IL148057A - Use of cgrp antagonists for preparing a pharmaceutical composition for treating menopausal hot flashes - Google Patents

Use of cgrp antagonists for preparing a pharmaceutical composition for treating menopausal hot flashes

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Publication number
IL148057A
IL148057A IL148057A IL14805700A IL148057A IL 148057 A IL148057 A IL 148057A IL 148057 A IL148057 A IL 148057A IL 14805700 A IL14805700 A IL 14805700A IL 148057 A IL148057 A IL 148057A
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piperidinyl
dibromo
dihydro
carbonyl
piperidine
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IL148057A
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Hebrew (he)
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IL148057A0 (en
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Boehringer Ingelheim Pharma
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Publication of IL148057A publication Critical patent/IL148057A/en

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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
    • 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
    • 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
    • A61K31/435—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
    • 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
    • A61K31/495—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
    • 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
    • A61K31/495—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
    • 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
    • A61K31/495—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
    • 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
    • A61K31/54—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (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)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

148057/3 i-ijittfl rifiipna o>on o»ptana ^o» o i v>sn man CGRP o ov>iiM?jitt v»e>v Use of CGRP antagonists for preparing a pharmaceutical composition for treating menopausal hot flashes Boehringer Ingelheim Pharma GmbH & Co. KG C. 137350 1 148057/2 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 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 CG P (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 antagonize the effects of CGRP (CGRP antagonists) , 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 for combating ? 148057/2 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 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 .
Any pharmaceutically acceptable active substances which antagonize 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.
Of the CGRP antagonists described in WO 98/11128, the following compounds, for example, may be used for the treatment of menopausal hot flushes, for the preparation of a corresponding pharmaceutical composition and as an ingredient of a corresponding pharmaceutical composition: (A) .1- [N2- [3 , 5-dibromo-N- [ [4- ( 3 , 4 -dihydro-2 (1H) - oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L- lysyl] -4- (4-pyridinyl) -piperazine, "(B) 1- [4 -amino-3 , 5-dibromo-N- [ [4- (2 , 3 , 4 , 5-tetrahydro-2 (1H) -oxo-1, 3 -benzodiazepin-3 -yl) -1-piperidinyl] carbonyl] -D-phenyl -alanyl] -4- (1-piperidinyl) -piperidine, (C) ■ 1- [N2- [4 -amino-3 , 5-dibromo-N- [ [4- (3 , 4 -dihydro-2 (1H) -oxo-quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (D) 1- [N2- [4-amino-3 , 5-dibromo-N- [ [4- (3, 4 -dihydro-2 (1H) -oxoquinazolin-3 -yl ) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) -piperidine, (E) 1- [N2- [3 , 5-dibromo-N- [ [4- (1, 3 -dihydro-4 -phenyl -2 (2H) -oxo