CN1166361C - 用于控制绝经热潮红的降钙素基因有关肽的拮抗剂及其释出的抑制剂 - Google Patents
用于控制绝经热潮红的降钙素基因有关肽的拮抗剂及其释出的抑制剂 Download PDFInfo
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- CN1166361C CN1166361C CNB008116156A CN00811615A CN1166361C CN 1166361 C CN1166361 C CN 1166361C CN B008116156 A CNB008116156 A CN B008116156A CN 00811615 A CN00811615 A CN 00811615A CN 1166361 C CN1166361 C CN 1166361C
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- piperidino
- carbonyl
- dihydro
- bromo
- oxo
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- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000033912 thigmotaxis Effects 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
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Abstract
本发明是关于用于治疗绝经热潮红用途的CGRP拮抗剂与CGRP释出抑制剂，以及含有一或多种CGRP拮抗剂及/或CGRP释出抑制剂作为活性物质的相应药物组合物，及其制备方法。
Description
热潮红为绝经时期/绝经后的综合症的一种常见症状，其生理学仍然不完全明了。激素替代疗法为一种复杂干涉，且由于其副作用，故不能经常长期使用，除了该疗法之外，直到目前为止，对于这种通常不易处理的症状，仍然没有大致上无副作用的简易疗法。
热潮红是因血管扩张及增加的血液流量所造成。许多刊物已指出CGRP(降钙素基因有关的肽)在产生绝经热潮红中，可能起作用，它是在雌激素缺乏的妇女中，由于这种神经肽的血管扩张性质所致[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)。CGRP拮抗剂对于治疗绝经期综合症的治疗用途，在文献中尚未提出。
目前已发现，通过拮抗CGRP作用的物质(CGRP拮抗剂)，或抑制或减少由感觉神经末梢释出的CGRP(CGRP释出抑制剂)，则绝经热潮红的病征，可有效防止，或其痛苦作用实质上可减轻，这种治疗途径优于激素替补疗法，特别是由于其没有副作用。
因此本发明是关于CGRP拮抗剂及/或CGRP释出抑制剂对抗绝经热潮红的用途，包括防止与急性治疗。根据本发明的用途，优选包括使用单一物质的单一疗法，但也包括，和由特定活性物质的多种物质一起的组合疗法。再者，根据本发明的治疗可另外再用习用的激素替补疗法进行。
本发明也关于CGRP拮抗剂及/或CGRP释出抑制剂在制备治疗绝经热潮红的药物组合物的用途，以及含有一种或多种CGRP拮抗剂及/或CGRP释出抑制剂作为活性物质的相应药物组合物。
拮抗已知CGRP作用或抑制由感觉神经末梢释出的CGRP的任何药物上可接受的活性物质，都可用于本发明的目的。
CGRP拮抗剂的实施例，包括描述于WO 98/11128或DE 19911039中的氨基酸衍生物，以及描述于WO 98/56779、WO 98/09630及WO 97/09046中的非肽活性物质。
CGRP释出抑制剂的实施例，包括血清素5-HT1D-激动剂，譬如阿维催坦(avitriptan)、也理催坦(eletriptan)、那拉催坦(naratriptan)、利杂催坦(rizatriptan)、沙马催坦(sumatriptan)或坐米催坦(zolmitriptan)，以及5-HT1F-激动剂或NPY-激动剂。
描述于WO 98/11128中的CGRP拮抗剂，其中例如下列化合物，可用于治疗绝经热潮红，用于制备相应的药物组合物，及用作相应药物组合物的成份：
(A)1-[N2-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(B)1-[4-氨基-3，5-二溴-N-[[4-(2，3，4，5-四氢-2(1H)-氧代-1，3-苯并二氮杂-3-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-吡啶基)-哌啶，
(C)1-[N2-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(D)1-[N2-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌啶，
(E)1-[N2-[3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(F)1-[N2-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(G)1-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代噻吩并[3，4-d]-嘧啶-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-哌啶基)-哌啶，
(H)1-[4-氨基-3，5-二溴-N-[[4-(2，4-二氢-5-苯基-3(3H)-氧代-1，2，4-三唑-2-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(I)1-[4-氨基-3，5-二溴-N-[[4-(2，4-二氢-5-苯基-3(3H)-氧代-1，2，4-三唑-2-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-哌啶基)-哌啶，
(J)1-[4-氨基-3，5-二溴-N-[[4-(2，4-二氢-5-苯基-3(3H)-氧代-1，2，4-三唑-2-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
(K)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代噻吩[3，2-d]嘧啶-3-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-哌啶基)-哌啶，
(L)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-乙基-4-哌啶基)-哌啶，
(M)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-己基-4-哌啶基)-哌啶，
(N)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-环丙基甲基-4-哌啶基)-哌啶，
(O)1-[N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-3-乙烯基-D，L-苯丙氨酰基]-4-(六氢-1H-1-氮杂基)-哌啶，
(P)(R，S)1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(4-羰基-3，5-二甲基苯基)甲基]-1，4-二氧代丁基]-4-(1-哌啶基)-哌啶，
(Q)1-[4-氨基-3，5-二溴-N-[[4-[N-(氨基羰基)-N-苯基-氨基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(R)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(5-甲氧基-4-嘧啶基)-哌嗪，
(S)1-[4-氨基-3，5-二溴-N-[[4-(1，1-二氧桥-3(4H)-氧代-1，2，4-苯并噻二嗪-2-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(T)1-[4-氨基-3，5-二溴-N-[[4-[2(1H)-氧代喹啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(U)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[3-(二甲氨基)丙基]-哌嗪，
(V)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(4-甲基-1-哌嗪基)-哌啶，
