SK285587B6 - Použitie CGRP-antagonistov a inhibítorov uvoľňovania CGRP - Google Patents
Použitie CGRP-antagonistov a inhibítorov uvoľňovania CGRP 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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- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 230000002265 prevention Effects 0.000 description 1
- 229960000425 rizatriptan Drugs 0.000 description 1
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
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- 210000003901 trigeminal nerve Anatomy 0.000 description 1
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Classifications
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- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Abstract
Opísané je použitie aminokyselinových derivátov santagonistickými účinkami na CGRP na prípravu farmaceutických prostriedkov na potláčanie menopauzálnych návalov horúčavy.
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.
Doterajší stav techniky
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.
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.
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.
Podstata vynálezu
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.
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.
Ďalej sa vynález týka aj farmaceutického prostriedku, ktorý obsahuje ako účinnú látku jeden alebo viaceré CGRP-antagonisty a/alebo inhibítory uvoľňovania CGRP.
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.
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.
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.
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:
(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.
(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:
(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) 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.
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.
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.
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.
Na potláčanie menopauzálnych návalov horúčavy sú zvlášť vhodné lieky, obsahujúce jednu z účinných látok:
(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-
- 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:
- kapsuly na inhalovanie prášku s 1 mg účinnej látky, výhodne látky (A) alebo (B),
- inhalačný roztok pre zhmľovače s 1 mg účinnej látky, výhodne látky (A) alebo (B),
- aerosól na dávkovanie pomocou hnacieho plynu s 1 mg účinnej látky, výhodne látky (A) alebo (B),
- nosový sprej s 1 mg účinnej látky, výhodne látky (A) alebo (B),
- tablety s 20 mg účinnej látky, výhodne látky (B),
- kapsuly s 20 mg účinnej látky, výhodne látky (B),
- vodný roztok na nazálnu aplikáciu s 10 mg účinnej látky, výhodne látky (A) alebo (B),
- vodný roztok na nazálnu aplikáciu s 5 mg účinnej látky, výhodne látky (A) alebo (B), alebo
- suspenzia na nazálnu aplikáciu s 20 mg účinnej látky, výhodne látky (A) alebo (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).
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 %:
(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.
Opis metódy
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).
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.
Prietok krvi v mikrocievach kože tváre sa sníma prostredníctvom laser-Dopplerovho merania prietoku pomocou zariadenia PeriFlux Laser Doppler Systém.
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.
Tabuľka 1 „50 %-dávka“ = intravenózna dávka, ktorá zníži endogénnym CGRP vyvolané zvýšené prekrvenie kože tváre o 50 %
| Látka | 50%-dávka |
| A | 0,003 mg/kg |
| B | 0,042 mg/kg |
| AC | 0,018 mg/kg |
| AM | 0,046 mg/kg |
| DA | 0,280 mg/kg |
| DB | 0,035 mg/kg |
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).
Príklady uskutočnenia vynálezu
Príklad 1
Kapsuly na inhaláciu prášku s 1 mg účinnej látky (A) alebo (B)
Zloženie:
kapsula na inhaláciu prášku obsahuje: účinná látka (A) alebo (B) 1,0 mg mliečny cukor 20,0 mg kapsuly z tvrdej želatíny 50,0 mg
71,0 mg
Spôsob výroby
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.
Príklad 2
Inhalačný roztok pre Respimat® s 1 mg účinnej látky (A) alebo (B)
Zloženie:
dávka obsahuje: účinná látka (A) alebo (B) benzalkóniumchlorid dinátriumetyléndiamíntetraacetát 0,0075 mg čistená voda ad 15,0 pl
Spôsob výroby
Účinná látka a benzalkóniumchlorid sa rozpustia vo vode a naplnia sa do Respimat® kartuši.
Príklad 3
Inhalačný roztok pre zhmľovače s 1 mg účinnej látky (A) alebo (B)
Zloženie:
1,0 mg
0.002 n
| 1 fľaštička obsahuje: | |
| účinná látka (A) alebo (B) | 1,0 g |
| chlorid sodný | 0,18g |
| benzalkóniumchlorid | 0,002 g |
| čistená voda | ad 20,0 ml |
Spôsob výroby
Účinná látka, chlorid sodný a benzalkóniumchlorid sa rozpustia vo vode.
