SK1972002A3 - Use of cgrp antagonists and cgrp release inhibitors for controlling menopausal hot flashes - Google Patents
Use of cgrp antagonists and cgrp release inhibitors for controlling menopausal hot flashes Download PDFInfo
- Publication number
- SK1972002A3 SK1972002A3 SK197-2002A SK1972002A SK1972002A3 SK 1972002 A3 SK1972002 A3 SK 1972002A3 SK 1972002 A SK1972002 A SK 1972002A SK 1972002 A3 SK1972002 A3 SK 1972002A3
- Authority
- SK
- Slovakia
- Prior art keywords
- piperidinyl
- carbonyl
- dihydro
- dibromo
- piperidine
- Prior art date
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Abstract
Description
Vynález sa týka použitia CGRP-antagonistov a inhibítorov uvoľňovania CGRP na potláčanie menopauzálnych návalov horúčavy, ako aj zodpovedajúcich liekov, ktoré obsahujú ako účinnú látku jeden alebo viaceré CGRP-antagonisty a/alebo inhibítory uvoľňovania CGRP, a ich výroby.The invention relates to the use of CGRP antagonists and CGRP release inhibitors for the control of menopausal hot flashes, as well as the corresponding medicaments containing as active ingredient one or more CGRP antagonists and / or CGRP release inhibitors, and the manufacture thereof.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Návaly horúčavy sú rozšíreným symptómom peri/postmenopauzálneho syndrómu, ktorého fyziológia nie je dodnes úplne objasnená. Okrem hormonálnej substitúcie (hormone replacement therapy - hormonálnej substitučnej liečby), ktorá predstavuje komplexný zásah a v dôsledku s tým spojených vedľajších účinkov sa často nemôže trvalo používať, doteraz neexistuje pre tento jav, ktorý sa vo všeobecnosti pociťuje ako nepríjemný, jednoducho uskutočniteľná terapia s malými vedľajšími účinkami.Hot flashes are a widespread symptom of peri / postmenopausal syndrome, whose physiology is not yet fully understood. Except for hormone replacement therapy, which is a complex intervention and as a result of which it can often not be permanently used due to the associated side effects, there is still no such phenomenon, which is generally perceived as an unpleasant, easily feasible therapy with small side effects. effects.
Návaly horúčavy sú spôsobené rozšírením ciev a zvýšeným prietokom krvi. Už viackrát sa publikovala domnienka, že CGRP (calcitonin gene-related peptide - s kacitonínovým génom súvisiaci peptid) hrá v dôsledku vazodilatačných vlastností tohto neuropeptidu úlohu pri vzniku menopauzálnych návalov horúčavy u žien s nedostatkom estrogénu ([1]: J. Endocrinol. 146(3), 431-437, 1995; [2]: Acta Physiol. Scand. 162(4). 517-522, 1998; [3]: Am. J. Obstet. Gynecol. 175(3. Pt. 1), 638-642, 1996). Terapeutické využitie CGRP-antagonistov na liečenie menopauzálneho syndrómu sa v literatúre doteraz nenavrhlo.Hot flashes are caused by dilatation of blood vessels and increased blood flow. It has been reported several times that the calcitonin gene-related peptide (CGRP), due to the vasodilatory properties of this neuropeptide, plays a role in the development of menopausal hot flushes in women with estrogen deficiency ([1]: J. Endocrinol. 146 ( 3), 431-437, 1995; [2] Acta Physiol. Scand. 162 (4): 517-522, 1998; [3] Am. J. Obstet. Gynecol. 175 (3. Pt. 1), 638-642, 1996). The therapeutic use of CGRP antagonists for the treatment of menopausal syndrome has not been suggested in the literature to date.
Teraz sa zistilo, že symptomatike menopauzálnych návalov horúčavy sa dá efektívne zabrániť alebo ich škodlivý účinok sa dá podstatne zoslabiť látkami, ktoré antagonizujú účinky CGRP (CGRP-antagonisty) alebo inhibujú alebo zmenšujú uvoľňovanie CGRP zo zmyslových nervových zakončení (inhibítory uvoľňovaniaIt has now been found that the symptomatics of menopausal hot flushes can be effectively prevented or their harmful effects can be substantially reduced by agents that antagonize the effects of CGRP (CGRP-antagonists) or inhibit or reduce the release of CGRP from the sensory nerve endings (release inhibitors)
CGRP), pričom sa toto terapeutické použitie v porovnaní s hormonálnou substitúciou vyznačuje najmä malými vedľajšími účinkami.CGRP), whereby this therapeutic use is characterized in particular by minor side effects compared to hormone replacement.
-2Podstata vynálezu2. Summary of the Invention
Podstatou vynálezu je použitie CGRP-antagonistov a/alebo inhibítorov uvoľňovania CGRP na výrobu lieku na potláčanie menopauzálnych návalov horúčavy, pričom je zahrnutá tak prevencia, ako aj akútna liečba.The present invention provides the use of CGRP-antagonists and / or CGRP release inhibitors for the manufacture of a medicament for controlling menopausal hot flashes, including both prevention and acute treatment.
Použitie podľa tohto vynálezu sa výhodne týka monoterapie jednotlivou látkou, zahrnuje však aj kombinovanú terapiu viacerými látkami uvedených skupín účinných látok. Ďalej sa použitie podľa tohto vynálezu môže uskutočniť na doplnenie bežne uskutočňovanej hormonálnej substitúcie.The use according to the invention preferably relates to single agent monotherapy, but it also encompasses combination therapy with multiple agents of the indicated classes of active substances. Furthermore, the use according to the invention can be carried out to supplement a commonly performed hormonal substitution.
Ďalej sa vynález týka aj farmaceutického prostriedku, ktorý obsahuje ako účinnú látku jeden alebo viaceré CGRP-antagonisty a/alebo inhibítory uvoľňovania CGRP.Furthermore, the invention also relates to a pharmaceutical composition comprising as active ingredient one or more CGRP antagonists and / or CGRP release inhibitors.
V zmysle predloženého vynálezu sa môžu použiť všetky farmaceutický prijateľné účinné látky, ktoré antagonizujú známe účinky CGRP, alebo inhibujú uvoľňovanie CGRP zo zmyslových zakončení nervov.Any pharmaceutically acceptable active ingredient that antagonizes the known effects of CGRP or inhibits the release of CGRP from the sensory nerve endings may be used in the context of the present invention.
Ako CGRP-antagonisty prichádzajú do úvahy napríklad deriváty aminokyselín, opísané vo WO 98/11128 alebo v DE 199 11 039, ďalej nepeptidické účinné látky, ktoré sú opísané vo WO 98/56779, WO 98/09630 a WO 97/09046.Suitable CGRP antagonists are, for example, the amino acid derivatives described in WO 98/11128 or in DE 199 11 039, furthermore the non-peptidic active substances described in WO 98/56779, WO 98/09630 and WO 97/09046.
Ako inhibítory uvoľňovania CGRP prichádzajú do úvahy napríklad agonisty serotonínu 5-HT-|D, ako avitriptan, eletriptan, naratriptan, rizatriptan, sumatriptan alebo zolmitriptan, ďalej 5-HT1F-agonisty alebo NPY-agonisty.Suitable inhibitors of CGRP release include, for example, serotonin 5-HT-1 agonists D , such as avitriptan, eletriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan, 5-HT 1F -agonists or NPY-agonists.
Z CGRP-antagonistov, opísaných vo WO 98/11128, prichádzajú na potláčanie menopauzálnych návalov horúčavy, na výrobu zodpovedajúceho lieku, ako aj ako zložky zodpovedajúceho lieku do úvahy výhodne nasledujúce zlúčeniny:Among the CGRP antagonists described in WO 98/11128, the following compounds are suitable for the control of menopausal hot flashes, for the manufacture of the corresponding medicament, as well as the constituent of the corresponding medicament:
(A) 1 -[Λ/2-[3,5-d i b róm-/V-[[4-(3,4-d i hyd ro-2 (1 /-/)-oxochinazolín-3-yl)-1 -piperid inyl]karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (B) 1 -[4-amino-3,5-dibróm-/\/-[[4-(2,3,4,5-tetrahydro-2(1 /7)-oxo-1,3-benzodiazepín-3-yl)-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, (C) 1 -[/V2-[4-amino-3,5-dibróm-/V-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolín-3-yl)-1 piperidinyl]-karbonyl]-D-fenylalanyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (D) 1 -[/V2-[4-amino-3,5-dibróm-A/-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolín-3-yl)-1 piperidinyl]-karbonyl]-D-fenylalanyl]-L-lyzyl]-4-(4-pyridinyl)-piperidín, (Ε) 1 -[Δ/2-[3,5-d i bró πί-Λ/-[[4-( 1,3-dihydro-4-fenyl-2(2H)-oxoimidazol-1 -y I)-1 piperidinyl]-karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (F) 1-[/V2-[4-amino-3,5-dibróm-/V-[[4-(1,3-dihydro-4-fenyl-2(2H)-oxoimidazol-1-yl)-(A) 1- [Λ / 2- [3,5-dibromo- N - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1] -piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (B) 1- [4-amino-3,5-dibromo-4 H - [[4] - (2,3,4,5-tetrahydro-2 (1 H) -oxo-1,3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (C) 1 - [N 2 - [4-amino-3,5-dibromo- N - [[4- (3,4-dihydro-2 (1 H)) -oxoquinazoline-3] -piperidine; -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (D) 1- [N 2 - [4-amino-3,5- dibromo- N - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1 piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) -piperidine, (E) 1- [η 2 - [3,5-di-bromo-η] - [[4- (1,3-dihydro-4-phenyl-2 (2H) - oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (F) 1 - [N 2 - [4-amino- 3,5-dibromo / V - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazo-1-yl) -
-piperidinyl]-karbonyl]-D-fenylalanyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (G) 1-[3,5-dibróm-A/-[[4-(3,4-dihydro-2(1H)-oxotieno[3,4-d]-pyrimidín-3-yl)-1piperidinyl]-karbonyl]-D-tyrozyl]-4-(1 -piperidinyl)-piperidín, (H) 1-[4-amino-3,5-dibróm-/V-[[4-(2,4-dihydro-5-fenyl-3(3H)-oxo-1,2,4-triazol-2yl)-1-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1-metyl-4-piperidinyl)-piperidín, (I) 1-[4-amino-3,5-dibróm-A/-[[4-(2,4-dihydro-5-fenyl-3(3/-/)-oxo-1,2,4-triazol-2yl)-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, (J) 1 -[4-amino-3,5-dibróm-A/-[[4-(2,4-dihydro-5-fenyl-3(3/-/)-oxo-1,2,4-triazol-2yl)-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1 -metyl-4-piperidinyl)-piperazín, (K) 1 -[4-amino-3,5-dibróm-/V-[[4-(3,4-dihydro-2(1 H)-oxotieno[3,2-d]-pyrimidín-3yl)-1-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1-piperidinyl)-piperidín, (L) 1 -[4-amino-3,5-dibróm-A/-[[4-[1,3-d i hyd ro-4-[3-(trifl uórmetyl )fenyl]-2(2A7)oxoimidazol-1 -y I]-1 -pi pe rid i nyl] ka rbonyl]-D-fenyl al a nyl]-4-( 1 -etyl-4-piperid iny I )piperidín, (M) 1-[4-amino-3,5-dibróm-/V-[[4-[3,4-dihydro-2(1H)-oxochinazolín-3-yl]-1piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1 -hexyl-4-piperidinyl)-piperidín, (N) 1 -[4-amino-3,5-dibróm-/V-[[4-[3,4-dihydro-2(1 /-/)-oxochinazolín-3-yl]-1 piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1-cyklopropylmetyl-4-piperidinyl)-piperidín, (O) 1 -[A/-[[4-[3,4-dihydro-2(1 H)-oxochinazolín-3-yl]-1 -piperidinyl]-karbonyl]-3etenyl-D,L-fenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidín, (P) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxochinazolín-3-yl)-1-piperidinyl]-2-[(4hydroxy-3,5-dimetylfenyl)metyl]-1,4-dioxobutyl]-4-(1 -piperidinyl)-piperidín.-piperidinyl] carbonyl] -D-phenylalanyl] -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 / V - [[4- (2,4-dihydro-5-phenyl-3 (3H) -oxo-1,2,4-triazol-2-yl) -1-piperidinyl ] -carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine; 4-Dihydro-5-phenyl-3 (3H) -oxo-1,2,4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) - piperidine, (J) 1- [4-amino-3,5-dibromo-N - [[4- (2,4-dihydro-5-phenyl-3 (3 H) -oxo-1,2)], 4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperazine, (K) 1- [4-amino-3,5-dibromo- N - [[4- (3,4-dihydro-2 (1H) -oxothieno [3,2-d] pyrimidin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- ( 1-piperidinyl) -piperidine, (L) 1- [4-amino-3,5-dibromo-N - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl]] -2 (2A7) oxoimidazol-1-yl] -1-piperidinyl] carbonyl (D) 1- [4-Amino-3,5-dibromo- N - [[4- [3]] -D-phenyl-allyl] -4- (1-ethyl-4-piperidinyl) piperidine 4-Dihydro-2 (1H) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-hexyl-4-piperidinyl) -piperidine, (N) 1- [4-] amino-3,5-dibromo- N - [[4- [3,4-dihydro-2 (1H) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 - (1-cyclopropylmethyl-4-piperidinyl) -piperidine, (O) 1- [N - [[4- [3,4-dihydro-2 (1H) -oxoquinazolin-3-yl] -1-piperidinyl] -carbonyl] -3-phenyl-D, L-phenylalanyl] -4- (hexahydro-1 H -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-dioxobutyl] -4- (1-piperidinyl) -piperidine.
