Indian Patents. 220229:PHARMACEUTICAL COMPOSITION FOR TREATING MENOPAUSAL HOT FLUSHES

Title of Invention	PHARMACEUTICAL COMPOSITION FOR TREATING MENOPAUSAL HOT FLUSHES
Abstract	The invention relates to the use of CGRP antagonists and CGRP relates inhibitors for treating menopausal hot flushes as well as corresponding pharmaceutical compositions containing as active sustance one or more CGRP antagonists and/or CGRP release inhibitors, and the preparation therof.

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] THE PATENTS (AMENDMENT) RULES 2006 COMPLETE SPECIFICATION [See Section 10; rule 13] "PHARMACEUTICAL COMPOSITION FOR TREATING MENOPAUSAL HOT FLUSHES" BOEHRINGER INGELHEIM PHARMA KG, a German company, of 55216 Ingelheim/Rhein, Germany, The following specification particularly describes the nature of the invention and the manner in which it is to be performed :- Hot flushes are a common symptom of peri/post-menopausal syndrome the physiology of which is still not fully understood. Apart from hormone replacement therapy, which is a complex intervention and frequently cannot be used long-term owing to its side effects, there has up until now been no simple therapy largely free from side effects for this generally troublesome condition. Hot flushes are caused by vasodilatation and increased blood flow. A number of publications have mentioned the possibility that CGRP (calcitonin gene-related peptide) plays a part in the occurrence of menopausal hot flushes in oestrogen-deficient women owing to the vasodilatory properties of this neuropeptide ([1]: J. Endocrinol. (1995), 146(3), 431-437; [2]: Acta Physiol. Scand. (1998), 162(4), 517-522; [3]: Am. J. Obstet. Gynecol. (1996), 175(3, Pt. 1), 638-642). The therapeutic use of CGRP antagonists for treating menopausal syndrome has not previously been proposed in the literature. It has now been found that the symptoms of menopausal hot flushes can be effectively prevented or their distressing effects substantially alleviated by substances which antagonise the effects of CGRP (CGRP antagonists) or inhibit or reduce the release of CGRP from sensory nerve endings (CGRP release inhibitors), this therapeutic approach being superior to hormone replacement therapy in particular because of its lack of side effects. The present invention thus relates to the use of CGRP antagonists and/or CGRP release inhibitors for combating 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)-1-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)-1-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-1-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-(l-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-l,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenyl¬alanyl] -4-(l-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¬ll luoromethyl) phenyl] -2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-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-(l-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-(l-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,l-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) l-[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, (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-[(l-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-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N"-methyl-D-tryptyl]-4-(4-methyl-l-piperazinyl)-piperidine, (L) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N"-(1,1-diraethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine, (M) (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-(l-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-(l,3-dihydro-2(2H)-oxobenzimidazol-1-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-1-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-1-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(IH)-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-(l-piperidinyl)carbonyl]-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, (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-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(l-methyl-4-piperidinyl)-piperidine, (AP) 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, (AQ) 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-(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-1-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-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-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-1H-1,4-diazepin-l-yl)piperidine, (AV) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-l-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-1-yl)-l-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-1-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-(l-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-1-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-1-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)-1-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-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro- lH-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-(l-methyl-4-piperidinyl)-piperidine, (BF) 1-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3- (trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-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-ti¬me thyl sulphonyl -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-1-yl)-1-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-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-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-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine, (BN) 1-[4-amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-1,3-dihy-dro-2(2H)-oxoimidazol-1-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-(l-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- (l-ethyl-4-piperidinyl)-piperazine, (BQ) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxy-phenyl)-2(2H)-oxoimidazol-1-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-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(l-methyl-4-piperidinyl)-piperazine, (BW) 1-[N2-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluorome¬thyl) phenyl] -2(2H)-oxoimidazol-1-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-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine, (BY) 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-(l-methyl-4-piperidinyl)-piperidine, (BZ) 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-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-(l-methyl-4-piperidinyl)-piperazine, (CB) 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-lH-1-azepinyl)-piperidine, (CC) 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, (CD) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimi- dazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(l-methyl-4- piperidinyl)-piperidine, (CE) 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, (CF) 1-[3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3- yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(l-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-(l-methyl-4-piperidinyl)-piperidine, (CH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxo-quinazolin-3-yl]-1-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)-1-piperidinyl]carbonyl]-D-phenyl¬alanyl] -4-(l-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, (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, (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-(l-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-(l,3-dihydro-2(2H)-oxobenzimidazol-1-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-phenyl-alanyl]-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 l/l 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, metering aerosols or suppositories. 