Príklad 4
Aerosól na dávkovanie pomocou hnacieho plynu s 1 mg účinnej látky (A) alebo (B)
Zloženie:
| 1 dávka obsahuje: | |
| účinná látka (A) alebo (B) | 1,0 mg |
| lecitín | 0,1 % |
| hnací plyn | ad 50,0 μΐ |
Spôsob výroby
Mikronizovaná účinná látka sa homogénne suspenduje v zmesi lecitínu a hnacieho plynu. Suspenzia sa naplní do tlakovej nádobky s dávkovacím ventilom.
Príklad 5
Nosový sprej s 1 mg účinnej látky (A) alebo (B)
Zloženie:
rozprašovaná dávka obsahuje:
| účinná látka (A) alebo (B) | 1,0 mg |
| manitol | 5,0 mg |
| dinátriumetyléndiamín- | |
| tetraacetát | 0,05 mg |
| kyselina askorbová | 1,0 mg |
| čistená voda | ad 0,1 ml |
| Spôsob výroby |
Účinná látka a pomocné látky sa rozpustia vo vode a naplnia sa do zodpovedajúcej nádobky.
mg
q. s.
250 mg mg
250 mg ml mg mg mg ad 1 ml
100 mg mg mg 180 mg mg mg ad 10 ml
Príklad 6
Injekčný roztok s 5 mg účinnej látky (A) alebo (B) na 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 ad
Výroba
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.
Príklad 7
Injekčný roztok na podkožnú aplikáciu s 5 mg účinnej látky (A) alebo (B) na 1 ml
Zloženie:
účinná látka (A) alebo (B) v bázickej forme glukóza polysorbát 80 = Tween 80 voda na injekčné účely
Výroba
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.
Príklad 8
Injekčný roztok so 100 mg účinnej látky (A) alebo (B) na 10 ml
Zloženie:
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 účely
Výroba
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.
mg
q. s.
300 mg ad 2 ml mg
200 mg ad 10 ml
Príklad 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 účely
Výroba
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.
Rozpúšťadlo pre lyofilizát: polysorbát 80 = Tween 80 manitol voda na injekčné účely
Výroba
Rozpustiť polysorbát 80 a manitol vo vode na injekčné účely (Wfi); naplniť do ampúl.
Príklad 10
Lyofilizát s 5 mg účinnej látky (A) alebo (B)
Zloženie: účinná látka (A) alebo (B) v bázickej forme 5 mg poláme alebo nepoláme rozpúšťadlo (ktoré sa dá odstrániť sušením vymrazovaním) ad 1 ml
Výroba
Rozpustiť účinnú látku vo vhodnom rozpúšťadle; naplniť do liekoviek; vysušiť vymrazovaním.
Rozpúšťadlo pre lyofilizát: polysorbát 80 = Tween 80 manitol voda na injekčné účely
Výroba
Rozpustiť polysorbát 80 a manitol vo vode na injekčné účely (Wfi); naplniť do ampúl.
Príklad 11
Tablety s 20 mg účinnej látky (A) alebo (B) Zloženie: účinná látka (A) alebo (B) laktóza kukuričný škrob stearan horečnatý Povidon K25
Výroba
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.
Príklad 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 mg
100 mg ad 2 ml mg
120 mg mg mg mg stearan horečnatý 2,5 mg
Výroba
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.
Príklad 13
Čapíky s 50 mg účinnej látky (A) alebo (B)
Zloženie:
účinná látka (A) alebo (B) 50 mg stužený tuk (Adeps solidus) q. s. ad 1700 mg
Výroba
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.
Príklad 14
Vodný roztok na nazálnu aplikáciu s 10 mg účinnej látky (A) alebo (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 voda
Výroba
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.
Príklad 15
Vodný roztok na nazálnu aplikáciu s 5 mg účinnej látky (A) alebo (B)
Zloženie: účinná látka (A) alebo (B) 1,2-propándiol hydroxyetylcelulóza kyselina sorbová čistená voda
Výroba
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.
Príklad 16
Vodný roztok na intravenóznu aplikáciu s 5 mg účinnej látky (A) alebo (B)
Zloženie:
účinná látka (A) alebo (B)
1,2-propándiol manitol voda na injekčné účely
Výroba
Účinná látka sa rozpustí v 1,2-propándiole; roztok sa s
Wfi doplní približne na stanovený objem; pridá sa manitol
10,0 mg
0,01 mg
0,005 mg ad 1,0 ml mg 300mg 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.