(Q) 1 -[4-amino-3,5-dibróm-/V-[[4-[/V-(aminokarbonyl)-/V-fenylamino]-1 -pi perid inyl]karbonyl]-D-fenylalanyl]-4-(1-piperidinyl)-piperidín, (R) 1 -[4-amino-3,5-dibróm-/\/-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolín-3-yl)-1 piperidinyl]-karbonyl]-D-fenylalanyl]-4-(5-metoxy-4-pyrimidinyl)-piperazín, (S) 1-[4-amino-3,5-dibróm-/V-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-benzotiadiazín-2yl)-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, (Τ) 1 -[4-amino-3,5-dibróm-A/-[[4-[2(1 /7)-oxochinolín-3-yl]-1 -piperidinylj-karbonyl]D-fenylalanyl]-4-(1-piperidinyl)-piperidín, (U) 1 -[4-amino-3,5-dibróm-A/-[[4-[3,4-dihydro-2(1 /7)-oxochinazolín-3-yl]-1 piperidinyl]-karbonyl]-D-fenylalanyl]-4-(3-(dimetylamino)propyl]-piperazín, (V) 1 -[4-amino-3,5-dibróm-/V-[[4-(3)4-dihydro-2(1 H)-oxochinazolín-3-yl]-1 piperidinyl]-karbonyl]-D-fenylalanyl]-4-(4-metyl-1 -piperazinylj-piperidín, (W) 1-[4-amino-3,5-dibróm-/V-[[4-(3,4-dihydro-2(1/7)-oxochinazolín-3-yl]-1piperidinyl]-karbonyl]-D-fenylalanyl]-4-[(1-metyl-4-piperidinyl)karbonyl]-piperazín, (X) 1-[4-amino-3,5-dibróm-/V-[[4-[3,4-dihydro-2(1H)-oxochinazolín-3-yl]-1piperidinyl]-karbonyl]-D-fenylalanyl]-4-((1-metyl-4-piperazinyl)karbonyl]-piperazín, (Y) 1-[4-amino-3,5-dibróm-/V-([4-(3,4-dihydro-2(1H)-oxochinazolín-3-yl)-1piperidinyl]-karbonyl]-D-fenylalanyl]-4-[4-[4-(dimetylamino)butyl]fenyl]-piperazín, (Z) 1 -[4-amino-3,5-dibróm-/7-[[4-(3,4-dihydro-2(1 /7)-oxochinazolín-3-yl)-1 piperidinyl]-karbonyl]-D-fenylalanyl]-4-[4-(dimetylamino)-1 -piperidinylj-piperidín, (AA) 1 -(/^-((4-(1,3-dihydro-4-fenyl-2(2H)-oxoimidazol-1 -yl)-1 -pi perid inyl]-ka rbonyl]Af-metyl-D-tryptyl]-4-(4-metyl-1 -piperazinyl)-piperid ín, (AB) 1-[A/2-[[4-(1,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1-yl)-1-piperidinyl]-karbonyl]ΛΓ-(1,1 -dimetyletoxykarbonyl)-D-tryptyl]-4-(1 -metyl-4-piperidinyl)-piperidín, (AC) (f?,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxochinazolín-3-yl)-1-piperidinyl]-2-[(3,5dÍbróm-4-metylfenyl)metyl]-1,4-dioxobutyl]-4-(4-metyl-1-piperazinyl)-piperidín, (AD) (R,S)-1-(4-(4-(3,4-dihydro-2(1/7)-oxochinazolín-3-yl)-1-piperidinyl]-2-[(3,5dibróm-4-metoxyfenyl)metyl]-1,4-dioxobutyl]-4-(1-metyl-4-piperidinyl)-piperidín, (AE) (R,S)-1 -(4-(4-(3,4-dihydro-2(1 H)-oxochinazolín-3-yl)-1 -piperidinyl]-2-[(3,4dibrómfenyl)metyl]-1,4-dioxobutyl]-4-(4-metyl-1-piperazinyl)-piperidín, (AF) 1 -(/^-(/7-((4-(1,3-dihydro-2(2/7)-oxobenzimidazol-1 -yl)-1 -pi perid i nyl]-karbonyl]-(Q) 1- [4-amino-3,5-dibromo- N - [[4 - [N - (aminocarbonyl) - N -phenylamino] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (R) 1- [4-amino-3,5-dibromo- N - [[4- (3,4-dihydro-2 (1 H)) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (5-methoxy-4-pyrimidinyl) -piperazine, (S) 1- [4-amino-3,5-dibromo] - N - [[4- (1,1-dioxido-3 (4H) -oxo-1,2,4-benzothiadiazin-2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) (P) 1- [4-Amino-3,5-dibromo-N - [[4- [2 (1/7) -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 (1/7)] - oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (3- (dimethylamino) propyl] -piperazine, (V) 1- [4-amino-3,5-dibromo] -N - [[4- (3 ) 4-dihydro-2 (1H) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-methyl-1-piperazinyl) -piperidine, (W) 1- [4-amino-3,5-dibromo- N - [[4- (3,4-dihydro-2 (1/7) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl ] - D -phenylalanyl] -4 - [(1-methyl-4-piperidinyl) carbonyl] -piperazine, (X) 1- [4-amino-3,5-dibromo-N - [[4- [3, 4-Dihydro-2 (1H) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 - ((1-methyl-4-piperazinyl) carbonyl] -piperazine, (Y) 1- [ 4-amino-3,5-dibromo / V - ([4- (3,4-dihydro-2 (1H) -oxochinazolín-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [ 4- [4- (dimethylamino) butyl] phenyl] -piperazine, (Z) 1- [4-amino-3,5-dibromo-7 - [[4- (3,4-dihydro-2 (1/7) 1-Oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [4- (dimethylamino) -1-piperidinyl] -piperidine, (AA) 1- (N - ((4- (dimethylamino) -1-piperidinyl) -1-piperidinyl) piperidine) 1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] N -methyl-D-tryptyl] -4- (4-methyl-1- piperazinyl) -piperidine, (AB) 1- [N - 2 - [[4- (1,3-dihydro-4-phenyl-2 (2/7) -oxoimidazol-1-yl) -1-piperidinyl] - carbonyl] N- (1,1-dimethylethoxycarbonyl) -D-tryptyl] -4- (1-methyl-4-piperidinyl) -piperidine, (AC) (R, S) -1- [4- [4- ( 3,4-dihydro-2 (1H) -oxochinazolín-3-yl) -1-piperidinyl] -2 - [(3,5-dibromo-4-methylphenyl) methyl] -1,4-dioxobutyl] -4 - (4-Methyl-1-piperazinyl) -piperidine, (AD) (R, S) -1- (4- (4- (3,4-dihydro-2 (1/7) -oxoquinazolin-3-yl)) -1-piperidinyl] -2 - [(3,5-dibromo-4-methoxyphenyl) methyl] -1,4-dioxobutyl] -4- (1-methyl-4-piperidinyl) -piperidine, (AE) (R, S) -1- (4- (4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl) -2 - [(3,4-dibromophenyl) methyl] -1,4-dioxobutyl -4- (4-Methyl-1-piperazinyl) -piperidine, (AF) 1- (N - (R) - ((4- (1,3-dihydro-2 (2/7)) -oxobenzimidazole-1)) -yl) -1-piperidinyl] -carbonyl] -
3,5-dibróm-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (AG) 1-[4-amino-3,5-dibróm-/7-[[4-(1,3-dihydro-6-hydroxy-2(2/7)-oxobenzimidazol1 -yl)-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, (AH) 1 -[/72-[4-amino-3,5-dibróm-/7-[[4-(1,3-dihydro-2(2/7)-oxobenzimidazol-1 -yl )-1 piperidinyl]-karbonyl]-D-fenylalanyl]-/\/6,/\/6-dimetyl-L-lyzyl]-4-(4-pyridinyl)-piperazín, (Al) 1-[/72-[4-amino-3,5-dibróm-/7-[[4-(3,4-dihydro-2(1H)-oxochinazolín-3-yl)-1piperidinyl]-karbonyl]-D-fenylalanyl]-/76,/\/6-dimetyl-L-lyzyl]-4-(4-pyridinyl)-piperazín,3,5-dibromo-D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (AG) 1- [4-amino-3,5-dibromo-7 - [[4- ( 1,3-dihydro-6-hydroxy-2 (2H) -oxobenzimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (AH) 1- [1-7 2- [4-amino-3,5-dibromo-] - [[4- (1,3-dihydro-2 (2/7) -oxobenzimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] - N, 6 ' , 6 -dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, (Al) 1- [ 2- (4-amino-3) -, dibromo-5/7 - [[4- (3,4-dihydro-2 (1H) -oxochinazolín-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] - / 7 6 / \ / 6 - dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine,
-5(AJ) (R,S)-1 -[2-(4-amino-3,5-dibrómbenzoyl)-4-[4-(3,4-dihydro-2(1 H)-oxochinazolín-3-yl)-1 -piperidinyl]-4-oxobutyl]-4-(1 -piperidinyl)-piperidín, (AK) 1-[4-amino-3,5-dibróm-/V-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzotiadiazín-3yl)-1-piperidinyl]karbonyl]-D-fenylalanyl]-4-(1-piperidinyl)-piperidín, (AL) 1 -[4-amino-3,5-dibróm-/\/-[[4-[1,3-dihydro-2(2/-/)-oxoimidazo[4,5-c]-chinolín-3yl]-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)karbonyl]-piperidín, (AM) 1-[4-amino-3,5-dibróm-A/-[[4-[3,4-dihydro-2(1H)-oxochinazolín-3-yl)-1piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, (AN) 1-[A/2-[3,5-dibróm-/\/-[[4-(3,4-dihydro-2(1/-/)-oxochinazolín-3-yl)-1-piperidinyl]karbonyl]-D-tyrozyl]-/\/6,/\/6-dimetyl-L-lyzyl]-4-(4rpyridinyl]-piperazín, (AO) 1 -[4-amino-A/-[[4-[4-(3-brómfenyl)-1,3-dihydro-2(2/-/)-oxoimidazol-1 -yl]-1 piperidinyl]karbonyl]-3,5-dibróm-D-fenylalanyl]-4-(1 -metyl-4-piperidinyl)-piperidín, (AP) 1 -[4-amino-3,5-dibróm-/V-[[4-[1,3-dihydro-4-fenyl-2(2H)-oxoimidazol-1 -yl]-1 piperidinyl]karbonyl]-D-fenylalanyl]-4-(4-metyl-1-piperazinyl)-piperidín, (AQ) 1-[4-amino-3,5-dibróm-A/-[[4-[1)3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2H)oxoimidazol-1 -yl]-1 -pi perid i nyl] ka rbonyl]-D-f enylala nyl]-4-( 1 -pipe rid i nyl )-pi pe rid í n, (AR) 1 -[4-amino-3,5-dibróm-/V-[[4-[1,3-d ihyd ro-4-[3-(trif I uórmetyl )fenyl]-2(2/-/)oxoimidazol-1-yl]-1-piperidinyl]karbonyl]-D-fenylalanyl]-4-(exo-8-metyl-8-azabicyklo[3,2,1 ]okt-3-yl)-piperazín, (AS) 1 -[3,5-dibróm-/V-[[4-(1,3-dihydro-4-fenyl-2(2H)-oxoimidazol-1 -yl)-1 piperidinyl]karbonyl]-D-tyrozyl]-4-(1 -piperidinyl)-piperidín, (AT) 1 -[4-amino-3,5-dibróm-/V-[[4-[1,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2H)oxoimidazol-1 -yl]-1 -pi pe rid i nyl] ka rbonyl]-D-fenylal a nyl]-4-( 1 -etyl-4-ρ i pe rid iny I )piperazín, (AU) 1-[4-amino-3,5-dibróm-A/-[[4-[1,3-dihydro-4-fenyl-2(2A/)-oxoimidazol-1-yl]-1piperidinyl]karbonyl]-D-fenylalanyl]-4-(hexahydro-4-metyl-1 H-1,4-diazepín-1 -yl)piperidín, (AV) 1 -[3,5-dibróm-A/-[[4-(3,4-dihydro-2(1 H)-oxochinazolín-3-yl)-1 -piperid i nyl]karbonyl]-D-tyrozyl]-4-[1-(metylsulfonyl)-4-piperidinyl]-piperidín, (AW) 1-[4-amino-3,5-dibróm-A/-[[4-(1,3-dihydro-4-fenyl-2(2H)-oxoimidazol-1-yl)-1piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -metyl-4-piperidinyl)-piperidín,-5 (AJ) (R, S) -1- [2- (4-Amino-3,5-dibromobenzoyl) -4- [4- (3,4-dihydro-2 (1H) -oxoquinazoline-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-phenylalanyl] -4- (1-piperidinyl) -piperidine, (AL) 1- [4- amino-3,5-dibromo- N - [[4- [1,3-dihydro-2 (2H) -oxoimidazo [4,5-c] quinolin-3-yl] -1-piperidinyl] carbonyl (D) 1- [4-Amino-3,5-dibromo-N- [[4- [3,4-dihydro-2]] -D-phenylalanyl] -4- (1-piperidinyl) carbonyl] -piperidine (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (AN) 1- [N 2 - [3,5-dibromo] -1- / - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] - / \ / 6, / \ / 6 - dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, (AO) 1- [4-amino-N - [[4- [4- (3-bromophenyl) -1,3-dihydro-2 (2-methyl) -benzyl] -4- (R) -Oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (AP) 1- [4] amino-3,5-dibromo / V - [[ 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- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] ] -1-piperidinyl] carbonyl] -Diphenylanyl] -4- (1-piperidinyl) -piperidine, (AR) 1- [4-amino-3,5-dibromo] - N - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-Phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -piperazine, (AS) 1- [3,5-dibromo- N - [ [4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine, (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-phenylallyl] -4- (1-ethyl-4-piperidinyl) piperazine, (AU) 1- [4-amino-3,5- dibromo-A / - [[4- [1,3-dihydro-4-phenyl-2 (2A /) - 1-oxoimidazo-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-4 methyl-1H-1,4-di azepin-1-yl) piperidine, (AV) 1- [3,5-dibromo-N - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperide] Indyl] carbonyl] -D-tyrosyl] -4- [1- (methylsulfonyl) -4-piperidinyl] -piperidine, (AW) 1- [4-amino-3,5-dibromo-N - [[4- (1,3-Dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine,
-6(ΑΧ) 1 -[3,5-dibróm-A/-[[4-[1,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2/7)-oxoimidazol1 -yl]-1 -piperidinyl]karbonyl]-D-tyrozyl]-4-(hexahydro-1 /7-1 -azepinyl)-piperidín, (AY) 1 -[3,5-dibróm-/V-[[4-[3,4-dihydiO-2(1 /7)-oxochinazolín-3-yl]-1 -piperidinyl]karbonyl]-D-tyrozyl]-4-[1-metyl-4-piperidinyl]-piperidin, (AZ) 1-[4-amino-3,5-dibróm-/V-[[4-[3,4-dihydro-2(1/7)-oxochinazolín-3-yl]-1piperidinyl]karbonyl]-D-fenylalanyl]-4-(exo-8-metyl-8-azabicyklo-[3,2,1]okt-3-yl)piperazín, (BA) 1-[4-amino-3,5-dibróm-A/-[[4-(1,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1-yl)-1piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -metyl-4-piperidinyl)-piperazín, (BB) 1 -[3,5-d i bró m-A/-[[4-[1,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2/7)-oxoimidazol1 -yl]-1 -piperidinyl]karbonyl]-D-tyrozyl]-4-(1 -piperidinyl)-piperidín, (BC) 1 -[/\/6-acetyl-/V2-[3,5-dibróm-/V-[[4-(3,4-dihydiO-2(1 /7)-oxochinazolín-3-yl)-1 piperidinyl]karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (BD) 1 -[3,5-d i b róm-/V-[[4-( 1,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1 -yl)-1 piperidinyl]karbonyl]-D-tyrozyl]-4-(hexahydro-1/7-1-azepinyl)-piperidín, (BE) 1 -[4-amino-3,5-dibróm-/\/-[[4-(1,3-dihydro-4-(3-tienyl)-2(2/7)-oxoimidazol-1 -yl)--6 (ΑΧ) 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-1 H -1-azepinyl) -piperidine, (AY) 1- [3,5-dibromo- N - [[4- [3] 4-Dihydro-2 (1H) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- [1-methyl-4-piperidinyl] -piperidine, (AZ) 1- [4-amino-3,5-dibromo / V - [[4- [3,4-dihydro-2 (1/7) -oxochinazolín-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 (2 H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperazine, ( BB) 1- [3,5-dibromo] - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1- piperidinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine, (BC) 1- [N- 6- acetyl] - N 2 - [3,5-dibromo] N - [[4] - (3,4-dihydiO-2 (1 H) -oxoquinazolin-3-yl) -1 piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (BD ) 1- [3,5-dibromo- / V - [[ 4- (1,3-dihydro-4-phenyl-2 (2 H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro-1 H -1-azepinyl) 1-piperidine, (BE) 1- [4-amino-3,5-dibromo- N - [[4- (1,3-dihydro-4- (3-thienyl) -2 (2/7)) -] - oxoimidazol-1-yl) -
1-piperidinyl]karbonyl]-D-fenylalanyl]-4-(1-metyl-4-piperidinyl)-piperidín, (BF) 1 -[4-amino-3,5-dibróm-/V-[[4-[1,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2H)oxoimidazol-1-yl]-1-piperidinyl]karbonyl]-D-fenylalanyl]-4-(1-metyl-4-piperidinyl)piperidín, (BG) 1-[3,5-dibróm-A/-[[4-(3,4-dihydro-2(1 H)-oxochinazolín-3-yl)-1-piperidinyl]karbonyl]-D-tyrozyl]-4-[1-(hydroxykarbonylmetyl)-4-piperidinyl]-piperidín, (BH) 1-[4-amino-3,5-dibróm-/V-[[4-[3,4-dihydro-2(1/7)-oxochinazolín-3-yl]-1piperidinyl]karbonyl]-D-fenylalanyl]-4-(1-metylsulfonyl-4-piperidinyl)-piperidín, (BI) 1 -[3,5-d ibróm-A/-[[4-(3,4-d i hyd ro-2(1 H)-oxochinazolín-3-yl)-1 -piperid inyl]karbonyl]-D-tyrozyl]-4-(4-piperidinyl)-piperidín, (B J) 1 -[4-amino-3,5-dibróm-A/-[[4-(1,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1 -yl)-1 piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -etyl-4-piperidinyl)-piperidín, (BK) 1 -[4-amino-3,5-dibróm-/V-[[4-(1,3-dihydro-4-(3-hydroxyfenyl)-2(2/7)-oxoimidazol-1-yl)-1-piperidinyl]karbonyl]-D-fenylalanyl]-4-(1-metyl-4-piperidinyl)piperidín,1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (BF) 1- [4-amino-3,5-dibromo- N - [[4- [ 1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazo-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- (hydroxycarbonylmethyl) -4-piperidinyl] -piperidine, (BH) 1- [4-amino-3,5-dibromo- N - [[4- [3,4-dihydro- 2 (1/7) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methylsulfonyl-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 (2/7) -oxoimidazol-1-yl)] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperidine, (BK) 1- [4-amino-3,5-dibromo- N - [[4- ( 1,3-dihydro-4- (3-hydroxyphenyl) -2 (2/7) -oxoimidazo-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl yl] -4- (1-methyl-4-piperidinyl) piperidine,
-7(BL) 1 -[3,5-dibróm-/V-[[4-(3,4-dihydro-2(1 /7)-oxochinazolín-3-yl)-1 -piperid inyl]karbonyl]-D-tyrozyl]-4-(hexahydro-1 /7-1 -azepinyl)-piperidín, (BM) 1 -[4-amino-3,5-dibróm-A/-[[4-(1,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1 -yl)-1 piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, (BN) 1 -[4-amino-3,5-dibróm-/V-[[4-[4-(3-brómfenyl)-1,3-dihydro-2(2/7)-oxoimidazol1 -yl]-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(exo-8-metyl-8-azabicyklo-[3,2,1]okt-3yl)-piperazín, (BO) 1 -[4-amino-3,5-dibróm-/V-[[4-(3,4-dihydiO-2(1 /7)-oxochinazolín-3-yl)-1 piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -etyl-4-piperidinyl)-piperidín, (BP) 1 -[4-amino-3,5-dibróm-/\/-[[4-(3,4-dihydro-2(1 /7)-oxochinazolín-3-yl)-1 piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -etyl-4-piperidinyl)-piperazín, (BQ) 1-[4-amino-3,5-dibróm-/V-[[4-[1,3-dihydro-4-(3-metoxyfenyl)-2(2/7)-oxoimidazol-1-yl]-1-piperidinyl]karbonyl]-D-fenylalanyl]-4-(exo-8-metyl-8-azabicyklo- [3,2,1]okt-3-yl)-piperazín, (BR) 1 -[3,5-dibróm-/\/-[[4-(3,4-dihydro-2(1 /7)-oxochinazolín-3-yl)-1 -piperidinyl]karbonyl]-D-tyrozyl]-4-[1-(cyklopropylmetyl)-4-piperidinyl]-piperidín, (BS) 1 -[4-amino-3,5-dibróm-A/-[[4-(3,4-dihydiO-2(1 H)-oxochinazolín-3-yl)-1 piperidinyl]karbonyl]-D-fenylalanyl]-4-(hexahydro-1 H-1-azepinyl)-piperidín, (BT) 1 -[4-amino-3,5-dibróm-/V-[[4-(3,4-dihydro-2(1 /7)-oxochinazolín-3-yl)-1 piperidinyl]karbonyl]-D-fenylalanyl]-4-(4-piperidinyl)-piperidín, (BU) 1 -[3,5-dibróm-/V-[[4-(1,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1 -yl)-1 piperidinyl]karbonyl]-D-tyrozyl]-4-(4-pyridinyl)-piperidín, (BV) 1 -[3,5-d ibróm-/V-[[4-[113-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2/7)-oxoimidazol--7 (BL) 1- [3,5-dibromo- N - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] - D-tyrosyl] -4- (hexahydro-1 H -1-azepinyl) -piperidine, (BM) 1- [4-amino-3,5-dibromo-N - [[4- (1,3-dihydro) -4-phenyl-2 (2/7) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (BN) 1- [4-amino- 3,5-dibromo- N - [[4- [4- (3-bromophenyl) -1,3-dihydro-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl -4- (exo-8-methyl-8-azabicyclo- [3,2,1] oct-3-yl) -piperazine, (BO) 1- [4-amino-3,5-dibromo- N - [[ 4- (3,4-dihydiO-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperidine, (BP 1- [4-Amino-3,5-dibromo-1H - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D -phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperazine, (BQ) 1- [4-amino-3,5-dibromo- N - [[4- [1,3-dihydro-4-] (3-Methoxyphenyl) -2 (2/7) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3.2.1.0 < 2,7 > 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- (cyclopropylmethyl) -4-piperidinyl] -piperidine, (BS) 1- [4-amino-3,5-dibromo-N - [[4- (3,4-dihydiO-2 (1H) -oxoquinazoline)] -3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1H-1-azepinyl) -piperidine, (BT) 1- [4-amino-3,5-dibromo] -N - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-piperidinyl) -piperidine, (BU) 1- [3,5-dibromo- N - [[4- (1,3-dihydro-4-phenyl-2 (2/7) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl ] -4- (4-pyridinyl) -piperidine, (BV) 1 - [3,5-ibróm- / V - [[4- [1 1 3-dihydro-4- [3- (trifluoromethyl) phenyl] - 2 (2/7) -oxoimidazol-
