CA2378428C - Use of cgrp antagonists and cgrp release inhibitors for combating menopausal hot flushes - Google Patents
Use of cgrp antagonists and cgrp release inhibitors for combating menopausal hot flushes Download PDFInfo
- Publication number
- CA2378428C CA2378428C CA002378428A CA2378428A CA2378428C CA 2378428 C CA2378428 C CA 2378428C CA 002378428 A CA002378428 A CA 002378428A CA 2378428 A CA2378428 A CA 2378428A CA 2378428 C CA2378428 C CA 2378428C
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- Prior art keywords
- piperidinyl
- carbonyl
- dihydro
- dibromo
- tautomer
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Classifications
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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.
Description
' 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;
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 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:
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 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:
(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, (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, -(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, (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, (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, (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, (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, (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, (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, (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 (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 (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, -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.
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), = - 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 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.
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):
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.
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.
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.
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 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 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.
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.
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 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 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 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.
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, -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.
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), = - 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 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.
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):
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.
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.
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.
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 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 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.
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.
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 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 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 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.
Claims (99)
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.
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.
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.
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.
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-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.
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)-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.
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.
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.
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.
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-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.
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-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.
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.
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.
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.
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-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.
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-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.
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.
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.
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.
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-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.
antagonist is 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, 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.
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.
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.
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.
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-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine, or a tautomer, a diastereomer, an enantiomer, or a physiologically acceptable salt thereof.
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-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.
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.
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.
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.
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-methylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine, or a tautomer, a diastereomer, an enantiomer, or a physiologically acceptable salt thereof.
antagonist is (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-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.
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.
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.
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.
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-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, or a tautomer, a diastereomer, an enantiomer, or a physiologically acceptable salt thereof.
antagonist is 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxo-benzimidazol-1-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.
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.
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.
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.
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.
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-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.
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-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.
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.
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.
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.
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-[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.
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-(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.
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.
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.
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.
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-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.
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)-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.
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.
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.
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.
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-(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.
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-(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.
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.
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.
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.
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)-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.
antagonist is 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, 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.
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.
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.
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.
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-(hexahydro-1H-1-azepinyl)-piperidine, or a tautomer, a diastereomer, an enantiomer, or a physiologically acceptable salt thereof.
