SK285587B6 - Use of CGRP antagonists and CGRP release inhibitors - Google Patents
Use of CGRP antagonists and CGRP release inhibitors Download PDFInfo
- Publication number
- SK285587B6 SK285587B6 SK197-2002A SK1972002A SK285587B6 SK 285587 B6 SK285587 B6 SK 285587B6 SK 1972002 A SK1972002 A SK 1972002A SK 285587 B6 SK285587 B6 SK 285587B6
- 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) má v dôsledku vazodilatačných vlastností tohto neuropeptidu úlohu pri vzniku menopauzálnych návalov horúčavy u žien s nedostatkom cstrogénu ([1]: J. Endocrinol. 14613), 431 - 437, 1995; [2J: 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 on several occasions that CGRP, due to the vasodilating properties of this neuropeptide, has a role in the development of menopausal hot flashes in cstrogen deficient women ([1]: J. Endocrinol. 14613) 431-437, 1995; [2J: Acta Physiol. Scand. 162 (4), 517-522, 1998; [3] Am 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 uvoľňovania CGRP), pričom sa toto terapeutické použitie v porovnaní s hormonálnou substitúciou vyznačuje najmä malými vedľajšími účinkami.It has now been found that the symptomatics of menopausal hot flushes can be effectively prevented or their harmful effects can be substantially reduced by substances that antagonize the effects of CGRP (CGRP-antagonists) or inhibit or reduce the release of CGRP from the sensory nerve endings (CGRP release inhibitors). this therapeutic use is characterized in particular by minor side effects compared to hormone replacement.
Podstata vynálezuSUMMARY 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 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-HT1D, ako avitrip tan, eletriptan, naratriptan, rizatriptan, sumatriptan alebo zolmitriptan, ďalej 5-HTlt.-agonisty alebo NPY-agonisty.As inhibitors of the release of CGRP are, for example, agonists of serotonin 5-HT 1D as avitrip tan, eletriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan, hereinafter 5-HT lt. 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) l-[A2-[3,5-dibróm-/V-[[4-(3,4-dihydro-2(lH)-oxochinazolín-3-yl)-l-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( 177)-oxo-1,3 -benzo-diazepín-3 -yl)-1 -piperidinyljkarbonyl]-D-fenylalanyl]-4-(l -piperidinylj-piperidin, (C) 1 -[W2-[ 4-amin o-3,5 -di bróm-Λ'- [ (4-(3,4-dihydro-2( 17/)-oxochinazolín-3-yl)-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-L-lyzyl]-4-(4-pyridinyl)-piperazin, (D) 1 -|7V2-[4-amino-3,5-dibróm-A'-[[4-(3,4-dihydro-2(l//)-oxochinazolin-3-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-L-lyzyl]-4-(4-pyridinyl)-piperidín, (E) l-[Aa-[3,5-dibrôm-7V-[[4-(l,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-l-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazin, (F) 1 -[A'2-[4-amino-3,5-dibróm-,V-[[4-(l ,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-l-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (G) 1 -[3,5-dibróm-7V-[[4-(3,4-dihydro-2(l//)-oxotieno[3,4-d]-pyrimidín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-(l-piperidinylj-piperidin, (H) 1 -[4-amino-3,5-dibróm-A'-[[4-(2,4-dihydro-5-fenyl-3(3F7)-oxo-l ,2,4-triazol-2-yl)-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-4-( 1 -metyl-4-piperidinyl)-piperidin, (I) 1 -['4-amíno-3,5-dibróm-W[[4-(2,4-dihydro-5-fenyl-3(3//)-oxo-l ,2,4-triazol-2-yl)-l -piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-piperidinylj-piperidin, (J) 1 -[4-amino-3,5-dibróm-/V-[[4-(2,4-dihydro-5-fenyl-3(3/7)-oxo-l,2,4-triazol-2-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperazín, (K) 1 -[4-amino-3,5-dibróm-/V-[[4-(3,4-dihydro-2( I //)-oxotieno[3,2-d]-pyrimidín-3-yl)-l -piperidinylj-karbonylj-D-fenylalanyl]-4-(l-piperidinylj-piperidin, (L) l-[4-amino-3,5-dibróm-.¥-[[4-[l,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(22/)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l -etyl-4-piperidinyl)-piperidín, (M) l-[4-amino-3,5-dibróm-A'-[[4-[3,4-dihydro-2(l//)-oxochinazolin-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-( 1 -h exyl-4-piperid inylj-piperidí n, (N) l-[4-amino-3,5-dibróm-Ar-[[4-[3,4-dihydro-2(lA')-oxochinazolín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-cyklopropylmetyl-4-piperidinyl)-piperidín, (O) 1 -[/V-[[4-[3,4-dihydro-2( 1 //)-oxochinazolín-3-ylj-1 -piperidinyl]-karbonyl]-3-etenyl-D,L-fenylalanyl]-4-(hexahydro-\H-1 -azepinyl )-piperidín, (P) (7f,S)-l-[4-[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-píperidinyl]-2-[(4-hydroxy-3,5-dimetylfenyl)metyl]-1,4-di oxobutyl ]-4-( 1 -piperidinylj-piperidin, (Q) l-[4-amíno-3,5-dibrórn-A'-[[4-[jV-(arnínokarbonyl)-Jť-fenylamino]-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1 -piperidinylj-piperidin, (R) l-[4-amino-3,5-dibMÓni-A'-[[4-(3,4-dihydiO-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(5-metoxy-4-pyrimidinyl)-piperazín, (S) 1 -[4-amino-3,5-díbróm-W-[[4-( í, 1 -dioxido-3(477)-oxo-1,2,4-benzotiadiazín-2-yl)-l -piperidinylj-karbonylj-D-fenylalanyl]-4-(l-piperidinylj-piperidin, (T) l-[4-ammo-3,5-díbróm-A;’-[[4-[2ílH)-oxochinolín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-piperidinyl)-piperidín, (U) 1 -[4-amino-3,5 -dibróm-A'-[[4-[3,4-dihydro-2( 1//)-oxochinazolín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylaIanyl]-4-(3-(dimetylamino)propyl]-piperazín, (V) 1 -[4-amino-3,5-dibróm-/V-[[4-[3,4-dihydro-2( 1H)-oxochinazolín-3-yl]-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-4-(4-metyl-l-pipcrazinyl]-pipcridín, (W) l-[4-amino-3,5-dibróm-A-[[4-[3,4-dihydro-2(l/7)-oxochinazolín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-[( 1 -metyl-4-piperidinyl)karbonyl] -piperazin, (X) 1 -[4-amino-3,5 -dibróm-Ä/-[[4-[3,4-dihydro-2( 1H)-oxochinazolín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-[( 1 -metyl-4-piperazinyl)karbonyl]-piperazín, (Y) 1 -[4-amino-3,5 -dibróm-7V-[[4-(3,4-dihydro-2( 1H)-oxochinazoIín-3-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-[4-[4-(dimetylamino)butyl]fenyl]-piperazín, (Z) 