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)-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, (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-(l-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-1-piperazinyl)-piperidine, (AF) 1-[N2-[N-[[4-(l,3-dihydro-2(2H)-oxobenzimidazol-1-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), 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 2 0 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 ([4]: 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 50% 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)-1-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. Description of method: 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 3 7°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 b ipolar 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: 10 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. Table 1: "50% dose" = i.v. dose which reduces by 50% the increased blood flow through the facial skin caused by endogenous CGRP Substance 50% dose A 0.0 03 mg/kg B 0.042 mg/kg AC 0.018 mg/kg AM 0.046 mg/kg DA 0.280 mg/kg DB 0.03 5 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): Example I capsules for powder inhalation with 1 mg of active substance (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 5 0.0 mg 71.0 mg Method of preparation: 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. Example II Tnhalable solution for Respimat® with 1 mg of active substance (A) or (R) 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 μl Method of preparation: The active substance and benzalkonium chloride are dissolved in water and packed in Respimat® cartridges. Example III Inhalable solution for nebulisers with 1 mg of active substance [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 preparation; Active substance, sodium chloride and benzalkonium chloride are dissolved in water. Example IV Propellant gas-operated metering aerosol with 1 mg of active substance (A) or (B) Composition: 1 spray contains: active substance (A) or (B) 1.0 mg lecithin 0.1 % propellant gas ad 50.0 μl Method of preparation: 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. Example. V Nasal spray with 1 mg of active substance (A) or (B) Composition: 1 spray jet contains active substance (A) or (B) mannitol disodium edetate ascorbic acid purified water ad Method of preparation: The active substance and the excipients are dissolved in water and transferred into a suitable container. Example VI Injectable solution with 5 mg of active substanre (A) or (B) Per 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 Preparation: 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. Examplp VII Injectable solution for subcutaneous administration containing 5 mg of active substance (A) Or (B) per 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 Preparation: Dissolve glucose and polysorbate in water for injections; dissolve active substance with heating or using ultrasound; make up to specified volume with Wfl; transfer into ampoules under inert gas. Example VIII Injectable solution containing 100 mg of active substance (A) or (n) per 10 ml Composition: active substance (A) or (B) 100 mg monopotassium dihydrogen phosphate = KH2P04 12 mg disodium hydrogen phosphate = Na2HP04-2H20 2 mg sodium chloride 18 0 mg human serum albumin 50 mg polysorbate 8 0 2 0 mg water for injections ad 10 ml Preparation: 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. Example. IX Lyophi1isae containing 10 mg nf active substance (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 3 00 mg water for injections ad 2 ml Preparation: Dissolve mannitol in water for injections (WfI); add salt-forming agent; dissolve active substance with heating; make up to specified volume with Wfl; transfer into vials; freeze-dry. Solvent, for 1yophi1isate: polysorbate 80 = Tween 80 2 0 mg mannitol 200 mg water for injections ad 10 ml Preparation; Dissolve polysorbate 80 and mannitol in water for injections (WfI); transfer into ampoules. Example X Lyophilisate containing 5 mg of active suhstance (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 Preparation: Dissolve active substance in suitable solvent; transfer into vials; freeze-dry. Solvent for 1yophilisate: polysorbate 80 = Tween 80 5 mg mannitol 100 mg water for injections ad 2 ml Preparation : Dissolve polysorbate 80 and mannitol in water for injections (WfI); transfer into ampoules. Example. XI Tablets containing 20 mg of active substance (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 Preparation: 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. Example XII Capsules containing 2 0 mg of active, substance—(A), or (B) Composition: active substance (A) or (B) 20- mg maize starch 80 mg highly dispersed silica 5 mg magnesium stearate 2.5 mg Preparation: 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. Example XIII Suppositories containing SO mg of active substance (A) Or (B) Composition: active substance (A) or (B) 50 mg hard fat (Adeps solidus) q.s. ad 1700 mg Preparation:., 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. 