 0.046 mg/kg
DA 0.280 mg/kg
DB 0.035 mg/kg
The Examples which follow describe pharmaceutical preparations
which contain as active substance a CGRP antagonist or CGRP
release inhibitor for use according to the invention,
preferably one of the amino acid derivatives described in WO
98/11128 or DE 199 11 039, for example one of the
abovementioned active substances (A) or (B):

CA 02378428 2002-02-08
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Rxa l= e T
raz _c;ul P,q for IDowder i nhal at ion wi th I mg of active ubstan .e
(A) or (B)
Composition:
1 capsule for powder inhalation contains:
active substance (A) or (B) 1.0 mg
lactose 20.0 mg
hard gelatine capsules 50-0 mg
71.0 mg
M hod of prep ra.ion_
The active substance is ground to the particle size needed for
inhalation. The ground active substance is homogeneously mixed
with the lactose. The mixture is packed into hard gelatine
capsules.
F.xamnl P T T
Tnhal al-l e sol Ltion for ReG i ma - wi th 1 mg of a_-i v suhs an .e
(A) or (B)
Composition:
1 spray contains:
active substance (A) or (B) 1.0 mg
benzalkonium chloride 0.002 mg
disodium edetate 0.0075 mg
purified water ad 15.0 l
MPtrod of pr.= aration:
The active substance and benzalkonium chloride are dissolved
in water and packed in Respimat cartridges.

CA 02378428 2002-02-08
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Rxa = l P T T T
Inhalab.le solution for nebulisers with 1 mg of active
,b. + r'^ (A) or (B)
Composition:
1 vial contains:
active substance (A) or (B) 0.1 g
sodium chloride 0.18 g
benzalkonium chloride 0.002 g
purified water ad 20.0 ml
Method of I)re= ra .ion:
Active substance, sodium chloride and benzalkonium chloride
are dissolved in water.
RxamnlP TV
Pro]:)PIlant gas-onera ed metering aerosol with I mg of active
Gubs an (A) or (B)
Composition:
1 spray contains:
active substance (A) or (B) 1.0 mg
lecithin 0.1 0
propellant gas ad 50.0 l
Method of lprelaaration:
The micronised active substance is homogeneously suspended in
the mixture of lecithin and propellant gas. The suspension is
transferred into a pressurised container with a metering
valve.

CA 02378428 2002-02-08
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Fxamrpl e V
Nasal sloray with . 1 mg of a. i v. substance (A) or (B )
Composition:
1 spray jet contains
active substance (A) or (B) 1.0 mg
mannitol 5.0 mg
disodium edetate 0.05 mg
ascorbic acid 1.0 mg
purified water ad 0.1 ml
Method of = rAt~Daration:
The active substance and the excipients are dissolved in water
and transferred into a suitable container.
F.xam=1e VT
Tnjert-able sol i_i on with 5 mg of a._i v- siibst.a (A) or (B)
t~Pr 5 ml
_
Composition:
active substance (A) or (B) in basic form 5 mg
acid/salt-forming agent in the amount needed
to form a neutral salt q.s.
glucose 250 mg
human serum albumin 10 mg
glycofurol 250 mg
water for injections ad 5 ml
prP= ara - i on =
Dissolve the glycofurol and glucose in water for injections
(WfI); add human serum albumin; add salt-forming agent;
dissolve active substance with heating; make up to specified
volume with WfI; transfer into ampoules under nitrogen gas.