1 -[4-amino-3,5-dibróm-;V-[[4-(3,4-dihydro-2( 1 //)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-[4-(dimetylamino)-l-piperidinyl]-piperidín, (AA) 1 -[tV2-[[4-( 1,3-dihydro-4-fenyl-2(2//)-oxoimidazol-l-yl)-l-piperidinyl]-karbonyl]-W-metyl-D-tryptyl]-4-(4-metyl-1 -piperazinyl)-piperidín, (AB) 1 -[jV2-[[4-( 1,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1 -yl)-l -piperidinyl]-karbonyl]-V-(l, 1 -dimetyletoxykarbonyl)-D-tryptyl]-4-( 1 -metyl-4-piperidinyl)-piperidín, (AC) (R, S)-1 -[4-[4-(3,4-dihydro-2( 1 77)-oxoch inazol ín-3 -yl)-1 -piperidinyl]-2-[(3,5-dibróm-4-mctylfcnyl)metyI]-l ,4-dioxobutyl]-4-(4-metyl-1 -piperazinyl)-piperidín, (AD) (Ä,1S)-l-[4-[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]-2-[(3,5-dibróm-4-metoxyfenyl)metyl]-1,4-dioxobutyl]-4-( 1 -metyl-4-piperidinyl)-piperidín, (AE) (R,S)-1 -[4-[4-(3,4-dihydro-2( l//)-oxochinazolin-3-yl)-l-piperidinyl]-2-[(3,4-dibrómfenyl)metyl]-l,4-dioxobutyl]-4-(4-metyl-1 -piperazinyl)-piperidin, (AF) l-[Af2-[JV-[[4-(l ,3-dihydro-2(2//)-oxobenzimidazol-1 -yl)-1 -piperidinyl]-karbonyl]-3,5-dibróm-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazin, (AG) 1 -[4-amino-3,5-dibróm-A'-[[4-( 1,3-dihydro-6-hydroxy-2(2//)-oxobenzimidazo 1-1 -yl)-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-piperidinyl)-piperidín, (AH) 1 -[A/2-[4-amino-3,5-dibróm-Á'-[[4-( 1,3-dihydro-2(2H)-oxobenzimidazol-l-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-A'6,A'6-dimetyl-L-lyzyl]-4-(4-pyridinyl)-piperazín, (Al) 1 -[jV2-[4-amino-3,5-dibróm-/V-[[4-(3,4-dihydro-2(lH)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-7V6,A'6-dimetyl-L-lyzyl]-4-(4-p>TÍdinyl)-piperazín, (AJ) (Ä,S)-l-[2-(4-amino-3,5-dibrómbenzoyl)-4-[4-(3,4-dihydro-2( 1 H)-oxo-ch inazolín-3-yl)-1 -piperidinyl] -4-oxobutyl]-4-( 1 -piperi dinyl)-piperidín, (AK) 1 -[4-amino-3,5-dibróm-jV-[[4-(3,4-diliydro-2,2-dioxido-2,1,3-benzotiadiazin-3-yl)-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-( 1 -piperidinyl)-piperidín, (AL) l-[4-amino-3,5-dibróm-.V-[[4-[l,3-dihydro-2(2//)-oxoimidazo[4,5-c] -chinolín-3-yl] -1 -piperidinyl]karbonyl] -D-fenylalanyl]-4-(l-piperidinyl)karbonyl]-piperidín, (AM) l-[4-amino-3,5-dibróm-Á/-[[4-[3,4-dihydro-2(l//)-oxochinazolín-3-yI)-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-( 1 -pipcridinyl)-piperidín, (AN) l-[.V2-[3,5-dibróm-A''-[[4-(3,4-díhydro-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-/Vť,/V6-dimetyl-L-lyzyl]-4-(4-pyridinyl]-piperazín, (AO) 1 -[4-amino-.V-[[4-[4-(3-brómfenylJ-1,3-dihydro-2(2//)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-3,5-dibróm-D-fenylalanyl]-4-( 1 -metyl-4-piperidinyl)-piperidín, (AP) l-[4-amino-3,5-dibróm-Y-[[4-[l,3-dihydro-4-fenyl-2(2//)-oxoimidazol-l -yl]-l -piperidinyl]karbonyl]-D-fenylalanyl]-4-(4-metyl-1 -piperazinyl)-piperidín, (AQ) l-[4-amino-3,5-dibróm-'V-[[4-[l,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2H)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-piperidinyl)-piperidm, (AR) 1 -[4-amino-3,5-dibróm-A'-[[4-[l,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2H)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(exo-8-metyl-8-azabicyklo-[3,2,l]okt-3-yl)-piperazín, (AS) 1 -[3,5-dibróm-A'-[[4-( 1,3 -dl hydro-4-fcn yl-2(2//)-oxoimidazol-1 -yl)-1 -piperidinyl]karbonyl]-D-tyrozyl]-4-(1 -piperidinyl)-pi perí dín, (AT) 1 -[4-amino-3,5-dibróm-/V-[[4-[l,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2ŕf)-oxoimidazol-1 -yl]-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(l -etyl-4-pipcridinyl)-piperazín, (AU) 1 -[4-amino-3,5-dibróm-/V-[[4-[l ,3-dihydro-4-fenyl-2(2H)-oxoimidazol-1 -yl]-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(hexahydro-4-metyl-1 H-1,4-diazepín-1 -yl)-piperidín, (A V) 1 -[3,5-dibróm-/V-[[4-(3,4-dihydro-2(lH)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-[l-(metylsulfonyl)-4-piperidinyl]-piperidín, (AW) 1 -[4-amino-3,5-díbróm-A'-[[4-f 1,3-dihydro-4-fenyl-2(2//)-oxoimídazol-1 -yl)-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperidín, (ΑΧ) 1 -[3,5-dibróm-Ar-[[4-[ 1,3-dihydro-4-[3-(tri fluórmetyl)fenyl]-2(2//)-oxoimidazol-1 -yl]-1 -pipcr id inyl] karbonyrj-D-tyrozyl]-4-(hexahydro-l/7-l-azepinyl)-piperidin, (A Y) l-[3,5-dibróm-7V-[[4-[3,4-dihydro-2(lH)-oxochina· zolín-3-yl]-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-[l-metyl-4-piperidinyl]-piperidin, (AZ) 1 -[4-amino-3,5-dibróm-A-[[4-[3,4-dihydro-2( 1H)-oxochinazolín-3-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(exo-8-metyl-8-azabicyklo-[3,2,l]okt-3-yl)-piperazín, (BA) l-[4-amino-3,5-dibróm-/V-[[4-(l ,3-dihydro-4-fenyl-2(2//J-oxoimidazol-1 -y])-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperazín, (BB) l-[3,5-dibróm-jV-[[4-[l,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2//)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-tyrozyl]-4-(l-piperidinyl)-piperidín, (BC) l-[A^cetyl-y-[3,5-dibróm-/V-[[4-(3,4-dihydro-2( 1 H)-oxochinazolín-3-yl)-1 -piperidinyl]karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (BD) l-[3,5-dibróm-.V-[[4-(l,3-dihydro-4-fényl-2(2//J-oxoimidazol-1 -yl)-1 -piperidinyl]karbonyl]-D-tyrozyl]-4-(hexahydro-1 H-1 -azepinyl)-piperidín, (BE) 1 -[4-amino-3,5-dibróm-Ar-[[4-( 1,3-dihydro-4-(3-tienyl)-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinYl)-piperidín, (BF) 1 -[4-amino-3,5-d i brótn-Y- [ [4-[ 1,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2H)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-fenylalanyI]-4-(l-metyl-4-piperidinyl)piperidín, (BG) 1 -[3,5 -dibróm-/V-[[4-(3,4-dihydro-2( 1 //)-oxochinazol i n-3-yl)-1 -piperidinyl]-karbonyl]-D-tyrozyl]-4-[ 1 -(hydroxykarbonylmetyl)-4-piperidinyl]-piperidin.