Príklad 17
Lipozómová formulácia na intravenóznu injekciu so 7,5 mg účinnej látky (A) alebo (B)
Zloženie:
účinná látka (A) alebo (B) vaječný lecitin, napríklad Lipoid E 80 cholesterol glycerín voda na injekčné účely
7,5 mg
100,0 mg
50,0 mg
50,0 mg ad 1,0 ml
Výroba
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.
Príklad 18
Suspenzia na nazálnu aplikáciu s 20 mg účinnej látky (A) alebo (B)
Zloženie:
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 voda
20,0 mg
20,0 mg
q. s.
8,0 mg
0,01 mg
0,003 mg ad 1,0 ml
Výroba
Účinná látka sa suspenduje vo vodnom roztoku CMC; ostatné zložky sa postupne pridajú k suspenzii a táto sa doplní čistenou vodou na stanovený objem.
Príklad 19
Vodný roztok na podkožnú aplikáciu s 10 mg účinnej látkv (A) alebo (B)
Zloženie:
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 ml
Výroba
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.
Príklad 20
Vodná suspenzia na podkožnú aplikáciu s 5 mg účinnej látky (A) alebo (B)
Zloženie:
účinná látka (A) alebo (B) 5,0 mg polysorbát 80 0,5 mg voda na injekčné účely ad 0,5 ml
Výroba
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.
Claims (3)
1. Použitie CGRP-antagonistu na prípravu farmaceutického prostriedku na potláčanie menopauzálnych návalov horúčavy, kde CGRP-anatagonista sa zvolí zo skupiny pozostávajúcej z:
(A) l-[Y2-[3,5-dibróm-A-[[4-(3,4-dihydro-2(lW)-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(17/)-oxo-l,3-benzo-diazepín-3-yl)-l-piperidinyl]karbonyl]-D-fcnylalanyl]-4-(l -piperidinylj-piperidín, (C) 1 -[AB-[4-amino-3,5-dibróm-A'-[[4-(3,4-dihydro-2(lH)-oxochinazolín-3-yi)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-L-lyzyl]-4-(4-pyridinyl)-piperazin, (D) l-[ŤV2-[4-amino-3,5-dibróm-Aľ-[[4-(3,4-dihydro-2(l/ú-oxochinazo!ín-3-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-L-lyzyl]-4-(4-pyridinyl)-piperidín, (E) l-[A2-[3,5-dibróm-A-[[4-(l,3-dihydro-4-fenyl-2(2//)-oxoimidazol-1 -yl)-1 -piperidinyl]-karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (F) l-[A2-[4-amino-3,5-díbróm-Aľ-[[4-(l ,3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1 -yl)-1 -piperidinylj-karbonylj-D-fenylalanyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (G) 1 -[3,5-dibróm-/v'-[[4-(3,4-dihydro-2( 1 //)-oxotieno[3,4-d]-pyrimidín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-(l-piperidinylj-piperidín, (H) l-[4-amino-3,5-dibróm-A-[[4-(2,4-dihydro-5-fenyl-3(32/)-oxo-l ,2,4-triazol-2-yl)-l-piperidinyI]-karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperidín, (I) l-[4-amino-3,5-dibróm-A-[[4-(2,4-dihydro-5-fenyl-3(3/7)-oxo-1,2,4-triazol-2-yl)-1 -pipcridinyl]-karbonyl]-D-fenylal anyl] -4-( 1 -piperidinylj-piperidín, (J) l-[4-amino-3,5-dibróm-A'-[[4-(2,4-dihydro-5-fenyl-3(3271-0X0-1,2,4-tri azol-2-yl)-l -piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperazín, (K) l-[4-amino-3,5-dibróm-/V-[[4-(3,4-dihydro-2(l/7)-oxotieno[3,2-d]-pyrimidin-3-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-piperidinylj-piperidín, (L) l-[4-amino-3,5-dibróm-A-[[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-/V-[[4-[3,4-dihydro-2(17f)-oxochínazolín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl] -4-( 