CA 02378428 2002-02-08
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Fxam=lp VT?
Injectable solution for subcutaneous administration containing
s mg of active substanrP (A) or (B) = er 1 ml
Composition:
active substance (A) or (B) 5 mg
glucose 50 mg
polysorbate 80 = Tween 80 2 mg
water for injections ad 1 ml
Pre'Cnara i on =
Dissolve glucose and polysorbate in water for injections;
dissolve active substance with heating or using ultrasound;
make up to specified volume with WfI; transfer into ampoules
under inert gas.
Fxamr,21P VT I T
Injectable solution containing 100 mg of active substance (A)
or (B) = er 'I 0 ml
Composition:
active substance (A) or (B) 100 mg
monopotassium dihydrogen phosphate
= KH2p04 12 mg
disodium hydrogen phosphate
= Na2HPO4=2H2O 2 mg
sodium chloride 180 mg
human serum albumin 50 mg
polysorbate 80 20 mg
water for injections ad 10 ml
PrPnaration=
Dissolve polysorbate 80, sodium chloride, monopotassium
dihydrogen phosphate and disodium hydrogen phosphate in water
for injections (WfI); add human serum albumin; dissolve active

CA 02378428 2002-02-08
- - 23 -
substance with heating; make up to specified volume with WfI;
transfer into ampoules.
FxamDle TX
Tyophi 1 isa ontaining 10 mg of a.tiv siffistance (A) or (B)
Composition:
active substance (A) or (B) in basic form 10 mg
acid/salt-forming agent in the amount needed
to form a neutral salt q.s.
mannitol 300 mg
water for injections ad 2 ml
Preparal-i on =
Dissolve mannitol in water for injections (WfI); add salt-
forming agent; dissolve active substance with heating; make up
to specified volume with WfI; transfer into vials; freeze-dry.
Bol v.nt for lyorphi l i sa -_
polysorbate 80 = Tween 80 20 mg
mannitol 200 mg
water for injections ad 10 ml
PYgpara - i on =
Dissolve polysorbate 80 and mannitol in water for injections
(WfI); transfer into ampoules.
Rx aml~g X
j1yo= hi l isa+-P containing S mg of a_-'ve -,Lhstance (A) or (B)
Composition:
active substance (A) or (B) in basic form 5 mg
polar or nonpolar solvent (which can be removed
by freeze-drying) ad 1 ml

CA 02378428 2002-02-08
- 24 -
PrPparai- i on =
Dissolve active substance in suitable solvent; transfer into
vials; freeze-dry.
Sol ven for 1yoiahil i sate :
polysorbate 80 = Tween 80 5 mg
mannitol 100 mg
water for injections ad 2 ml
PrPnar ion=
_
Dissolve polysorbate 80 and mannitol in water for injections
(WfI); transfer into ampoules.
Pxatnnl e XT
Tablets ontaining20mg of activP sLbstance (A) or (B)
Composition:
active substance (A) or (B) 20 mg
lactose 120 mg
maize starch 40 mg
magnesium stearate 2 mg
Povidone K 25 18 mg
Prenaration=
Homogeneously mix the active substance, lactose and maize
starch; granulate with an aqueous solution of Povidone; mix
with magnesium stearate; press in a tablet press; weight of
tablet 200 mg.

CA 02378428 2002-02-08
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Rxamp l-X T I
ra=sulPs containing 20 mg o a ive sib-s-ance (A) or (R)
Composition:
active substance (A) or (B) 20 mg
maize starch 80 mg
highly dispersed silica 5 mg
magnesium stearate 2.5 mg
Prre= ara i on =
Homogeneously mix the active substance, maize starch and
silica; mix with magnesium stearate; transfer mixture into
size 3 hard gelatine capsules in a capsule filling machine.
Fxami l e X T T T
SuppoGi ori g con ai ni ngS0 mg of active giihq an e(A) or (B)
Composition:
active substance (A) or (B) 50 mg
hard fat (Adeps solidus) q.s. ad 1700 mg
Pre]para i on :
Melt the hard fat at about 38 C; homogeneously disperse the
ground active substance in the molten hard fat; after cooling
to about 35 C, pour into chilled moulds.