(W)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[(1-甲基-4-哌啶基)羰基]-哌嗪，
(X)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[(1-甲基-4-哌嗪基)-羰基]-哌嗪，
(Y)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[4-[4-(二甲氨基)丁基]苯基]-哌嗪，
(Z)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[4-(二甲氨基)-1-哌啶基]-哌啶，
(AA)1-[N2-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-N′-甲基-D-色酰基(tryptyl)]-4-(4-甲基-1哌嗪基)-哌啶，
(AB)1-[N2-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-N′-(1，1-二甲基乙氧羰基)-D-色酰基]-4-(1-甲基-4哌啶基)-浓啶，
(AC)(R，S)-1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(3，5-二溴-4-甲基苯基)甲基]-1，4-二氧基-丁基]-4-(4-甲基-1-哌嗪基)-哌啶，
(AD)(R，S)-1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(3，5-二溴基-4-甲氧苯基)甲基]-1，4-二氧基丁基]-4-(1-甲基-4-哌啶基)-哌啶，
(AE)(R，S)-1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(3，4-二溴苯基)甲基]-1，4-二氧基丁基]-4-(4-甲基-1-哌嗪基)-哌啶，
(AF)1-[N2-[N-[[4-(1，3-二氢-2(2H)-氧代苯并咪唑-1-基)-1-哌啶基]羰基]-3，5-二溴-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(AG)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-6-羟基-2(2H)-氧代苯并咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-吡啶基)-哌啶，
(AH)1-[N2-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-2(2H)-氧代-苯并咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-N6，N6-二甲基-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(AI)1-[N2-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-N6，N6-二甲基-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(AJ)(R，S)-1-[2-(4-氨基-3，5-二溴基苯甲酰基)-4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-4-氧代丁基]-4-(1-哌啶基)-哌啶，
(AK)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2，2-二氧桥-2，1，3-苯并噻二嗪-3-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-哌啶基)-哌啶，
(AL)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-2(2H)-氧代咪唑并[4，5-c]喹啉基-3-基]-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-哌啶基)羰基]-哌啶，
(AM)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(AN)1-[N2-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-N6，N6-二甲基-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(AO)1-[4-氨基-N-[[4-[4-(3-溴苯基)-1，3-二氢-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-3，5-二溴-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(AP)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(4-甲基-1-哌嗪基)-哌啶，
(AQ)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌嗪基)-哌啶，
(AR)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(外-8-甲基-8-氮杂双环并[3，2，1]辛-3-基)-哌嗪，
(AS)1-[3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-哌啶基)-哌啶，
(AT)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-乙基-4-哌啶基)-哌嗪，
(AU)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(六氢-4-甲基-1H-1，4-二氮杂-1-基)-哌啶，
(AV)1-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-[1-(甲基磺酰基)-4-哌嗪基]-哌啶，
(AW)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(AX)1-[3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(六氢-1H-一氮杂基)-哌啶，
(AY)1-[3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(AZ)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(外-8-甲基-8-氮杂双环并[3，2，1]辛-3-基)-哌嗪，
(BA)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
(BB)1-[3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)-苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-哌啶基)-哌啶，
(BC)1-[N6-乙酰基-N2-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(BD)1-[3，5-二溴-N-[[4-(1，3-二氢-4苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(六氢-1H-氮杂基)-哌啶，
(BE)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-(3-噻吩基)-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(BF)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(BG)1-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-[1-(羟羰基-甲基)-4-哌啶基)-哌啶，
(BH)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代-喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基磺酰基-4-哌啶基)-哌啶，
(BI)1-[3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(4-哌啶基)-哌啶，