antagonist is 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, 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.
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.
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.
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.
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-(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.
antagonist is 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine, 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.
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.
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.
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.
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-(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.
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-(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.
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.
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.
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.
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-[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.
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)-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.
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.
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.
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.
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)-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.
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)-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.
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.
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.
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.
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 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.
antagonists and CGRP release inhibitors in preparation of a 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.
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.
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.
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.
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.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19937304.3 | 1999-08-10 | ||
| DE19937304A DE19937304C2 (en) | 1999-08-10 | 1999-08-10 | Use of CGRP antagonists to combat menopausal hot flashes |
| PCT/EP2000/007613 WO2001010425A2 (en) | 1999-08-10 | 2000-08-05 | Use of cgrp antagonists and cgrp release inhibitors for controlling menopausal hot flashes |
Publications (2)
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| CA2378428A1 CA2378428A1 (en) | 2001-02-15 |
| CA2378428C true CA2378428C (en) | 2009-10-20 |
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| CA002378428A Expired - Fee Related CA2378428C (en) | 1999-08-10 | 2000-08-05 | Use of cgrp antagonists and cgrp release inhibitors for combating menopausal hot flushes |
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| DE19952147A1 (en) | 1999-10-29 | 2001-05-03 | Boehringer Ingelheim Pharma | New cyclopropanes, pharmaceutical compositions containing these compounds and process for their preparation |
| DE10139410A1 (en) * | 2001-08-17 | 2003-02-27 | Boehringer Ingelheim Pharma | Use of BIBN4096 in combination with other anti-migraine drugs for the treatment of migraines |
| EP1456198A1 (en) * | 2001-12-12 | 2004-09-15 | Eli Lilly And Company | Alanyl-piperidine heterocyclic derivatives useful against cardiovascular diseases |
| DE10206770A1 (en) * | 2002-02-19 | 2003-08-28 | Boehringer Ingelheim Pharma | New, stable acid addition salts of the quinazolinone derivative CGRP antagonist BIBN4096, useful for the treatment of migraine, in the form of an inhalable powder |
| US6900317B2 (en) | 2002-02-19 | 2005-05-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Salts of the CGRP antagonist BIBN4096 and inhalable powdered medicaments containing them |
| DE10207026A1 (en) * | 2002-02-20 | 2003-08-28 | Boehringer Ingelheim Kg | Stable inhalable powder of the calcitonin gene-related peptide antagonist, BIBN4096, useful for treating migraine, in the form of spherical nano-structured particles obtained by spray-drying |
| DE10227294A1 (en) * | 2002-06-19 | 2004-01-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Preparations for intranasal application of selected amino acid-derived CGRP antagonists and processes for their preparation |
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| US7595312B2 (en) | 2002-10-25 | 2009-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions |
| DE10300973A1 (en) * | 2003-01-14 | 2004-07-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New carboxylic acids and their esters, medicaments containing these compounds and processes for their preparation |
| WO2005004869A1 (en) * | 2003-07-07 | 2005-01-20 | Boehringer Ingelheim International Gmbh | Use of cgrp antagonists in treatment and prevention of hot flushes in prostate cancer patients |
| US20060173046A1 (en) * | 2003-07-15 | 2006-08-03 | Bell Ian M | Hydroxypyridine cgrp receptor antagonists |
| DE10338399A1 (en) * | 2003-08-18 | 2005-03-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Microparticles containing the CGRP antagonist 1- [N 2 - [3,5-dibromo-N - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, process for their preparation and their use as inhalation powder |
| DE102004015723A1 (en) | 2004-03-29 | 2005-10-20 | Boehringer Ingelheim Pharma | Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals |
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| US7696195B2 (en) | 2004-04-22 | 2010-04-13 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
| DE102004063752A1 (en) * | 2004-12-29 | 2006-07-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of selected CGRP antagonists to combat menopausal hot flashes |
| DE102004063755A1 (en) * | 2004-12-29 | 2006-07-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of CGRP antagonists for the treatment and prevention of hot flushes in patients with prostate cancer |
| US7491717B2 (en) | 2005-03-23 | 2009-02-17 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
| EP1770091A1 (en) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP-antagonists, process for their preparation as well as their use as medicaments |
| US7439237B2 (en) | 2005-04-15 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
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| BR9610375A (en) * | 1995-09-07 | 1999-07-06 | Oreal | Cell extract cosmetic or pharmaceutical composition use of at least one cell extract and cosmetic treatment process |
| US5910482A (en) | 1996-03-19 | 1999-06-08 | Board Of Regents, The University Of Texas System | Treatment or prevention of preeclampsia, eclampsia with calcitonin gene related peptide, CGRP analog, progestational agent, nitric oxide source, and cyclooxygenase inhibitor |
| US5710024A (en) * | 1996-07-23 | 1998-01-20 | Smithkline Beecham Corporation | Polynucleotides that encode the calcitonin gene-related peptide receptor coponent factor (HOUNDC44) |
| DE59711622D1 (en) * | 1996-09-10 | 2004-06-17 | Boehringer Ingelheim Pharma | MODIFIED AMINO ACIDS, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, AND METHOD FOR THE PRODUCTION THEREOF |
| DE19911039A1 (en) * | 1999-03-12 | 2000-09-14 | Boehringer Ingelheim Pharma | Modified amino acid amides, pharmaceutical compositions containing these compounds and process for their preparation |
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2000
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- 2000-08-05 CN CNB008116156A patent/CN1166361C/en not_active Expired - Fee Related
- 2000-08-05 BR BR0013009-5A patent/BR0013009A/en active Pending
- 2000-08-05 JP JP2001514945A patent/JP2003506403A/en active Pending
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- 2000-08-05 ES ES00958385T patent/ES2231243T3/en not_active Expired - Lifetime
- 2000-08-05 EP EP00958385A patent/EP1207884B1/en not_active Expired - Lifetime
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- 2000-08-05 CA CA002378428A patent/CA2378428C/en not_active Expired - Fee Related
- 2000-08-05 AU AU69928/00A patent/AU777709B2/en not_active Ceased
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- 2000-08-05 HU HU0202397A patent/HUP0202397A3/en unknown
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- 2000-08-05 DE DE50008527T patent/DE50008527D1/en not_active Expired - Lifetime
- 2000-08-05 PT PT00958385T patent/PT1207884E/en unknown
- 2000-08-05 TR TR2002/00359T patent/TR200200359T2/en unknown
- 2000-08-05 CZ CZ20020497A patent/CZ300513B6/en not_active IP Right Cessation
- 2000-08-08 MY MYPI20003601A patent/MY129668A/en unknown
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