imidazol-l-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] - 4- (4-pyridinyl) -piperazine, (F) 1- [N2- [4-amino-3 , 5-dibromo-N- [ [4- (1, 3 -dihydro-4 -phenyl-2 (2H) -oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (G) 1- [3, 5-dibromo-N- [ [4- (3 , 4 -dihydro-2 (1H) -oxothieno [3 , 4 -d] pyrimidin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine, (H) 1- [4-amino-3 , 5-dibromo-N- [ [4- (2 , 4-dihydro-5-phenyl-3 (3H) oxo-1 , 2 , 4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-methyl-4-piperidinyl) -piperidine, (I) 1- [4-amino-3 , 5-dibromo-N- [ [4- (2 , 4 -dihydro-5-phenyl -3 (3H) oxo-1 , 2 , 4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (J) 1- [4 -amino-3 , 5-dibromo-N- [ [4- (2 , 4-dihydro-5-phenyl-3 (3H) -oxo-1, 2 , 4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-methyl-4-piperidinyl) -piperazine, (K) 1- [4-amino-3, 5-dibromo-N- [ [4- (3 , 4-dihydro-2 (1H) -oxo-thieno [3 , 2-d] pyrimidin-3 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (L) 1- [4-amino-3 , 5-dibromo-N- [ [4- [1 , 3 -dihydro-4 - [3- (tri-fluoromethyl) phenyl] -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-ethyl-4-piperidinyl) -piperidine, (M) , 1- [4-amino-3 , 5-dibromo-N- [ [4- [3 , 4 -dihydro-2 (1H) -oxoquinazolin-3 -yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-riexyl-4-piperidinyl) -piperidine, (N) 1- [4-amino-3 , 5-dibromo-N- [ [4- [3 , 4 -dihydro-2 (1H) -oxoquinazolin-3 -yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-cyclopropylmethyl-4-piperidinyl) -piperidine, (0) 1- [N- [ [4- [3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl] -1-piperidinyl] carbonyl] -3-ethenyl-D, L-phenylalanyl] -4- (hexahydro-lH-1-azepinyl) -piperidine, (P) (R,S)-l-[4-[4- (3 , 4 -dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] -2- [ (4 -hydroxy-3 , 5-dimethylphenyl) methyl] -1, 4-di-oxobutyl] -4- (1-piperidinyl) -piperidine, (Q) 1- [4-amino-3 , 5-dibromo-N- [ [4- [N- (aminocarbonyl ) -N-phenyl-amino] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (R) 1- [4-amino-3 , 5-dibromo-N- [ [4- ( 3 , 4 -dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4-( 5 -methoxy-4 -pyrimidinyl ) -piperazine , (S) 1- [4 -amino- 3 , 5-dibromo-N- [ [4- (1, l-dioxido-3 (4H) -oxo- 1,2,4 -benzothiadiazin-2 -yl ) -1 -piperidinyl] carbonyl] -D- phenylalanyl] -4- (1 -piperidinyl) -piperidine, . (T) 1- [4-amino-3 , 5-dibromo-N- [ [4- [2 (1H) -oxoquinolin-3 -yl] -1 piperidinyl] carbonyl] -D-phenylalanyl] -4- ( 1 -piperidinyl ) -piperidine, (U) 1- [4-amino-3, 5-dibromo-N- [ [4- [3, 4-dihydro-2 (1H) -oxoquinazolin-3 -yl] τΐ -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-l-piperazinyl) -piperidine, ( ) 1- [4-amino-3 , 5-dibromo-N- [ [4- [3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 [ (l-methyl-4-piperidinyl) carbonyl] -piperazine, (X) 1- [4-amino-3 , 5-dibromo-N- [ [4- [3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4 [ (1 -methyl -4 -piperazinyl) carbonyl] -piperazine, (Y) 1- [4-amino-3 , 5-dibromo-N- [ [4- (3 , 4 -dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [4- [4- (dimethylamino) butyl] phenyl] -piperazine, (Z) 1- [4-amino-3 , 5-dibromo-N- [ [4- (3 , 4 -dihydro-2 (1H) -oxoquinazolin-3 -yl )- 1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- [4- (dimethylamino) -1-piperidinyl] -piperidine, (AA) 1- [N2- [ [4- (1, 3-dihydro-4-phenyl-2 (2H) -oxoimidazol-l-yl) · 1-piperidinyl] carbonyl] -N' -methyl-D-tryptyl] -4- (4-methyl-l-piperazinyl) -piperidine, (AB) 1- [N2- [ [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)-l-[4-[4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl ) -1-piperidinyl] -2- [ (3, 5-dibromo-4 -methylphenyl ) methyl] -1, 4-dioxo butyl] -4- (4-methyl-l-piperazinyl) -piperidine, (AD) (R, S) -1- [4- [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] -2- [ (3 (<5-dibromo-4-methoxyphenyl) methyl] -1,4-dioxobutyl] -4- (1-methyl -4 -piperidinyl) -piperidine, (AE) (R,S) -1- [4- [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] -2- [ (3 , 4-dibromphenyl) methyl] -1, 4 -dioxobutyl] -4- (4 -methyl-1-piperazinyl ) -piperidine , (AF) 1- [N2- [N- [ [4- (1, 3-dihydro-2 (2H) -oxobenzimidazol-l-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-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (AH) 1- [N2- [4-amino-3 , 5-dibromo-N- [ [4- (1, 3-dihydro-2 (2H) -oxo benzimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -N6,N6-dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, (AI) 1- [N2- [4 -amino-3 , 5-dibromo-N- [ [4- (3 , 4 -dihydro-2 (1H) -oxo quinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] - N6 , N6-dimethyl-L-lysyl] -4- (4-pyridinyl) -piperazine, (AJ) (R, S) -1- [2- (4-amino-3 , 5-dibromobenzoyl) -4- [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl ) -1-piperidinyl] -4-oxobutyl] -4- (1-piperidinyl) -piperidine, (AK) 1- [4-amino-3 , 5-dibromo-N- [ [4- (3 , 4-dihydro-2 , 2-dioxido- 2,1, 3-benzothiadiazin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -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-phenylalanyl] -4- (1-piperidinyl) carbonyl] -piperidine (AM) 1- [4-amino-3 , 5-dibromo-N- [ [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3-yl) τΐ-piperidinyl] carbonyl] -D-phenylalanyl] -4- ( 1-piperidinyl) -piperidine, (AN) 1- [N2- [3, 5-dibromo-N- [ [4- (3, 4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -N6,N6-dimethyl-L-lysyl] -4- (4 -pyridinyl) -piperazine, (AO) 1- [4-amino-N- [ [4- [4- (3 -bromophenyl ) -1, 3-dihydro-2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -3 , 5 -dibromo-D-phenylalanyl] -4- (l-methyl-4-piperidinyl) -piperidine, (AP) 1- [4-amino-3 , 5-dibromo-N- [ [4- [1 , 3 -dihydro-4 -phenyl -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4 -methyl-1-piperazxnyl) -piperidine , (AQ) 1- [4-amino-3 , 5-dibromo-N- [ [4- [1 , 3 -dihydro-4 - [3- (tri-fluoromethyl) phenyl] -2 (2H) -oxoimidazol-l-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-iiluoromethyl ) phenyl] -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo- 8 -methyl - 8 -azabicyclo [3,2,1] oct-3-yl) -piperazine, (AS) 1- [3 , 5-dibromo-N- [ [4- (1, 3 -dihydro-4 -phenyl-2 (2H) -oxoimidazol-l-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) henyl] -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-ethyl-4- ■piperidinyl) -piperazine, (AU) 1- [4-amino-3 , 5-dibromo-N- [ [4- [1, 3-dihydro-4-phenyl-2 (2H) oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-4 -methyl - IH- 1 , 4 -diazepin- 1-yl ) piperidine , (AV) 1- [3 , 5-dibromo-N- [ [4- (3 , 4-dihydro-2 (IH) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- [1- (methylsulphonyl ) -4 -piperidinyl] -piperidine, (AW)i 1- [4-amino-3 , 5-dibromo-N- [ [4- (1, 3 -dihydro-4 -phenyl -2 (2H) oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-methyl-4-piperidinyl) -piperidine, (AX) 1- [3 , 5-dibromo-N- [ [4- [1 , 3 -dihydro-4 - [3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro-lH-l-azepinyl) -piperidine, (AY) 1- [3 , 5-dibromo-N- [ [4- (3 , 4-dihydro-2 (IH) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (l-methyl-4-piperidinyl) -piperidine, (AZ) 1- [4 -amino- 3 , 5-dibromo-N- [ [4- (3 , 4-dihydro-2 (IH) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8 -methyl- 8 -azabicyclo [3,2,1] oct-3-yl) -piperazine, (BA) 1- [4-amino-3 , 5-dibromo-N- [ [4- ( 1 , 3 -dihydro-4 -phenyl -2 (2H) oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- ( 1 -methyl -4 -piperidinyl ) -piperazine , (BB) 1- [3 , 5-dibromo-N- [ [4- [1 , 3 -dihydro-4 - [3- (trifluoromethyl ) phenyl] -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine, (BC) 1- [N6-acetyl-N2- [3 , 5 -dibromo-N- [ [4- (3 , 4-dihydro-2 (1H) - oxoquinazolin-3 -yl ) -1-piperidinyl] carbonyl] -D-tyrosyl] -L- lysyl] -4- (4 -pyridinyl ) -piperazine, (BD) 1- [3 , 5 -dibromo-N- [ [4- (1, 3 -dihydro-4-phenyl-2 (2H) -oxoimi dazol-l-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro- lH-l-azepinyl) -piperidine, (BE) 1- [4 -amino-3 , 5-dibromo-N- [ [4- ( 1 , 3 -dihydro-4 - (3-thienyl) 2 (2H) -oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4 -piperidinyl) -piperidine, (BF)~- 1- [4-amino-3 , 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3- (triifluoromethyl) phenyl] -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-methyl-4-piperidinyl) -piperidine, (BG) 1- [3 , 5-dibromo-N- [ [4- ( 3 , 4 -dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- [1- (hydroxycarbonyl -methyl) -4 -piperidinyl] -piperidine, (BH) 1- [4-amino-3, 5-dibromo-N- [ [4- [3 , 4 -dihydro-2 (1H) -oxoquinazolin-3 -yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methylsulphonyl-4 -piperidinyl ) -piperidine , (BI) 1- [3 , 5-dibromo-N- [ [4- (3 , 4 -dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (4 -piperidinyl) -piperidine, (BJ) 1- [4-amino-3 , 5-dibromo-N- [ [4- (1, 3 -dihydro-4 -phenyl-2 (2H) oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-ethyl-4-piperidinyl) -piperidine, (BK) 1- [4-amino-3 , 5-dibromo-N- [ [4- (1, 3-dihydro-4- (3-hydroxy-phenyl) -2 (2H) -oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-methyl-4-piperidinyl) -piperidine, (BL) 1- [3 , 5-dibromo-N- [ [4- (3 , 4 -dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro- lH-1-azepinyl) -piperidine, (BM) 1- [4-amino-3 , 5-dibromo-N- [ [4- (1, 3 -dihydro-4 -phenyl-2 (2H) oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -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-l-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3,2,1] oct-3-yl) -piperazine , (BO); 1- [4-amino-3 , 5-dibromo-N- [ [4- ( 3 , 4 -dihydro-2 (1H) -oxo-quiriazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-ethyl-4-piperidinyl) -piperidine, (BP) 1- [4-amino-3 , 5-dibromo-N- [ [4- (3 , 4 -dihydro-2 (1H) -oxo-quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-ethyl-4-piperidinyl) -piperazine, (BQ) 1- [4-amino-3 , 5-dibromo-N- [ [4- [1, 3-dihydro-4- (3-methoxy-phenyl) -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo [3,2,1] oct-3-yl) -piperazine , (BR) 1- [3 , 5-dibromo-N- [ [4- (3 , 4 -dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- [1- (cyclopropyl -methyl) -4-piperidinyl] -piperidine, (BS) 1- [4-amino-3 , 5-dibromo-N- [ [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4-(hexahydro-1H-1-azepinyl ) -piperidine , (BT) 1- [4-amino-3 , 5 -dibromo-N- [ [4- (3 , 4-dihydro-2 (1H) -oxo- quinazolin-3 -yl ) - 1 -piperidinyl] carbonyl] -D-phenylalanyl] -4- (4 -piperidinyl) -piperidine, .(BU) 1- [3 , 5 -dibromo-N- [ [4- (1, 3 -dihydro-4-phenyl-2 (2H) -oxo- imidazol-l-yl) -1 -piperidinyl] carbonyl] -D-tyrosyl] -4- (4-pyridinyl) -piperidine, (BV) 1- [3 , 5-dibromo-N- [.[4- [1 , 3 -dihydro-4 - [3- ( trifluoromethyl ) -phenyl] -2 (2H) -oxoimidazol-l-yl] - 1-piperidinyl] carbonyl] -D-tyrosyl] -4- (l-methyl-4-piperidinyl) -piperazine, (BW) 1- [N2- [3 , 5-dibromo-N- [ [4- [1 , 3 -dihydro-4 - [3- (trifluorome-thylj phenyl] -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, (BX) 1- [3, 5-dibromo-N- [ [4- ( 1 , 3 -dihydro-4 - (3-thienyl) -2 (2H) -oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-piperidinyl) -piperidine, (BY) 1- [4-amino-N- [ [4- [4- (3-chlorophenyl) -1 , 3 -dihydro-2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -3 , 5-dibromo-D-phenylalanyl] -4- (1 -methyl - -piperidinyl) -piperidine, (BZ) 