(A) 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, (B) 1- [4-amino-3,5-dibromo- N - [[4- (2,3,4, 5-tetrahydro-2 (177) -oxo-1,3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine, (C) 1- [W] 2- [4-Amino-3,5-di-bromo-4 '- [(4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-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, 4-pyridinyl)] - 4-Dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) -piperidine, (E) 1 - [N a - [3,5-Dibromo-7 H - [[4- (1,3-dihydro-4-phenyl-2 (2 H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] - -D-Tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (F) 1- [N '- 2- [4-amino-3,5-dibromo-, N - [[4- ( 1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) - piperazine, (G) 1- [3,5-dibromo-7H - [[4- (3,4-dihydro-2 (1 H) -O)] - xothieno [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 (3F7) -oxo-1,2,4-triazol-2-yl) -1-piperidinyl] carbonyl] - D-Phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (I) 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-piperidinyl) piperidine, (J) 1 - [4-amino-3,5-dibromo / V - [[4- (2,4-dihydro-5-phenyl-3 (3/7) oxo-l, 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] - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2 H) -oxoimidazole -1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperidine, (M) 1- [4-amino-3,5-dibromo-A ' - [[4- [3,4-dihydro-2 (l //) - oxoquinazolin-3-yl] - l-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-h exyl-ynyl-piperidin-4-piperidin, (S) l- [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-ethenyl-D, L-phenylalanyl] -4- (Hexahydro-1H-1-azepinyl) -piperidine, (P) (7f, S) -1- [4- [4- (3,4-dihydro-2 (1H) -oxoquinazoline-3)] -yl) -1-piperidinyl] -2 - [(4-hydroxy-3,5-dimethylphenyl) methyl] -1,4-dioxobutyl] -4- (1-piperidinyl) piperidine, (Q) 1- [4] -amino-3,5-dibromo-N '- [[4- [N - (aminocarbonyl) -1 H -phenylamino] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine, (R) 1- [4-Amino-3,5-dibmonium-N '- [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl ] - D -phenylalanyl] -4- (5-methoxy-4-pyrimidinyl) -piperazine, (S) 1- [4-amino-3,5-dibromo-N - [[4- (1,1-dioxido- 3- (477) -oxo-1,2,4-benzothiadiazin-2-yl) -1-piperidinyl-carbonyl-D-phenylalanyl] -4- (1- piperidinyl-piperidine, (T) 1- [4-amino-3,5-dibromo-A ; 1 - [[4- [2H] -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-phenylaanyl] -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-A - [[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) 1- [4-Amino-3,5-dibromo-7H] - [[4- (3,4)] - D-phenylalanyl] -4 - [(1-methyl-4-piperazinyl) carbonyl] -piperazine -dihydro-2 (1H) -oxoquinazolin-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) -oxoquinazolin-3-yl) -1-piperidine] yl] -carbonyl] -D-phenylalanyl] -4- [4- (dimethylamino) -1-piperidinyl] -piperidine, (AA) 1- [N 2 - [[4- (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) 1-D-tryptyl] -4- (1-methyl-4-piperidinyl) -piperidine, (AC) (R, S) -1- [4- [4- (3,4-dihydro-2 (17))] -oxoquinazolin-3-yl) -1-piperidinyl] -2 - [(3,5-dibromo-4-methylphenyl) methyl] -1,4-dioxobutyl] -4- (4-methyl-1-piperazinyl) piperidine, (AD) (R, 1S) -l- [4- [4- (3,4-dihydro-2 (l //) - oxoquinazolin-3-yl) -l-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 2 - [N - [[4- (1,3-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) -oxobenzimidazo-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (AH) 1- [A / 2 - [4-amino-3,5-dibromo-N - [[4- (1,3-dihydro-2 (2H) -oxobenzimidazol-l-yl) -l-piperidinyl] carbonyl] - D-phenylalanyl] - N ', 6 ', 6 -dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, (Al) 1- [N 2 - [4-amino-3,5-dibromo- / V - [[4- (3,4-dihydro-2 (H) -oxochinazolín-3-yl) -l-piperidinyl] carbonyl] -D-phenylalanyl] -7V 6, N- dimethyl-L-6 lysyl] -4- (4-piperidinyl) -piperazine, (AJ) (R, S) -1- [2- (4-amino-3,5-dibromobenzoyl) -4- [4- (3,4) -dihydro-2 (1H) -oxo-quinazolin-3-yl) -1-piperidinyl] -4-oxobutyl] -4- (1-piperidinyl) -piperidine, (AK) 1- [4-amino- 3,5-dibromo-N - [[4- (3,4-diliydro-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-piperidine dinyl] carbonyl] -D-phenylalanyl] -4- (1-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- [ 2- [3] , 5-dibromo-N '- [[4- (3,4-dihydro-2 (l //) - oxoquinazolin-3-yl) -l-piperidinyl] carbonyl] -D-tyrosyl] - / V T , / V-dimethyl-6 L-lysyl] -4- (4-pyridinyl] piperazine, (AO) 1 - [4-amino-.V - [[4- [4- (3-1,3-brómfenylJ -dihydro-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, ( AP) 1- [4-amino-3,5-dibromo-Y - [[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] -D-phenylalanyl] -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] - l-piperidine inyl] 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-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperazine, (AU) 1- [4-amino-3, 5-Dibromo- N - [[4- [1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro) -4-methyl-1H-1,4-diazepin-1-yl) -piperidine, (AV) 1- [3,5-dibromo-N - [[4- (3,4-dihydro-2 (1H)]) 1-Oxoquinazolin-3-yl) -1-piperidinyl] 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- (l-methyl-4-piperidinyl) -piperidine, (ΑΧ) 1 - [3,5-dibromo-N - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] - 2 (2 //) - oxo imidazol-1-yl] -1-piperidinyl] carbonyl-D-tyrosyl] -4- (hexahydro-1H-1-azepinyl) -piperidine, (AY) 1- [3,5-dibromo-7H- [[4- [3,4-dihydro-2 (H) x -O and the hin c · oxazoline-3-yl] -l-piperidinyl] carbonyl] -D-tyrosyl] -4- [l-methyl- 4-piperidinyl] -piperidine, (AZ) 1- [4-amino-3,5-dibromo-A - [[4- [3,4-dihydro-2 (1H) -oxoquinazolin-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- [N -acetyl-y- [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) -oxoimidazole-1- yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4 - (hexahydro-1H-azepinyl 1) 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-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (BF) 1- [4-amino- 3,5-di-bromo-N - [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] - D-phenylalanyl] -4- (1-methyl-4-piperidinyl) piperidine, (BG) 1- [3,5-dibromo- N - [[4- (3,4-dihydro-2 (1 H))] - -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- [1- (hydroxycarbonylmethyl) -4-piperidinyl] -piperidine.