1 -hexyl-4-p i p cr idi n yl)-pip er idí n, (N) l-[4-amíno-3,5-dibróm-,V-[[4-[3,4-dihydro-2('l//|-oxochinazolín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(l-cyklopropylmetyl-4-piperidinyl)-piperidín, (O) l-[A-[[4-[3,4-dihydro-2(12/)-oxochinazolin-3-yl]-l-piperidinyl]-karbonyl]-3-etenyl-D,L-fenylalanyl]-4-(hexahydro-l//-l-azcpínyl)-píperidín, (P) (R,S)-l-[4-[4-(3,4-dihydro-2(l/7)-oxochinazolín-3-yl)-l-piperidinyl]-2-[(4-hydroxy-3,5-dimetylfenyl)metyl]-l,4-dioxobutyl]-4-(l-piperidinylj-piperidín, (Q) l-[4-amino-3,5-dibróm-/V-[[4-[.'V-(aminokarbonyl)-V-fenyiamino]-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-4-(1 -piperidinylj-piperidín, (R) l-[4-amino-3,5-dibróm-Aľ-[[4-(3,4-dihydro-2(17/)-oxochinazolin-3-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(5-metoxy-4~pyrimidinyl)-piperazín, (S) l-[4-amino-3,5-dibróm-.'V-[[4-('l,l-dioxido-3(4//)-oxo-1,2,4-benzotiadiazín-2-yl)-1 -piperidinyl]-karbonyl] -D-fenylalanyl]-4-(l-piperidinyl)-piperidín, (T) l-[4-arnino-3,5-dibrórn-Aľ-[[4-[2(l/7)-oxochinolín-3-yl]-l-piperidinyl!]-karbonyl]-D-fenylalanyl]-4-(l-piperidinyl)-piperidín, (U) l-[4-amino-3,5-dibróm-A-[[4-[3,4-dihydro-2(l//)-oxochina7.olín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(3-(dimetylamino)propyl]-piperazín, (V) 1 -[4-amino-3,5-dibróm-Ar-[[4-[3,4-dihydro-2(l//)-oxochinazolín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-(4-metyl-l -piperazinyl]-piperidín, (W) l-[4-amino-3,5-dibróm-N-[[4-[3,4-dihydro-2(l//)-oxochinazolín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl] -4-[( 1 -metyI-4-piperidinyl)karbonyl] -piperazin, (X) l-[4-amino-3,5-dibróm-AI-[[4-[3,4-dihydro-2(l//)-oxochinazolín-3-yl]-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-[(l-metyl-4-piperazinyl)karbonyl]-piperazín, (Y) l-[4-amino-3,5-dibróm-A-[[4-(3,4-dihydro-2(l//J-oxochinazolín-3 -yl)-1 -piperidinyl]-karbonyl] -D-fenylalanyI]-4-[4-[4-(dimetylamino)butyl]fenyl]-piperazin, (Z) l-[4-amino-3,5-dibrórn-A-[[4-('3,4-dihydro-2(l//'|-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-4-[4-(dimetylarnino)-l-piperidinyl]-piperidin, (AA) l-[Y2-[[4-(l >3-dihydro-4-fenyl-2(2//)-oxoi’T>'dazol-1 -yl)-1 -piperidinyl]-karbonyl]-M-metyl-D-tryptyl]-4-(4-metyl-1 -piperazinyl)-piperidín, (AB) 1 -[.'V2-[[4-(l .3-dihydro-4-fenyl-2(2/7)-oxoimidazol-1 -yl)-1 -p iperidtnyl J-karbonyl]-iV-( 1,1 -dimetyletoxykarbonyl )-D-tryptyl] -4-( 1 -metyl-4-piperi dinyl)-piperidí n, (AC) (R, S)-1 -[4-[4-(3,4-dihydro-2( 1 //)-oxoch inazolin-3 -yl)-1 -piperidinyl]-2-[(3,5-dibróm-4-metylfenyl)metyl]-1,4-dioxobutyl]-4-(4-metyl-l-piperazinyl)-piperidin, (AD) (Ä,5)-l-[4-[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-1 -piperidinyl]-2-[(3,5-dibróm-4-metoxyfcnyl)metyl]-1,4-dioxobutyl]-4-( 1 -metyl-4-piperidinyl)-piperidín, (AE) (R, S)-1 -[4-[4-(3,4-dihydro-2( 1 ŕ/)-oxochinazolín-3 -yl)-1 -piperidinyl]-2-[(3,4-dibrómfenyl)metyl]-1,4-dioxobutyl]-4-(4-metyl-1 -piperazinyl)-piperidín, (AF) 1 -|W2-[JV-[[4-(l ,3-dihydro-2(27/)-oxobenzimidazol-l-yl)-l-piperidinyl]-karbonyl]-3,5-dibróm-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (AG) l-[4-amino-3,5-dibróm-A'-[[4-(l,3-dihydro-6-hydroxy-2(2//)-oxobenzimidazol-1 -yl)-1 -piper idinyl]-karbonyl]-D-fenylalanyl]-4-( 1 -piperidinyl)-piperidín, (AH) 1 -[A'2-[4-ami no-3,5-dibróm-M-[[4-( 1,3-dihydro-2(2//)-oxobenzimidazol-1 -yl)-1 -piperidinyl]-karbonyl]-D-fenylalanyl]-A6,7V6-dimetyl-L-lyzyl]-4-(4-pyridinyl)-piperazín, (Al) 1 -[A2-[4-amino-3,5-dibróm-A-[[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-fenylalanyl]-Al6,7V6-dimetyl-L-lyzyl]-4-(4-pyridinyl)-piperazín, (AJ) (R,S)-1 -[2-(4-amino-3,5-dibrómbenzoyl)-4-[4-(3,4-dihydro-2(l//)-oxo-chinazolín-3-yl)-l-piperidinyl]-4-oxobutyl]-4-(l-piperidinyl)-piperidin, (AK) 1 -[4-amino-3,5-dibróm-iV-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzotiadiazín-3-yl)-1 -piperidinyl Jkarbonyll-D-fenylalanyl]-4-( 1 -piperidinyl)-piperidín, (A L) 1 -[4-ami no-3,5-dibróm-.V-[[4-[ 1,3-d i h yd ro-2(2//)-oxoimidazo[4,5-c]-chinolin-3-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-( 1 -piperidinyl)karbonyl]-piperidín, (AM) l-[4-amino-3,5-dibróm-Ar-[[4-[3,4-dihydro-2(lH)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-fenyIalanyl]-4-( 1 -piperidinyl)-piperidín, (ΑΝ) 1 -[.V2-[3,5-dibróm-N-[[4-(3,4-dihydro-2( 1 H)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-A6,Ms-dimetyl-L-lyzyl]-4-(4-pyridinyl]-piperazín, (AO) l-[4-amino-/V-[[4-[4-(3-brómfenyl)-l,3-dihydro-2(2H)-oxoimidazol -1 -yl]-1 -piperidinyl]karbonyl]-3,5-dibróm-D-fenylalanyl]-4-( 1 -metyl-4-piperidinyl)-piperidín, (AP) 1 -[4-amino-3,5-dibróm-A'-[[4-[ 1,3-dihydro-4-fenyl-2(2H)-°xo™>dazol-1 -yl]-1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(4-metyl-l-piperazinyl)-piperidín, (AQ) l-[4-amino-3,5-dibróm-A-[[4-[l,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2Z/)-oxoimidazoI-l-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-piperidinyl)-piperidín, (AR) l-[4-amino-3,5-dibróm-A-[[4-[l,3-dihydro-4-[3-(trifluórmetyl)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) l-[3,5-dibróm-A-[[4-(l,3-dihydro-4-fenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-(1 -piperidinyl)-piperidín, (AT) 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-( 1 -etyl-4-piperidinyl )-piperazin, (AU) 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-(hexahydro-4-metyl-177-1,4-diazepín-l-yl)-piperidín, (AV) l-[3,5-dibróm-Y-[[4-(3,4-dihydro-2(l/7)-oxochinazolín-3 -yl)-1 -piper idinyl ] -karbonyl] -D-tyrozyl] -4-[ 1 -(metylsulfonyl)-4-piperidinyl]-piperidín, (AW) l-[4-amino-3,5-dibróm-A'~[[4-(l,3-dihydro-4-fenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperidín, (ΑΧ) 1 -[3,5-dibróm-jV-[[4-[l ,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(27/)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-tyrozyl]-4-(hexahydro-17/-l-azepinyl)-piperidín, (AY) l-[3,5-dibróm-Y-[[4-[3,4-dihydro-2(177)-oxochinazolín-3-yl]-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-[l-metyl-4-piperidinyl]-piperidín, (AZ) 