1- [4-amino-3 , 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3- (trifluoromethyl) phenyl] -2(2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-lH-1-azepinyl) -piperidine, (CA) 1- [4-amino-3 , 5-dibromo-N- [ [4- [1, 3-dihydro-4- [3- (trifluoromethyl) henyl] -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-methyl-4-piperidinyl) -piperazine, (CB) 1- [4-amino-N- [ [4- [4- (3-chlorophenyl) -1, 3 -dihydro-2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -3 , 5-dibromo-D-phenylalanyl] -4- (hexahydro-lH-l-azepinyl) -piperidine, (CO 1- [4-amino-3 , 5-dibromo-N- [ [4- (1, 3 -dihydro-4 -phenyl -2 (2H) oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-pyridinyl) -piperazine, (CD) 1- [3, 5-dibromo-N- [ [4- ( 1 , 3 -dihydro-4 -phenyl -2 (2H) -oxoimidazol-l-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-l-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] -jl-piperidinyl] carbonyl] -D-tyrosyl] -4- (l-methyl-4-pipe'ridinyl) -piperazine, (CG) 1- [4-amino-3 , 5-dibromo-N- [ [4- [1, 3-dihydro-4- (3-nitrophe-nyl) -2 (2H) -oxoimidazol-l-yl] -1-piperidinyl] carbonyl] -D-phenyl-alahyl] -4- (1-methyl-4 -piperidinyl) -piperidine, (CH) 1- [4-amino-3 , 5-dibromo-N- [ [4- [3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl] - 1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-pyrrolidinyl) -piperidine, (CI) 1- [4-amino-3 , 5-dibromo-N- [ [4- (1, 3-dihydro-4-phenyl-2 (2H) oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4-(hexahydro-lH-l-azepinyl ) -piperidine and (CJ) 1- [4-amino-3 , 5-dibromo-N- [ [4- (1, 3-dihydro-4- (3-thienyl) -2 (2H) -oxoimidazol-l-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (l-methyl-4-piperidinyl) -piperazine, the tautomers, the diastereomers , the enantiomers, the mixtures thereof and the physiologically acceptable salts thereof, while the compounds (A) 1- [N2- [3 , 5-dibromo-N- [ [4- ( 3 , 4 -dihydro-2 (1H) - oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L- lysyl] -4- (4 -pyridinyl ) -piperazine, .(B) 1- [4 -amino-3 , 5-dibromo-N- [ [4- (2 , 3 , 4 , 5-tetrahydro-2 (1H) - oxo- 1 , 3 -benzodiazepin-3 -yl ) - 1-piperidinyl] carbonyl] -D-phenyl -alanyl] -4- (1-piperidinyl) -piperidine, (I), 1- [4-amino-3, 5-dibromo-N- [ [4- (2 , 4-dihydro-5-phenyl-3 (3H) oxo-1, 2 , 4-triazol-2-tyl) -1-piperidinyl] carbonyl] -D-phenyl-alanyl] -4- (1-piperidinyl) -piperidine, (J) 1- [4-amino-3 , 5-dibromo-N- [ [4- (2 , 4-dihydro-5 -phenyl -3 (3H) oxo-1 , 2 , 4 -triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenyl -alanyl] -4- (l-methyl-4-piperidinyl) -piperazine, (AC) (R,S) -1- [4- [4- (3, 4 -dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] -2- [ (3 , 5 -dibromo-4 -methylphenyl ) methyl] -1, 4-dioxo-butyl] -4- (4-methyl-l-piperazinyl) -piperidine, (AF) 1- [N2- [N- [ [4- (1, 3 -dihydro-2 (2H) -oxobenzimidazol-l-yl) -1-piperidinyl] carbonyl] -3 , 5 -dibromo-D-tyrosyl] -L-lysyl] -4- (4 -pyridinyl) -piperazine and (AM) 1- [4-amino-3 , 5-dibromo-N- [ [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4-( 1-piperidinyl) -piperidine, the tautomers, the diastereomers , the enantiomers, the mixtures thereof and the physiologically acceptable salts thereof, and especially the compounds (A) 1- [N2- [3 , 5-dibromp-N- [ [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl ) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4 -pyridinyl ) -piperazine and (B) 1- [4 -amino- 3 , 5-dibromo-N- [ [4- (2 , 3 , 4 , 5 - etrahydro- 2 (1H) -oxo-1, 3 -benzodiazepin-3 -yl) -1 -piperidinyl] carbonyl] -D-phenyl -alanyl] -4- ( 1 -piperidinyl ) -piperidine, the tautomers, the diastereomers , the enantiomers, the mixtures thereof and the physiologically acceptable salts thereof are particularly preferred.