1-yl]-1-piperidinyl]karbonyl]-D-tyrozyl]-4-(1-metyl-4-piperidinyl)-piperazín, (BW) 1 -[N2-[3,5-dibróm-A/-[[4-[1,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2/7)-oxoimidazol-1-yl]-1 -piperidinyl]karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (BX) 1-[3,5-dibróm-/V-[[4-(1,3-dihyd:ro-4-(3-tienyl)-2(2/7)-oxoimidazol-1-yl)-1piperidinyl]karbonyl]-D-tyrozyl]-4-(1 -piperidinyl)-piperidín, (BY) 1-[4-amino-/V-[[4-[4-(3-chlórfenyl)-1,3-dihydro-2(2/7)-oxoimidazol-1-yl]-1piperidinyl]karbonyl]-3,5-dibróm-D-fenylalanyl]-4-(1-metyl-4-piperidinyl)-piperidín,1-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-methyl-4-piperidinyl) -piperazine, (BW) 1- [N 2 - [3,5-dibromo-N-] - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -L- lysyl] -4- (4-pyridinyl) -piperazine, (BX) 1- [3,5-dibromo- N - [[4- (1,3-dihydroxy-4- (3-thienyl) -2] -) (2/7) -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 (2/7) -oxoimidazo-1-yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (1- methyl-4-piperidinyl) piperidine,
-8(ΒΖ) 1 -[4-a m i ηο-3,5-d i bróm-/\/-[[4-[ 1,3-d i hyd ro-4-[3-(trif I uórmetyl )fe nyl]-2(2/7)oxoimidazol-1 -yl]-1 -piperid inyl] karbonyl]-D-fenylala nyl]-4-(hexa hyd ro-1 /7-1 -azepinyl)piperidín, (CA) 1 -[4-amino-3,5-dibróm-/V-[[4-[1,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2/7)oxoimidazol-1 -yl]-1 -pi pe rid inyl] ka rbonyl]-D-f enylalanyl]-4-( 1 -metyl-4-pi pe rid i nyl )piperazín, (CB) 1 -[4-amino-A/-[[4-[4-(3-chlórfenyl)-1,3-dihydro-2(2/7)-oxoimidazol-1 -yl]-1 piperidinyl]karbonyl]-3,5-dibróm-D-fenylalanyl]-4-(hexahydro-1/7-1-azepinyl)piperidín, (CC) 1-[4-amino-3,5-dibróm-/V-[[4-(1,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1-yl)-1piperidinyl]karbonyl]-D-fenylalanyl]-4-(4-pyridinyl)-piperazín, (CD) 1 -[3,5-dibróm-A/-[[4-(1,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1 -yl)-1 piperidinyl]karbonyl]-D-tyrozyl]-4-(1 -metyl-4-piperidinyl)-piperidín, (CE) 1 -[4-amino-3,5-dibróm-/V-[[4-[1,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1 -yl]-1 piperidinyl]karbonyl]-D-fenylalanyl]-4-[4-(1-oxoetyl)fenyl]-piperazín, (CF) 1 -[3,5-dibróm-/V-[[4-[3,4-dihydiO-2(1 /7)-oxochinazolín-3-yl]-1 -pi perid i nyl]karbonyl]-D-tyrozyl]-4-(1-metyl-4-piperidinyl)-piperazín, (CG) 1 -[4-amino-3,5-dibróm-/V-[[4-[1,3-dihydro-4-(3-nitrofenyl)-2(2/7)-oxoimidazol1 -yl]-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -metyl-4-piperidinyl)-piperidín, (CH) 1-[4-amino-3,5-dibróm-W-[[4-[3,4-dihydro-2(1/7)-oxochinazolín-1-yl]-3piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -pyrolidinyl)-piperidín, (Cl) 1-[4-amino-3,5-dibróm-/V-[[4-(1,3-dihydro-4-fenyl-2(2/7)-oxoirnidazol-1-yl)-1piperidinyl]karbonyl]-D-fenylalanyl]-4-(hexahydro-1 /7-1 -azepinyl)-piperidín a (CJ) 1-[4-amino-3)5-dibróm-A/-[[4-(1,3-dihydro-4-(3-tienyl)-2(2/7)-oxoimidazol-1-yl)1-piperidinyl]karbonyl]-D-fenylalanyl]-4-(1-metyl-4-piperidinyl)-piperazín, ich tautoméry, ich diastereoméry, ich enantioméry, ich zmesi a ich fyziologicky prijateľné soli, pričom zlúčeniny:-8 (ΒΖ) 1- [4-Amino-3,5-di-bromo-N - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl]] -2 (2/7) oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylanyl] -4- (hexahydro-1H-azepinyl) piperidine, (CA) 1- [4-amino-3,5-dibromo- N - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2/7) oxoimidazol-1-yl] -1 -piperidinyl] carbonyl] -Diphenylalanyl] -4- (1-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-1) (7-1-azepinyl) piperidine, (CC) 1- [4-amino-3,5-dibromo- N - [[4- (1,3-dihydro-4-phenyl-2 (2/7)) - 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 (2/7) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-methyl-4-piperidinyl) -piperidine, (CE) 1 - [4-amino-3,5-dibromo- N - [[4- [1,3-dihydro-4-phenyl-2 (2/7) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] - D-phenylalanyl] -4- [4- (1-oxoethyl (l) phenyl] -piperazine, (CF) 1- [3,5-dibromo- N - [[4- [3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl] -1-β] peridinyl] carbonyl] -D-tyrosyl] -4- (1-methyl-4-piperidinyl) -piperazine, (CG) 1- [4-amino-3,5-dibromo- N - [[4- [ 1,3-dihydro-4- (3-nitrophenyl) -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) - piperidine, (CH) 1- [4-amino-3,5-dibromo-N - [[4- [3,4-dihydro-2 (1/7) -oxoquinazolin-1-yl] -3-piperidinyl] carbonyl] - D-Phenylalanyl] -4- (1-pyrrolidinyl) -piperidine, (C1) 1- [4-amino-3,5-dibromo-N- [[4- (1,3-dihydro-4-phenyl-2)]] (2/7) -oxinimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1 H -azepinyl) -piperidine and (CJ) 1- [4-amino-3] ) 5-dibromo-A / - [[4- (1,3-dihydro-4- (3-thienyl) -2 (2/7) -oxoimidazo-1-yl) 1-piperidinyl] carbonyl] -D-phenylalanyl -4- (1-methyl-4-piperidinyl) -piperazine, their tautomers, their diastereomers, their enantiomers, their mixtures and their physiologically acceptable salts, wherein the compounds:
(A) 1-[A/2-[3,5-dibróm-/V-[[4-(3,4-dihydro-2(1/7)-oxochinazolin-3-yl)-1-piperidinyl]karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (B) 1 -[4-amino-3,5-dibróm-A/-[[4-(2,3,4,5-tetrahydro-2(1 Z7)-oxo-1,3benzodiazepín-3-yl)-1-piperidinyl]karbonyl]-D-fenylalanyl]-4-(1-piperidinyl)-piperidín, (I) 1 -[4-amino-3,5-dibróm-A/-[[4-(2,4-dihydro-5-fenyl-3(3ŕ7)-oxo-1,2,4-triazol-2yl)-1-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1-piperidinyl)-piperidín, (J) 144-amino-3,5-dibróm-/V-[[4-(2,4-dihydro-5-fenyl-3(3/-/)-oxo-1,2,4-triazol-2yl)-1-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1-metyl-4-piperidinyl)-piperažín, (AC) (/?,S)-1 -[4-[4-(3,4-dihydro-2(1 H)-oxochinazolin-3-yl)-1 -piperidinyl]-2-[(3,5dibróm-4-metylfenyl)metyl]-1,4-dioxobutyl]-4-(4-metyl-1-piperazinyl)-piperidín, (AF) 1 -[A/2-[/V-[[4-( 1,3-dihydro-2(2ŕ/)-oxobenzimidazol-1 -yl)-1 -pi perid i n yl]-karbonyl]-(S) -1- [A / 2 - [3,5-dibromo / V - [[4- (3,4-dihydro-2 (1/7) -oxochinazolin-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 (11,7) -oxo-1,3benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (I) 1- [4-amino-3,5-dibromo-A / - [[4- (2,4-dihydro-5-phenyl-3 (3R7) -oxo-1,2,4-triazol-2-yl) -1-piperidinyl (J) 144-Amino-3,5-dibromo- N - [[4- (2,4-dihydro-5-phenyl) -carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine -3 (3H) -oxo-1,2,4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperazine, ( AC) (R, S) -1- [4- [4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] -2 - [(3,5-dibromo- 4-Methylphenyl) methyl] -1,4-dioxobutyl] -4- (4-methyl-1-piperazinyl) -piperidine, (AF) 1- [N / 2 - [N - [[4- (1,3) -dihydro-2 (2H-oxobenzimidazol-1-yl) -1-piperidinyl] carbonyl] -
3,5-dibróm-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín a (AM) 1-[4-amino-3,5-dibróm-/V-[[4-[3,4-dihydro-2(1/-/)-oxochinazolín-3-yl)-1piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, ich tautoméry, ich diastereoméry, ich enantioméry, ich zmesi a ich fyziologicky prijateľné soli sú výhodné, pričom však zlúčeniny: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, their tautomers, their diastereomers, their enantiomers, mixtures thereof and physiologically acceptable salts thereof are preferred, but the compounds:
(A) 1 - [/^-[3,5-d i b róm-/V-[[4-(3,4-d i hyd ro-2( 1 /-/)-oxochinazolín-3-yl)-1 - pi perid inyl]karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, a (B) 1-[4-amino-3,5-dibróm-A/-[[4-(2,3,4,5-tetrahydro-2(1/-/)-oxo-1,3-benzodiazepín-3-yl)-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -piperidinylj-piperidín, ich tautoméry, ich diastereoméry, ich enantioméry, ich zmesi a ich fyziologicky prijateľné soli sú zvlášť výhodné.(A) 1- [N - [3,5-Dibromo- N - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1] - piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, and (B) 1- [4-amino-3,5-dibromo-N - [[4] - (2,3,4,5-tetrahydro-2 (1H) -oxo-1,3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1- piperidinyl-piperidine, their tautomers, their diastereomers, their enantiomers, mixtures thereof and their physiologically acceptable salts are particularly preferred.