(BJ)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-乙基-4-哌啶基)-哌啶，
(BK)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-(3-羟基-苯基)-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(BL)1-[3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(六氢-1H-1-一氮杂基)-哌啶，
(BM)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(BN)1-[4-氨基-3，5-二溴-N-[[4-[4-(3-溴苯基)-1，3-二氢-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(外-8-甲基-8-氮杂双环并[3，2，1]辛-3-基)-哌嗪，
(BO)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代-喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-乙基-4-哌啶基)-哌啶，
(BP)1-[4-氨基-3，5-二溴-N-[[4-(3 ， 4-二氢-2(1H)-氧代-喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-乙基-4-哌啶基)-哌嗪，
(BQ)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-(3-甲氧基-苯基)-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(外-8-甲基-8-氮杂双环并[3，2，1]辛-3-基)-哌嗪，
(BR)1-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-[1-(环丙基-甲基)-4-哌啶基]-哌啶，
(BS)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(六氢-1H-1-氮杂基)-哌啶，
(BT)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(4-哌啶基)-哌啶，
(BU)1-[3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(4-吡啶基)-哌啶，
(BV)1-[3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
(BW)1-[N2-[3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-L赖氨酰基]-4-(4-吡啶基)-哌嗪，
(BX)1-[3，5-二溴-N-[[4-(1，3-二氢-4-(3-噻吩基)-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-哌啶基)-哌啶，
(BY)1-[4-氨基-N-[[4-[4-(3-氯苯基)-1，3-二氢-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-3，5-二溴-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(BZ)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(六氢-1H-1-氮杂基)-哌啶，
(CA)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
(CB)1-[4-氨基-N-[[4-[4-(3-氯苯基)-1，3-二氢-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-3，5-二溴-D-苯丙氨酰基]-4-(六氢-1H-1-氮杂基)-哌啶，
(CC)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(4-哌啶基)-哌嗪，
(CD)1-[3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(CE)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[4-(1-氧代乙基)苯基]-哌嗪，
(CF)1-[3，5-二溴-N-[[4-[3，4-二氢-2(2H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-甲基-4-吡啶基)-哌嗪，
(CG)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4(3-硝基苯基)-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(CH)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代-喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-吡咯烷基)-哌啶，
(CI)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(六氢-1H-1-氮杂基)-哌啶，及
(CJ)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-(3-噻吩基)-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，其互变异构体，非对映异构体，对映异构体，其混合物，及其生理学上可接受的盐，而以下化合物
(A)1-[N2-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(B)1-[4-氨基-3，5-二溴-N-[[4-(2，3，4，5-四氢-2(1H)-氧代-1，3-苯并二氮杂-3-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-吡啶基)-哌啶，
(I)1-[4-氨基-3，5-二溴-N-[[4-(2，4-二氢-5-苯基-3(3H)-氧代-1，2，4-三唑-2-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-哌啶基)-哌啶，
(J)1-[4-氨基-3，5-二溴-N-[[4-(2，4-二氢-5-苯基-3(3H)-氧代-1，2，4-三唑-2-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
(AC)(R，S)-1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(3，5-二溴-4-甲基苯基)甲基]-1，4-二氧基-丁基]-4-(4-甲基-1-哌嗪基)-哌啶，
(AF)1-[N2-[N-[[4-(1，3-二氢-2(2H)-氧代苯并咪唑-1-基)-1-哌啶基]羰基]-3，5-二溴-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，及
(AM)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，其互变异构体，非对映异构体，对映异构体，其混合物，及其生理学上可接受的盐，且尤其是以下化合物
(A)1-[N2-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，与
(B)1-[4-氨基-3，5-二溴-N-[[4-(2，3，4，5-四氢-2(1H)-氧代-1，3-苯并二氮杂-3-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-吡啶基)-哌啶，其互变异构体，非对映异构体，对映异构体，其混合物，及其生理学上可接受的盐，是特别优选的。
为产生所要求的作用所需要的剂量，对静脉内或皮下投药而言，适当地为0.0001至3毫克/公斤体重，优选为0.01至1毫克/公斤体重，而对通过口服或鼻途径或通过吸入投药而言，为0.01至10毫克/公斤体重，优选为0.1至10毫克/公斤体重，于各情况中，都是一天1至3次。
若以CGRP拮抗剂和/或CGRP释出抑制剂治疗，是作为习用激素替补疗法的补充，则最好降低上述的剂量，且在这情况中，其剂量范围可从上述所指定的下限的1/5至高达上述所指定的上限的1/1。