The dosage required to produce the desired effect is appropriately O.OOOvL 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. ί If the treatment i¾¾ fo-i^or-s is given as a supplement to conventional hormone replacement therapy, it is advisable to reduce the doses given above, and in this case the dosage may range from 1/5 of the lower limits specified above up to l/l of the upper limits specified above. - For this purpose, the CGRP antagonists may be formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol , water/glycerol , water/sorbitol , water/polyethyleneglycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metering aerosols or suppositories.
Preparations which are particularly suitable for treating menopausal hot flushes are those which contain one of the active substances .(A) 1- [N2- [3 , 5-dibromo-N- [ [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -.4- (4 -pyridinyl ) -piperazine, (B) 1- [4-amino-3 , 5-dibromo-N- [ [4- (2 , 3 , 4 , 5-tetrahydro-2 (1H) -oxo-1 , 3 -benzodiazepin-3 -yl) -1-piperidinyl] carbonyl] -D-phenyl-alanyl] -4- (1-piperidinyl) -piperidine, (I) 1- [4-amino-3 , 5-dibromo-N- [ [4- (2 , 4 -dihydro-5 -phenyl -3 (3H) oxo-1 , 2 , - triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenyl -alanyl] -4- (1-piperidinyl) -piperidine, (J) 1- [4 -amino-3 , 5-dibromo-N- [ [4- (2 , -dihydro-5-phenyl-3 (3H) oxo-1, 2 , 4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenyl-alanyl] -4- (l-methyl-4-piperidinyl) -piperazine, (AC) (R, S) -1- [4- [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl ) -1-piperidinyl] -2- [ (3 , 5-dibromo-4-methylphenyl) methyl] -1,4-dioxo-butyl] -4- (4 -methyl -1-piperazinyl) -piperidine, (AF) 1- [N2- [N- [[4- (1, 3-dihydro-2 (2H) -oxobenzimidazol-l-yl ) -1-piperidinyl] carbonyl] -3 , 5-dibromo-D-tyrosyl] -L-lysyl] -4- (4 -pyridinyl) -piperazine or (AM) 1- [4-amino-3 , 5-dibromo-N- [ [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4-(1-piperidinyl) -piperidine, in one of the following pharmaceutical formulations: capsules for powder inhalation containing 1 mg of active substance, preferably active substance (A) or (B) , inhalable solution for nebulisers containing 1 mg of active substance, preferably active substance (A) or (B) , propellant gas-operated metering aerosol containing 1 mg of active substance, preferably active substance (A) or (B) , nasal spray containing 1 mg of active substance, preferably active substance (A) or (B) , tablets containing 20 mg of active substance, preferably active substance (B) , capsules containing 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 , an increased release of endogenous CGRP was induced in marmosets by stimulating the trigeminal ganglion, leading to increased blood flow through the blood vessels of the skin. The efficacy of the following test substances was characterised by- determining the dose administered i.v. which reduces by 50% the increased blood flow through the skin of the face which has been brought about by endogenous CGRP : (A) = 1- [N2- [3, 5-dibromo-N- [ [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl ) - 1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4 -pyridinyl) -piperazine, (B) = 1- [4-amino-3 , 5-dibromo-N- [ [4- (2 , 3 , 4 , 5-tetrahydro-2 (1H) -oxo-1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenyl-alanyl] -4- (1-piperidinyl) -piperidine, (AC)- = (R, S) -1- [4- [4- (3 , 4-dihydro-2 (1H) -oxoquinazolin-3 -yl ) -1-piperidinyl] -2- [ (3 , 5-dibromo-4 -methylphenyl ) methyl] -1, 4-dioxo-butyl] -4- (4 -methyl-l-piperazinyl ) -piperidine, (AM) = 1- [4-amino-3, 5-dibromo-N- [ [4- (3, 4-dihydro-2 (1H) -oxoquinazolin-3 -yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- ( 1-piperidinyl) -piperidine, (DA) = sumatriptan and (DB) = zolmitriptan .