26 Example XIV Aqueous.solution for nasal administration containing 10 mg of active. substance [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 Preparation• 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. Example XV Aqueous solution for nasal administration containing 5 mg of active substance (A) or (B) Composition: active substance (A) or (B) 5 mg 1,2-propanediol 3 00 mg hydroxyethylcellulose 5 mg sorbic acid 1 mg purified water ad 1 ml Preparation: 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. Example XVI Aqueous solution for intravenous administration containing 5 mg of active substance [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 Preparation: The active substance is dissolved in 1,2-propanediol; the solution is made up to approximately the specified volume with Wfl; the mannitol is added and made up to approximately the specified volume with Wfl; the solution is filtered sterile, transferred into individual containers and autoclaved. Example XVII 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 5 0.0 mg water for injections ad 1.0 ml Preparation: 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. Example XVIII Suspension for nasal administration containing 2 0 mg of active substance (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 0.0 03 mg purified water ad 1.0 ml Preparation : 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. Example XIX Aqueous solution for subcutaneous administration with 10 mg of antive substance (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 Preparation; 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. Example XX Aqueous suspension for subcutaneous administration containing .5 mg of active substance (A) or (B) Composition: active substance (A) or (B) 5.0 mg polysorbate 8 0 0.5 mg water for injections 0.5 ml Preparation: The active substance is suspended in the polysorbate 8 0 solution and comminuted to a particle size of about 1 μm 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. WE CLAIM: 1. A pharmaceutical composition for treating menopausal hot flushes comprising CGRP antagonists and CGRP release inhibitors selected from the group consisting of: (A) 1-[N2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl) 1- piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-pipera2;ine; (B) l-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(lH)-oxo-l,3- benzodiazep in-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)- piperidine; (C) 1-[N2 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l- piper idinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine; (D) 1-[N2 -[4-amino-3,5-dibromo-N-[[4-(3?4-dihydro-2(lH)-oxoquinazolin-3-yl)- 1-piper idinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine; (E) 1-[N2 -[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l- piperi dinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine; (F) 1-[N2 -[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol- 1 -yl) - 1 -piperidinyl] carbonyl] -D-phenyl-alanyl] -L-ly syl] -4 - (4-pyridinyl) - piperazine; (G) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxothieno[3,4-d]pyrimidin-3-yl)-l- piperidinyl]carbonyl]-D-tyrosyl]-4-(l-piperidinyl)-piperidine; (H) l-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-l,2,4-triazol -2-yl)-1 -piperidinyl]carbonyl]-D-phenyl-alanyl]-4-( 1 -methyl-4-piperidinyl)-piperidine; (I) l-[4-amino-3,5-dibromo-N-[[4-(2J4-dihydro-5-phenyl-3(3H)-oxo-l,2,4-triazol -2-yl)-1 -piperidinyl]carbonyl]-D-phenyl-alanyl]-4-( 1 -piperidinyl)-piperidine; (J) l-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-l,2,4-triazol -2-yl) -1 -piperidinyl] carbonyl] -D-phenyl-alanyl] -4-( 1 -methyl-4-piperidinyl) -piperazine; (K) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxothieno[3,2- d] pyrimidin- 3-yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1 -piperidinyl) - piperidine; (L) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(tri-fluoromethyl)phenyl]-2 (2H)-oxoimidazol-l-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-ethyl-4 piperidinyl) -piperidine; (M) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l- pipe ridinyl]carbonyl]-D-phenylalanyl] -4-(1 -hexyl-4-piperidinyl) -piperidine; (N) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(l-cyclopropylmethyl-4-piperidinyl)- piperidine; (O) l-[N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H-1 -azepinyl) -piperidine; (P) (R,S)-l-[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(4- hydroxy-3,5-dimethylphenyl)methyl]-l,4-dioxobutyl]-4-(l-piperidinyl)- piperidine; (Q) 1 - [4-amino-3,5-dibromo-N- [ [4- [N-(aminocarbonyl) -N-phenylamino] -1 - piperidin yl]carbonyl]-D-phenylalanyl]-4-(1 -piperidinyl)-piperidine; (R) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine; (S) l-[4-amino-3,5-dibromo-N-[[4-(l,l-dioxido-3(4H)-oxo-l,2,4-benzothiadiazin-2 -yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1 -piperidinyl) -piperidine; (T) l-[4-amino-3,5-dibromo-N-[t4-[2(lH)-oxoquinolin-3-yl]-l-piperidinyl]carbon yl]-D-phenylalanyl]-4-( 1 -piperidinyl)-piperidine; (U) l-[4-amino-3,5-dibrorno-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine; (V) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-l-piperazinyl)-piperidine; (W) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l- pipe ridinyl]carbonyl]-D-phenylalanyl]-4-[(l-methyl-4-piperidinyl)carbonyl]- piperazine; (X) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-[(l-methyl-4-piperazinyl)carbonyl]- piperazine; (Y) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinylicarbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylaniino)butyl]phenyl]- piperazine; (Z) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-l-piperidinyl]- piperidine; (K) 1-[N2 -[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]carbonyl] -N"-methyl-D-tryptyl]-4-(4-methyl-l-piperazinyl)-piperidine; (L) 1-[N2 -[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]carbonyl] -N"-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine; (M) (R,S)-l-[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(3, 5-dibromo-4-methylphenyl) methyl] -1,4-dioxobutyl] -4-(4-methyl-1 -piperazinyl) piperidine; (N) (R,S)-l-[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(3, 5-dibromo-4-methoxyphenyl)methyl]-l,4-dioxobutyl]-4-(-methyl-4-piperidinyl) piperidine; (AE) (R,S)-l-[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(3J 4- dibromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine; (AF) 1-[N2 -[N-[[4-(l,3-dmydro-2(2H)-oxobenzimidazol-l-yl)-l- piperidinyl]carbonyl]-3 ,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine; (AG) l-[4-amino-3,5-dibromo-N-[[4-(l)3-dihydro-6-hydroxy-2(2H)- oxobenzimidazol- l-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l- piperidinyl) -piperidine; (AH) 1-[N2 -[4-amino-3,5-dibromo-N-[[4-(lJ3-dihydro-2(2H)-oxobenzimidazol-l-yl)-1-pip eridinyl]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(lH)-oxoquinazolin-3-yl)- 1-piper idinyl]carbonyl]-D-phenylalanyl]-N6,N6 -dimethyl-L-lysyl]-4-(4- pyridinyl) -piperazine; (AJ) (R,S)-l-[2-(4-amino-3,5-dibromobenzoyI)-4-[4-(3,4-dihydro-2(lH)- oxoquinazo lin-3-yl)-l-piperidinyl]-4-oxobutyl]-4-(l-piperidinyl)-piperidine; (AK) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,l,3- benzothiadiazi n-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine; (AL) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-2(2H)-oxoimidazo[4,5- c]quinolin- 3yl]-l-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(l- piperidinyl)carbonyl]-piperidine; (AM) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine; (AN) 1-[N2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l- piperidinyl]carbonyl]-D-tyrosyl]-N6,N6 -dimethyl-L-lysyl]-4-(4-pyridinyl)- piperazine; (AO) l-[4-amino-N-[[4-[4-(3-bromophenyl)-l,3-dihydro-2(2H)-oxoimidazol-l- yl]-l- piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(l-methyl-4- piperidinyl )-piperidine; (AP) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-phenyl-2(2H)-oxoimida2;ol-l- yl] - l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl- 1-piperazinyl)- piperidine; (AQ) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoroniethyl)phenyl]-2( 2H)-oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1 -piperidi nyl)-piperidine; (AR) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2( 2H)-oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-meth yl-8-azabicyclo[3,2,l]oct-3-yl)-piperazine; (AS) l-[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l- piper idinyl]carbonyl]-D-tyrosyl]-4-(l-piperidinyl)-piperidine; (AT) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2 ( 2 H) -oxoimidazol-1 -yl] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1 -ethyl-4-piperidinyl)-piperazine; (AU) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-phenyl-2(2H)-oxoimida2;ol-1-yl] -l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-lH-l,4-diaze pin-l-yl)piperidine; (AV) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-[l-(methylsulfonyl)-4-piperidinyl]-piperidine; (AW) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidine; (AX) l-[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoi midazol- 1-yl]-1-piperidinyl] carbonyl]-D-tyrosyl]-4-(hexahydro- 1H- 1-azepinyl )-piperidine; (AY) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-( 1 -methyl-4-piperidinyl)-piperidine; (AZ) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,l]oct-3- yl)-piperazine; (BA) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol- 1 -yl) -1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1 -methyl-4-piperidinyl)- piperaz ine; (BB) l-[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)- oxoi midazol-1-yl]-l-piperidinyl]carbonyl]-D-tyrosyl]-4-(l-piperidinyl)- piperidine; (BC) 1-[N6 -Acetyl-N2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3- yl)-l-piperidinyl]c arbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine; (BD) l-[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l- piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-lH-l-azepinyl)-piperidine; (BE) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-(3-thienyl)-2(2H)- oxoimidazol- l-yl)-l-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(l-methyl-4- piperidinyl)-piperidine; (BF) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]- 2( 2H)-oxoimidazol-l-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-methyl-4 -piperidinyl)-piperidine; (BG) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine ; (BH) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1 -methylsulphonyl-4-piperidinyl) -piperidine; (BI) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine; (BJ) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-ethyl-4-piperidinyl)-piperidine; (BK) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-(3-hydroxyphenyl)-2(2H)- oxoimidazol-1 -yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4-( 1 -methyl-4-piperidin yl)-piperidine; (BL) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine; (BM) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl) - l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine; (BN) l-[4-amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-l,3-dihydro-2(2H)- oxoimida zol-1-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-piperazine; (BO) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-ethyl-4-piperidinyl)-piperidine; (BP) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(l-ethyl-4-piperidinyl)-piperazine; (BQ) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimi dazol-1-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabi cyclo[3,2, l]oct-3-yl)-piperazine; (BR) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-[l-(cyclopropyl-methyl)-4-piperidinyl]-piperidine; (BS) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro- 1H-l-azepinyl)-piperidine; (BT) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine; (BU) l-[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l- piper idinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine; (BV) l-[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoi midazol-1-yl] -1-piperidinyl] carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl) piperazine; (BW) l-[N.sup.2 -[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]- 2(2H)-oxoim idazol-l-yl]-l-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4- pyridinyl)-pi perazine; (BX) l-[3,5-dibromo-N-[[4-(l,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-l-yl)-l-piperidinyl] carbonyl] -D-tyrosyl] -4-( 1 -piperidinyl) -piperidine; (BY) l-[4-amino-N-[[4-[4-(3-chlorophenyl)-l,3-dihydro-2(2H)-oxoimidazol- 1-yl]-1 -piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidiny1)-piperidine; (BZ) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2( 2H)-oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1 -azepinyl) -piperidine; (CA) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]- 2( 2H)-oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl] -4-(1 -methyl-4 -piperidinyl) -piperazine; (CB) l-[4-amino-N-[[4-[4-(3-chlorophenyl)-l,3-dihydro-2(2h)-oxoimidazol-l-yl]-l -piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(hexahydro-1H-1-azepin yl)-piperidine; (CC) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol- 1-yl) -1-piperidinyl] carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine; (CD) l-[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l- piper idinyl]carbonyl]-D-tyrosyl]-4-(l-methyl-4-piperidinyl)-piperidine; (CE) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-phenyl-2(2H)-oxoimidazol- 1-yl] -l-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(l-oxoethyl)phenyl]- piperazin e; (CF) l-[3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl] carbonyl] -D-tyrosyl] -4- (1 -methyl-4-piperidinyl) -piperazine; (CG) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-(3-nitrophenyl)- 2(2H)-oxoimida zol-1 -yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1 -methyl-4- piperidinyl )-piperidine; (CH) l-[4-amino-3,5-dibromo-N-[[4-[3?4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-pipe ridinyl]Carbonyl]-D-phenylalanyl]-4-(l-pyrrolidinyl)-piperidine; (CI) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol- 1-yl) -l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-lH-l-azepinyl)- piperidine; and (CJ) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-(3-thienyl)-2(2H)- oxoimidazol- l-yl)-l-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(l-methyl-4- piperidinyl)-piperazine, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the physiologically acceptable salts as herein described, further comprising one or more inert carriers and/or diluents. Dated this January 30, 2002. (SHUKADEV KHURAIJAM) OF REMFRY AND SAGAR ATTORNEY FOR THE APPLICANTS