对目的而言，可将CGRP拮抗剂及/或CGRP释出抑制剂与一种或多种习用惰性载剂及/或稀释剂一起调配，例如使用玉米淀粉、乳糖、葡萄糖、微晶性纤维素、硬脂酸镁、聚乙烯基吡咯烷酮、柠檬酸、酒石酸、水、水/乙醇、水/甘油、水/山梨醇、水/聚乙二醇、丙二醇、鲸蜡基硬脂基醇、羟甲基纤维素或脂肪物质，如硬质脂肪，或其适当混合物，在习用盖伦制剂中，如片剂或涂层片剂、胶囊、粉末、悬浮液、溶液、计量气溶胶或栓剂。
特别适用于治疗绝经热潮红的制剂，是含有以下活性物质之一
(A)1-[N2-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(B)1-[4-氨基-3，5-二溴-N-[[4-(2，3，4，5-四氢-2(1H)-氧代-1，3-苯并二氮杂-3-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-吡啶基)-哌啶，
(I)1-[4-氨基-3，5-二溴-N-[[4-(2，4-二氢-5-苯基-3(3H)-氧代-1，2，4-三唑-2-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-哌啶基)-哌啶，
(J)1-[4-氨基-3，5-二溴-N-[[4-(2，4-二氢-5-苯基-3(3H)-氧代-1，2，4-三唑-2-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
(AC)(R，S)-1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(3，5-二溴-4-甲基苯基)甲基]-1，4-二氧基-丁基]-4-(4-甲基-1-哌嗪基)-哌啶，
(AF)1-[N2-[N-[[4-(1，3-二氢-2(2H)-氧代苯并咪唑-1-基)-1-哌啶基]羰基]-3，5-二溴-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，或
(AM)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
在下述药物配方中之一中：
供粉末吸入用的胶囊，含有1毫克活性物质，优选为活性物质(A)或(B)，
供雾化器用的可吸入溶液，含有1毫克活性物质，优选为活性物质(A)或(B)，
推进剂气体操作的计量气溶胶，含有1毫克活性物质，优选为活性物质(A)或(B)，
鼻喷雾剂，含有1毫克活性物质，优选为活性物质(A)或(B)，
片剂，含有20毫克活性物质，优选为活性物质(B)，
胶囊，含有20毫克活性物质，优选为活性物质(B)，
供鼻施用的水溶液，含有10毫克活性物质，优选为活性物质(A)或(B)，
供鼻施用的水溶液，含有5毫克活性物质，优选为活性物质(A)或(B)，或
供鼻施用的悬浮液，含有20毫克活性物质，优选为活性物质(A)或(B)，
CGRP是通过感觉神经释出，例如三叉神经，它是神经支配部分脸部皮肤，已证实在人类中刺激三叉神经节会导致增加CGRP血浆含量，并造成脸部变红([4]：P.J.Goadsby等人，神经学年鉴，第23卷，第2期，1988，193-196)。
为证实热潮红可成功地使用CGRP拮抗剂与CGRP释出抑制剂治疗，故在狨中，通过刺激三叉神经节，导致增加流经皮肤血管的血液流量，引致内源CGRP的释出增加。下列试验物质的功效，是通过由测定静脉内投药的剂量而表征的，它使流经脸部皮肤而因内源CGRP导致所增加的血液流量降低50％：
(A)＝1-[N2-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(B)＝1-[4-氨基-3，5-二溴-N-[[4-(2，3，4，5-四氢-2(1H)-氧代-1，3-苯并二氮杂-3-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-吡啶基)-哌啶，
(AC)＝(R，S)-1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(3，5-二溴基-4-甲基苯基)甲基]-1，4-二氧基-丁基]-4-(4-甲基-1-哌嗪基)-哌啶，
(AM)＝1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(DA)＝沙马催坦(sumatriptan)及
(DB)＝坐米催坦(zolmitriptan)。
方法的说明：
将两种性别的狨(300-400克)以戊巴比妥麻醉(首先使用30毫克/公斤腹膜内，接着为肌肉内注射6毫克/公斤/小时)。使用加热板，使体温保持在37℃下。投予盘可明(Pancurmium)作为肌肉松弛剂(首先为1毫克/kg，其后每一小时为0.5毫克)。使动物的头部固定在立体定向装置中。在头皮已使用纵向切开术打开后，在头颅中钻一小孔，并使双极电极(Rhodes SNES 100)降低至三叉神经节中。神经节的定位，是较简易地使用X-射线进行，它显示出头颅的骨骼结构。岩骨用作放置电极(CCX-数字X-射线装置)的导沟。电极在神经节中的位置，是在每次实验结束时监测。刺激参数为：
10Hz，2mA，2毫秒，历经30秒。
脸部皮肤微血管中的血液流量，是通过激光多普勒(Doppler)流量度量法，使用PeriFlux激光多普勒系统测定。
于各情况中，每隔30分钟，使动物经受至2至3次刺激周期。第一次刺激是作为其他刺激的参考值。试验物质是在第2次及第3次刺激周期的前5分钟，以静脉内投药。
表1：“50％剂量”＝能使因内源CGRP所造成流经脸部皮肤所增加的血液流量降低50％的静脉内剂量
| 物质 | 50％剂量 |
| A | 0.003毫克/公斤 |
| B | 0.042毫克/公斤 |
| AC | 0.018毫克/公斤 |
| AM | 0.046毫克/公斤 |
| DA | 0.280毫克/公斤 |
| DB | 0.035毫克/公斤 |
下述实施例是说明本发明使用的药物制剂，含有CGRP拮抗剂或CGRP释出抑制剂作为活性物质，优选为4在WO 98/11128或DE 199 11 039中所述的氨基酸衍生物之一，例如上述活性物质(A)或(B)之一：
实施例I
供粉末吸入的胶囊，具有1毫克活性物质(A)或(B)
组成：
1个供粉末吸入的胶囊含有：
活性物质(A)或(B) 1.0毫克
乳糖 20.0毫克
硬质明胶胶囊
50.0毫克
71.0毫克
制备方法：
将活性物质研磨成供吸入所需要的粒子大小。将已研磨的活性物质与乳糖均匀混合。将混合物装填至硬质明胶胶囊中。
实施例II
供Respimat
用的可吸入溶液，具有1毫克活性物质(A)或(B)
组成：
1份喷雾剂含有：
活性物质(A)或(B) 1.0毫克
氯苄烷铵 0.002毫克
乙二胺四乙酸二钠 0.0075毫克
纯水加至 15.0微升
制备方法：
使活性物质与氯苄烷铵溶于水中，并将其装入Respimate药筒中。
实施例III
供雾化器用的可吸入溶液，具有1毫克活性物质(A)或(B)
组成：
1个小玻瓶含有：
活性物质(A)或(B) 0.1克
氯化钠 0.18克
氯苄烷铵 0.002克
纯水至 20.0毫升
制备方法：
使活性物质、氯化钠及氯苄烷铵溶于水中。
实施例IV
推进剂气体操作的计量气溶胶，具有1毫克活性物质(A)或(B)
组成：
1份喷雾剂含有：
活性物质(A)或(B) 1.0毫克
卵磷脂 0.1％
推进剂气体至 50.0微升
制备方法：
使微粉化活性物质均匀地悬浮于卵磷脂与推进剂气体的混合物中。将此悬浮液转移至具有计量阀的加压容器中。
实施例V
鼻喷雾剂，具有1毫克活性物质(A)或(B)
组成：
1份喷雾剂含有：
活性物质(A)或(B) 1.0毫克
甘露醇 5.0毫克
乙二铵四乙酸二钠 0.05毫克
抗坏血酸 1.0毫克
纯水至 0.1毫升
制备方法：
使活性物质与赋形剂溶于水中，并转移至适当容器。
实施例VI
可注射溶液，每5毫升具有5毫克活性物质(A)或(B)
组成：
呈碱式的活性物质(A)或(B) 5毫克
酸/盐形成剂，形成中性盐所必须的量 足量
葡萄糖 250毫克
人类血清白蛋白 10毫克
糖糠醛 250毫克
注射用水至 5毫升
制备：
使糖糠醛与葡萄糖溶于注射用水(WfI)中；添加人类血清白蛋白；添加盐形成剂；加热以溶解活性物质；以WfI补足至所指定的体积；于氮气下转移至安瓿瓶。
实施例VII
供皮下投药的可注射溶液，每1毫升含有5毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 5毫克
葡萄糖 50毫克
聚山梨酸酯80＝Tween 80 2毫克
注射用水至 1毫升
制备：
使葡萄糖与聚山梨酸酯溶于注射用水中；以加热或使用超音波，使活性物质溶解；以WfI补足至所指定的体积；于惰性气体下，转移至安瓿瓶。