Dávkovanie, potrebné na dosiahnutie zodpovedajúceho účinku, je pri intravenóznom alebo podkožnom podaní účelne 0,0001 až 3 mg/kg telesnej hmotnosti, výhodne 0,01 až 1 mg/kg telesnej hmotnosti, a pri orálnom, nazálnom alebo inhalačnom podaní 0,01 až 10 mg/kg telesnej hmotnosti, výhodne 0,1 až 10 mg/kg telesnej hmotnosti, vždy 1 až 3 x denne.The dosage required to achieve a corresponding effect is suitably 0.0001 to 3 mg / kg body weight, preferably 0.01 to 1 mg / kg body weight, for intravenous or subcutaneous administration, and 0.01 to 1 mg / kg body weight for oral, nasal or inhalation administration. 10 mg / kg body weight, preferably 0.1 to 10 mg / kg body weight, 1 to 3 times daily.
Pokiaľ sa liečenie CGRP-antagonistami a/alebo inhibítormi uvoľňovania CGRP uskutočňuje ako doplnenie bežnej hormonálnej substitúcie, odporúča sa znížiť predtým uvedené dávky, pričom takáto dávka potom môže byť 1/5 predtým uvedených spodných hraníc až 1/1 predtým uvedených horných hraníc.When treatment with CGRP antagonists and / or CGRP release inhibitors is performed in addition to conventional hormone replacement, it is recommended that the above-mentioned doses be reduced, and such a dose may then be 1/5 of the aforementioned lower bounds to 1/1 of the aforementioned upper bounds.
Na tento účel sa môžu CGRP-antagonisty a/alebo inhibítory uvoľňovaniaFor this purpose, CGRP antagonists and / or release inhibitors may be used
CGRP zapracovať spolu s jednou alebo viacerými inertnými, bežnými nosnými látkami a/alebo riedidlami, napríklad s kukuričným škrobom, mliečnym cukrom, trstinovým cukrom, mikrokryštalickou celulózou, stearanom horečnatým, polyvinylpyrolidónom, kyselinou citrónovou, kyselinou vínnou, vodou, vodou/etanolom,CGRP can be incorporated with one or more inert, conventional carriers and / or diluents, for example, corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol
-10vodou/glycerínom, vodou/sorbitom, vodou/polyetylénglykolom, propylénglykolom, cetylstearylalkoholom, karboxymetylcelulózou alebo látkami s obsahom tuku, ako je stužený tuk alebo jeho vhodné zmesi, do bežných galenických prípravkov, ako sú tablety, dražé, kapsuly, prášky, suspenzie, roztoky, dávkovacie aerosóly alebo čapíky.-Water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fat-containing substances, such as hardened fat or suitable mixtures thereof, into conventional galenic preparations such as tablets, dragees, capsules, powders, suspensions solutions, dispensing aerosols or suppositories.
Na potláčanie menopauzálnych návalov horúčavy sú zvlášť vhodné lieky, obsahujúce jednu z účinných látok:Medicines containing one of the active substances are particularly suitable for controlling menopausal hot flashes:
(A) 1 -[N2-[3,5-dibróm-/\/-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolín-3-yl)-1 -piperidinyl]karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (B) 1 -[4-amino-3,5-dibróm-/V-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1,3-benzodiazepín-3-yl)-1-piperidinyl]karbonyl]-D-fenylalanyl]-4-(1-piperidinyl)-piperidín, (I) 1-[4-amino-3,5-dibróm-/\/-[[4-(2,4-dihydro-5-fenyl-3(3/-/)-oxo-1,2,4-triazol-2yl)-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, (J) 1-[4-amino-3,5-dibróm-/\/-[[4-(2,4-dihydro-5-fenyl-3(3H)-oxo-1,2,4-triazol-2yl)-1-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1-metyl-4-piperidinyl)-piperazín, (AC) (R, S)-1 -[4-[4-(3,4-d i hyd ro-2( 1 /7)-oxochinazolín-3-yl)-1 -pi perid i nyl]-2-[(3,5dibróm-4-metylfenyl)metyl]-1,4-dioxobutyl]-4-(4-metyl-1-piperazinyl)-piperidín, (AF) 1 -[A/2-[/V-[[4-( 1,3-dihydro-2(2H)-oxobenzimidazol-1 -yl)-1 -piperid i nyl]-ka rbonyl]-(A) 1- [N 2 - [3,5-dibromo- N - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl]] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (B) 1- [4-amino-3,5-dibromo- N - [[4- (2,3) 4,5-tetrahydro-2 (1H) -oxo-1,3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (I 1- [4-Amino-3,5-dibromo] -N - [[4- (2,4-dihydro-5-phenyl-3 (1H) -oxo-1,2,4-triazole)] (2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine; (J) 1- [4-amino-3,5-dibromo-1H-[[4 - (2,4-dihydro-5-phenyl-3 (3H) -oxo-1,2,4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl- 4-piperidinyl) -piperazine, (AC) (R, S) -1- [4- [4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-pi peridinyl] -2 - [(3,5-dibromo-4-methylphenyl) methyl] -1,4-dioxobutyl] -4- (4-methyl-1-piperazinyl) -piperidine, (AF) 1- [A / 2] - [N - [[4- (1,3-dihydro-2 (2H) -oxobenzimidazol-1-yl) -1-piperidinyl] carbonyl] -
3,5-dibróm-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, a (AM) 1-[4-amino-3,5-dibróm-/V-[[4-[3,4-dihydro-2(1H)-oxochinazolín-3-yl)-1piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, v niektorej z nasledujúcich farmaceutických foriem na podávanie: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, in any of the following pharmaceutical forms for administration:
- kapsuly na inhalovanie prášku s 1 mg účinnej látky, výhodne látky (A) alebo (B),- powder inhalation capsules with 1 mg of active substance, preferably of substance (A) or (B),
- inhalačný roztok pre zhmľovače s 1 mg účinnej látky, výhodne látky (A) alebo (B),- inhaler solution for nebulizers with 1 mg of active substance, preferably of substance (A) or (B),
- aerosól na dávkovanie pomocou hnacieho plynu s 1 mg účinnej látky, výhodne látky (A) alebo (B),- a propellant-dispensing aerosol with 1 mg of active substance, preferably of substance (A) or (B),
- nosový sprej s 1 mg účinnej látky, výhodne látky (A) alebo (B),- nasal spray with 1 mg of active substance, preferably of substance (A) or (B),
- tablety s 20 mg účinnej látky, výhodne látky (B),- tablets containing 20 mg of the active substance, preferably substance (B),
- kapsuly s 20 mg účinnej látky, výhodne látky (B),- capsules containing 20 mg of the active substance, preferably substance (B),
- vodný roztok na nazálnu aplikáciu s 10 mg účinnej látky, výhodne látky (A) alebo (B),- an aqueous solution for nasal administration with 10 mg of active substance, preferably of substance (A) or (B),
- vodný roztok na nazálnu aplikáciu s 5 mg účinnej látky, výhodne látky (A) alebo (B), aleboan aqueous solution for nasal administration with 5 mg of the active ingredient, preferably of (A) or (B), or
- suspenzia na nazálnu aplikáciu s 20 mg účinnej látky, výhodne látky (A) alebo (B).a suspension for nasal administration with 20 mg of the active ingredient, preferably of (A) or (B).
CGRP uvoľňujú zmyslové nervy, napríklad Nervus Trigeminus (trojklaný nerv), ktorý inervuje časť kože tváre. Už sa ukázalo, že dráždenie trigeminálneho ganglionu u ľudí vedie k zvýšeniu hladiny CGRP v plazme a vyvoláva sčervenanie tváre ([4j: P. J. Goadsby a ďalší, Annals of Neuroloqy 23(2), 193-196, 1988).CGRP releases sensory nerves, such as the Nervus Trigeminus (trigeminal nerve) that innervates part of the skin of the face. Irritation of the trigeminal ganglion in humans has already been shown to increase plasma CGRP levels and induce facial flushing ([4j: P.J. Goadsby et al., Annals of Neuroloqy 23 (2), 193-196, 1988).