Full Text

FORM 2
THE PATENTS ACT 1970 [39 OF 1970]
THE PATENTS (AMENDMENT) RULES 2006 COMPLETE SPECIFICATION
[See Section 10; rule 13]
"PHARMACEUTICAL COMPOSITION FOR TREATING MENOPAUSAL HOT FLUSHES"
BOEHRINGER INGELHEIM PHARMA KG, a German company, of 55216 Ingelheim/Rhein, Germany,
The following specification particularly describes the nature of the invention and the manner in which it is to be performed :-

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

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)-1-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)-1-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-1-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-(l-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-l,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenyl¬alanyl] -4-(l-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¬ll luoromethyl) phenyl] -2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-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-(l-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-(l-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,l-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) l-[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,
(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-[(l-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-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N"-methyl-D-tryptyl]-4-(4-methyl-l-piperazinyl)-piperidine,

(L) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N"-(1,1-diraethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(M) (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-(l-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-(l,3-dihydro-2(2H)-oxobenzimidazol-1-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-1-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-1-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(IH)-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-(l-piperidinyl)carbonyl]-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,
(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-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(l-methyl-4-piperidinyl)-piperidine,
(AP) 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,
(AQ) 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-(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-1-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-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-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-1H-1,4-diazepin-l-yl)piperidine,
(AV) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-l-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-1-yl)-l-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-1-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-(l-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-1-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-1-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)-1-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-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-
lH-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-(l-methyl-4-piperidinyl)-piperidine,
(BF) 1-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-
(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-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-ti¬me thyl sulphonyl -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-1-yl)-1-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-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-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-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine,
(BN) 1-[4-amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-1,3-dihy-dro-2(2H)-oxoimidazol-1-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-(l-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- (l-ethyl-4-piperidinyl)-piperazine,
(BQ) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxy-phenyl)-2(2H)-oxoimidazol-1-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-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(l-methyl-4-piperidinyl)-piperazine,
(BW) 1-[N2-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluorome¬thyl) phenyl] -2(2H)-oxoimidazol-1-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-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine,
(BY) 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-(l-methyl-4-piperidinyl)-piperidine,
(BZ) 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-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-(l-methyl-4-piperidinyl)-piperazine,
(CB) 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-lH-1-azepinyl)-piperidine,

(CC) 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,
(CD) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimi-
dazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(l-methyl-4-
piperidinyl)-piperidine,
(CE) 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,
(CF) 1-[3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-
yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(l-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-(l-methyl-4-piperidinyl)-piperidine,
(CH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxo-quinazolin-3-yl]-1-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)-1-piperidinyl]carbonyl]-D-phenyl¬alanyl] -4-(l-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,
(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,
(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-(l-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-(l,3-dihydro-2(2H)-oxobenzimidazol-1-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-phenyl-alanyl]-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 l/l 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, metering aerosols or suppositories.

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)-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,
(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-(l-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-1-piperazinyl)-piperidine,
(AF) 1-[N2-[N-[[4-(l,3-dihydro-2(2H)-oxobenzimidazol-1-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),

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 2 0 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 ([4]: 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 50% 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)-1-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.
Description of method:
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 3 7°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 b ipolar 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:
10 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.
Table 1: "50% dose" = i.v. dose which reduces by 50% the increased blood flow through the facial skin caused by endogenous CGRP

Substance 50% dose
A 0.0 03 mg/kg
B 0.042 mg/kg
AC 0.018 mg/kg
AM 0.046 mg/kg
DA 0.280 mg/kg
DB 0.03 5 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):

Example I
capsules for powder inhalation with 1 mg of active substance (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 5 0.0 mg
71.0 mg
Method of preparation:
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.
Example II
Tnhalable solution for Respimat® with 1 mg of active substance (A) or (R)
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 μl
Method of preparation:
The active substance and benzalkonium chloride are dissolved
in water and packed in Respimat® cartridges.

Example III
Inhalable solution for nebulisers with 1 mg of active
substance [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 preparation;
Active substance, sodium chloride and benzalkonium chloride
are dissolved in water.
Example IV
Propellant gas-operated metering aerosol with 1 mg of active substance (A) or (B)
Composition:
1 spray contains:
active substance (A) or (B) 1.0 mg
lecithin 0.1 %
propellant gas ad 50.0 μl
Method of preparation:
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.

Example. V
Nasal spray with 1 mg of active substance (A) or (B)

Composition:
1 spray jet contains
active substance (A) or (B)
mannitol
disodium edetate
ascorbic acid
purified water ad

Method of preparation:
The active substance and the excipients are dissolved in water
and transferred into a suitable container.
Example VI
Injectable solution with 5 mg of active substanre (A) or (B) Per 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
Preparation:
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.

Examplp VII
Injectable solution for subcutaneous administration containing
5 mg of active substance (A) Or (B) per 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
Preparation:
Dissolve glucose and polysorbate in water for injections; dissolve active substance with heating or using ultrasound; make up to specified volume with Wfl; transfer into ampoules under inert gas.
Example VIII
Injectable solution containing 100 mg of active substance (A)
or (n) per 10 ml
Composition:
active substance (A) or (B) 100 mg
monopotassium dihydrogen phosphate
= KH2P04 12 mg
disodium hydrogen phosphate
= Na2HP04-2H20 2 mg
sodium chloride 18 0 mg
human serum albumin 50 mg
polysorbate 8 0 2 0 mg
water for injections ad 10 ml
Preparation:
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.
Example. IX
Lyophi1isae containing 10 mg nf active substance (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 3 00 mg
water for injections ad 2 ml
Preparation:
Dissolve mannitol in water for injections (WfI); add salt-forming agent; dissolve active substance with heating; make up to specified volume with Wfl; transfer into vials; freeze-dry.
Solvent, for 1yophi1isate:
polysorbate 80 = Tween 80 2 0 mg
mannitol 200 mg
water for injections ad 10 ml
Preparation;
Dissolve polysorbate 80 and mannitol in water for injections (WfI); transfer into ampoules.
Example X
Lyophilisate containing 5 mg of active suhstance (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

Preparation:
Dissolve active substance in suitable solvent; transfer into
vials; freeze-dry.
Solvent for 1yophilisate:
polysorbate 80 = Tween 80 5 mg
mannitol 100 mg
water for injections ad 2 ml
Preparation :
Dissolve polysorbate 80 and mannitol in water for injections (WfI); transfer into ampoules.
Example. XI
Tablets containing 20 mg of active substance (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
Preparation:
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.