CA 02378428 2002-02-08
- 26 -
F'.xam= l P xTV
Aqueous.solution for nasal administration containing 10 mg of
,^};ve gLbqtance (A) or (B)
Composition:
active substance (A) or (B) 10.0 mg
hydrochloric acid in the amount needed to form a neutral salt
methyl parahydroxybenzoate (PHB) 0.01 mg
propyl parahydroxybenzoate (PHB) 0.005 mg
purified water ad 1.0 ml
P_ret='.2arat i on =
The active substance is dissolved in purified water;
hydrochloric acid is added until the solution is clear; methyl
and propyl PHB are added; the solution is made up to the
specified volume with purified water; the solution is filtered
sterile and transferred into a suitable container.
F,xamlpl P XV
Aqueous solution for nasal administration containing 5 mg of
art- ivP substance (A) or (B)
Composition:
active substance (A) or (B) 5 mg
1,2-propanediol 300 mg
hydroxyethylcellulose 5 mg
sorbic acid 1 mg
purified water ad 1 ml
PYgparation=
The active substance is dissolved in 1,2-propanediol; a
hydroxyethyl-cellulose solution in purified water containing
sorbic acid is prepared and added to the solution of active

CA 02378428 2002-02-08
- 27 -
substance; the solution is filtered sterile and transferred
into a suitable container.
Examp 1 e XVT
Aqueous solution for intravenous administration containing
mg of a iv Gibstance (A) or (B)
Composition:
active substance (A) or (B) 5 mg
1,2-propanediol 300 mg
mannitol 50 mg
water for injections (WfI) ad 1 ml
Pre]paration=
The active substance is dissolved in 1,2-propanediol; the
solution is made up to approximately the specified volume with
WfI; the mannitol is added and made up to approximately the
specified volume with WfI; the solution is filtered sterile,
transferred into individual containers and autoclaved.
Rxamp 1 e XVT T
Liposomal formulation for intravenous injection containing
7 5 mg of active substance (A) or (B)
Composition:
active substance (A) or (B) 7.5 mg
egg lecithin, e.g. Lipoid E 80 100.0 mg
cholesterol 50.0 mg
glycerol 50.0 mg
water for injections ad 1.0 ml
rPlparat i on =
The active substance is dissolved in a mixture of lecithin and
cholesterol; the solution is added to a mixture of glycerol
and WfI and homogenised by high pressure homogenisation or by

CA 02378428 2002-02-08
- 28 -
the Microfluidizer technique; the liposomal formulation
obtained is transferred into a suitable container under
aseptic.conditions.
Rxa r2l P XVTIT
Suspension for nasal administration containing 20 mg of active
subs an (A) or (B)
Composition:
active substance (A) or (B) 20.0 mg
carboxymethylcellulose (CMC) 20.0 mg
sodium monohydrogen phosphate/sodium
dihydrogen phosphate buffer pH 6.8 q.s.
sodium chloride 8.0 mg
methyl parahydroxybenzoate 0.01 mg
propyl parahydroxybenzoate 0.003 mg
purified water ad 1.0 ml
P_re= arat i on =
The active substance is suspended in an aqueous CMC solution;
the other ingredients are added successively to the suspension
and the suspension is topped up to the specified volume with
purified water.
F.xampl e XTX
Aqueous solution for subcutaneous administration with 10 mg of
active gLbgtanc=e (A) or (B)
Composition:
active substance (A) or (B) 10.0 mg
sodium monohydrogen phosphate/sodium
dihydrogen phosphate buffer q.s. ad pH 7.0
sodium chloride 4.0 mg
water for injections ad 0.5 ml

CA 02378428 2002-02-08
- 29 -
Pra})ara i on =
The active substance is dissolved in the phosphate buffer
solution, after the addition of the common salt the solution
is made up to the specified volume with water. The solution is
filtered sterile, transferred into a suitable container and
autoclaved.
Fxamr2l e XX
Aqueous suspension for subcutaneous administration containing
i v substance (A) or (g)
mg of a
c-tL
Composition:
active substance (A) or (B) 5.0 mg
polysorbate 80 0.5 mg
water for injections 0.5 ml
PrE?lparal- i on =
The active substance is suspended in the polysorbate 80
solution and comminuted to a particle size of about 1 m using
a suitable dispersing technique (e.g. wet grinding, high
pressure homogenisation, microfluidisation, etc.). The
suspension is transferred into a corresponding container under
aseptic conditions.