Na dôkaz, že pomocou CGRP-antagonistov a inhibitorov uvoľňovania CGRP sa návaly horúčavy dajú úspešne liečiť, sa u kozmáčov navodilo zvýšené uvoľňovanie endogénneho CGRP stimuláciou trigeminálneho ganglionu, čo viedlo k zvýšenému prekrveniu kožných ciev. Účinnosť nasledujúcich testovaných účinných látok sa charakterizovala určením tej intravenózne aplikovanej dávky, ktorá zníži zvýšené prekrvenie kože tváre, vyvolané endogénnym CGRP, o 50 %:To demonstrate that hot flushes can be successfully treated with CGRP-antagonists and CGRP-release inhibitors, increased release of endogenous CGRP by stimulating the trigeminal ganglion was induced in the cosmos, resulting in increased blood vessels in the skin. The efficacy of the following active ingredients tested was characterized by the determination of that intravenous dose which reduces the increased perfusion of the facial skin induced by endogenous CGRP by 50%:
(A) 1 -[/V2-[3,5-dibróm-/V-[[4-(3,4-dihydro-2(1 /-/)-oxochinazolín-3-yl)-1 -piperid inyljkarbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (B) 1 -[4-amino-3,5-dibróm-/V-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1,3-benzodiazepín-3-yl)-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, (AC) (R, S)-1 -[4-[4-(3,4-d i hyd ro-2 (1 /-/)-oxochinazolín-3-yl)-1 -piperid i nyl]-2-[(3,5dibróm-4-metylfenyl)metyl]-1,4-dioxobutyl]-4-(4-metyl-1-piperazinyl)-piperidín, (AM) 1 -[4-amino-3,5-dibróm-/V-[[4-[3,4-dihydro-2(1 /7)-oxochinazolín-3-yl)-1 piperidinyl]karbonyl]-D-fenylalanyl]-4-(1 -piperidinyl)-piperidín, (DA) = sumatriptan, a (DB) = zolmitriptan.(A) 1- [N 2 - [3,5-dibromo- N - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] [D] -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-phenylalanyl] -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-dioxobutyl] -4- (4-methyl-1-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.
Opis metódyDescription of the method
Kozmáče oboch pohlaví (300 až 400 g) sa narkotizujú pentobarbitalom (na začiatku 30 mg/kg, i.p. (intraperitoneálne), infúzia 6 mg/kg/h, i.m. (intramuskuláme)). Telesná teplota sa udržiava pri 37 °C vyhrievacou platňou. Ako relaxancium sa podáva pankurmium (na začiatku 1 mg/kg, 0,5 mg po každej ďalšej hodine).Both sexes (300-400 g) are anesthetized with pentobarbital (initially 30 mg / kg, i.p. (intraperitoneally), infusion 6 mg / kg / h, i.m. (intramuscular)). Body temperature is maintained at 37 ° C by heating plate. Pancurmium is administered as a relaxant (initially 1 mg / kg, 0.5 mg after each additional hour).
Hlava zvierat sa fixuje v stereotaktickom prístroji. Po otvorení kože hlavy pozdĺžnymThe animal head is fixed in a stereotactic apparatus. After opening the skin of the head longitudinal
-12rezom sa do lebky vyvŕta malá dierka a do trigeminálneho ganglionu sa zapustí bipolárna elektróda (Rhodes SNES 100).A small hole is drilled into the skull and a bipolar electrode (Rhodes SNES 100) is embedded in the trigeminal ganglion.
Nájdenie ganglionu sa uľahčí róntgenovou snímkou, ktorá zviditeľní kostenú štruktúru lebky. Ako orientácia na umiestnenie elektródy (róntgenový prístroj CCXDigital) slúži skalná kosť. Poloha elektródy v ganglione sa na konci každého experimentu kontroluje. Stimulačné parametre sú: 10 Hz, 2 mA, 2 ms, 30 s dlho.Finding the ganglion is facilitated by X-ray imaging, which makes the bone structure of the skull visible. The rock bone serves as the orientation of the electrode (CCXDigital X-ray machine). The position of the electrode in the ganglion is checked at the end of each experiment. Pacing parameters are: 10 Hz, 2 mA, 2 ms, 30 s long.
Prietok krvi v mikrocievach kože tváre sa sníma prostredníctvom laserDopplerovho merania prietoku pomocou zariadenia PeriFlux Laser Doppler Systém.Blood flow in the microvessels of the facial skin is sensed by laser-Doppler flow measurement using the PeriFlux Laser Doppler System.
Zvieratá sa vystavia 2 až 3 stimulačným periódam v odstupe vždy 30 minút. Prvá stimulácia pritom slúži ako referenčná hodnota pre ďalšie stimulácie. Testované látky sa aplikujú intravenózne 5 minút pred 2., resp. 3. stimulačnou periódou.Animals are exposed to 2 to 3 stimulation periods at 30 minute intervals. The first stimulation serves as a reference for further stimulations. Test substances are administered intravenously 5 minutes before the 2 nd and 2 rd, respectively. 3. pacing period.
Tabuľka 1Table 1
50%-dávka = intravenózna dávka, ktorá zníži endogénnym CGRP vyvolané zvýšené prekrvenie kože tváre o 50 %50% -dose = intravenous dose to reduce endogenous CGRP-induced increased perfusion of the facial skin by 50%
Nasledujúce príklady opisujú formy na farmaceutické použitie, ktoré obsahujú ako účinnú látku CGRP-antagonistu alebo inhibitor uvoľňovania CGRP na použitie podľa tohto vynálezu, výhodne jeden z derivátov aminokyseliny, opísaných vo WO 98/11128 alebo v DE 199 11 039, napríklad jednu z predtým uvedených účinných látok (A) alebo (B):The following examples describe forms for pharmaceutical use which contain as active ingredient a CGRP antagonist or inhibitor of CGRP release for use according to the invention, preferably one of the amino acid derivatives disclosed in WO 98/11128 or in DE 199 11 039, for example one of the foregoing. of the active substances (A) or (B):
- 13Príklady uskutočnenia vynálezuExamples of embodiments of the invention
Príklad 1Example 1
Kapsuly na inhaláciu prášku s 1 mg účinnej látky (A) alebo (B)Powder inhalation capsules with 1 mg of active substance (A) or (B)
Zloženie:Ingredients:
kapsula na inhaláciu prášku obsahuje: účinná látka (A) alebo (B) mliečny cukor kapsuly z tvrdej želatínypowder inhalation capsule contains: active ingredient (A) or (B) milk sugar hard gelatin capsules
1.0 mg 20,0 mg 50,0 mg 71.0 mg1.0 mg 20.0 mg 50.0 mg 71.0 mg
Spôsob výrobyMethod of production
Účinná látka sa zomelie na veľkosť častíc, potrebnú pre inhalované látky. Zomletá účinná látka sa homogénne zmieša s mliečnym cukrom. Zmes sa naplní do kapsúl z tvrdej želatíny.The active substance is ground to the particle size required for inhaled substances. The milled active ingredient is homogeneously mixed with milk sugar. The mixture is filled into hard gelatin capsules.
Príklad 2Example 2
Inhalačný roztok pre Respimat® s 1 mg účinnej látky (A) alebo (B)Respimat® inhalation solution with 1 mg of active substance (A) or (B)
Zloženie:Ingredients:
dávka obsahuje:dose contains:
Spôsob výrobyMethod of production
Účinná látka a benzalkóniumchlorid sa rozpustia vo vode a naplnia sa doThe active substance and benzalkonium chloride are dissolved in water and filled into water
Respimat® kartuší.Respimat® cartridge.
-14Príklad 3-14Example 3
Inhalačný roztok pre zhmľovače s 1 mg účinnej látky (A) alebo (B)Inhaler solution for nebulizers with 1 mg of active substance (A) or (B)
Zloženie:Ingredients:
fľaštička obsahuje:bottle contains:
účinná látka (A) alebo (B)active substance (A) or (B)
1,0 g chlorid sodný1.0 g sodium chloride
0,18 g benzalkóniumchlorid0.18 g benzalkonium chloride
0,002 g čistená voda ad 20,0 ml0.002 g purified water ad 20.0 ml
Spôsob výrobyMethod of production
Účinná látka, chlorid sodný a benzalkóniumchlorid sa rozpustia vo vode.The active substance, sodium chloride and benzalkonium chloride are dissolved in water.
Príklad 4Example 4
Aerosól na dávkovanie pomocou hnacieho plynu s 1 mg účinnej látky (A) alebo (B)Aerosol for propellant dosing with 1 mg of active substance (A) or (B)
Zloženie:Ingredients:
dávka obsahuje:dose contains:
účinná látka (A) alebo (B)active substance (A) or (B)
1,0 mg lecitín1.0 mg lecithin
0,1 % hnací plyn ad 50,0 μΙ0.1% propellant ad 50.0 μΙ
Spôsob výrobyMethod of production
Mikronizovaná účinná látka sa homogénne suspenduje v zmesi lecitínu a hnacieho plynu. Suspenzia sa naplní do tlakovej nádobky s dávkovacím ventilom.The micronized active substance is homogeneously suspended in a mixture of lecithin and propellant. The suspension is filled into a pressure vessel with a metering valve.
Príklad 5Example 5
Nosový sprej s 1 mg účinnej látky (A) alebo (B)Nasal spray with 1 mg of active substance (A) or (B)
Zloženie:Ingredients:
rozprašovaná dávka obsahuje:the sprayed dose contains:
účinná látka (A) alebo (B)active substance (A) or (B)
1,0 mg1.0 mg
-15manitol-15manitol
5,0 mg dinátriumetyléndiamíntetraacetát 0,05 mg kyselina askorbová5.0 mg disodium ethylenediaminetetraacetate 0.05 mg ascorbic acid
1,0 mg čistená voda ad 0,1 ml1.0 mg purified water ad 0.1 ml
Spôsob výrobyMethod of production
Účinná látka a pomocné látky sa rozpustia vo vode a naplnia sa do zodpovedajúcej nádobky.The active substance and excipients are dissolved in water and filled into a corresponding container.
Príklad 6Example 6
Injekčný roztok s 5 mg účinnej látky (A) alebo (B) na 5 mlSolution for injection with 5 mg of active substance (A) or (B) per 5 ml
Zloženie:Ingredients:
účinná látka (A) alebo (B) v bázickej forme 5 mg kyselina/látka, vytvárajúca soľ, v množstve, potrebnom na vytvorenie neutrálnej soli q. s.active ingredient (A) or (B) in base form 5 mg of acid / salt-forming agent in an amount necessary to form the neutral salt q. with.
VýrobaProduction
Rozpustiť glykofurol a glukózu vo vode na injekčné účely (Wfi); pridať albumín ľudského séra; pridať látku, vytvárajúcu soľ; rozpustiť účinnú látku pri zahrievaní; s Wfi naplniť na stanovený objem; pod prúdom dusíka naplniť do ampúl.Dissolve glycofurol and glucose in water for injection (Wfi); add human serum albumin; add a salt-forming agent; dissolve the active ingredient upon heating; with Wfi to fill to the specified volume; Fill into ampoules under a stream of nitrogen.
