AU6992800A - Use of CGRP antagonists for combating menopausal hot flushes - Google Patents
Use of CGRP antagonists for combating menopausal hot flushes Download PDFInfo
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- AU6992800A AU6992800A AU69928/00A AU6992800A AU6992800A AU 6992800 A AU6992800 A AU 6992800A AU 69928/00 A AU69928/00 A AU 69928/00A AU 6992800 A AU6992800 A AU 6992800A AU 6992800 A AU6992800 A AU 6992800A
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- Prior art keywords
- piperidinyl
- dibromo
- dihydro
- carbonyl
- amino
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- 238000005259 measurement Methods 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- HBYABCRZKRAJCW-UHFFFAOYSA-N n,n-dimethyl-1-piperidin-4-ylpiperidin-4-amine Chemical compound C1CC(N(C)C)CCN1C1CCNCC1 HBYABCRZKRAJCW-UHFFFAOYSA-N 0.000 description 1
- 229960005254 naratriptan Drugs 0.000 description 1
- UNHGSHHVDNGCFN-UHFFFAOYSA-N naratriptan Chemical compound C=12[CH]C(CCS(=O)(=O)NC)=CC=C2N=CC=1C1CCN(C)CC1 UNHGSHHVDNGCFN-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 210000001311 petrous bone Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 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
- 230000001953 sensory effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940086766 sodium chloride 180 mg Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000003901 trigeminal nerve Anatomy 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- 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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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
- A61P5/22—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of calcitonin
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- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Boehringer Ingelheim Pharma KG Case 5/1268-Ro D-55216 Ingelheim/Rhein Use of CGRP antagonists and CGRP release inhibitors for combating menopausal hot flushes Hot flushes are a common symptom of peri/post-menopausal syndrome the physiology of which is still not fully understood. Apart from hormone replacement therapy, which is a complex intervention and frequently cannot be used long-term owing to its side effects, there has up until now been no simple therapy largely free from side effects for this generally troublesome condition. Hot flushes are caused by vasodilatation and increased blood flow. A number of publications have mentioned the possibility that CGRP (calcitonin gene-related peptide) plays a part in the occurrence of menopausal hot flushes in oestrogen deficient women owing to the vasodilatory properties of this neuropeptide ([1]: J. Endocrinol. (1995), 146(3), 431-437; [2]: Acta Physiol. Scand. (1998) , 162 (4) , 517-522; [3]: Am. J. Obstet. Gynecol. (1996), 175(3, Pt. 1), 638-642). The therapeutic use of CGRP antagonists for treating menopausal syndrome has not previously been proposed in the literature. It has now been found that the symptoms of menopausal hot flushes can be effectively prevented or their distressing effects substantially alleviated by substances which antagonise the effects of CGRP (CGRP antagonists) or inhibit or reduce the release of CGRP from sensory nerve endings (CGRP release inhibitors), this therapeutic approach being superior to hormone replacement therapy in particular because of its lack of side effects. The present invention thus relates to the use of CGRP antagonists and/or CGRP release inhibitors for combating - 2 menopausal hot flushes, including both prevention and acute treatment. The use according to the invention preferably comprises monotherapy with a single substance, but also includes combined therapy with a number of substances from the specified groups of active substances. Moreover, the treatment according to the invention may be carried out in addition to conventional hormone replacement therapy. The invention also relates to the use of CGRP antagonists and/or CGRP release inhibitors for preparing a pharmaceutical composition for treating menopausal hot flushes as well as the corresponding pharmaceutical compositions containing as active substance one or more CGRP antagonists and/or CGRP release inhibitors. Any pharmaceutically acceptable active substances which antagonise the known effects of CGRP or inhibit the release of CGRP from sensory nerve endings may be used for the purposes of the present invention. Examples of CGRP antagonists include the amino acid derivatives described in WO 98/11128 or DE 199 11 039, as well as the non-peptidic active substances described in WO 98/56779, WO 98/09630 and WO 97/09046. Examples of CGRP release inhibitors include serotonin 5-HTmD agonists such as avitriptan, eletriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan, as well as 5-HTF agonists or NPY-agonists. Of the CGRP antagonists described in WO 98/11128, the following compounds, for example, may be used for the treatment of menopausal hot flushes, for the preparation of a corresponding pharmaceutical composition and as an ingredient of a corresponding pharmaceutical composition: -3 (A) 1- [N 2 -[3,5-dibromo-N-H14-(3,4-dihydro-2(lH) oxoquinazolin-3-yl) -1-piperidinyl~carbonyl] -D-tyrosyl] -L lysyl] -4- (4-pyridinyl) -piperazine, (B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H) oxo-1,3-benzodiazepil-3-yl) -1-piperidinyilcarbonyll -D-phenyl alanyl] -4- (1-piperidinyl) -piperidine, (C) 1- [N 2 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH) -oxo quinazolin-3-yl) -i-piperidinyllcarbonyl] -D-phenylalanyll]-L lysyl] -4- (4-pyridinyl) -piperazine, (D) 1-[N 2 - [4-amino-3,5-dibromo-N- [[4-(3,4-dihydro-2(1H)-oxo quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L lysyl] -4- (4-pyridinyl) -piperidine, (E) 1-[N 2 -[3,5-dibromo-N-[[4-(1,3-dihydro-4-phefl-2(2H-oxo imidazol-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-4phefl 2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenyl alanyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (G) 1- [3,5-dibromo-N- [[4- (3,4-dihydro-2 (1H) -oxothienoll3,4-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-5phefl13(3H) oxo-1,2,4-triazol-2-yl) -i-piperidinyllcarbonyl] -D-phenyl alanyl] -4- (l-methyl-4-piperidinyl) -piperidine, (I) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5phefylY3(3H) oxo-1,2,4-triazol-2-Yl) -i-piperidinyllcarbonyl] -D-phenyl alanyl] -4- (1-piperidinyl) -piperidine, -4 (J) 1- [4-amino-3,5-dibromo-N- [[4- (2,4-dihydro-5-phenyl-3 (3H) oxo-1,2,4-triazol-2-yl) -1-piperidinyllcarbonyl] -D-phenyl alanyl] -4- (1-methyl-4-piperidinyl) -piperazine, (K) 1- [4-amino-3,5-dibromo-N- [[4-(3,4-dihydro-2(1H)-oxo thieno[3,2-dlpyrimidin-3-yl) -1-piperidinyl] carbonyll -D-phenyl alanyl] -4- (1-piperidinyl) -piperidine, (L) 1- [4-amino-3,5-dibromo-N-[t4-[1,3-dihydro-4-[3-(tri fluoromethyl) phenyll -2 (2H) -oxoimidazol-1-yl] -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4 piperidinyl) -piperidine, oxoqluinazolin-3-yl] -l-piperidinyll carbonyl] -D-phenylalanyl] -4 (1-hexyl-4-piperidinyl) -piperidine, (N) 1- [4-amino-3,5-dibromo-N- [[4- [3,4-dihydro-2 (1H) oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (1-cyclopropylmethyl-4-piperidinyl) -piperidine, (0) 1-[N- [[4- [3,4-dihydro-2(1H) -oxoquinazolin-3-yl] -1-pipe ridinyl] carbonyl] -3-ethenyl-D,L-phenylalanyl] -4- (hexahydro-1H 1-azepinyl) -piperidine, (P) (R,S)-l-[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l piperidinyl] -2- [(4-hydroxy-3, 5-dimethylphenyl)methyl] -1, 4-di oxobutyl] -4- (1-piperidinyl) -piperidine, (Q) 1- [4-amino-3,5-dibromo-N- [[4- [N- (aminocarbonyl) -N-phenyl amino] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1 piperidinyl) -piperidine, (R) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (5-methoxy-4-pyrimidinyl) -piperazine, -5 (S) 1- [4-amino-3,5-dibromo-N- [[4-(1,1-dioxido-3(4H)-oxo 1,2,4-benzothiadiazin-2-y1) -1-piperidinyl] carbonyl] -D phenylalanyl] -4- (1-piperidinyl) -piperidine, (T) 1- [4-amino-3,5-dibromo-N- [[4- [2(1H)-oxoquinolin-3-yll -1 piperidinyll carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine, (U) 1- [4-amino-3,5-dibromo-N- [[4- [3,4-dihydro-2(1H) oxoquinazolin-3-yl] -l-piperidinyl] carbonyl] -D-phenylalanyl] -4 [3- (dimethylamino) propyl] -piperazine, (V) 1- [4-amino-3,5-dibromo-N- [[4- [3,4-dihydro-2(1H) oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (4-methyl-1-piperazinyl) -piperidine, (W) 1-[4-amino-3,5-dibromo-N- [[4- [3,4-dihydro-2(1H) oxoquinazolin-3-yl] -l-piperidinylLcarbonyl] -D-phenylalanyl] -4 [(l-methyl-4-piperidinyl) carbonyl] -piperazine, WX 1- [4-amino-3,5-dibromo-N- [[4- [3,4-dihydro-2 (11) oxoquinazolin-3-yl] -l-piperidinyl] carbonyl] -D-phenylalanyl] -4 [(1-methyl-4-piperazinyl) carbonyl] -piperazine, (Y) 1- [4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] 4- [4- [4- (dimethylamino)butyl] phenyl] -piperazine, (Z) 1- [4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH-oxo quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] 4- [4- (dimethylamino) -1-piperidinyl] -piperidine, (AA) 1- [N 2 - [[4- (1,3-dihydro-4-pheflyl-2 (2H) -oxoimidazol-1-yl) 1-piperidinyl] carbonyl] -N' -methyl-D-tryptyl] -4- (4-methyl-i piperazinyl) -piperidine, -6 (AB) 1- [N 2 -[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl) 1-piperidinyl] carbonyl] -N' -(1, 1-dimethylethoxycarbonyl) -D tryptyl] -4- (1-methyl-4-piperidinyl) -piperidine, (AC) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1 piperidinyl] -2- [(3,5-dibromo-4-methylphenyl)methyl] -1,4-dioxo butyll -4- (4-methyl-1-piperazinyl) -piperidine, (AD) (R,S)-l-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1 piperidinyl] -2- [(3 ,,-dibromo-4-methoxyphenyl)methy1] -1,4 dioxobutyl] -4- (l-methyl-4-piperidinyl) -piperidine, (AE) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1 pipEridiny1] -2- [(3,4-dibromphenyl)methyl] -1,4-dioxobutyl] -4 (4-nethyl-1-piperazinyl) -piperidine, (AF) 1- [N 2 - [N- [[4- (1,3-dihydro-2 (2H) -oxobenzimidazol-1-yl) 1-piperidinyll carbonyl] -31 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 (211)-oxobenzimidazol-1-yl) -i-piperidinyl] carbonyl] -D phenylalanyl] -4- (1-piperidinyl) -piperidine, (All) 1- [N 2 - [4-amino-3,5-dibromo-N- [[4- (1,3-dihydro-2 (21) -oxo benzimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] N 6
,N
6 -dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, (AI) 1- [N 2 - [4-amino-3,5-dibromo-N- [[4- (3;4-dihydro-2 (1H) -oxo quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] N 6
,N
6 -dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, (AJ) (R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4 dihydro-2 (11) -oxoquinazolin-3-yl) -1-piperidinyl] -4-oxobutyl] 4- (1-piperidinyl) -piperidine, -7 (AK) 1- [4-amino-3,5-dibromo-N- [[4- (3,4-dihydro-2,2-dioxido 2,1, 3-benzothiadiazin-3-yl) -1-piperidinyl] carbonyl] -D-phenyl alanyl] -4- (1-piperidinyl) -piperidine, (AL) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-2(2H)-oxoimi dazo [4,5-c] quinolin-3-yl] -1-piperidinyl] carbonyl] -D-phenyl alanyl] -4- (l-piperidinyl) carbonyl] -piperidine (AM) 1- [4-amino-3,5-dibromo-N-[114-(3,4-dihydro-2(lH) oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (1-piperidinyl) -piperidine, (AN) 1-[N 2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -N 6
,N
6 dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, (AO) 1- [4-amino-N- [[4- [4- (3-bromophenyl) -1,3-dihydro-2 (2H) oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -3, 5-dibromo-D phenylalanyl] -4- (l-methyl-4-piperidinyl) -piperidine, (AP) 1- [4-amino-3,5-dibromo-N- [14- [1,3-dihydro-4-phenyl-2 (211) oxoimidazol-1-yl] -1-piperidinyl] carbonyll -D-phenylalanyl] -4 (4-methyl-1-piperazinyl) -piperidine, (AQ) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4- [3-(tri fluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine, (AR) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4- [3-(tri fluoromethyl)phenyl] -2 (2H) -oxoimidazol-1-yl] -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8 azabicyclo[3,2,1]oct-3-yl) -piperazine, (AS) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxo imidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1 piperidinyl) -piperidine, -8 (AT) 1-[4-amino-3,5-dibromo-N- [[4- [1,3-dihydro-4- [3 (trifluoromethyl)phenyl] -2 (2H) -oxoimidazol-1-yl] -1 piperidinyl] carbonyll -D-phenylalanyll -4- (1-ethyl-4 piperidinyl) -piperazine, (AU) 1- [4-amino-3,5-dibromo-N-[[4-[I1,3-dihydro-4-phenyl-2(2H) oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (hexahydro-4-methyl-lH-1,4-diazepin-l-yl)piperidine, (AV) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3 yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- [1-(methylsuiphonyl) 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-phenylalanyll-4 (1-methyl-4-piperidinyl) -piperidine, (AX) 1- [3,5-dibromo-N- [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyll-2 (211)-oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D tyrosyl] -4- (hexahydro-1H-1-azepinyl) -piperidine, (AY) 1- [3,5-dibromo-N-[114- (3,4-dihydro-2 (111)-oxoquinazolin-3 yl) -i-piperidinyllcarbonyl] -D-tyrosyl] -4- (1-methyl-4 piperidinyl) -piperidine, (AZ) 1- [4-amino-3,5-dibromo-N- [[4- (3,4-dihydro-2 (1H) -oxo quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl) -piperazine, (BA) 1- [4-amino-3,5-dibromo-N- [[4- (1,3-dihydro-4-phenyl-2 (211) oxoimidazol-1-yl) -1-piperidinyll carbonyl] -D-phenylalanyl] -4 (1-methyl-4-piperidinyl) -piperazine, (13B) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl) phenyl] -2 (211)-oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D tyrosyl] -4- (1-piperidinyl) -piperidine, - 9 (BC) 1- [N 6 -acetyl-N 2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) oxoquinazolin-3-yl) -1-piperidinylicarbonyl] -D-tyrosyl] -L lysyl] -4- (4-pyridinyl) -piperazine, (BD) 1- [3,5-dibromo-N- [[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimi dazol-1-yl) -1-piperidinyll carbonyl] -D-tyrosyl] -4- (hexahydro 1H-1-azepinyl) -piperidine, (BE) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thielyl) 2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyll -D-phenyl alanyl] -4- (l-methyl-4-piperidinyl) -piperidine, (BF) 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-methyl-4 piperidinyl) -piperidine, (BG) 1- [3,5-dibromo-N- [[4- (3,4-dihydro-2 (1-) -oxoquinazolin-3 yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- [1-(hydroxycarbonyl methyl) -4-piperidinyl] -piperidine, (BH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-0x0 quinazolin-3-yl] -l-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1 methylsuiphonyl -4 -piperidinyl) -piperidine, (BI) 1- [3,5-dibromo-N- [[4- (3,4-dihydro-2(1H) -oxoquinazolin-3 yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (4-piperidinyl) piperidine, (BJ) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4phefl-2(2H) oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] 4- (1-ethyl-4-piperidinyl) -piperidine, (BK) 1- [4-amino-3,5-dibromo-N- [[4- (1,3-dihydro-4- (3-hydroxy phenyl) -2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, - 10 (BL) 1-[3,5-dibromo-N-[[4-(3,4--dihydro-2(lH)-oxoquinazolin-3 yl) -i-piperidinyllcarbonyl] -D-tyrosyl] -4-(hexahydro-lH-1 azepinyl) -piperidine, (BM) 1- [4-amino-3,5-dibromo-N- [[4-(1,3-dihydro-4-phenyl-2(2H) oxoimidazol-1-yl) -1-piperidinyll carbonyll -D-phenylalanyl] -4 (1 -piperidinyl) -piperidine, (BN) 1- [4-amino-3, 5-dibromo-N- [[4- [4- (3-bromophenyl) -1,3-dihy dro-2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenyl alanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-y1) piperazine, (BO); 1- [4-amino-3,5-dibromo-N- [[4- (3,4-dihydro-2 (lH) -oxo quinazolin-3-yl) -i-piperidinyl] carbonyll -D-phenylalanyl] 4- (1-ethyl-4-piperidinyl) -piperidine, (B3P) 1- [4-amino-3,5-dibromo-N- [[4- (3,4-dihydro-2(1H) -oxo quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] 4- (1-ethyl-4-piperidinyl) -piperazine, (BQ) 1- [4-amino-3,5-dibromo-N- [[4- [1,3-dihydro-4- (3-methoxy phenyl) -2(211)-oxoimidazol-1-yl] -l-piperidinyl] carboriyl] -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-tyrosyll -4- [1-(cyclopropyl methyl) -4 -piperidinyl] -piperidine, (BS) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (hexahydro-1H-l-azepinyl) -piperidine, - 11 (BT) 1-[14-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo quinazolin-3-yl) -i-piperidinyllcarbonyl] -D-phenylalanyll -4 (4-piperidinyl) -piperidine, (BU) 1- [3,5-dibromo-N-[[4-(1,3-dihydro-4-pheflyl-2(2H)-oxo imidazol-1-yl) -i-piperidinyllcarbonyl] -D-tyrosyl] -4- (4 pyridinyl) -piperidine, (BV) 1- [3,5-dibromo-N-E[4- E1,3-dihydro-4- [3-(trifluoromethyl) phenyll -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D tyrosyl] -4- (1-methyl-4-piperidilyl) -piperazile, (BW) 1-[N2-[3,5-dibromo-N-[[4-[1,3-dihydro-4- [3-(trifluorome thyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] D-tyrosyl] -Li-lysyl] -4- (4-pyridinyl) -piperazine, oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1 piperidinyl) -piperidine, (BY) 1-4aioN[4[-3clrpey)13dhdo22) oxoimidazol-1-yl] -l-piperidinyl] carbonyl] -3, 5-dibromo-D phenylalanyll-4- (l-methyl-4-piperidinyl)-piperidine, (BZ) 1-[14-amino-3,5-dibromo-N-[1i4-[1,3-dihydro-4- [3 (trifluoromethyl)phelyl]-2 (211)-oxoimidazol-1-yl] -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1H-1 azepinyl) -piperidine, (CA) 1-[4-amino-3,5-dibromfo-N-[[4-[1,3-dihydro-4-[3 (trifluoromethyl)phenyl] -2 (2H) -oxoimidazol-1-yl] -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4 piperidinyl) -piperazime, (CB) 1-[4-amino-N-[[4-[4-(3-choropheny)1,3dihydro-2(2H) oxoimidazol-1-yl] -l-piperidinyl] carbonyl] -3, 5-dibromo-D phenylalanyl] -4- (hexahydro-1H-1-azepinyl) -piperidine, - 12 (CC) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H) oxoimidazol-1-yl)-1-piperidinyllcarbonyl]-D-phenylalanyl]-4 (4-pyridinyl)-piperazine, (CD) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimi dazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(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-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3 yl] -1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4 piperidinyl)-piperazine, (CG) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-nitrophe nyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenyl alanyl]-4-(l-methyl-4-piperidinyl)-piperidine, (CH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxo quinazolin-3-yl]-1-piperidinyllcarbonyl]-D-phenylalanyl]-4 (1-pyrrolidinyl)-piperidine, (CI) 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-1H-1-azepinyl)-piperidine and (CJ) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl) 2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenyl alanyl]-4-(1-methyl-4-piperidinyl)-piperazine, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the physiologically acceptable salts thereof, while the compounds - 13 (A) 1-[N 2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyll-L lysyl]-4-(4-pyridinyl)-piperazine, (B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H) oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenyl alanyl]-4-(1-piperidinyl)-piperidine, (I) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H) oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyll-D-phenyl alanyl]-4-(1-piperidinyl)-piperidine, (J) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H) oxo-1,2,4-triazol-2-yl)-i-piperidinyl]carbonyl]-D-phenyl alanyll-4-(l-methyl-4-piperidinyl)-piperazine, (AC) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1 piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxo butyl]-4-(4-methyl-1-piperazinyl)-piperidine, (AF) 1-[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 and (AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH) oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4 (1-piperidinyl)-piperidine, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the physiologically acceptable salts thereof, and especially the compounds (A) 1-[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 and - 14 (B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(lH) oxo-1,3-benzodiazepin-3-yl)-1-piperidinyllcarbonyl]-D-phenyl alanyl]-4-(1-piperidinyl)-piperidine, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the physiologically acceptable salts thereof are particularly preferred. The dosage required to produce the desired effect is appropriately 0.000W to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight for intravenous or subcutaneous administration and 0.01 to 10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight for administration by oral or nasal route or by inhalation, 1 to 3 times a day in each case. If the treatment with CGRP antagonists and/or CGRP release inhibitors is given as a supplement to conventional hormone replacement therapy, it is advisable to reduce the doses given above, and in this case the dosage may range from 1/5 of the lower limits specified above up to 1/1 of the upper limits specified above. For this purpose, the CGRP antagonists and/or CGRP release inhibitors may be formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metering aerosols or suppositories.