Example XII
Capsules containing 2 0 mg of active, substance—(A), or (B)
Composition:
active substance (A) or (B) 20- mg
maize starch 80 mg
highly dispersed silica 5 mg
magnesium stearate 2.5 mg
Preparation:
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.
Example XIII
Suppositories containing SO mg of active substance (A) Or (B)
Composition:
active substance (A) or (B) 50 mg
hard fat (Adeps solidus) q.s. ad 1700 mg
Preparation:.,
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.

26
Example XIV
Aqueous.solution for nasal administration containing 10 mg of
active. substance [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
Preparation•
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.
Example XV
Aqueous solution for nasal administration containing 5 mg of
active substance (A) or (B)
Composition:
active substance (A) or (B) 5 mg
1,2-propanediol 3 00 mg
hydroxyethylcellulose 5 mg
sorbic acid 1 mg
purified water ad 1 ml
Preparation:
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.
Example XVI
Aqueous solution for intravenous administration containing
5 mg of active substance [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
Preparation:
The active substance is dissolved in 1,2-propanediol; the solution is made up to approximately the specified volume with Wfl; the mannitol is added and made up to approximately the specified volume with Wfl; the solution is filtered sterile, transferred into individual containers and autoclaved.
Example XVII
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 5 0.0 mg
water for injections ad 1.0 ml
Preparation:
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.
Example XVIII
Suspension for nasal administration containing 2 0 mg of active
substance (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 0.0 03 mg
purified water ad 1.0 ml
Preparation :
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.
Example XIX
Aqueous solution for subcutaneous administration with 10 mg of
antive substance (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

Preparation;
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.
Example XX
Aqueous suspension for subcutaneous administration containing
.5 mg of active substance (A) or (B)
Composition:
active substance (A) or (B) 5.0 mg
polysorbate 8 0 0.5 mg
water for injections 0.5 ml
Preparation:
The active substance is suspended in the polysorbate 8 0 solution and comminuted to a particle size of about 1 μm 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.

WE CLAIM:
1. A pharmaceutical composition for treating menopausal hot flushes comprising CGRP antagonists and CGRP release inhibitors selected from the group consisting of:
(A) 1-[N2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl) 1-
piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-pipera2;ine;
(B) l-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(lH)-oxo-l,3-
benzodiazep in-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-
piperidine;
(C) 1-[N2 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-
piper idinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
(D) 1-[N2 -[4-amino-3,5-dibromo-N-[[4-(3?4-dihydro-2(lH)-oxoquinazolin-3-yl)-
1-piper idinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
(E) 1-[N2 -[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-
piperi dinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
(F) 1-[N2 -[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-
1 -yl) - 1 -piperidinyl] carbonyl] -D-phenyl-alanyl] -L-ly syl] -4 - (4-pyridinyl) -
piperazine;
(G) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxothieno[3,4-d]pyrimidin-3-yl)-l-
piperidinyl]carbonyl]-D-tyrosyl]-4-(l-piperidinyl)-piperidine;

(H) l-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-l,2,4-triazol -2-yl)-1 -piperidinyl]carbonyl]-D-phenyl-alanyl]-4-( 1 -methyl-4-piperidinyl)-piperidine;
(I) l-[4-amino-3,5-dibromo-N-[[4-(2J4-dihydro-5-phenyl-3(3H)-oxo-l,2,4-triazol -2-yl)-1 -piperidinyl]carbonyl]-D-phenyl-alanyl]-4-( 1 -piperidinyl)-piperidine;
(J) l-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-l,2,4-triazol -2-yl) -1 -piperidinyl] carbonyl] -D-phenyl-alanyl] -4-( 1 -methyl-4-piperidinyl) -piperazine;
(K) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxothieno[3,2-
d] pyrimidin- 3-yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1 -piperidinyl) -
piperidine;
(L) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(tri-fluoromethyl)phenyl]-2 (2H)-oxoimidazol-l-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-ethyl-4 piperidinyl) -piperidine;
(M) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-
pipe ridinyl]carbonyl]-D-phenylalanyl] -4-(1 -hexyl-4-piperidinyl) -piperidine;
(N) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-pipe
ridinyl]carbonyl]-D-phenylalanyl]-4-(l-cyclopropylmethyl-4-piperidinyl)-
piperidine;
(O) l-[N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H-1 -azepinyl) -piperidine;

(P) (R,S)-l-[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(4-
hydroxy-3,5-dimethylphenyl)methyl]-l,4-dioxobutyl]-4-(l-piperidinyl)-
piperidine;
(Q) 1 - [4-amino-3,5-dibromo-N- [ [4- [N-(aminocarbonyl) -N-phenylamino] -1 -
piperidin yl]carbonyl]-D-phenylalanyl]-4-(1 -piperidinyl)-piperidine;
(R) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine;
(S) l-[4-amino-3,5-dibromo-N-[[4-(l,l-dioxido-3(4H)-oxo-l,2,4-benzothiadiazin-2 -yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1 -piperidinyl) -piperidine;
(T) l-[4-amino-3,5-dibromo-N-[t4-[2(lH)-oxoquinolin-3-yl]-l-piperidinyl]carbon yl]-D-phenylalanyl]-4-( 1 -piperidinyl)-piperidine;
(U) l-[4-amino-3,5-dibrorno-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine;
(V) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-l-piperazinyl)-piperidine;
(W) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-
pipe ridinyl]carbonyl]-D-phenylalanyl]-4-[(l-methyl-4-piperidinyl)carbonyl]-
piperazine;
(X) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-pipe
ridinyl]carbonyl]-D-phenylalanyl]-4-[(l-methyl-4-piperazinyl)carbonyl]-
piperazine;