实施例VIII
可注射溶液，每10毫升含有100毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 100毫克
磷酸二氢钾＝KH2PO4 12毫克
磷酸氢二钠＝Na2HPO4·2H2O 2毫克
氯化钠 180毫克
人类血清白蛋白 50毫克
聚山梨酸酯80 20毫克
注射用水至 10毫升
制备：
使聚山梨酸酯80、氯化钠、磷酸二氢钾及磷酸氢二钠溶于注射用水(WfI)中；添加人类血清白蛋白；以加热使活性物质溶解；以WfI补足至所指定的体积；转移至安瓿瓶。
实施例IX
冻干物，含有10毫克活性物质(A)或(B)
组成：
呈碱式的活性物质(A)或(B) 10毫克
酸/盐形成剂，形成中性盐所必须的量 足量
甘露醇 300毫克
注射用水至 2毫升
制备：
使甘露醇溶于注射用水(WfI)中；添加盐形成剂；以加热使活性物质溶解；以WfI补足至所指定的体积；转移至小玻瓶；冻干。
冻干物用的溶剂：
聚山梨酸酯80＝Tween 80 20毫克
甘露醇 200毫克
注射用水至 10毫升
制备：
使聚山梨酸酯80与甘露醇溶于注射用水(WfI)中；转移至安瓿瓶。
实施例X
冻干物，含有5毫克活性物质(A)或(B)
组成：
呈碱式的活性物质(A)或(B) 5毫克
极性或非极性溶剂(其可通过冷冻干燥除去)至 1毫升
制备：
使活性物质溶于适当溶剂中；转移至小玻瓶；冻干。
冻干物用的溶剂：
聚山梨酸酯80＝Tween 80 5毫克
甘露醇 100毫克
注射用水至 2毫升
制备：
使聚山梨酸酯80与甘露醇溶于注射用水(WfI)中；转移至安瓿瓶。
实施例XI
片剂，含有20毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 20毫克
乳糖 120毫克
玉米淀粉 40毫克
硬脂酸镁 2毫克
聚乙烯吡咯烷酮(povidone)K 25 18毫克
制备：
将活性物质、乳糖及玉米淀粉均匀地混合；以聚乙烯吡咯烷酮的水溶液造粒；与硬脂酸镁混合；在压片机中压制；片剂重量200毫克。
实施例XII
胶囊，含有20毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 20毫克
玉米淀粉 80毫克
高度分散的硅石 5毫克
硬脂酸镁 2.5毫克
制备：
将活性物质、玉米淀粉及硅石均匀地混合；与硬脂酸镁混合；在胶囊充填机中，将混合物转移至3号硬质明胶胶囊中。
实施例XIII
栓剂，含有50毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 50毫克
硬质脂肪(动物脂，固体)足量至 1700毫克
制备：
使硬质脂肪在约38℃下熔融；使已磨碎的活性物质均匀地分散于熔融态硬质脂肪中；于冷却至约35℃后，倾倒至急冷模具中。
实施例XIV
供鼻投药的水溶液，含有10毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 10.0毫克
盐酸，形成中性盐所必须的量
对羟基苯甲酸(PHB)甲酯 0.01毫克
对羟基苯甲酸(PHB)丙酯 0.005毫克
纯水至 1.0毫升
制备：
使活性物质溶于纯水中；添加盐酸直到溶液透明为止；添加PHB的甲酯与丙酯；以纯水将该溶液补足至所指定的体积；将此溶液杀菌过滤，并转移至适当容器中。
实施例XV
供鼻投药的水溶液，含有5毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 5毫克
1，2-丙二醇 300毫克
羟乙基纤维素 5毫克
山梨酸 1毫克
纯水至 1毫升
制备：
使活性物质溶于1，2-丙二醇中；在纯水中制备含有山梨酸的羟乙基纤维素溶液，并将其添加至活性物质的溶液中；将该溶液杀菌过滤，并转移至适当容器中。
实施例XVI
供静脉内投药的水溶液，含有5毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 5毫克
1，2-丙二醇 300毫克
甘露醇 50毫克
注射用水(WfI)至 1毫升
制备：
使活性物质溶于1，2-丙二醇中；以WfI将此溶液补足至大约所指定的体积；添加甘露醇，并以WfI补足至大约所指定的体积；将此溶液杀菌过滤，转移至个别容器中，并进行热压处理。
实施例XVII
供静脉内注射的脂质体配方，含有7.5毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 7.5毫克
蛋卵磷脂，例如Lipoid E 80 100.0毫克
胆固醇 50.0毫克
甘油 50.0毫克
注射用水至 1.0毫升
制备：
使活性物质溶于卵磷脂与胆固醇的混合物中；将此溶液添加至甘油与WfI的混合物中，并通过高压均化作用或通过微流化床技术进行均化；于无菌状态下，将所获得的脂质体制剂转移至适当容器中。
实施例XVIII
供鼻投药的悬浮液，含有20毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 20.0毫克
羧甲基纤维素(CMC) 20.0毫克
磷酸单氢钠/磷酸二氢钠缓中剂，pH6.8 适量
氯化钠 8.0毫克
对羟基苯甲酸甲酯 0.01毫克
对羟基苯甲酸丙酯 0.003毫克
纯水至 1.0毫升
制备：
使活性物质悬浮于CMC水溶液中；将其他成分依次添加至该悬浮液中，并用纯水添加到所指定的体积的顶部。
实施例XIX
供皮下投药的水溶液，具有10毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 10.0毫克
磷酸单氢钠/磷酸二氢钠缓中剂，足量至pH 7.0
氯化钠 4.0毫克
注射用水至 0.5毫升
制备：
使活性物质溶于磷酸盐缓中溶液中，于添加食盐后，以水将此溶液补足至所指定的体积。将此溶液杀菌过滤，转移至适当容器中，并进行高压釜处理。
实施例XX
供皮下投药的含水悬浮液，含有5毫克活性物质(A)或(B)
组成：
活性物质(A)或(B) 5.0毫克
聚山梨酸酯80 0.5毫克
注射用水 0.5毫克
制备：
使活性物质悬浮于聚山梨酸酯80溶液中，并使用适当分散技术(例如湿磨、高压均化、微流体化等)，粉碎至约1微米的粒子大小。于无菌状态下，将该悬浮液转移至相应容器中。
Claims (6)
1.选自CGRP拮抗剂的活性物质在制备用于治疗绝经热潮红的药物组合物中的用途，其特征在于，CGRP拮抗剂选自以下物质：
(A)1-[N2-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(B)1-[4-氨基-3，5-二溴-N-[[4-(2，3，4，5-四氢-2(1H)-氧代-1，3-苯并二氮杂卓-3-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-吡啶基)-哌啶，
(C)1-[N2-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(D)1-[N2-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌啶，
(E)1-[N2-[3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(F)1-[N2-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(G)1-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代噻吩并[3，4-d]-嘧啶-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-哌啶基)-哌啶，
(H)1-[4-氨基-3，5-二溴-N-[[4-(2，4-二氢-5-苯基-3(3H)-氧代-1，2，4-三唑-2-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(I)1-[4-氨基-3，5-二溴-N-[[4-(2，4-二氢-5-苯基-3(3H)-氧代-1，2，4-三唑-2-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-哌啶基)-哌啶，
(J)1-[4-氨基-3，5-二溴-N-[[4-(2，4-二氢-5-苯基-3(3H)-氧代-1，2，4-三唑-2-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
(K)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代噻吩[3，2-d]嘧啶-3-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-哌啶基)-哌啶，