1 -[4-amino-3,5-dibróm-/V-[[4-[3,4-dihydro-2(l/7)-oxochinazolín-3-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(cx°-8-mctyl-8-azabicyklo-[3,2,l]okt-3-yl)-piperazín, (BA) 1 -[4-amino-3,5-dibróm-7V-[[4-( 1,3-dihydro-4-fenyl-2(277)-oxoimidazol-1 -yl)-1 -piperidinyl] karbonyl] -D-fenylalanyI]-4-( 1 -metyl-4-piperidinyl)-piperazín, (BB) 1 -[3,5-dibróm-'V-[[4-[ 1,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2/7)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-tyrozyl]-4-( 1 -piperidinyl)-piperidín, (BC) 1 -[Aŕ-acctyl-A2-[3,5-dibrómW-[[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazín, (BD) 1 -[3,5-dibróm-A'-[[4-( 1,3-dihydro-4-fenyl-2(2//)-oxoimidazol-1 -yl)-1 -piperidinyl]-karbonvl]-D-tyrozyl]-4-(hexahydro-1 H-1 -azepinyl)-piperidín, (BE) l-[4-amino-3,5-dibróm-/V-[[4-(l,3-dihydro-4-(3-tienyl)-2(277)-oxoimidazol-l-yl)-l-piperidinyl]karbonyl]D-fenylalanyl]-4-( 1 -metyl-4-piperidmyl)-piperidín, (BF) l-[4-amino-3,5-dibróm-.V-[[4-[l,3-dihydro-4-[3-(t ri fl uó rmc t yl )fe n y 1 ]-2 (2/Z)-o xo i mi d azo 1 -1 -yl] -1 -piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)piperidín, (BG) l-[3,5-dibróm-N-[[4-(3,4-dihydro-2(l//)-oxochinazolin-3-yl)-1 -piperidinyl]-karbonyl]-D-tyrozyl]-4-[ 1 -(hydroxykarbonylmetyl)-4-piperidinyl]-piperidín, (BH) l-[4-amino-3,5-dibróm-W-[[4-[3,4-dihydro-2(l/f)-oxochinazolín-3-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-( 1 -metylsulfonyl-4-piperidinyl)-piperidín, (BI) l-[3,5-dibróm-.V-[[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-(4-piperidinyl)-piperidín, (BJ) l-[4-amino-3,5-dibróm-ýV-[[4-(l,3-dihydro-4-fenyl-2(2ŕ/)-oxoimidazol-l-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-etyl-4-piperidinyl)-piperidín, (BK) l-[4-amino-3,5-dibrórtwV-[[4-(l,3-dihydro-4-(3-hydroxyfenyl)-2(2/7)-oxo-ímídazol-l-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-( 1 -metyl-4-piperidinyl)-piperidín, (BL) l-[3,5-dibróm-iV-[[4-(3,4-dihydro-2(l//)-oxoehinazolin-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-(hexahydro-1 H-1 -azepinyl (-piperidín, (BM) l-[4-amino-3,5-dibróm-7V-[[4-(l,3-dihydro-4-fenyl-2(2Z/)-oxoimidazol-1 -yl)-1 -piperidinyl]karbonyl]-D-fenylal anyl]-4-( 1 -piperidinyl)-piperidín, (BN) l-[4-amino-3,5-dibróm-W-[[4-[4-(3-brómfenyl)-1,3-dihydro-2(2//)-oxoimidazol-1 -yl]-1 -píperídinyljkarbonyl]-D-fenylalanyl]-4-(exo-8-metyl-8-azabicyklo-[3,2,l]okt-3-yl)-piperazín, (BO) l-[4-amino-3,5-dibróm-7V-[[4-(3,4-dihydro-2(l//)-oxochinazolin-3-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl] -4-( 1 -etyl -4-piper id inyl )-piperidín, (BP) l-[4-amino-3,5-dibróm-;V-[[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l -etyl-4-piperidinyl)-piperazín, (BQ) l-[4-amino-3,5-dibróm-A'-[[4-[l ,3-dihydro-4-(3-metoxyfenyl)-2(2//)-oxo-imidazol-1 -yl]-l -píperidinyl Jkarbonyl]-D-fenylalanyl]-4-(exo-8-metyi-8-azabicyklo[3,2,1 ]okt-3-yl)-pi