(Y) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe
ridinylicarbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylaniino)butyl]phenyl]-
piperazine;
(Z) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe
ridinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-l-piperidinyl]-
piperidine;
(K) 1-[N2 -[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]carbonyl] -N"-methyl-D-tryptyl]-4-(4-methyl-l-piperazinyl)-piperidine;
(L) 1-[N2 -[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]carbonyl] -N"-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine;

(M) (R,S)-l-[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(3, 5-dibromo-4-methylphenyl) methyl] -1,4-dioxobutyl] -4-(4-methyl-1 -piperazinyl) piperidine;
(N) (R,S)-l-[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(3, 5-dibromo-4-methoxyphenyl)methyl]-l,4-dioxobutyl]-4-(-methyl-4-piperidinyl) piperidine;
(AE) (R,S)-l-[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(3J 4-
dibromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine;
(AF) 1-[N2 -[N-[[4-(l,3-dmydro-2(2H)-oxobenzimidazol-l-yl)-l-
piperidinyl]carbonyl]-3 ,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;

(AG) l-[4-amino-3,5-dibromo-N-[[4-(l)3-dihydro-6-hydroxy-2(2H)-
oxobenzimidazol- l-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-
piperidinyl) -piperidine;
(AH) 1-[N2 -[4-amino-3,5-dibromo-N-[[4-(lJ3-dihydro-2(2H)-oxobenzimidazol-l-yl)-1-pip eridinyl]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(lH)-oxoquinazolin-3-yl)-
1-piper idinyl]carbonyl]-D-phenylalanyl]-N6,N6 -dimethyl-L-lysyl]-4-(4-
pyridinyl) -piperazine;
(AJ) (R,S)-l-[2-(4-amino-3,5-dibromobenzoyI)-4-[4-(3,4-dihydro-2(lH)-
oxoquinazo lin-3-yl)-l-piperidinyl]-4-oxobutyl]-4-(l-piperidinyl)-piperidine;
(AK) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,l,3-
benzothiadiazi n-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine;
(AL) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-2(2H)-oxoimidazo[4,5-
c]quinolin- 3yl]-l-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(l-
piperidinyl)carbonyl]-piperidine;
(AM) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine;
(AN) 1-[N2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-
piperidinyl]carbonyl]-D-tyrosyl]-N6,N6 -dimethyl-L-lysyl]-4-(4-pyridinyl)-
piperazine;

(AO) l-[4-amino-N-[[4-[4-(3-bromophenyl)-l,3-dihydro-2(2H)-oxoimidazol-l-
yl]-l- piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(l-methyl-4-
piperidinyl )-piperidine;
(AP) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-phenyl-2(2H)-oxoimida2;ol-l-
yl] - l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl- 1-piperazinyl)-
piperidine;
(AQ) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoroniethyl)phenyl]-2( 2H)-oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1 -piperidi nyl)-piperidine;
(AR) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2( 2H)-oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-meth yl-8-azabicyclo[3,2,l]oct-3-yl)-piperazine;
(AS) l-[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-
piper idinyl]carbonyl]-D-tyrosyl]-4-(l-piperidinyl)-piperidine;
(AT) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2 ( 2 H) -oxoimidazol-1 -yl] -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (1 -ethyl-4-piperidinyl)-piperazine;
(AU) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-phenyl-2(2H)-oxoimida2;ol-1-yl] -l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-lH-l,4-diaze pin-l-yl)piperidine;
(AV) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-[l-(methylsulfonyl)-4-piperidinyl]-piperidine;

(AW) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-
piperidine;
(AX) l-[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoi midazol- 1-yl]-1-piperidinyl] carbonyl]-D-tyrosyl]-4-(hexahydro- 1H- 1-azepinyl )-piperidine;
(AY) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-( 1 -methyl-4-piperidinyl)-piperidine;
(AZ) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,l]oct-3- yl)-piperazine;
(BA) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-
1 -yl) -1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1 -methyl-4-piperidinyl)-
piperaz ine;
(BB) l-[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-
oxoi midazol-1-yl]-l-piperidinyl]carbonyl]-D-tyrosyl]-4-(l-piperidinyl)-
piperidine;
(BC) 1-[N6 -Acetyl-N2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-
yl)-l-piperidinyl]c arbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
(BD) l-[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-
piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-lH-l-azepinyl)-piperidine;

(BE) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-(3-thienyl)-2(2H)-
oxoimidazol- l-yl)-l-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(l-methyl-4-
piperidinyl)-piperidine;
(BF) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-
2( 2H)-oxoimidazol-l-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-methyl-4
-piperidinyl)-piperidine;
(BG) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]
carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine ;
(BH) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1 -methylsulphonyl-4-piperidinyl) -piperidine;
(BI) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine;
(BJ) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-ethyl-4-piperidinyl)-piperidine;
(BK) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-
oxoimidazol-1 -yl) -1 -piperidinyl] carbonyl] -D-phenylalanyl] -4-( 1 -methyl-4-piperidin yl)-piperidine;
(BL) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine;
(BM) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl) - l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine;