(L)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-乙基-4哌啶基)-哌啶，
(M)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-己基-4-哌啶基)-哌啶，
(N)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-环丙基甲基-4-哌啶基)-哌啶，
(O)1-[N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-3-乙烯基-D，L-苯丙氨酰基]-4-(六氢-1H-1-氮杂卓基)-哌啶，
(P)(R，S)1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(4-羰基-3，5-二甲基苯基)甲基]-1，4-二氧代丁基]-4-(1-哌啶基)-哌啶，
(Q)1-[4-氨基-3，5-二溴-N-[[4-[N-(氨基羰基)-N-苯基-氨基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(R)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(5-甲氧基-4-嘧啶基)-哌嗪，
(S)1-[4-氨基-3，5-二溴-N-[[4-(1，1-二氧桥-3(4H)-氧代-1，2，4-苯并噻二嗪-2-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(T)1-[4-氨基-3，5-二溴-N-[[4-[2(1H)-氧代喹啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(U)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[3-(二甲氨基)丙基]-哌嗪，
(V)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(4-甲基-1-哌嗪基)-哌啶，
(W)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[(1-甲基-4-哌啶基)羰基]-哌嗪，
(X)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[(1-甲基-4-哌嗪基)-羰基]-哌嗪，
(Y)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[4-[4-(二甲氨基)丁基]苯基]-哌嗪，
(Z)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[4-(二甲氨基)-1-哌啶基]-哌啶，
(AA)1-[N2-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-N′-甲基-D-色酰基(tryptyl)]-4-(4-甲基-1哌嗪基)-哌啶，
(AB)1-[N2-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-N′-(1，1-二甲基乙氧羰基)-D-色酰基]-4-(1-甲基-4哌啶基)-哌啶，
(AC)(R，S)-1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(3，5-二溴-4-甲基苯基)甲基]-1，4-二氧基-丁基]-4-(4-甲基-1-哌嗪基)-哌啶，
(AD)(R，S)-1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(3，5-二溴基-4-甲氧苯基)甲基]-1，4-二氧基丁基]-4-(1-甲基-4-哌啶基)-哌啶，
(AE)(R，S)-1-[4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-2-[(3，4-二溴苯基)甲基]-1，4-二氧基丁基]-4-(4-甲基-1-哌嗪基)-哌啶，
(AF)1-[N2-[N-[[4-(1，3-二氢-2(2H)-氧代苯并咪唑-1-基)-1-哌啶基]羰基]-3，5-二溴-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(AG)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-6-羟基-2(2H)-氧代苯并咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-吡啶基)-哌啶，
(AH)1-[N2-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-2(2H)-氧代-苯并咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-N6，N6-二甲基-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(AI)1-[N2-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-N6，N6-二甲基-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(AJ)(R，S)-1-[2-(4-氨基-3，5-二溴基苯甲酰基)-4-[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]-4-氧代丁基]-4-(1-哌啶基)-哌啶，
(AK)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2，2-二氧桥-2，1，3-苯并噻二嗪-3-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-哌啶基)-哌啶，
(AL)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-2(2H)-氧代咪唑并[4，5-c]喹啉基-3-基]-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-哌啶基)羰基]-哌啶，
(AM)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(AN)1-[N2-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-N6，N6-二甲基-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(AO)1-[4-氨基-N-[[4-[4-(3-溴苯基)-1，3-二氢-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-3，5-二溴-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(AP)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(4-甲基-1-哌嗪基)-哌啶，
(AQ)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌嗪基)-哌啶，
(AR)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(外-8-甲基-8-氮杂双环并[3，2，1]辛-3-基)-哌嗪，
(AS)1-[3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-哌啶基)-哌啶，
(AT)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-乙基-4-哌啶基)-哌嗪，
(AU)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(六氢-4-甲基-1H-1，4-二氮杂卓-1-基)-哌啶，
(AV)1-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-[1-(甲基磺酰基)-4-哌嗪基]-哌啶，
(AW)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(AX)1-[3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(六氢-1H-一氮杂卓基)-哌啶，