(BH) l-[4-amino-3,5-dibróm-A''-[[4-[3,4-díhydro-2f 1/7)-oxochinazolín-3-yl]-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-metylsulfonyl-4-piperidinyl)-piperidin, (BI) l-[3,5-dibróm-A-[[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-(4-pipcridinyl)-piperidín, (BJ) l-[4-amino-3,5-dibróm-N-[[4-(l,3-dihydro-4-fenyl-2 (2 /7)-oxoi m i dazo I -1 -y 1)-1 -pi perí dinyl] karbonyl]-D-fenylalanyl]-4-(l-etyl-4-piperidinyl)-piperidin, (BK.) l-[4-amino-3,5-dibróm-Á-[[4-(l, 3-dihydro-4-(3-hydroxyfenyl)-2(2//)-oxo-imidazol-1 -yl)-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-( 1 -metyl-4-piperidinyl)-piperidin, (BL) 1 -[3,5 -dibróm-.\'- [[4 - (3,4-dihydro-2( 1 //)-oxoch inazolín-3-yl)-1 -piperidinyl]-karbonyl]-D-tyrozyl]-4-(hexahydro-1 H-1 -azepinyl)-piperidín, (BM) l-[4-amino-3,5-dibróm-/V4[4-(l,3-dihydro-4-fcnyl-2(2/7)-oxoimidazol-l-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-( 1 -piperidinyl)-piperidín, (BN) 1 -[4-amino-3,5-dibróm-A,-[[4-[4-(3-brómfenyl)-1,3-dihydro-2(2//)-oxoimidazol-1 -yl]-1 -piperidinyl]karbonyI]-D-fenylalanyi]-4-(exo-8-metyl-8-azabicyklo-[3,2,l]okt-3-yl)-piperazín, (BO) l-[4-amino-3,5-dibróm-AL[[4-(3,4-dihydro-2(l/7)-oxochinazolín-3-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-( 1 -etyl-4-piperidinyl)-piperidín, (BP) l-[4-amino-3,5-dibróm-Af-[[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-píperidinyl]karbonyl]-D-fenylalanyl]-4-(l-etyl-4-piperidinyl)-piperazin, (BQ) l-[4-amino-3,5-dibróm-A-[[4-[l,3-dihydro-4-(3-metoxyfenyl)-2(2//)-oxo-imidazol-l -yl]-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(exo-8-metyl-8-azabicyklo-[3,2, l]okt-3-yl)-piperazin, (BR) 1 -[3,5-dibróm-A-[[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-[l-(cyklopropylmetyl)-4-piperidinyl]-piperidín, (BS) 1 -[4-amino-3,5-dibróm-Aí-[[4-(3,4-dihydro-2(l//)-oxochinazolin-3-yl)-l-piperidinyl]karbonyI]-D-fenylalany 1]-4-(hexahydro-1II-1 -azepinylj-piperidín, (BT) 1 -[4-amino-3,5-dibróm-A'-[[4-(3,4-dihydro-2( 1H)-oxochinazolín-3-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(4-piperidinyl)-piperidín, (BU) l-[3,5-dibróm-.Y-[[4-(l ,3-dihydro-4-fenyl-2(2H)-oxoimidazol-1 -yl)-1 -piperidinyl]karbonyl]-D-tyrozyl]-4-(4-pyridinyl)-piperidín, (B V) l-[3,5-dibróm-JV-[[4-[l,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2W)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-tyrozyl]-4-(l-metyl-4-piperidinyl)-piperazín, (BW) 1 -[N2-[3,5-dibróm-iV-[[4-[ 1,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2/f)-oxo-imidazol-1 -yl]-1 -pipcridinyl ] karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (BX) 1 -[3,5-dibróm-A/-[[4-(l ,3-dihydro-4-(3-tienyl)-2(2/7)-oxoimidazol-l-yl)-l-piperidinyl]karbonyl]-D-tyrozyl]-4-( 1 -pi perid i nyl)-piperid in, (BY) l-[4-amino-Ý-[[4-[4-(3-chlórfenyI)-l,3-dihydro-2(2//)-oxoimidazol-1 -yl]-1 -piperid i nyljkarbon yl]-3,5-dibróm-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperidín, (BZ) l-[4-amino-3,5-dibróm-7Y[[4-[l,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2W)-oxoimidazol-1 -yl]-1 -piperidinyl]karbonyl]-D-fenyIalanyl]-4-(hexahydro-177-1 -azepinyl)-piperidín, (CA) l-[4-amino-3,5-dibróm-Y-[[4-[l,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2//)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperazín, (CB) l-[4-amino-A-[[4-[4-(3-chlórfenyl)-l,3-dihydro-2(2//)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-3,5-dibróm-D-fenylalanyl]-4-(hexahydro-1/7-1 -azepinyl)-piperidín, (CC) 1 -[4-amino-3,5-dibróm-,V-[[4-f 1,3-dihydro-4-fenyl-2(2//)-oxoimidazol-l-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(4-pyridinyl)-piperazín, (CD) 1 -[3,5 -dibróm-JV-[ [4-( 1,3 -dihydro-4-fenyl-2(2//)-oxoimidazol-l-yl)-l -piperidinyl]karbonyl]-D-tyrozyl]-4-(1 -metyl-4-piperidinyl)-piperidín, (CE) l-[4-amino-3,5-dibróm-JV-[[4-[l, 3-dihydro-4-fenyl-2(2//)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-[4-(l-oxoetyl)fenyl]-piperazín, (CF) l-[3,5-dibróm-A4[4-[3,4-dihydro-2(l//)-oxochinazolín-3-yl]-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-(l-metyl-4-piperidinyl)-pipcrazín, (CG) l-[4-amino-3,5-dibróm-A''-[[4-[1.3-dihydro-4-(3-mtrofenyl)-2(2/7)-oxoimidazol-l -yl]-l -piperidinyljkarbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperidín, (CH) l-[4-amino-3,5-dibróm-Ar-[[4-[3,4-dihydro-2(l/7)-oxochinazolín-l-yl]-3-pipcridinyl]karbonyl]-D-fenylalanyl]-4-(l-pyTolidinyl)-piperidín, (CJ) 1 -[4-amino-3,5-dibróm-Aí-[[4-(l,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1 -yl)-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(hexahydro-1 H-1 -azepinyl)-piperidín a (CJ) 1 -[4-amino-3,5-dibróm-A''-í[4-(l ,3-dihydro-4-(3-tienyl)-2(2//)-oxoimidazol-1 -yl)-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperazín, ich tautoméry, ich diastereoméry, ich enantioméry, ich zmesi a ich fyziologicky prijateľné soli, pričom zlúčeniny:(BH) 1- [4-Amino-3,5-dibromo-N '- [[4- [3,4-dihydro-2 H 1 -7) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-Phenylalanyl] -4- (1-methylsulfonyl-4-piperidinyl) -piperidine, (BI) 1- [3,5-dibromo-A - [[4- (3,4-dihydro-2 (1 H)] - 1-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) -oxidazol-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 H) -oxo-imidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (BL) 1- [3,5] Dibromo- N - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro) -1H-1-azepinyl) -piperidine, (BM) 1- [4-amino-3,5-dibromo- N4 [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-A , - [[ 4- [4- (3-bromophenyl l) -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- L [[4- (3,4-dihydro-2 (1/7)) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4-piperidinyl) -piperidine, (BP) 1- [4-amino-3,5-dibromo-A f - [[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-A - [[4- [1,3-dihydro-4- (3-methoxyphenyl) -2 (2H) -oxo-imidazole] -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- (cyclopropylmethyl) -4-piperidinyl] -piperidine, (BS) 1- [4-amino-3,5-dibromo- 1H - [[4- (3,4-dihydro-2 (1 H)] - 1-Oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1 H -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-Y- [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-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 (2 H) -oxoimidazol-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) -oxo-imidazol-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 (2/7) -oxoimidazole-1)] - -yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine, (BY) 1- [4-amino-1 - [[4- [4- ( 3-chlorophenyl) -1,3-dihydro-2 (2H) -oxoimidazol-1-yl] -1-piperidinylcarbonyl] -3,5-dibromo-D-phenylalanyl] -4- (1-methyl) -4-piperidinyl) -piperidine, (BZ) 1- [4-amino-3,5-dibromo-7Y [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2 (2W)]. 1-Oxoimidazol-1-yl -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-177-1-azepinyl) -piperidine, (CA) 1- [4-amino-3,5-dibromo-Y - [[4- [l, 3-dihydro-4- [3- (trifluoromethyl) phenyl] -2- (2 //) - oxoimidazo-yl] -l-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-methyl- -4-piperidinyl) -piperazine, (CB) 1- [4-amino-N - [[4- [4- (3-chlorophenyl) -1,3-dihydro-2 (2H) -oxoimidazole-1 -] - yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D-phenylalanyl] -4- (hexahydro-1H-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) -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 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [4- (1-oxoethyl) phenyl] -piperazine, (CF) 1- [3,5-dibromo-A4 [4- [3,4-dihydro-2 (1H) -oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] - 4- (l-me (CG) 1- [4-amino-3,5-dibromo-N '- [[4- [1,3-dihydro-4- (3-morphophenyl) -2 (2 H) -tyl-4-piperidinyl] piperazinyl] -. (7) -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 (l / 7) -oxochinazolín-yl] -3-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-pyTolidinyl) -piperidine, (CJ) 1 - [4-amino-3,5-dibromo-A I - [[4- (l, 3-dihydro-4-phenyl-2 (2/7) -oxoimidazo-1-yl) -1 - piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1H-1-azepinyl) -piperidine; and (CJ) 1- [4-amino-3,5-dibromo-4 '- [4- ( 1,3-dihydro-4- (3-thienyl) -2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) ) -piperazine, their tautomers, their diastereomers, their enantiomers, mixtures thereof and their physiologically acceptable salts, wherein the compounds:
(A) l-[A2-[3,5-dibróm-Y-[[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (B) l-[4-amino-3,5-dibróm-A’-[[4-(2,3,4,5-tetrahydro-2(l/7)-oxo-l ,3-benzodiazepin-3-yl)-l piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-piperidinyl)-piperidín, (I) 1 -[4-amino-3,5-dibróm-A'-[[4-(2,4-dihydro-5-fenyl-3(3//)-oxo-1,2,4-1 ri azo 1-2-yl)-1 -piperid i n yl]-kar bon y] ]-Ď-fenylalanyl]-4-(l -piperidinyl)-piperidín, (J) l-[4-amino-3,5-dibróm-AL[[4-(2,4-dihydro-5-fenyl-3(3/7)-oxo-l,2,4-triazol-2-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidínyl)-piperazín, (AC) (R,S)- i-[4-[4-(3,4-dihydro-2(l f/)-oxochinazolín-3-yl)-l-piperidinyl]-2-[(3,5-dibróm-4-metylfenyl)metyl]-l,4-dioxobutyl]-4-(4-metyl-1 -piperazinyl)-piperidín, (AF) 1 -[V2-[A'-[[4-(l ,3-dihydro-2(2//)-oxobcnzimidazol-1 -yl)-1 -piperidinyl] -karbonyl]-3,5 -dibróm-D-tyrozyl] -L-lyzyl]-4-(4-pyridinyl)-piperazín a (AM) l-[4-amino-3,5-dibróm-A'-[[4-[3,4-dihydro-2(l//)-oxochinazo!ín-3-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl] -4-( 1 -piper idinyl)-pi per id í n, ich tautoméry, ich diastereoméry, ich enantioméry, ich zmesi a ich fyziologicky prijateľné soli sú výhodné, pričom však zlúčeniny:(A) 1- [A 2- [3,5-dibromo-Y - [[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 (1 H) -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 (3 H) -oxo-1,2,4-1] azo 1- 2-yl) -1-piperidinyl] -carbonyl] -N-phenylalanyl] -4- (1-piperidinyl) -piperidine, (J) 1- [4-amino-3,5-dibromo-A L [[4- (2,4-dihydro-5-phenyl-3 (3/7) -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- [V 2 - [N '- [[4- (1,3-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, their tautomers, their diastereomers, their enantiomers, mixtures thereof, and their physiologically acceptable salts are preferred, but the compounds:
(A) l-[jV2-[3,5-dibróm-A-[[4-(3,4-dihydro-2(l//)-oxochinazolln-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín a (B) l-[4-amino-3,5-dibróm-/V-[[4-(2,3,4>5-tetrahydro-2( 1 //)-oxo-1,3 -benzo-diazepín-3 -yl)-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-( 1 -piperidinyl)-piperidín, ich tautoméry, ich diastereoméry, ich enantioméry, ich zmesi a ich fyziologicky prijateľné soli sú zvlášť výhodné.