perazín, (BR) l-[3,5-dibróm-N-[[4-(3,4-dihydro-2(l//)-oxochinazolín-3-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-[l-(cyklopropylmetyl)-4-piperidinyl]-piperidín, (BS) l-[4-amino-3,5-dibróm-,V-[[4-(3,4-dihydro-2(lŕf)-oxochinazolín-3-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(hexahydro-1 H-1 -azepinyl)-piperidín, (BT) 1 -[4-amino-3,5-dibróm-JV-[[4-(3,4-dihydro-2(lH)-oxochinazolín-3-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(4-piperidinyl)-piperidín, (BU) l-[3,5-dibróm-X-[[4-(l,3-dihydro-4-fenyl-2(2//)-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(2/í)-oxoimidazol-l-yl]-l-piperidmyl]karbonyl]-D-tyrozyl]-4-(l-metyl-4-piperidinyl)-piperazín, (BW) 1 -pV2-[3,5-dibróm-ÍV-[[4-[ 1,3 -dihydro-4-[3-(trifluórmetyl)fenyl]-2(2//)-oxo-imtdazol-l-yl]-l-piperidinyl]karbonyl]-D-tyrozyl]-L-lyzyl]-4-(4-pyridinyl)-piperazin, (BX) l-[3,5-dibróm-;V-[[4-(l,3-dihydro-4-(3-tienyl)-2(2W)-oxoimidazol-l-yl)-l-piperidinyl]karbonyl]-D-tyrozyl]-4-( I -píperidinyl )-pí peridín, (BY) l-[4-amino-Ar-[[4-[4-(3-chlórfenyl)-l,3-dihydro-2(2//)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-3,5-dibróm-D-fenylalanyl]-4-( 1 -metyl-4-piperidinyl)-piperidín, (BZ) l-[4-amino-3,5-dibróm-N-[[4-[l,3-dihydro-4-[3-(trifluórmetyl)fenyl]-2(2ŕ/)-oxoimidazol-1 -yl]-1 -piperidínyl]karbonyl]-D-fenylalanyl]-4-(hexahydro-l//-l-azepinyl)-piperidín, (CA) 1 -[4-amino-3,5-dibróm-N-[[4-[ 1,3-d ihydro-4-[3 -(trifluórmetyl)fenyl]-2(2W)-oxoimidazol-l-yl]-l-piperi dinyl]karbonyl]-D-fenylalanyl]-4-( 1 -metyl-4-piperidinyl)-pipcridín, (CB) l-[4-amino-N-[[4-[4-(3-chlórfenyl)-l ,3-dihydro-2(2/f)-oxoimidazol-1 -yl]-1 -píperidinyl] karbonyl]-3,5-dibróm-D-fenylalanyl]-4-(hexahydro-1 H-1 -azepinylj-piperidín, (CC) l-[4-amino-3,5-dibróm-A'-[[4-(l,3-dihydro-4-fcnyl-2(2//)-oxoimidazol-l-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(4-pyridinyl)-piperazín, (CD) l-[3,5-dibróm-Aí-[[4-(l,3-dihydro-4-fenyI-2(2//)-oxoimidazol-l-yl)-l-piperidinyl]-karbonyl]-D-tyrozyl]-4-(1 -metyl-4-piperidín yl )-p iperidín, (CE) 1 -[4-amino-3,5-dibróm-7V-[[4-[ 1,3-dihydro-4-fenyl-2(2/í)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-[4-(l-oxoetyl)fenyl]-piperazín, (CF) 1 -[3,5-dibróm-A'-[[4-[3,4-dihydro-2( 1 //)-oxochinazoIín-3 -yl] -1 -piperidinyl]-karbonyl]-D-tyrozyl]-4-( I -mctyl-4-piperidinyl)-piperazín, (CG) l-[4-amino-3,5-dibróm-/V-[[4-[l,3-dihydro-4-(3-nitrofenyl)-2(2//)-oxoimidazol-l-yl]-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperidín, (CH) l-[4-amino-3,5-dibróm-A-[[4-[3,4-dihydro-2(l//)-oxochinazolín-l-yl]-3-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-pyrolidinyl)-piperidín, (Cl) 1 -[4-amino-3,5-dibróm-<V-[[4-( 1,3-dihydro-4-fenyl-2(2//)-oxoimidazol-1 -yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(hcxahydro-l/7-1-azepinyl (-piperidín a (CJ) l-[4-amino-3,5-dibróm-/V-[[4-(l,3-dihydro-4-(3-tienyl)-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]karbonyl]-D-fenylalanyl]-4-(l-metyl-4-piperidinyl)-piperazin, ich tautoméry, ich diastereoméry, ich enantioméry, ich zmesi a ich fyziologicky prijateľné soli.