- 15 Preparations which are particularly suitable for treating menopausal hot flushes are those which contain one of the active substances (A) 1-[N 2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH) oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L lysyll-4-(4-pyridinyl)-piperazine, (B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(lH) oxo-1,3-benzodiazepin-3-yl)-1-piperidinyllcarbonyll-D-phenyl alanyl]-4-(1-piperidinyl)-piperidine, (I) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H) oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenyl alanyl]-4-(1-piperidinyl)-piperidine, (J) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H) oxo-1,2,4-triazol-2-yl)-1-piperidinyllcarbonyl]-D-phenyl alanyl]-4-(1-methyl-4-piperidinyl)-piperazine, (AC) (R,S)-1-[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-1 piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxo butyl]-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 or (AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4 (1-piperidinyl)-piperidine, in one of the following pharmaceutical formulations: capsules for powder inhalation containing 1 mg of active substance, preferably active substance (A) or (B), - 16 inhalable solution for nebulisers containing 1 mg of active substance, preferably active substance (A) or (B), propellant gas-operated metering aerosol containing 1 mg of active substance, preferably active substance (A) or (B), nasal spray containing 1 mg of active substance, preferably active substance (A) or (B), tablets containing 20 mg of active substance, preferably active substance (B), capsules containing 20 mg of active substance, preferably active substance (B), aqueous solution for nasal application containing 10 mg of active substance, preferably active substance (A) or (B), aqueous solution for nasal application containing 5 mg of active substance, preferably active substance (A) or (B), or suspension for nasal application containing 20 mg of active substance, preferably active substance (A) or (B). CGRP is released by sensory nerves, e.g. the trigeminal nerve which innervates part of the skin of the face. It has already been shown that stimulation of the trigeminal ganglion in humans leads to an increase in the CGRP plasma level and causes reddening of the face ([4]: P.J. Goadsby et al., Annals of Neurology, Vol. 23, No. 2, 1988, 193-196,). To demonstrate that hot flushes can be successfully treated using CGRP antagonists and CGRP release inhibitors, an increased release of endogenous CGRP was induced in marmosets by stimulating the trigeminal ganglion, leading to increased blood flow through the blood vessels of the skin. The efficacy - 17 of the following test substances was characterised by determining the dose administered i.v. which reduces by 50% the increased blood flow through the skin of the face which has been brought about by endogenous CGRP: (A) = 1-[N 2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH) oxoquinazolin-3-yl)-1-piperidinylicarbonyl]-D-tyrosyl]-L lysyl]-4-(4-pyridinyl)-piperazine, (B) = 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(lH) oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenyl alanyl]-4-(1-piperidinyl)-piperidine, (AC) = (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1 piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxo butyl]-4-(4-methyl-1-piperazinyl)-piperidine, (AM) = 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4 (1-piperidinyl)-piperidine, (DA) = sumatriptan and (DB) = zolmitriptan. Description of method: Marmosets of both sexes (300-400 g) are anaesthetised with pentobarbital (initially with 30 mg/kg, i.p., followed by infusion of 6mg/kg/h, i.m.). The body temperature is maintained at 37 0 C using a heating plate. Pancurmium is administered as a muscle relaxant (initially 1 mg/kg, 0.5 mg after each hour thereafter). The animal's head is secured in a stereotactical apparatus. After the skin on the head has been opened using a lengthwise incision, a small hole is drilled in the skull and a bipolar electrode (Rhodes SNES 100) is lowered into the trigeminal ganglion.
- 18 Locating the ganglion is made easier by the use of an X-ray which shows up the bone structure of the skull. The petrous bone serves as a guide for placing the electrode (CCX-Digital X-ray apparatus). The position of the electrode in the ganglion is monitored at the end of each experiment. The stimulation parameters are: 10 Hz, 2 mA, 2 msec, for 30 sec. The blood flow in the micro-vessels of the facial skin is determined by laser Doppler flow measurement using a PeriFlux Laser Doppler System. The animals are exposed to 2 to 3 stimulation periods at intervals of 30 min in each case. The first stimulation serves as a reference value for the other stimulations. The test substances are administered i.v. 5 min before the 2nd and 3rd stimulation periods. Table 1: "50% dose" = i.v. dose which reduces by 50% the increased blood flow through the facial skin caused by endogenous CGRP Substance 50% dose A 0.003 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 The Examples which follow describe pharmaceutical preparations which contain as active substance a CGRP antagonist or CGRP release inhibitor for use according to the invention, preferably one of the amino acid derivatives described in WO 98/11128 or DE 199 11 039, for example one of the abovementioned active substances (A) or (B): - 19 Example I Capsules for powder inhalation with 1 mg of active substance (A) or (B) Composition: 1 capsule for powder inhalation contains: active substance (A) or (B) 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mg Method of preparation: The active substance is ground to the particle size needed for inhalation. The ground active substance is homogeneously mixed with the lactose. The mixture is packed into hard gelatine capsules. Example II Inhalable solution for Respimat with 1 mg of active substance (A) or (B) Composition: 1 spray contains: active substance (A) or (B) 1.0 mg benzalkonium chloride 0.002 mg disodium edetate 0.0075 mg purified water ad 15.0 pl Method of preparation: The active substance and benzalkonium chloride are dissolved in water and packed in Respimat cartridges.
- 20 Example III Inhalable solution for nebulisers with 1 mg of active substance (A) or (B) Composition: 1 vial contains: active substance (A) or (B) 0.1 g sodium chloride 0.18 g benzalkonium chloride 0.002 g purified water ad 20.0 ml Method of preparation: Active substance, sodium chloride and benzalkonium chloride are dissolved in water. Example IV Propellant gas-operated metering aerosol with 1 mg of active substance (A) or (B) Composition: 1 spray contains: active substance (A) or (B) 1.0 mg lecithin 0.1 % propellant gas ad 50.0 pl Method of preparation: The micronised active substance is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurised container with a metering valve.
21 Example V Nasal spray with 1 mg of active substance (A) or (B) Composition: 1 spray jet contains active substance (A) or (B) 1.0 mg mannitol 5.0 mg disodium edetate 0.05 mg ascorbic acid 1.0 mg purified water ad 0.1 ml Method of preparation: The active substance and the excipients are dissolved in water and transferred into a suitable container. Example VI Injectable solution with 5 mg of active substance (A) or (B) per 5 ml Composition: active substance (A) or (B) in basic form 5 mg acid/salt-forming agent in the amount needed to form a neutral salt q.s. glucose 250 mg human serum albumin 10 mg glycofurol 250 mg water for injections ad 5 ml Preparation: Dissolve the glycofurol and glucose in water for injections (WfI); add human serum albumin; add salt-forming agent; dissolve active substance with heating; make up to specified volume with WfI; transfer into ampoules under nitrogen gas.