(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 and (B) 1- [4-amino-3,5-dibromo-N - [[4- (2,3,4) > 5-tetrahydro-2 (1 H) -oxo-1,3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, their tautomers, diastereomers, enantiomers, mixtures thereof, and physiologically acceptable salts thereof 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 uvoľňovania 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, polyvinyl-pyrolidónom, kyselinou citrónovou, kyselinou vínnou, vodou, vodou/etanolom, vodou/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.For this purpose, CGRP antagonists and / or CGRP release inhibitors may be formulated together with one or more inert, conventional carriers and / or diluents, for example, corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl-pyrrolidone. , citric acid, tartaric acid, water, water / ethanol, water / glycerine, 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 galenical 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) l-[N2-[3,5-dibróm-/V-[[4-(3,4-dihydro-2(lZ/)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (B) 1 -[4-amino-3,5-dibróm-Af-[[4-(2,3,4,5-tetrahydro-2(lH)-oxo-l,3-benzo-diazepín-3-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-piperidinyl)-piperidín, (I) I-[4-amino-3,5-dibróm-A'-[[4-(2,4-dihydro-5-fcnyl-3(3ŕ/)-oxo-l,2,4-triazol-2-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-piperidinyl)-piperidín, (J) 1 -[4-amíno-3,5-dibróm-/V-[[4-(2,4-dihydro-5-fenyl-3(3//)-oxo-l,2,4-triazol-2-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperazin, (AC) (R,5)-l-[4-[4-(3,4-dihydro-2(lH)-oxochinazolín-3-yl)-l -piperidinyl]-2-[(3,5-dibróm-4-metylfenyl)metyl]-l ,4-dioxobutyl]-4-(4-metyl-l-piperazinyl)-pipcridín, (AF) l-[Ar2-[/V-[[4-(l,3-dihydro-2(27/)-oxobenzimidazol-(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-A f - [[4- (2,3,4- 5-tetrahydro-2 (1H) -oxo-1,3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (I) I- [4-amino-3,5-dibromo-N - [[4- (2,4-dihydro-5-phenyl-3 (3 R /) - oxo-2,4-triazol-2-yl (1) -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 //) - oxo-2,4-triazol-2-yl) -l-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-methyl- -4-piperidinyl) -piperazine, (AC) (R, 5) -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- (l, 3-dihydro-2 (27 /) - oxobenzimidazol-
- l-yl)-l-piperidinyl]-karbonyl]-3,5-dibróm-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín a (AM) l-[4-amino-3,5-dibróm-A-[[4-[3,4-dihydro-2(lH)-oxochinazolín-3-yl)-1 -piperidinyl]karbonyl]-D-fenylalanyl] -4-( 1 -pi perid inyl)-pi peridín, v niektorej z nasledujúcich farmaceutických foriem na podávanie:-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-piperidide) inyl) -pi peridine, 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 incrvujc časť kože tváre. Už sa ukázalo, že dráždenie trigeminálneho ganglionu u ľudí vedie k zvýšeniu hladiny CGRP v plazme a vyvoláva sčervenanie tváre ([4]: P. J. Goadsby a ďalší, Annals of Neurology 23(2), 193-196, 1988).CGRP releases sensory nerves, such as the Nervus Trigeminus (trigeminal nerve), which increments part of the skin of the face. Irritation of the trigeminal ganglion in humans has already been shown to lead to elevated plasma CGRP levels and to induce facial flushing ([4]: P.J. Goadsby et al., Annals of Neurology 23 (2), 193-196, 1988).
Na dôkaz, že pomocou CGRP-antagonistov a inhibítorov uvoľňovania CGRP sa návaly horúčavy dajú úspešne liečiť, sa pri kozmáčoch 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 cervical release of endogenous CGRP was induced by stimulation of the trigeminal ganglion, resulting in increased vascular blood flow. 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) l-[7V!-[3,5-dibróm-iV-[[4-(3,4-dihydro-2(lÄ)-oxochinazolín-3-yl)-1 -piperidinyl]-karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (B) 1 -[4-amino-3,5-dibróm-7V-[[4-(2,3,4,5-tetrahydro-2(1 W)-oxo-l,3-benzo-diazepín-3-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-piperidinyl)-piperidin, (AC) (Ä,5)-l-[4-[4-(3,4-dihydro-2(l/ŕ)-oxochinazolín-3-yl)-l-piperidinyl]-2-[(3,5-dibróm-4-metylfenyl)metyI]-l,4-dioxobutyl]-4-(4-metyl-1 -piperazinylj-piperidín, (AM) l-[4-amino-3,5-dibróm-A-[[4-[3,4-dihydro-2(l//)-oxochinazolín-3-yl)-1 -piperidinyl]karbonyl]-D-feny]alanyl]-4-(l-piperidinyl)-piperidín, (DA) = sumatriptan a (DB) = zolmitriptan.(A) 1- [7V ! - [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-7H - [[4- (2,3,4,5-tetrahydro-2 (1W)] - oxo-1,3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (AC) (R, 5) -1- [4] - [4- (3,4-dihydro-2 (l / t) -oxochinazolín-3-yl) -l-piperidinyl] -2 - [(3,5-dibromo-4-methylphenyl) methyl] -l, 4 -dioxobutyl] -4- (4-methyl-1-piperazinyl) -piperidine, (AM) 1- [4-amino-3,5-dibromo-N - [[4- [3,4-dihydro-2 (1 H)] - N-Oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenyl-alanyl] -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). Hlava zvierat sa fixuje v stereotaktickom prístroji. Po otvorení kože hlavy pozdĺžnym rezom sa do lebky vyvŕta malá dierka a do trigeminálneho ganglionu sa zapustí bipoláma elektróda (Rhodes SNES 100).Both sexes (300-400 g) are anesthetized with pentobarbital (initially 30 mg / kg, i.p. (intraperitoneal), 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). The animal head is fixed in a stereotactic apparatus. After opening the scalp with a longitudinal incision, 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 rôntgenovou snímkou, ktorá zviditeľni kostenú štruktúru lebky. Ako orientácia na umiestnenie elektródy (rôntgenový prístroj CCX-Digital) 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. Rock bone is used as the orientation of the electrode (CCX-Digital 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 laser-Dopplerovho merania prietoku pomocou zariadenia PeriFlux Laser Doppler Systém.Blood flow in the microvessels of the facial skin is measured 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 1 „50 %-dávka“ = intravenózna dávka, ktorá zníži endogénnym CGRP vyvolané zvýšené prekrvenie kože tváre o 50 %Table 1 "50% -dose" = intravenous dose that reduces 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, naprí5 klad 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, e.g. of said active substances (A) or (B).