2. Použitie podľa nároku 1, kde je farmaceutický prostriedok ako doplnok hormonálnej substitučnej terapie.
3. Použitie podľa nároku 1, kde farmaceutický prostriedok obsahuje len jednu účinnú látku.
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| DE19937304A DE19937304C2 (de) | 1999-08-10 | 1999-08-10 | Verwendung von CGRP-Antagonisten zur Bekämpfung menopausaler Hitzewallungen |
| PCT/EP2000/007613 WO2001010425A2 (de) | 1999-08-10 | 2000-08-05 | Verwendung von cgrp-antagonisten und cgrp-release-hemmern zur bekämpfung menopausaler hitzewallungen |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19952147A1 (de) | 1999-10-29 | 2001-05-03 | Boehringer Ingelheim Pharma | Neue Cyclopropane, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
| DE10139410A1 (de) * | 2001-08-17 | 2003-02-27 | Boehringer Ingelheim Pharma | Verwendung von BIBN4096 in Kombination mit anderen Arzneistoffen gegen Migräne für die Behandlung von Migräne |
| WO2003050109A1 (en) * | 2001-12-12 | 2003-06-19 | Eli Lilly And Company | Alanyl-piperidine heterocyclic derivatives useful against cardiovascular diseases |
| US6900317B2 (en) | 2002-02-19 | 2005-05-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Salts of the CGRP antagonist BIBN4096 and inhalable powdered medicaments containing them |
| DE10206770A1 (de) * | 2002-02-19 | 2003-08-28 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung eines Pulverinhalativums enthaltend ein Salz des CGRP-Antagonisten BIBN4096 |
| DE10207026A1 (de) * | 2002-02-20 | 2003-08-28 | Boehringer Ingelheim Kg | Pulverinhalativum, enthaltend den CGRP-Antagonisten BIBN4096 und Verfahren zu dessen Herstellung |
| DE10227294A1 (de) * | 2002-06-19 | 2004-01-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Zubereitungen zur intranasalen Applikation ausgewählter, von Aminosäuren abgeleiteter CGRP-Antagonisten sowie Verfahren zu deren Herstellung |
| 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 (de) * | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| DE10300973A1 (de) * | 2003-01-14 | 2004-07-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Carbonsäuren und deren Ester, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
| CA2531407A1 (en) * | 2003-07-07 | 2005-01-20 | Boehringer Ingelheim International Gmbh | Use of cgrp antagonists in treatment and prevention of hot flushes in prostate cancer patients |
| JP2007523870A (ja) * | 2003-07-15 | 2007-08-23 | メルク エンド カムパニー インコーポレーテッド | ヒドロキシピリジンｃｇｒｐ受容体拮抗薬 |
| DE10338399A1 (de) * | 2003-08-18 | 2005-03-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Mikropartikel, enthaltend den CGRP-Antagonisten 1-[N2-[3,5-Dibrom-N-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-Iysyl]-4-(4-pyridinyl)-piperazin, Verfahren zu deren Herstellung sowie deren Verwendung als Inhalaltionspulver |
| DE102004015723A1 (de) | 2004-03-29 | 2005-10-20 | Boehringer Ingelheim Pharma | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| 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 |
| DE102004019492A1 (de) * | 2004-04-22 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| DE102004063752A1 (de) * | 2004-12-29 | 2006-07-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung ausgewählter CGRP-Antagonisten zur Bekämpfung menopausaler Hitzewallungen |
| DE102004063755A1 (de) * | 2004-12-29 | 2006-07-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von CGRP-Antagonisten zur Behandlung und Vorbeugung von Hitzewallungen bei Patienten mit Prostatakrebs |
| EP1770091A1 (de) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| US7491717B2 (en) | 2005-03-23 | 2009-02-17 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
| US7439237B2 (en) | 2005-04-15 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997009056A1 (fr) * | 1995-09-07 | 1997-03-13 | L'oreal | Extrait d'iridacees et compositions le contenant |
| 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) |
| DE59712953D1 (de) * | 1996-09-10 | 2008-09-04 | Boehringer Ingelheim Pharma | Abgewandelte Aminosäuren, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
| DE19911039A1 (de) * | 1999-03-12 | 2000-09-14 | Boehringer Ingelheim Pharma | Abgewandelte Aminosäureamide, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
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- 2000-08-05 WO PCT/EP2000/007613 patent/WO2001010425A2/de active Application Filing
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- 2000-08-05 ES ES00958385T patent/ES2231243T3/es not_active Expired - Lifetime
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