- 22 Example VII Injectable solution for subcutaneous administration containing 5 mg of active substance (A) or (B) per 1 ml Composition: active substance (A) or (B) 5 mg glucose 50 mg polysorbate 80 = Tween 80 2 mg water for injection's ad 1 ml Preparation: Dissolve glucose and polysorbate in water for injections; dissolve active substance with heating or using ultrasound; make up to specified volume with WfI; transfer into ampoules under inert gas. Example VIII Injectable solution containing 100 mg of active substance (A) or (B) per 10 ml Composition: active substance (A) or (B) 100 mg monopotassium dihydrogen phosphate = KH 2
PO
4 12 mg disodium hydrogen phosphate = Na 2 HP04-2H 2 0 2 mg sodium chloride 180 mg human serum albumin 50 mg polysorbate 80 20 mg water for injections ad 10 ml Preparation: Dissolve polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for injections (WfI); add human serum albumin; dissolve active - 23 substance with heating; make up to specified volume with WfI; transfer into ampoules. Example IX Lyophilisate containing 10 mg of active substance (A) or (B) Composition: active substance (A) or (B) in basic form 10 mg acid/salt-forming agent in the amount needed to form a neutral salt q.s. mannitol 300 mg water for injections ad 2 ml Preparation: Dissolve mannitol in water for injections (WfI); add salt forming agent; dissolve active substance with heating; make up to specified volume with WfI; transfer into vials; freeze-dry. Solvent for lyophilisate: polysorbate 80 = Tween 80 20 mg mannitol 200 mg water for injections ad 10 ml Preparation: Dissolve polysorbate 80 and mannitol in water for injections (WfI); transfer into ampoules. Example X Lyophilisate containing 5 mg of active substance (A) or (B) Composition: active substance (A) or (B) in basic form 5 mg polar or nonpolar solvent (which can be removed by freeze-drying) ad 1 ml - 24 Preparation: Dissolve active substance in suitable solvent; transfer into vials; freeze-dry. Solvent for lyophilisate: polysorbate 80 = Tween 80 5 mg mannitol 100 mg water for injections ad 2 ml Preparation: Dissolve polysorbate 80 and mannitol in water for injections (WfI); transfer into ampoules. Example XI Tablets containing 20 mg of active substance (A) or (B) Composition: active substance (A) or (B) 20 mg lactose 120 mg maize starch 40 mg magnesium stearate 2 mg Povidone K 25 18 mg Preparation: Homogeneously mix the active substance, lactose and maize starch; granulate with an aqueous solution of Povidone; mix with magnesium stearate; press in a tablet press; weight of tablet 200 mg.
- 25 Example XII Capsules containing 20 mg of active substance (A) or (B) Composition: active substance (A) or (B) 20 mg maize starch 80 mg highly dispersed silica 5 mg magnesium stearate 2.5 mg Preparation: Homogeneously mix the active substance, maize starch and silica; mix with magnesium stearate; transfer mixture into size 3 hard gelatine capsules in a capsule filling machine. Example XIII Suppositories containing 50 mg of active substance (A) or (B) Composition: active substance (A) or (B) 50 mg hard fat (Adeps solidus) q.s. ad 1700 mg Preparation: Melt the hard fat at about 38 0 C; homogeneously disperse the ground active substance in the molten hard fat; after cooling to about 35 0 C, pour into chilled moulds.
- 26 Example XIV Aqueous solution for nasal administration containing 10 mg of active substance (A) or (B) Composition: active substance (A) or (B) 10.0 mg hydrochloric acid in the amount needed to form a neutral salt methyl parahydroxybenzoate (PHB) 0.01 mg propyl parahydroxybenzoate (PHB) 0.005 mg purified water ad 1.0 ml Preparation: The active substance is dissolved in purified water; hydrochloric acid is added until the solution is clear; methyl and propyl PHB are added; the solution is made up to the specified volume with purified water; the solution is filtered sterile and transferred into a suitable container. Example XV Aqueous solution for nasal administration containing 5 mg of active substance (A) or (B) Composition: active substance (A) or (B) 5 mg 1,2-propanediol 300 mg hydroxyethylcellulose 5 mg sorbic acid 1 mg purified water ad 1 ml Preparation: The active substance is dissolved in 1,2-propanediol; a hydroxyethyl-cellulose solution in purified water containing sorbic acid is prepared and added to the solution of active - 27 substance; the solution is filtered sterile and transferred into a suitable container. Example XVI Aqueous solution for intravenous administration containing 5 mg of active substance (A) or (B) Composition: active substance (A) or (B) 5 mg 1,2-propanediol 300 mg mannitol 50 mg water for injections (WfI) ad 1 ml Preparation: The active substance is dissolved in 1,2-propanediol; the solution is made up to approximately the specified volume with WfI; the mannitol is added and made up to approximately the specified volume with WfI; the solution is filtered sterile, transferred into individual containers and autoclaved. Example XVII Liposomal formulation for intravenous injection containing 7.5 mg of active substance (A) or (B) Composition: active substance (A) or (B) 7.5 mg egg lecithin, e.g. Lipoid E 80 100.0 mg cholesterol 50.0 mg glycerol 50.0 mg water for injections ad 1.0 ml Preparation: The active substance is dissolved in a mixture of lecithin and cholesterol; the solution is added to a mixture of glycerol and WfI and homogenised by high pressure homogenisation or by - 28 the Microfluidizer technique; the liposomal formulation obtained is transferred into a suitable container under aseptic conditions. Example XVIII Suspension for nasal administration containing 20 mg of active substance (A) or (B) Composition: active substance (A) or (B) 20.0 mg carboxymethylcellulose (CMC) 20.0 mg sodium monohydrogen phosphate/sodium dihydrogen phosphate buffer pH 6.8 q.s. sodium chloride 8.0 mg methyl parahydroxybenzoate 0.01 mg propyl parahydroxybenzoate 0.003 mg purified water ad 1.0 ml Preparation: The active substance is suspended in an aqueous CMC solution; the other ingredients are added successively to the suspension and the suspension is topped up to the specified volume with purified water. Example XIX Aqueous solution for subcutaneous administration with 10 mg of active substance (A) or (B) Composition: active substance (A) or (B) 10.0 mg sodium monohydrogen phosphate/sodium dihydrogen phosphate buffer q.s. ad pH 7.0 sodium chloride 4.0 mg water for injections ad 0.5 ml - 29 Preparation: The active substance is dissolved in the phosphate buffer solution, after the addition of the common salt the solution is made up to the specified volume with water. The solution is filtered sterile, transferred into a suitable container and autoclaved. Example XX Aqueous suspension for subcutaneous administration containing 5 mg of active substance (A) or (B) Composition: active substance (A) or (B) 5.0 mg polysorbate 80 0.5 mg water for injections 0.5 ml Preparation: The active substance is suspended in the polysorbate 80 solution and comminuted to a particle size of about 1 ptm using a suitable dispersing technique (e.g. wet grinding, high pressure homogenisation, microfluidisation, etc.). The suspension is transferred into a corresponding container under aseptic conditions.