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION 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) 1,0 mg mliečny cukor 20,0 mg kapsuly z tvrdej želatíny 50,0 mgpowder inhalation capsule contains: active ingredient (A) or (B) 1.0 mg milk sugar 20.0 mg hard gelatin capsules 50.0 mg
71,0 mg71.0 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: účinná látka (A) alebo (B) benzalkóniumchlorid dinátriumetyléndiamíntetraacetát 0,0075 mg čistená voda ad 15,0 pldose contains: active ingredient (A) or (B) benzalkonium chloride disodium ethylenediamine tetraacetate 0.0075 mg purified water ad 15.0 µl
Spôsob výrobyMethod of production
Účinná látka a benzalkóniumchlorid sa rozpustia vo vode a naplnia sa do Respimat® kartuši.The active ingredient and benzalkonium chloride are dissolved in water and filled into a Respimat® cartridge.
Príklad 3Example 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:
1,0 mg1.0 mg
0.002 n0.002 n
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:
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 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.
mgmg
q. s.q. with.
250 mg mg250 mg mg
250 mg ml mg mg mg ad 1 ml250 mg ml mg mg mg ad 1 ml
100 mg mg mg 180 mg mg mg ad 10 ml100 mg mg mg 180 mg mg mg ad 10 ml
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: účinná látka (A) alebo (B) v bázickej forme kyselina/látka, vytvárajúca soľ, v množstve, potrebnom na vytvorenie neutrálnej soli glukóza albumín ľudského séra glykofurol voda na injekčné účely adIngredients: active ingredient (A) or (B) in acid / salt-forming base in an amount necessary to form the neutral salt glucose albumin human serum glycofurol water for injection purposes ad
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 polysorbát 80 = Tween 80 voda na injekčné účelyactive substance (A) or (B) in basic form glucose polysorbate 80 = Tween 80 water for injection
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:
účinná látka (A) alebo (B) v bázickej forme d i hyd rogen fosforečn an draselný = KH2PO4 hydrogenfosforečnan disodný = Na2HPO4-2H2O chlorid sodný albumín ľudského séra polysorbát 80 voda na injekčné účelyactive ingredient (A) or (B) in basic form potassium phosphate dibasic = KH 2 PO 4 disodium hydrogen phosphate = Na 2 HPO 4 -2H 2 O sodium chloride human serum albumin polysorbate 80 water for injections
VýrobaProduction
Polysorbát 80, chlorid sodný, dihydrogenfosforečnan draselný a hydrogenfosforečnan disodný rozpustiť vo vode na injekčné účely (Wfi); pridať albumín ľudského séra;Dissolve polysorbate 80, sodium chloride, potassium dihydrogen phosphate and disodium hydrogen phosphate in water for injection (Wfi); add human serum albumin;
rozpustiť účinnú látku pri zahrievaní; s Wfi doplniť na stanovený objem; naplniť do ampúl.dissolve the active ingredient upon heating; make up to volume with Wfi; fill into ampoules.
mgmg
q. s.q. with.
300 mg ad 2 ml mg300 mg ad 2 ml mg
200 mg ad 10 ml200 mg ad 10 ml
Príklad 9Example 9
Lyofilizát s 10 mg účinnej látky (A) alebo (B) Zloženie: účinná látka (A) alebo (B) v bázickej forme kyselina/látka, vytvárajúca soľ, v množstve, potrebnom na vytvorenie neutrálnej soli manitol voda na injekčné účelyLyophilisate with 10 mg of active ingredient (A) or (B) Ingredients: active ingredient (A) or (B) in acid / salt form, in the amount required to form the neutral salt of mannitol water for injections
VýrobaProduction
Rozpustiť manitol vo vode na injekčné účely (Wfi); pridať látku, vytvárajúcu soľ; rozpustiť účinnú látku pri zahrievaní; s Wfi doplniť na stanovený objem; naplniť do liekoví ek; vysušiť vymrazovaním.Dissolve mannitol in water for injection (Wfi); add a salt-forming agent; dissolve the active ingredient upon heating; make up to volume with Wfi; refill into medicines; freeze-dry.
Rozpúšťadlo pre lyofilizát: polysorbát 80 = Tween 80 manitol voda na injekčné účelySolvent for lyophilisate: polysorbate 80 = Tween 80 mannitol water for injections
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: účinná látka (A) alebo (B) v bázickej forme 5 mg poláme alebo nepoláme rozpúšťadlo (ktoré sa dá odstrániť sušením vymrazovaním) ad 1 mlIngredients: active ingredient (A) or (B) in base form 5 mg of 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.
Rozpúšťadlo pre lyofilizát: polysorbát 80 = Tween 80 manitol voda na injekčné účelySolvent for lyophilisate: polysorbate 80 = Tween 80 mannitol water for injections
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) Zloženie: účinná látka (A) alebo (B) laktóza kukuričný škrob stearan horečnatý Povidon K25Tablets of 20 mg active ingredient (A) or (B) Ingredients: active ingredient (A) or (B) lactose maize starch magnesium stearate Povidone K25
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) Zloženie: účinná látka (A) alebo (B) 20 mg kukuričný škrob 80 mg vysokodisperzná kyselina kremičitá 5 mg mgCapsules with 20 mg of active substance (A) or (B) Ingredients: active substance (A) or (B) 20 mg corn starch 80 mg highly disperse silicic acid 5 mg mg
100 mg ad 2 ml mg100 mg ad 2 ml mg
120 mg mg mg mg stearan horečnatý 2,5 mg120 mg mg mg mg magnesium stearate 2.5 mg
VýrobaProduction
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: účinná látka (A) alebo (B) kyselina soľná v množstve, potrebnom na vytvorenie neutrálnej soli metylester kyseliny parahydroxybenzoovej (PHB) propylester kyseliny parahydroxybenzoovej (PHB) čistená vodaIngredients: active 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
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 čistenou vodou na stanovený objem; roztok sa sterilizuje filtráciou a naplní sa do vhodnej nádoby.The 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 to volume with purified water; 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: účinná látka (A) alebo (B) 1,2-propándiol hydroxyetylcelulóza kyselina sorbová čistená vodaIngredients: active ingredient (A) or (B) 1,2-propanediol hydroxyethylcellulose sorbic acid purified water
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:
účinná látka (A) alebo (B)active substance (A) or (B)
1,2-propándiol manitol voda na injekčné účely1,2-propanediol mannitol water for injection purposes
VýrobaProduction
Účinná látka sa rozpustí v 1,2-propándiole; roztok sa sThe active substance is dissolved in 1,2-propanediol; solution with
Wfi doplní približne na stanovený objem; pridá sa manitolWfi makes up to approximately the determined volume; Mannitol is added
10,0 mg10.0 mg
0,01 mg0.01 mg
0,005 mg ad 1,0 ml mg 300mg mg mg ad 1 ml mg0.005 mg ad 1.0 ml mg 300 mg mg ad 1 ml mg
300 mg mg ad 1 ml a s Wfi sa doplní na stanovený objem; roztok sa sterilizuje filtráciou, naplní sa do jednotlivých nádob a autoklávuje sa.300 mg mg ad 1 ml and make up to volume with Wfi; the solution is sterilized by filtration, filled into individual containers and autoclaved.