(AY)1-[3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(AZ)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(外-8-甲基-8-氮杂双环并[3，2，1]辛-3-基)-哌嗪，
(BA)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
(BB)1-[3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)-苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-哌啶基)-哌啶，
(BC)1-[N6-乙酰基-N2-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(BD)1-[3，5-二溴-N-[[4-(1，3-二氢-4苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(六氢-1H-氮杂卓基)-哌啶，
(BE)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-(3-噻吩基)-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(BF)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(BG)1-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-[1-(羟羰基-甲基)-4-哌啶基)-哌啶，
(BH)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代-喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基磺酰基-4-哌啶基)-哌啶，
(BI)1-[3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(4-哌啶基)-哌啶，
(BJ)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-乙基-4-哌啶基)-哌啶，
(BK)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-(3-羟基-苯基)-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(BL)1-[3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(六氢-1H-1-氮杂卓基)-哌啶，
(BM)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶，
(BN)1-[4-氨基-3，5-二溴-N-[[4-[4-(3-溴苯基)-1，3-二氢-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(外-8-甲基-8-氮杂双环并[3，2，1]辛-3-基)-哌嗪，
(BO)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代-喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-乙基-4-哌啶基)-哌啶，
(BP)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代-喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基基]-4-(1-乙基-4-哌啶基)-哌嗪，
(BQ)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-(3-甲氧基-苯基)-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(外-8-甲基-8-氮杂双环并[3，2，1]辛-3-基)-哌嗪，
(BR)1-[3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-[1-(环丙基-甲基)-4-哌啶基]-哌啶，
(BS)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(六氢-1H-1-氮杂卓基)-哌啶，
(BT)1-[4-氨基-3，5-二溴-N-[[4-(3，4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(4-哌啶基)-哌啶，
(BU)1-[3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(4-吡啶基)-哌啶，
(BV)1-[3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
(BW)1-[N2-[3，5-二溴-N-[[4-[1，3-二氢-4-[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-吡啶基)-哌嗪，
(BX)1-[3，5-二溴-N-[[4-(1，3-二氢-4-(3-噻吩基)-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-哌啶基)-哌啶，
(BY)1-[4-氨基-N-[[4-[4-(3-氯苯基)-1，3-二氢-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-3，5-二溴-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(BZ)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(六氢-1H-1-氮杂卓基)-哌啶，
(CA)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4[3-(三氟甲基)苯基]-2(2H)-氧代咪唑-1-基]-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
(CB)1-[4-氨基-N-[[4-[4-(3-氯苯基)-1，3-二氢-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-3，5-二溴-D-苯丙氨酰基]-4-(六氢-1H-1-氮杂卓基)-哌啶，
(CC)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(4-哌啶基)-哌嗪，
(CD)1-[3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(CE)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-[4-(1-氧代乙基)苯基]-哌嗪，
(CF)1-[3，5-二溴-N-[[4-[3，4-二氢-2(2H)-氧代喹唑啉-3-基)-1-哌啶基]羰基]-D-酪氨酰基]-4-(1-甲基-4-吡啶基)-哌嗪，
(CG)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4(3-硝基苯基)-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶，
(CH)1-[4-氨基-3，5-二溴-N-[[4-[3，4-二氢-2(1H)-氧代-喹唑啉-3-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(1-吡咯烷基)-哌啶，
(CI)1-[4-氨基-3，5-二溴-N-[[4-[1，3-二氢-4-苯基-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯丙氨酰基]-4-(六氢-1H-1-氮杂卓基)-哌啶，及
(CJ)1-[4-氨基-3，5-二溴-N-[[4-(1，3-二氢-4-(3-噻吩基)-2(2H)-氧代咪唑-1-基)-1-哌啶基]羰基]-D-苯基-丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪，
其互变异构体，非对映异构体，对映异构体，其混合物及其生理学上可接受的盐。
2.根据权利要求1的用途，其特征在于，所述用于治疗绝经热潮红是以单一疗法，使用单一活性物质而实施的。
3.根据权利要求1的用途，其特征在于，所述用于治疗绝经热潮红是作为激素替补疗法的补充而实施的。