Príklad 7Example 7
Injekčný roztok na podkožnú aplikáciu s 5 mg účinnej látky (A) alebo (B) na 1 mlSolution for injection subcutaneously with 5 mg of active substance (A) or (B) per ml
Zloženie:Ingredients:
účinná látka (A) alebo (B) v bázickej forme glukóza mg mgactive ingredient (A) or (B) in base form glucose mg mg
VýrobaProduction
Rozpustiť glukózu a polysorbát vo vode na injekčné účely; rozpustiť účinnú látku pri zahrievaní, resp. pomocou ultrazvuku; s Wfi doplniť na stanovený objem; pod prúdom inertného plynu naplniť do ampúl.Dissolve glucose and polysorbate in water for injection purposes; dissolve the active substance upon heating, resp. by ultrasound; make up to volume with Wfi; Fill into ampoules under a stream of inert gas.
Príklad 8Example 8
Injekčný roztok so 100 mg účinnej látky (A) alebo (B) na 10 mlSolution for injection with 100 mg of active substance (A) or (B) per 10 ml
Zloženie:Ingredients:
VýrobaProduction
Polysorbát 80, chlorid sodný, dihydrogenfosforečnan draselný a hydrogenfosforečnan disodný rozpustiť vo vode na injekčné účely (Wfi); pridať albumín ľudského séra; rozpustiť účinnú látku pri zahrievaní; s Wfi doplniť na stanovený objem; naplniť do ampúl.Dissolve polysorbate 80, sodium chloride, potassium dihydrogen phosphate and disodium hydrogen phosphate in water for injection (Wfi); add human serum albumin; dissolve the active ingredient upon heating; make up to volume with Wfi; fill into ampoules.
Príklad 9Example 9
Lyofilizát s 10 mg účinnej látky (A) alebo (B)Lyophilisate with 10 mg of active substance (A) or (B)
Zloženie:Ingredients:
účinná látka (A) alebo (B) v bázickej forme mgactive ingredient (A) or (B) in base form mg
- 17kyselina/látka, vytvárajúca soľ, v množstve, potrebnom na vytvorenie neutrálnej soli manitol- 17acid / salt-forming agent in an amount necessary to form the neutral salt of mannitol
q. s.q. with.
300 mg voda na injekčné účely ad 2 ml300 mg water for injection ad 2 ml
VýrobaProduction
Rozpustiť manitol vo vode nä injekčné účely (Wfi); pridať látku, vytvárajúcu soľ; rozpustiť účinnú látku pri zahrievaní; s Wfi doplniť na stanovený objem; naplniťDissolve mannitol in water for injection purposes (Wfi); add a salt-forming agent; dissolve the active ingredient upon heating; make up to volume with Wfi; to fill
VýrobaProduction
Rozpustiť polysorbát 80 a manitol vo vode na injekčné účely (Wfi); naplniť do ampúl.Dissolve polysorbate 80 and mannitol in water for injection (Wfi); fill into ampoules.
Príklad 10Example 10
Lyofilizát s 5 mg účinnej látky (A) alebo (B)Lyophilisate with 5 mg of active substance (A) or (B)
Zloženie:Ingredients:
účinná látka (A) alebo (B) v bázickej forme 5 mg polárne alebo nepoláme rozpúšťadlo (ktoré sa dá odstrániť sušením vymrazovaním) ad 1 mlactive ingredient (A) or (B) in base form 5 mg polar or non-polar solvent (which can be removed by freeze-drying) ad 1 ml
VýrobaProduction
Rozpustiť účinnú látku vo vhodnom rozpúšťadle; naplniť do liekoviek; vysušiť vymrazovaním.Dissolve the active ingredient in a suitable solvent; fill into vials; freeze-dry.
- 18Rozpúšťadlo pre lyofilizát:- 18Solvent for lyophilisate:
polysorbát 80 = Tween 80 mg manitolpolysorbate 80 = Tween 80 mg mannitol
100 mg voda na injekčné účely ad 2 ml100 mg water for injection ad 2 ml
VýrobaProduction
Rozpustiť polysorbát 80 a manitol vo vode na injekčné účely (Wfi); naplniť do ampúl.Dissolve polysorbate 80 and mannitol in water for injection (Wfi); fill into ampoules.
Príklad 11Example 11
Tablety s 20 mg účinnej látky (A) alebo (B)Tablets of 20 mg of active substance (A) or (B)
Zloženie:Ingredients:
účinná látka (A) alebo (B) mg laktózaactive ingredient (A) or (B) mg lactose
120 mg kukuričný škrob mg stearan horečnatý mgMagnesium stearate
Povidon K25 mgPovidone K25 mg
VýrobaProduction
Účinnú látku, laktózu a kukuričný škrob homogénne zmiešať; granulovať s vodným roztokom Povidonu; zmiešať so stearanom horečnatým; vylisovať na tabletovacom lise; hmotnosť tabliet 200 mg.Mix the active substance, lactose and corn starch homogeneously; granulate with an aqueous solution of Povidone; mixed with magnesium stearate; pressed on a tablet press; tablet weight 200 mg.
Príklad 12Example 12
Kapsuly s 20 mg účinnej látky (A) alebo (B)Capsules containing 20 mg of active substance (A) or (B)
Zloženie:Ingredients:
účinná látka (A) alebo (B) 20mg kukuričný škrob 80mg vysokodisperzná kyselina kremičitá 5mg stearan horečnatý 2,5 mgActive Substance (A) or (B) 20mg Corn Starch 80mg High Disperse Silicic Acid 5mg Magnesium Stearate 2.5mg
- 19Výroba- 19Production
Účinnú látku, kukuričný škrob a kyselinu kremičitú homogénne zmiešať; zmiešať so stearanom horečnatým; zmes naplniť na stroji na plnenie kapsúl do kapsúl z tvrdej želatíny, veľkosť 3.Mix the active substance, corn starch and silicic acid homogeneously; mixed with magnesium stearate; fill the mixture on a capsule filling machine into hard gelatin capsules, size 3.
Príklad 13Example 13
Čapíky s 50 mg účinnej látky (A) alebo (B)Suppositories containing 50 mg of active ingredient (A) or (B)
Zloženie:Ingredients:
účinná látka (A) alebo (B) 50 mg stužený tuk (Adeps solidus) q. s. ad 1700 mgactive ingredient (A) or (B) 50 mg hardened fat (Adeps solidus) q. with. ad 1700 mg
VýrobaProduction
Stužený tuk roztopiť pri asi 38 °C; zomletú účinnú látku homogénne dispergovať v roztopenom stuženom tuku; po ochladení na asi 35 °C vyliať do predchladených foriem.Melt the hardened fat at about 38 ° C; disperse the milled active substance homogeneously in molten hardened fat; after cooling to about 35 ° C pour into pre-cooled molds.
Príklad 14Example 14
Vodný roztok na nazálnu aplikáciu s 10 mg účinnej látky (A) alebo (B)Aqueous solution for nasal administration with 10 mg of active ingredient (A) or (B)
Zloženie:Ingredients:
účinná látka (A) alebo (B) kyselina soľná v množstve, potrebnom na vytvorenie neutrálnej soli metylester kyseliny parahydroxybenzoovej (PHB) propylester kyseliny parahydroxybenzoovej (PHB) čistená voda adactive ingredient (A) or (B) hydrochloric acid in an amount necessary to form a neutral salt of parahydroxybenzoic acid methyl ester (PHB) propyl parahydroxybenzoic acid ester (PHB) purified water and
10,0mg10.0 mg
0,01mg0,01mg
0,005mg0.005mg
1,0ml1.0 ml
VýrobaProduction
Účinná látka sa rozpustí v čistenej vode; pridáva sa kyselina soľná, kým sa roztok nevyčíri; pridajú sa PHB-metyl- a propylester; roztok sa doplní čistenouThe active substance is dissolved in purified water; hydrochloric acid is added until the solution is clear; PHB-methyl and propyl ester are added; make up the solution with purified
-20vodou na stanovený objem; roztok sa sterilizuje filtráciou a naplní sa do vhodnej nádoby.-20 by water to the specified volume; the solution is sterilized by filtration and filled into a suitable container.
Príklad 15Example 15
Vodný roztok na nazálnu aplikáciu s 5 mg účinnej látky (A) alebo (B)Aqueous solution for nasal administration with 5 mg of active ingredient (A) or (B)
Zloženie:Ingredients:
VýrobaProduction
Účinná látka sa rozpustí v 1,2-propándiole; pripraví sa roztok hydroxyetylcelulózy v čistenej vode, obsahujúcej kyselinu sorbovú, a pridá sa k roztoku účinnej látky; roztok sa sterilizuje filtráciou a naplní sa do vhodnej nádoby.The active substance is dissolved in 1,2-propanediol; a solution of hydroxyethylcellulose in purified water containing sorbic acid is prepared and added to the solution of the active ingredient; the solution is sterilized by filtration and filled into a suitable container.
Príklad 16Example 16
Vodný roztok na intravenóznu aplikáciu s 5 mg účinnej látky (A) alebo (B)Aqueous solution for intravenous administration with 5 mg of active substance (A) or (B)
Zloženie:Ingredients:
VýrobaProduction
Účinná látka sa rozpustí v 1,2-propándiole; roztok sa s Wfi doplní približne na stanovený objem; pridá sa manitol a s Wfi sa doplní na stanovený objem; roztok sa sterilizuje filtráciou, naplní sa do jednotlivých nádob a autoklávuje sa.The active substance is dissolved in 1,2-propanediol; make up the solution to approximately the determined volume with Wfi; mannitol is added and made up to volume with Wfi; the solution is sterilized by filtration, filled into individual containers and autoclaved.
-21 Príklad 17-21 Example 17
Lipozómová formulácia na intravenóznu injekciu so 7,5 mg účinnej látky (A) alebo (B)Liposome formulation for intravenous injection with 7.5 mg of active ingredient (A) or (B)
Zloženie:Ingredients:
účinná látka (A) alebo (B) 7,5mg vaječný lecitín, napríklad Lipoid E 80 100,0mg cholesterol 50,0mg glycerín 50,0mg voda na injekčné účely ad 1,0 mlactive substance (A) or (B) 7.5 mg egg lecithin, for example Lipoid E 80 100.0 mg cholesterol 50.0 mg glycerin 50.0 mg water for injections ad 1.0 ml
VýrobaProduction
Účinná látka sa rozpustí v zmesi lecitínu a cholesterolu; roztok sa pridá k zmesi glycerínu a Wfi a homogenizuje sa pomocou vysokotlakovej homogenizácie alebo mikrofluidizačnej techniky; takto získaná lipozómová formulácia sa pri aseptických podmienkach naplní do zodpovedajúcej nádoby.The active ingredient is dissolved in a mixture of lecithin and cholesterol; the solution is added to a mixture of glycerin and Wfi and homogenized by high pressure homogenization or microfluidization technique; the liposome formulation thus obtained is filled into a corresponding container under aseptic conditions.
Príklad 18Example 18
Suspenzia na nazálnu aplikáciu s 20 mg účinnej látky (A) alebo (B)Nasal suspension with 20 mg of active ingredient (A) or (B)
Zloženie:Ingredients:
-22Výroba-22Výroba
Účinná látka sa suspenduje vo vodnom roztoku CMC; ostatné zložky sa postupne pridajú k suspenzii a táto sa doplní čistenou vodou na stanovený objem.The active ingredient is suspended in an aqueous solution of CMC; the other ingredients are gradually added to the suspension and made up to volume with purified water.