Príklad 17Example 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) vaječný lecitin, napríklad Lipoid E 80 cholesterol glycerín voda na injekčné účelyactive ingredient (A) or (B) egg lecithin, for example Lipoid E 80 cholesterol glycerin water for injection
7,5 mg7,5 mg
100,0 mg100.0 mg
50,0 mg50.0 mg
50,0 mg ad 1,0 ml50.0 mg 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:
účinná látka (A) alebo (B) karboxymetylcelulóza (CMC) pufer hydrogenfosforečnan disodný/ dihydrogenfosforečnan sodný s pH 6,8 chlorid sodný metylester kyseliny parahydroxybenzoovcj propylester kyseliny parahydroxybenzoovej čistená vodaActive ingredient (A) or (B) Carboxymethylcellulose (CMC) Disodium hydrogen phosphate / Sodium dihydrogen phosphate buffer pH 6.8 Sodium chloride Methyl parahydroxybenzoate propyl Parahydroxybenzoic acid propyl ester Purified water
20,0 mg20.0 mg
20,0 mg20.0 mg
q. s.q. with.
8,0 mg8.0 mg
0,01 mg0.01 mg
0,003 mg ad 1,0 ml0.003 mg ad 1.0 ml
VýrobaProduction
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 látkv (A) alebo (B)Aqueous solution for subcutaneous administration with 10 mg of active substance (A) or (B)
Zloženie:Ingredients:
účinná látka (A) alebo (B) 10,0 mg pufer hydrogenfosforečnan disodný/ dihydrogenfosforečnan sodný q. s. ad pH 7,0 chlorid sodný 4,0 mg voda na injekčné účely ad 0,5 mlactive ingredient (A) or (B) 10.0 mg disodium hydrogen phosphate / sodium dihydrogen phosphate buffer q. with. ad pH 7.0 sodium chloride 4.0 mg water for injections ad 0.5 ml
VýrobaProduction
Účinná látka sa rozpusti 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 ingredient 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) 5,0 mg polysorbát 80 0,5 mg voda na injekčné účely ad 0,5 mlactive ingredient (A) or (B) 5.0 mg polysorbate 80 0.5 mg water for injections ad 0.5 ml
VýrobaProduction
Účinná látka sa suspenduje v polysorbáte 80 a pomocou vhodnej dispergačnej metódy (napríklad mletie za mokra, vysokotlaková homogenizácia, mikrofluidizácia atď.) 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 (3)
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 |
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| SK1972002A3 SK1972002A3 (en) | 2002-06-04 |
| SK285587B6 true SK285587B6 (en) | 2007-04-05 |
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| SK197-2002A SK285587B6 (en) | 1999-08-10 | 2000-08-05 | Use of CGRP antagonists and CGRP release inhibitors |
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| 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) |
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| ZA (1) | ZA200200997B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| AU2002359458A1 (en) | 2001-12-12 | 2003-06-23 | Eli Lilly And Company | Alanyl-piperidine heterocyclic derivatives useful against cardiovascular diseases |
| US6900317B2 (en) | 2002-02-19 | 2005-05-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Salts of the CGRP antagonist BIBN4096 and inhalable powdered medicaments containing them |
| DE10206770A1 (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 |
| 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 |
| 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 |
| US7595312B2 (en) | 2002-10-25 | 2009-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions |
| DE10300973A1 (en) * | 2003-01-14 | 2004-07-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New carboxylic acids and their esters, medicaments containing these compounds and processes for their preparation |
| CA2531407A1 (en) * | 2003-07-07 | 2005-01-20 | Boehringer Ingelheim International Gmbh | Use of cgrp antagonists in treatment and prevention of hot flushes in prostate cancer patients |
| AU2004259675A1 (en) * | 2003-07-15 | 2005-02-03 | Merck & Co., Inc. | Hydroxypyridine CGRP receptor antagonists |
| DE10338399A1 (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 |
| DE102004063752A1 (en) * | 2004-12-29 | 2006-07-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of selected CGRP antagonists to combat menopausal hot flashes |
| DE102004063755A1 (en) * | 2004-12-29 | 2006-07-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of CGRP antagonists for the treatment and prevention of hot flushes in patients with prostate cancer |
| 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 |
| US7491717B2 (en) | 2005-03-23 | 2009-02-17 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
| US7439237B2 (en) | 2005-04-15 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX9710479A (en) * | 1995-09-07 | 1998-03-31 | Oreal | Extract of iridaceae and compositions containing such extract. |
| US5910482A (en) * | 1996-03-19 | 1999-06-08 | Board Of Regents, The University Of Texas System | Treatment or prevention of preeclampsia, eclampsia with calcitonin gene related peptide, CGRP analog, progestational agent, nitric oxide source, and cyclooxygenase inhibitor |
| US5710024A (en) * | 1996-07-23 | 1998-01-20 | Smithkline Beecham Corporation | Polynucleotides that encode the calcitonin gene-related peptide receptor coponent factor (HOUNDC44) |
| JP3483893B2 (en) * | 1996-09-10 | 2004-01-06 | ドクトル カルル トーマエ ゲゼルシャフト ミット ベシュレンクテル ハフツング | Modified amino acids, drugs containing these compounds and methods 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 |
-
1999
- 1999-08-10 DE DE19937304A patent/DE19937304C2/en not_active Expired - Fee Related
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2000
- 2000-05-08 UA UA2002031932A patent/UA73137C2/en unknown
- 2000-08-05 JP JP2001514945A patent/JP2003506403A/en active Pending
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- 2000-08-05 EE EEP200200061A patent/EE04928B1/en not_active IP Right Cessation
- 2000-08-05 CN CNB008116156A patent/CN1166361C/en not_active Expired - Fee Related
- 2000-08-05 CZ CZ20020497A patent/CZ300513B6/en not_active IP Right Cessation
- 2000-08-05 WO PCT/EP2000/007613 patent/WO2001010425A2/en active Application Filing
- 2000-08-05 ES ES00958385T patent/ES2231243T3/en not_active Expired - Lifetime
- 2000-08-05 BR BR0013009-5A patent/BR0013009A/en active Pending
- 2000-08-05 AT AT00958385T patent/ATE281168T1/en not_active IP Right Cessation
- 2000-08-05 MX MXPA02001373A patent/MXPA02001373A/en active IP Right Grant
- 2000-08-05 YU YU8302A patent/YU8302A/en unknown
- 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 EA EA200200207A patent/EA007531B1/en not_active IP Right Cessation
- 2000-08-05 CA CA002378428A patent/CA2378428C/en not_active Expired - Fee Related
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- 2000-08-05 DE DE50008527T patent/DE50008527D1/en not_active Expired - Lifetime
- 2000-08-05 AU AU69928/00A patent/AU777709B2/en not_active Ceased
- 2000-08-05 ZA ZA200200997A patent/ZA200200997B/en unknown
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- 2000-08-05 PL PL364049A patent/PL198483B1/en not_active IP Right Cessation
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2002
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- 2002-02-07 NO NO20020605A patent/NO20020605L/en not_active Application Discontinuation
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