Claims (10)
1. Use of an active substance selected from CGRP antagonists and CGRP release inhibitors for treating menopausal hot flushes.
2. Use according to claim 1, characterised in that it is effected as a monotherapy with a single active substance.
3. Use according to claim 1, characterised in that it is effected as a supplement to hormone replacement therapy.
4. Use according to claim 1, characterised in that the active substance is a CGRP antagonist.
5. Use according to claim 4, characterised in that the CGRP antagonist is selected from among: (A) 1-[N 2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH) oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L lysyll-4-(4-pyridinyl)-piperazine, (B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H) oxo-1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenyl alanyl] -4- (1-piperidinyl) -piperidine, (C) 1-[N 2 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxo quinazolin-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-dihydro-2(lH)-oxo quinazolin-3-yl) -1-piperidinyl]carbonyl] -D-phenylalanyl] -L lysyl]-4-(4-pyridinyl)-piperidine, - 31 (E) 1-[N 2 - [3,5-dibromo-N-[[4-(1,3-dihydro-4-pheflyl-2(2H)-oxo imidazol-1-yl) -1-piperidinyll carbonyl] -D-tyrosyl] -L-lysyl] -4 (4 -pyridinyl) -piperazine, (F) 1-EN 2 - [4-amino-3,5-dibromo-N-[[I4-(1,3-dihydro-4-phenyl 2 (2H) -oxoimidazol-1-yl) -l-piperidinyll carbonyll -D-phenyl alanyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (G) 1-[3,5-dibromo-N- [[4-(3,4-dihydro--2(lH)-oxothieno[3,4-dl pyrimidin-3-yl) -1-piperidinyll carbonyl] -D-tyrosyl] -4- (1 piperidinyl) -piperidine, (H) 1- E4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H) oxo-1 2,4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenyl alanyll -4- (l-methyl-4-piperidinyl) -piperidine, (I) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phelyl-3(3H) oxo-1,2,4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenyl alanyl] -4- (1-piperidinyl) -piperidine, (J) 1- [4-amino-3,5-dibromo-N- [[4- (2,4-dihydro-5-phenyl-3 (3H) oxo-1,2,4-triazol-2-yl) -1-piperidinyl] carboriyl] -D-phenyl alanyl] -4- (1-methyil-4-piperidinyl) -piperazine, (K)- 1- [4-amino-3,5-dibromo-N- [[4- (3,4-dihydro-2 (lH) -oxo thieno [3, 2-d] pyrimidin-3-yl) -1-piperidinyl] carbonyl] -D-phenyl alanyl] -4- (1-piperidinyl) -piperidine, (L) 1-[4-amino-3,5-dibromo-N-[[4-[1,3dihydro-4-[3-(tri fluoromethyl)phenyl] -2 (2H) -oxoimidazol-1-yl] -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4 piperidinyl) -piperidine, (M) 1-[4-amino-3,5-dibromo-N-[[4-[3,4dihydro-2(1H) oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (1-hexyl-4-piperidilyl) -piperidine, - 32 (N) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H) oxoquinazolin-3-yll-1-piperidinyl]carbonyl]-D-phenylalanyl]-4 (1-cyclopropylmethyl-4-piperidinyl)-piperidine, (0) 1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yll-1-pipe ridinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H 1-azepinyl)-piperidine, (P) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1 piperidinyl] -2- [(4hydroxy-3,5-dimethylphenyl)methyl) -1,4-di oxobutyl] -4- (1-piperidinyl) -piperidine, (Q) 1-[4-amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenyl amino] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1 piperidinyl)-piperidine, (R) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4 (5-methoxy-4-pyrimidinyl)-piperazine, (S) 1-[4-amino-3,5-dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo 1,2,4-benzothiadiazin-2-yl)-1-piperidinyl]carbonyl]-D phenylalanyl] -4- (1-piperidinyl) -piperidine, (T) 1-[4-amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) piperidine, (U) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H) oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4 [3-(dimethylamino)propyl]-piperazine, (V) 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, - 33 MW 1- [4-amino-3,5-dibromo-N-[[4- [3,4-dihydro-2(1H) oxoquinazolin-3-yl] -l-piperidinyl] carbonyl] -D-phenylalanyll -4 [(1-methyl-4-piperidinyl)carbonyll -piperazine, (X 1- [4-amino-3,5-dibromo-N- [[4- [3,4-dihydro-2(1H) oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyll -4 [(1-methyl-4-piperazinyl)carbonyl] -piperazine, (Y) 1- [4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo quinazolin-3-yl) -i-piperidinyllcarbonyl] -D-phenylalanyll -4 [4- [4- (dimethylamino) butyl] phenyl] -piperazine, WZ 1- [4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo quinazolin-3-yl) -1-piperidinyl] carbonyll -D-phenylalanyl] -4 [4- (dimethylamino) -1-piperidinyl] -piperidine, (AA) 1- [N 2 - [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) 1-piperidinyll carbonyl] -N' -methylL-D-tryptyl] -4- (4-methyl-i piperazinyl) -piperidine, (A13) 1- [N 2 -[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl) 1-piperidinyl] carbonyl] -N' -(1, i-dimethylethoxycarbonyl) -D tryptyl] -4- (l-methyl-4-piperidilyl) -piperidine, (AC) (RS--4[-34dhdo2l)oounzln3y)l piperidinyl] -2- [(3,5-dibromo-4-methylphenyl)methyl] -1,4-dioxo butyl] -4- (4-methyl-l-piperazinyl) -piperidine, piperidinyl] -2- [(3,5-dibromo-4-methoxyphelyl)methyl] -1,4 dioxobutyl] -4- (1-methyl-4-piperidinyl) -piperidine, (AE) (RS--4[-34dhdo2l)oounzln3y)i piperidinyl] -2- [(3, 4-dibromophenyl)methyl] -1, 4-dioxobutyl] -4 (4-methyl-1-piperazilyl) -piperidine, - 34 (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) -oxobenzimidazol-1-yl) -1-piperidinyll carbonyl] -D phenylalanyll -4- (1-piperidinyl) -piperidine, (All) 1- [N 2 -[4-amino-3,5-dibromo-N-E[4-(1,3-dihydro-2(2H)-oxo benzimidazoi-yl) -'-piperidinyl] carbonyl] -D-phenylalanyl] N 6 ,N 6 -dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, (AI) 1-[N 2 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo quiniazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] N 6 1 N 6 -dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, (AJ) (R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4 dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] -4-oxobutyl] 4- (1-piperidinyl) -piperidine, (AK) 1- [4-amino-3,5-dibromo-N- II[4- (3,4-dihydro-2,2-dioxido 2,1, 3-benzothiadiazin-3-yl) -1-piperidinyl] carbonyl] -D-phenyl alanyl] -4- (1-piperidinyl) -piperidine, (AL) 1- [4-amino-3,5-dibromo-N- [14- [1,3-dihydro-2 (2H) -oxoimi dazo [4,5-c] quinolin-3-yl] -1-piperidinyllcarbonyl] -D-phenyl alanyl] -4- (l-piperidinyl) carbonyl] -piperidine, (AM) 1- [4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH) oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (1-piperidinyl) -piperidine, (AN) 1- [N 2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -N 6 ,N 6 dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, - 35 (AO) 1-[4-amino-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H) oxoimidazol-1-yll-1-piperidinyl]carbonyll-3,5-dibromo-D phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine, (AP) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H) oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4 (4-methyl-1-piperazinyl)-piperidine, (AQ) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(tri fluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yll-1 piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl) piperidine, (AR) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(tri fluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1 piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8 azabicyclo[3,2,1]oct-3-yl)-piperazine, (AS) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxo imidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1 piperidinyl)-piperidine, (AT) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3 (trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1 piperidinyl]carbonyl]-D-phenylalanyl]-4-(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-l1-yl)piperidine, (AV) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3 yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(methylsulphonyl) 4-piperidinyl)-piperidine, - 36 (AW) 1-[4-amino-3,5-dibramo-N-[[4-(l,3-dihydro-4-phenyl-2(21) oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyll -4 (1-methyl -4 -piperidinyl) -piperidine, (AX) 1-[3,5-dibromo-N- [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyll -2 (2H) -oxoimidazol-1-yll -l-piperidinyl] carbonyl] -D tyrosyl] -4- (hexahydro-1H-1-azepinyl) -piperidine, (AY) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3 yl) -1-piperidinylLc~arbony1] -D-tyrosyl] -4- (1-methyl-4 piperidinyl) -piperidine, (AZ) 1-[4-amino-3,5-dibromo-N-[114-(3,4-dihydro-2(1H)-oxo quix~azolin-3-y1) -1-piperidinyl] carbonyll -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-phenylalanyll -4 (1-methyl-4-piperidinyl) -piperazine, (BB) 1- [3,5-dibromo-N- [[4- [1,3-dihydro-4- [3- (trifluoromethyl) phenyl] -2(211)-oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D tyrosyl] -4- (1-piperidinyl) -piperidine, (BC) 1- [N 6 -Acetyl-N 2 - [3,5-dibromo-N- [[4- (3,4-dihydro-2 (11) oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L lysyll -4- (4-pyridinyl) -piperazine, (BD) 1- [3,5-dibromo-N- [[4- (1,3-dihydro-4-phenyl-2 (2H) -oxoimi dazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro 1H-1-azepinyl) -piperidine, (BE) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)V 2 (211)-oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenyl alanyl] -4- (1-methyl-4-piperidinyl) -piperidine, - 37 (BF) 1- [4-amino-3,5-dibromo-N-[[4-[1~,3-dihydro-4- [3 (trifluoromethyl)phenyl] -2 (2H) -oxoimidazol-l-yl] -1 piperidinyl] carbonyll -D-phenylalanyl] -4- (l-methyl-4 piperidinyl) -piperidine, (BG) 1- [3,5-dibromo-N- [[4-(3,4-dihydro-2(lH)-oxoquinazolin-3 yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- [1-(hydroxycarbonyl methyl) -4 -piperidinyl] -piperidine, (BH) 1- [4-amino-3,5-dibromo-N-[E4-(3,4-dihydro-2(lH-oxo quinazolin-3-yll -l-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1 methylsuiphonyl -4 -piperidinyl) -piperidine, (BI) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquilazolifl3 yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (4-piperidinyl) piperidine, (BJ) 1- [4-amino-3,5-dibromo-N-[[4-(,3-dihydro-4phefyl-2(2H) oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] 4- (l-ethyl-4-piperidinyl) -piperidine, (BK) 1- [4-amino-3,5-dibromo-N-[[4-(,3-dihydro-4(3-hydroxy phenyl) -2 (2H) -oxoimidazol-l-yl) -l-piperidinyl] carbonyl] -D phenylalanyl] -4- (l-methyl-4-piperidinyl) -piperidine, (BL) 1- [3,5-dibromo-N- [[4- (3,4-dihydro-2 (lH) -oxoquinazolin-3 yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro-lH-l azepinyl) -piperidine, (BM) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4phefl-2(2H) oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (1-piperidinyl) -piperidine, (BN) 1- [4-amino-3,5-dibromo-N-[[4-[4-(3bromophenyl1,3-di hydro-2 (211)-oxoimidazol-l-yl] -l-piperidinyl] carbonyl] -D-phe nylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2u1]oct3yl) piperazine, - 38 (BO) 1- [4-amino-3,5-dibromo-N- [[4-(3,4-dihydro-2(lH) -oxo quinazolin-3-yl) -1-piperidinyl] carbonyll -D-phenylalanyl] 4- (1-ethyl-4-piperidinyl) -piperidine, (BP) 1- [4-amino-3,5-dibromo-N-[E4-(3,4-dihydro-2(1H)-oxo quinazolin-3-yl) -1-piperidinyl] carbonyll -D-phenylalanyl] 4- (l-ethyl-4-piperidinyl) -piperazine, (BQ) 1-[14-amino-3, '5-dibromo-N-[[4-[,3-dihydro-4-(3-methoxy phenyl) -2 (2H) -oxoimidazol-l-yl] -1-piperidinyll carbonyl] -D phenylalanyll-4- (exo-8-methyl-8-azabicyclo[3,2,l]oct-3-yl) piperazine, (BR). 1- [3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3 yl) -1-piperidinyl] carbonyll -D-tyrosyll -4- [1-(cyclopropyl methyl) -4-piperidinyl] -piperidine, (BS) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(-H) oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (hexahydro-lH-1-azepinyl) -piperidine, (BT) 1- [4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxo quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (4-piperidinyl) -piperidine, (BU) 1- [3,5-dibromo-N- [14- (1,3-dihydro-4-phenyl-2 (2H) -oxo imidazol-l-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (4 pyridinyl) -piperidine, (By) 1-[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)V phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D tyrosyl] -4- (l-methyl-4-piperidilyl) -piperazine, (BW) 1-[N2- [3,5-dibromo-N-[14- (l,3-dihydro-4- [3- (trifluorome thyl)phenyl] -2 (2H) -oxoimidazol-l-yl] -l-piperidinyl] carbonyl] D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, - 39 (BX) 1-[3,5-dibromo-N-f[4-(1,3-dihydro-4-(3-thienyl)-2(2H) oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1 piperidinyl) -piperidine, (BY) 1-[14-amino-N-E4-4-(3-chlorophenyl)-1,3-dihydro-2(2H) oxoimidazol-1-yl] -1-piperidinyll carbonyl] -3,5-dibromo-D phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (BZ) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3 (trifluoromethyl)phenyl] -2 (2H) -oxoimidazol-1-yl] -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1H-1 azepinyl) -piperidine, (CA) 1-[4-amino-3,5-dibromo-N- E[4-[1,3-dihydro-4-[3 (trifluoromethyl)phenyl] -2 (2H) -oxoimidazol-1-yl] -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4 piperidinyl) -piperazine, (CB) 1- [4-amino-N-E[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H) oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -3' 5-dibromo-D phenylalanyl] -4- (hexahydro-1H-1-azepinyl) -piperidine, (CC) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H) oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 (4-pyridinyl) -piperazine, (CD) 1- [3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimi dazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-methyl-4 piperidinyl) -piperidine, (CE) 1-[4-amino-3,5-dibromo-N- [[4- [1,3-dihydro-4-phenyl-2 (2H) oxoimidazol-1-yl] -l-piperidinyilcarbonyl] -D-phenylalanylL]-4 [4- (1-oxoethyl)phenyl] -piperazine, - 40 (CF) 1-[3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3 yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(l-methyl-4 piperidinyl)-piperazine, (CG) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-nitro phenyl)-2(2H)-oxoimidazol-1-yll-1-piperidinyl]carbonyl]-D-phe nylalanyl]-4-(l-methyl-4-piperidinyl)-piperidine, (CH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxo quinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 pyrrolidinyl)-piperidine, (CI) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H) oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4 (hexahydro-lH-1-azepinyl)-piperidine and (CJ) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl) 2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyll-D-phenyl alanyl]-4-(l-methyl-4-piperidinyl)-piperazine, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the physiologically acceptable salts thereof.