Príklad 19Example 19
Vodný roztok na podkožnú aplikáciu s 10 mg účinnej látky (A) alebo (B)Aqueous solution for subcutaneous administration with 10 mg of active substance (A) or (B)
Zloženie:Ingredients:
VýrobaProduction
Účinná látka sa rozpustí v roztoku fosfátového pufra; po pridaní kuchynskej soli sa vodou doplní na stanovený objem. Roztok sa sterilizuje filtráciou a po naplnení do zodpovedajúcej nádoby sa autoklávuje.The active substance is dissolved in a phosphate buffer solution; after addition of table salt, make up to volume with water. The solution is sterilized by filtration and autoclaved after filling into an appropriate container.
Príklad 20Example 20
Vodná suspenzia na podkožnú aplikáciu s 5 mg účinnej látky (A) alebo (B)Aqueous suspension for subcutaneous administration with 5 mg of active substance (A) or (B)
Zloženie:Ingredients:
účinná látka (A) alebo (B) polysorbát 80active substance (A) or (B) polysorbate 80
5,0 mg5.0 mg
0,5 mg voda na injekčné účely ad 0,5 ml0.5 mg water for injection ad 0.5 ml
VýrobaProduction
Účinná látka sa suspenduje v polysorbáte 80 a pomocou vhodnej dispergačnej metódy (napríklad mletie za mokra, vysokotlaková homogenizácia, mikrofluidizácia atd’.) sa rozmelí na veľkosť častíc asi 1 pm. Suspenzia sa pri aseptických podmienkach naplní do vhodnej nádoby.The active ingredient is suspended in polysorbate 80 and ground to a particle size of about 1 µm by a suitable dispersion method (e.g. wet grinding, high pressure homogenization, microfluidization, etc.). The suspension is filled into a suitable container under aseptic conditions.
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19937304A DE19937304C2 (en) | 1999-08-10 | 1999-08-10 | Use of CGRP antagonists to combat menopausal hot flashes |
| PCT/EP2000/007613 WO2001010425A2 (en) | 1999-08-10 | 2000-08-05 | Use of cgrp antagonists and cgrp release inhibitors for controlling menopausal hot flashes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SK1972002A3 true SK1972002A3 (en) | 2002-06-04 |
| SK285587B6 SK285587B6 (en) | 2007-04-05 |
Family
ID=7917551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK197-2002A SK285587B6 (en) | 1999-08-10 | 2000-08-05 | Use of CGRP antagonists and CGRP release inhibitors |
Country Status (32)
| Country | Link |
|---|---|
| EP (1) | EP1207884B1 (en) |
| JP (1) | JP2003506403A (en) |
| KR (1) | KR100713573B1 (en) |
| CN (1) | CN1166361C (en) |
| AR (1) | AR025078A1 (en) |
| AT (1) | ATE281168T1 (en) |
| AU (1) | AU777709B2 (en) |
| BG (1) | BG65366B1 (en) |
| BR (1) | BR0013009A (en) |
| CA (1) | CA2378428C (en) |
| CZ (1) | CZ300513B6 (en) |
| DE (2) | DE19937304C2 (en) |
| EA (1) | EA007531B1 (en) |
| EE (1) | EE04928B1 (en) |
| ES (1) | ES2231243T3 (en) |
| HK (1) | HK1046854B (en) |
| HR (1) | HRP20020117A2 (en) |
| HU (1) | HUP0202397A3 (en) |
| IL (1) | IL148057A (en) |
| MX (1) | MXPA02001373A (en) |
| MY (1) | MY129668A (en) |
| NO (1) | NO20020605L (en) |
| NZ (1) | NZ517367A (en) |
| PL (1) | PL198483B1 (en) |
| PT (1) | PT1207884E (en) |
| SK (1) | SK285587B6 (en) |
| TR (1) | TR200200359T2 (en) |
| TW (1) | TWI285550B (en) |
| UA (1) | UA73137C2 (en) |
| WO (1) | WO2001010425A2 (en) |
| YU (1) | YU8302A (en) |
| ZA (1) | ZA200200997B (en) |
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| DE19952147A1 (en) | 1999-10-29 | 2001-05-03 | Boehringer Ingelheim Pharma | New cyclopropanes, pharmaceutical compositions containing these compounds and process for their preparation |
| DE10139410A1 (en) * | 2001-08-17 | 2003-02-27 | Boehringer Ingelheim Pharma | Use of BIBN4096 in combination with other anti-migraine drugs for the treatment of migraines |
| US7115609B2 (en) | 2001-12-12 | 2006-10-03 | Eli Lilly And Company | Alanyl-piperidine heterocyclic derivatives useful against cardiovascular diseases |
| DE10206770A1 (en) * | 2002-02-19 | 2003-08-28 | Boehringer Ingelheim Pharma | New, stable acid addition salts of the quinazolinone derivative CGRP antagonist BIBN4096, useful for the treatment of migraine, in the form of an inhalable powder |
| US6900317B2 (en) | 2002-02-19 | 2005-05-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Salts of the CGRP antagonist BIBN4096 and inhalable powdered medicaments containing them |
| DE10207026A1 (en) * | 2002-02-20 | 2003-08-28 | Boehringer Ingelheim Kg | Stable inhalable powder of the calcitonin gene-related peptide antagonist, BIBN4096, useful for treating migraine, in the form of spherical nano-structured particles obtained by spray-drying |
| DE10227294A1 (en) * | 2002-06-19 | 2004-01-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Preparations for intranasal application of selected amino acid-derived CGRP antagonists and processes for their preparation |
| US7595312B2 (en) | 2002-10-25 | 2009-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions |
| DE10250080A1 (en) * | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals |
| DE10300973A1 (en) * | 2003-01-14 | 2004-07-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New carboxylic acids and their esters, medicaments containing these compounds and processes for their preparation |
| EP1648466A1 (en) * | 2003-07-07 | 2006-04-26 | Boehringer Ingelheim International GmbH | Use of cgrp antagonists in treatment and prevention of hot flushes in prostate cancer patients |
| AU2004259675A1 (en) * | 2003-07-15 | 2005-02-03 | Merck & Co., Inc. | Hydroxypyridine CGRP receptor antagonists |
| DE10338399A1 (en) * | 2003-08-18 | 2005-03-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Microparticles containing the CGRP antagonist 1- [N 2 - [3,5-dibromo-N - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, process for their preparation and their use as inhalation powder |
| DE102004015723A1 (en) | 2004-03-29 | 2005-10-20 | Boehringer Ingelheim Pharma | Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals |
| DE102004019492A1 (en) * | 2004-04-22 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals |
| US7696195B2 (en) | 2004-04-22 | 2010-04-13 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
| DE102004063755A1 (en) * | 2004-12-29 | 2006-07-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of CGRP antagonists for the treatment and prevention of hot flushes in patients with prostate cancer |
| DE102004063752A1 (en) * | 2004-12-29 | 2006-07-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of selected CGRP antagonists to combat menopausal hot flashes |
| US7491717B2 (en) | 2005-03-23 | 2009-02-17 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
| EP1770091A1 (en) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP-antagonists, process for their preparation as well as their use as medicaments |
| US7439237B2 (en) | 2005-04-15 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
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|---|---|---|---|---|
| DE69601765T2 (en) * | 1995-09-07 | 1999-07-08 | Oreal | Iridaceae extract and compositions containing it |
| US5910482A (en) * | 1996-03-19 | 1999-06-08 | Board Of Regents, The University Of Texas System | Treatment or prevention of preeclampsia, eclampsia with calcitonin gene related peptide, CGRP analog, progestational agent, nitric oxide source, and cyclooxygenase inhibitor |
| US5710024A (en) * | 1996-07-23 | 1998-01-20 | Smithkline Beecham Corporation | Polynucleotides that encode the calcitonin gene-related peptide receptor coponent factor (HOUNDC44) |
| EE04375B1 (en) * | 1996-09-10 | 2004-10-15 | Dr. Karl Thomae Gmbh | Modified amino acids, drugs containing these compounds, and process for their preparation |
| DE19911039A1 (en) * | 1999-03-12 | 2000-09-14 | Boehringer Ingelheim Pharma | Modified amino acid amides, pharmaceutical compositions containing these compounds and process for their preparation |
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1999
- 1999-08-10 DE DE19937304A patent/DE19937304C2/en not_active Expired - Fee Related
-
2000
- 2000-05-08 UA UA2002031932A patent/UA73137C2/en unknown
- 2000-08-05 AU AU69928/00A patent/AU777709B2/en not_active Ceased
- 2000-08-05 YU YU8302A patent/YU8302A/en unknown
- 2000-08-05 DE DE50008527T patent/DE50008527D1/en not_active Expired - Lifetime
- 2000-08-05 AT AT00958385T patent/ATE281168T1/en not_active IP Right Cessation
- 2000-08-05 CZ CZ20020497A patent/CZ300513B6/en not_active IP Right Cessation
- 2000-08-05 SK SK197-2002A patent/SK285587B6/en unknown
- 2000-08-05 NZ NZ517367A patent/NZ517367A/en unknown
- 2000-08-05 KR KR1020027001796A patent/KR100713573B1/en not_active IP Right Cessation
- 2000-08-05 PL PL364049A patent/PL198483B1/en not_active IP Right Cessation
- 2000-08-05 WO PCT/EP2000/007613 patent/WO2001010425A2/en active Application Filing
- 2000-08-05 PT PT00958385T patent/PT1207884E/en unknown
- 2000-08-05 CN CNB008116156A patent/CN1166361C/en not_active Expired - Fee Related
- 2000-08-05 ES ES00958385T patent/ES2231243T3/en not_active Expired - Lifetime
- 2000-08-05 JP JP2001514945A patent/JP2003506403A/en active Pending
- 2000-08-05 EE EEP200200061A patent/EE04928B1/en not_active IP Right Cessation
- 2000-08-05 ZA ZA200200997A patent/ZA200200997B/en unknown
- 2000-08-05 MX MXPA02001373A patent/MXPA02001373A/en active IP Right Grant
- 2000-08-05 BR BR0013009-5A patent/BR0013009A/en active Pending
- 2000-08-05 HU HU0202397A patent/HUP0202397A3/en unknown
- 2000-08-05 EA EA200200207A patent/EA007531B1/en not_active IP Right Cessation
- 2000-08-05 TR TR2002/00359T patent/TR200200359T2/en unknown
- 2000-08-05 EP EP00958385A patent/EP1207884B1/en not_active Expired - Lifetime
- 2000-08-05 CA CA002378428A patent/CA2378428C/en not_active Expired - Fee Related
- 2000-08-05 IL IL148057A patent/IL148057A/en not_active IP Right Cessation
- 2000-08-08 MY MYPI20003601A patent/MY129668A/en unknown
- 2000-08-08 TW TW089115923A patent/TWI285550B/en not_active IP Right Cessation
- 2000-08-09 AR ARP000104098A patent/AR025078A1/en not_active Suspension/Interruption
-
2002
- 2002-02-06 BG BG106391A patent/BG65366B1/en active Active
- 2002-02-07 NO NO20020605A patent/NO20020605L/en not_active Application Discontinuation
- 2002-02-07 HR HR20020117A patent/HRP20020117A2/en not_active Application Discontinuation
- 2002-11-19 HK HK02108347.1A patent/HK1046854B/en not_active IP Right Cessation
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