(BN) l-[4-amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-l,3-dihydro-2(2H)-
oxoimida zol-1-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-piperazine;
(BO) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-ethyl-4-piperidinyl)-piperidine;
(BP) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(l-ethyl-4-piperidinyl)-piperazine;
(BQ) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimi dazol-1-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabi cyclo[3,2, l]oct-3-yl)-piperazine;
(BR) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-[l-(cyclopropyl-methyl)-4-piperidinyl]-piperidine;
(BS) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro- 1H-l-azepinyl)-piperidine;
(BT) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-pipe ridinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine;
(BU) l-[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-
piper idinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine;
(BV) l-[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoi midazol-1-yl] -1-piperidinyl] carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl) piperazine;

(BW) l-[N.sup.2 -[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-
2(2H)-oxoim idazol-l-yl]-l-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-
pyridinyl)-pi perazine;
(BX) l-[3,5-dibromo-N-[[4-(l,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-l-yl)-l-piperidinyl] carbonyl] -D-tyrosyl] -4-( 1 -piperidinyl) -piperidine;
(BY) l-[4-amino-N-[[4-[4-(3-chlorophenyl)-l,3-dihydro-2(2H)-oxoimidazol- 1-yl]-1 -piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidiny1)-piperidine;
(BZ) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2( 2H)-oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1 -azepinyl) -piperidine;
(CA) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-
2( 2H)-oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl] -4-(1 -methyl-4
-piperidinyl) -piperazine;
(CB) l-[4-amino-N-[[4-[4-(3-chlorophenyl)-l,3-dihydro-2(2h)-oxoimidazol-l-yl]-l
-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(hexahydro-1H-1-azepin
yl)-piperidine;
(CC) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-
1-yl) -1-piperidinyl] carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine;
(CD) l-[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-
piper idinyl]carbonyl]-D-tyrosyl]-4-(l-methyl-4-piperidinyl)-piperidine;

(CE) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-
1-yl] -l-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(l-oxoethyl)phenyl]-
piperazin e;
(CF) l-[3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl]
carbonyl] -D-tyrosyl] -4- (1 -methyl-4-piperidinyl) -piperazine;
(CG) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-(3-nitrophenyl)-
2(2H)-oxoimida zol-1 -yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-( 1 -methyl-4-
piperidinyl )-piperidine;
(CH) l-[4-amino-3,5-dibromo-N-[[4-[3?4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-pipe ridinyl]Carbonyl]-D-phenylalanyl]-4-(l-pyrrolidinyl)-piperidine;
(CI) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-
1-yl) -l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-lH-l-azepinyl)-
piperidine; and
(CJ) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-(3-thienyl)-2(2H)-
oxoimidazol- l-yl)-l-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(l-methyl-4-
piperidinyl)-piperazine,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the physiologically acceptable salts as herein described, further comprising one or more inert carriers and/or diluents.
Dated this January 30, 2002.
(SHUKADEV KHURAIJAM) OF REMFRY AND SAGAR ATTORNEY FOR THE APPLICANTS

Documents:

in-pct-2002-00130-mum-cancelled pages(10-9-2007).pdf

in-pct-2002-00130-mum-claims(granted)-(10-9-2007).doc

in-pct-2002-00130-mum-claims(granted)-(10-9-2007).pdf

in-pct-2002-00130-mum-correspondence(10-9-2007).pdf

in-pct-2002-00130-mum-correspondence(ipo)-(21-5-2008).pdf

in-pct-2002-00130-mum-form 1(10-9-2007).pdf

in-pct-2002-00130-mum-form 1(30-1-2002).pdf

in-pct-2002-00130-mum-form 13(10-9-2007).pdf

in-pct-2002-00130-mum-form 13(5-5-2003).pdf

in-pct-2002-00130-mum-form 18(22-12-2005).pdf

in-pct-2002-00130-mum-form 2(granted)-(10-9-2007).doc

in-pct-2002-00130-mum-form 2(granted)-(10-9-2007).pdf

in-pct-2002-00130-mum-form 3(10-9-2007).pdf

in-pct-2002-00130-mum-form 3(29-1-2002).pdf

in-pct-2002-00130-mum-form 5(25-1-2002).pdf

in-pct-2002-00130-mum-petition under rule 137(10-9-2007).pdf

in-pct-2002-00130-mum-power of authority(10-9-2007).pdf

in-pct-2002-00130-mum-power of authority(23-4-2002).pdf

in-pct-2002-00130-mum-power of authority(30-1-2002).pdf

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Patent Number

220229

Indian Patent Application Number

IN/PCT/2002/00130/MUM

PG Journal Number

33/2008

Publication Date

15-Aug-2008

Grant Date

21-May-2008

Date of Filing

30-Jan-2002

Name of Patentee

BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG

Applicant Address

55216 INGELHEIM/RHEIN, GERMANY

Inventors:

#	Inventor's Name	Inventor's Address
1	WOLFGANG EBERLEIN
2	WOLFHARD ENGEL
3	HENRI DOODS
4	KLAUS RUDOLF

PCT International Classification Number

A61K31/00

PCT International Application Number

PCT/EP00/07613

PCT International Filing date

2000-08-05

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	199 37 304.3	1999-08-10	Germany