6. Use of an active substance selected from CGRP antagonists and CGRP release inhibitors for the preparation of a pharmaceutical composition for treating menopausal hot flushes.
7. Use according to claim 6, characterised in that the pharmaceutical composition contains only one active substance.
8. Use according to claim 6, characterised in that the active substance is a CGRP antagonist.
9. Use according to claim 8, characterised in that the CGRP antagonist is selected from the group according to claim 5. - 41
10. Pharmaceutical composition for treating menopausal hot flushes, containing as active substance one or more CGRP antagonists selected from the group according to claim 5 optionally together with one or more inert carriers and/or diluents.
Applications Claiming Priority (3)
| 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 |
| DE19937304 | 1999-08-10 | ||
| PCT/EP2000/007613 WO2001010425A2 (en) | 1999-08-10 | 2000-08-05 | Use of cgrp antagonists and cgrp release inhibitors for controlling menopausal hot flashes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6992800A true AU6992800A (en) | 2001-03-05 |
| AU777709B2 AU777709B2 (en) | 2004-10-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU69928/00A Ceased AU777709B2 (en) | 1999-08-10 | 2000-08-05 | Use of CGRP antagonists for combating menopausal hot flushes |
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| Country | Link |
|---|---|
| EP (1) | EP1207884B1 (en) |
| JP (1) | JP2003506403A (en) |
| KR (1) | KR100713573B1 (en) |
| CN (1) | CN1166361C (en) |
| AR (1) | AR025078A1 (en) |
| AT (1) | ATE281168T1 (en) |
| AU (1) | AU777709B2 (en) |
| BG (1) | BG65366B1 (en) |
| BR (1) | BR0013009A (en) |
| CA (1) | CA2378428C (en) |
| CZ (1) | CZ300513B6 (en) |
| DE (2) | DE19937304C2 (en) |
| EA (1) | EA007531B1 (en) |
| EE (1) | EE04928B1 (en) |
| ES (1) | ES2231243T3 (en) |
| HK (1) | HK1046854B (en) |
| HR (1) | HRP20020117A2 (en) |
| HU (1) | HUP0202397A3 (en) |
| IL (1) | IL148057A (en) |
| MX (1) | MXPA02001373A (en) |
| MY (1) | MY129668A (en) |
| NO (1) | NO20020605L (en) |
| NZ (1) | NZ517367A (en) |
| PL (1) | PL198483B1 (en) |
| PT (1) | PT1207884E (en) |
| SK (1) | SK285587B6 (en) |
| TR (1) | TR200200359T2 (en) |
| TW (1) | TWI285550B (en) |
| UA (1) | UA73137C2 (en) |
| WO (1) | WO2001010425A2 (en) |
| YU (1) | YU8302A (en) |
| ZA (1) | ZA200200997B (en) |
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| DE19952147A1 (en) | 1999-10-29 | 2001-05-03 | Boehringer Ingelheim Pharma | New cyclopropanes, pharmaceutical compositions containing these compounds and process for their preparation |
| DE10139410A1 (en) * | 2001-08-17 | 2003-02-27 | Boehringer Ingelheim Pharma | Use of BIBN4096 in combination with other anti-migraine drugs for the treatment of migraines |
| EP1456198A1 (en) * | 2001-12-12 | 2004-09-15 | Eli Lilly And Company | Alanyl-piperidine heterocyclic derivatives useful against cardiovascular diseases |
| DE10206770A1 (en) * | 2002-02-19 | 2003-08-28 | Boehringer Ingelheim Pharma | New, stable acid addition salts of the quinazolinone derivative CGRP antagonist BIBN4096, useful for the treatment of migraine, in the form of an inhalable powder |
| US6900317B2 (en) | 2002-02-19 | 2005-05-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Salts of the CGRP antagonist BIBN4096 and inhalable powdered medicaments containing them |
| DE10207026A1 (en) * | 2002-02-20 | 2003-08-28 | Boehringer Ingelheim Kg | Stable inhalable powder of the calcitonin gene-related peptide antagonist, BIBN4096, useful for treating migraine, in the form of spherical nano-structured particles obtained by spray-drying |
| DE10227294A1 (en) * | 2002-06-19 | 2004-01-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Preparations for intranasal application of selected amino acid-derived CGRP antagonists and processes for their preparation |
| 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 |
| WO2005004869A1 (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 |
| US20060173046A1 (en) * | 2003-07-15 | 2006-08-03 | Bell Ian M | 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 |
| US7491717B2 (en) | 2005-03-23 | 2009-02-17 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
| EP1770091A1 (en) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP-antagonists, process for their preparation as well as their use as medicaments |
| US7439237B2 (en) | 2005-04-15 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| BR9610375A (en) * | 1995-09-07 | 1999-07-06 | Oreal | Cell extract cosmetic or pharmaceutical composition use of at least one cell extract and cosmetic treatment process |
| 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) |
| DE59711622D1 (en) * | 1996-09-10 | 2004-06-17 | Boehringer Ingelheim Pharma | MODIFIED AMINO ACIDS, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, AND METHOD FOR THE PRODUCTION THEREOF |
| DE19911039A1 (en) * | 1999-03-12 | 2000-09-14 | Boehringer Ingelheim Pharma | Modified amino acid amides, pharmaceutical compositions containing these compounds and process for their preparation |
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- 2000-08-05 ES ES00958385T patent/ES2231243T3/en not_active Expired - Lifetime
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- 2000-08-05 WO PCT/EP2000/007613 patent/WO2001010425A2/en active Application Filing
- 2000-08-05 CA CA002378428A patent/CA2378428C/en not_active Expired - Fee Related
- 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 KR KR1020027001796A patent/KR100713573B1/en not_active IP Right Cessation
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