4.根据权利要求1的用途，其特征在于，所述药物组合物仅含有一种活性物质。
5.根据权利要求1或4的用途，其特征在于，所述药物组合物为用于单一治疗的药物组合物。
6.根据权利要求1的用途，其特征在于，所述药物组合物为用于激素替补疗法的补充的药物组合物。
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| DE19937304.3 | 1999-08-10 | ||
| DE19937304A DE19937304C2 (de) | 1999-08-10 | 1999-08-10 | Verwendung von CGRP-Antagonisten zur Bekämpfung menopausaler Hitzewallungen |
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| DE19952147A1 (de) | 1999-10-29 | 2001-05-03 | Boehringer Ingelheim Pharma | Neue Cyclopropane, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
| DE10139410A1 (de) * | 2001-08-17 | 2003-02-27 | Boehringer Ingelheim Pharma | Verwendung von BIBN4096 in Kombination mit anderen Arzneistoffen gegen Migräne für die Behandlung von Migräne |
| AU2002359458A1 (en) | 2001-12-12 | 2003-06-23 | Eli Lilly And Company | Alanyl-piperidine heterocyclic derivatives useful against cardiovascular diseases |
| 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 |
| DE10206770A1 (de) * | 2002-02-19 | 2003-08-28 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung eines Pulverinhalativums enthaltend ein Salz des CGRP-Antagonisten BIBN4096 |
| DE10207026A1 (de) * | 2002-02-20 | 2003-08-28 | Boehringer Ingelheim Kg | Pulverinhalativum, enthaltend den CGRP-Antagonisten BIBN4096 und Verfahren zu dessen Herstellung |
| DE10227294A1 (de) * | 2002-06-19 | 2004-01-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Zubereitungen zur intranasalen Applikation ausgewählter, von Aminosäuren abgeleiteter CGRP-Antagonisten sowie Verfahren zu deren Herstellung |
| DE10250080A1 (de) * | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| 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 (de) * | 2003-01-14 | 2004-07-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Carbonsäuren und deren Ester, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
| CA2531407A1 (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 |
| AU2004259675A1 (en) * | 2003-07-15 | 2005-02-03 | Merck & Co., Inc. | Hydroxypyridine CGRP receptor antagonists |
| DE10338399A1 (de) * | 2003-08-18 | 2005-03-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Mikropartikel, enthaltend den CGRP-Antagonisten 1-[N2-[3,5-Dibrom-N-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-Iysyl]-4-(4-pyridinyl)-piperazin, Verfahren zu deren Herstellung sowie deren Verwendung als Inhalaltionspulver |
| DE102004015723A1 (de) | 2004-03-29 | 2005-10-20 | Boehringer Ingelheim Pharma | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| DE102004019492A1 (de) * | 2004-04-22 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| 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 (de) * | 2004-12-29 | 2006-07-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung ausgewählter CGRP-Antagonisten zur Bekämpfung menopausaler Hitzewallungen |
| DE102004063755A1 (de) * | 2004-12-29 | 2006-07-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von CGRP-Antagonisten zur Behandlung und Vorbeugung von Hitzewallungen bei Patienten mit Prostatakrebs |
| EP1770091A1 (de) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| 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 |
| 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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| MX9710479A (es) * | 1995-09-07 | 1998-03-31 | Oreal | Extracto de iridaceas y composiciones que la contienen. |
| 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) |
| JP3483893B2 (ja) * | 1996-09-10 | 2004-01-06 | ドクトル カルル トーマエ ゲゼルシャフト ミット ベシュレンクテル ハフツング | 修飾アミノ酸、これらの化合物を含む薬物及びそれらの調製方法 |
| DE19911039A1 (de) * | 1999-03-12 | 2000-09-14 | Boehringer Ingelheim Pharma | Abgewandelte Aminosäureamide, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
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