Description of method: Marmosets of both sexes (300-400 g) are anaesthetised with pentobarbital (initially with 30 mg/kg, i.p., followed by infusion of 6mg/kg/h, i.m.) . The body temperature is maintained at 37°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.
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: 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 The Examples which follow describe pharmaceutical preparations which contain as active substance a CGRP antagonist or CGRP release inhibitor for use according to the invention, preferably one of the amino acid derivatives described in WO 98/11128 or DE 199 11 039, for example one of the abovementioned active substances (A) or (B) : Example I Capsules for powder inhalation with 1 mg of active substance (A) or (B) Composition: 1 capsule for powder inhalation contains: active substance (A) or (B) 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mg Method of preparation: The active substance is ground to the particle size needed for inhajLation. 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 μΐ Method of preparation: The active substance and benzalkonium chloride are dissolved in water and packed m Respimat cartridges .
Example III Inhalable solution for nebulisers with 1 mg of active substance (A) or (B) .
Composition: 1 vial contains : active substance (A) or (B) 0.1 9 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 μΐ Method of preparation: The micronised active substance is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurised container with a metering valve .
Example V Nasal spray with 1 mg of active substance (A) or (B) Composition: 1 spray jet contains active substance (A) or (B) 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 (Wfl) ; add human serum albumin; add salt -forming agent; dissolve active substance with heating; make up to specified volume with Wfl; transfer into ampoules under nitrogen gas.
Example VII Injectable solution for subcutaneous administration containing 5 mq 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 Wfl; 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 = KH2P04 12 mg disodium hydrogen phosphate = Na2HP04-2H20 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 (Wfl) ; add human serum albumin; dissolve active substance with heating; make up to specified volume with Wfl; transfer into ampoules.
Example IX Lvophilisate containing 10 mg of active substance (A) or (B) Composition : active substance (A) or (B) in basic form 10 mg acid/sal -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 (Wfl) ; add salt-forming agent; dissolve active substance with heating; make up to specified volume with Wfl; 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 (Wfl); 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 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 injec (Wfl) ; transfer into ampoules.
Example XI Tablets containing 20 mg of active substance (A) or (B) Composition : active substance (A) or (B) 20 mg lactose 120 mg maize starch 40 mg magnesium stearate 2 mg Povidone K 25 18 mg Preparation : Homogeneously mix the active substance, lactose and maize starch; granulate with an aqueous solution of Povidone; mix with magnesium stearate; press in a tablet press; weight of tablet 200 mg.
( Example XII Capsules containing 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 °C; homogeneously disperse the ground active substance in the molten hard fat; after cooling to about 35°C, pour into chilled moulds.
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 jactive 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 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 (Wfl) ad 1 ml Preparation : The active substance is dissolved in 1 , 2 -propanediol ; the solution is made up to approximately the specified volume with Wfl; the mannitol is added and made up to approximately the specified volume with Wfl; the solution is filtered sterile, transferred into individual containers and autoclaved.
Example XVII Liposomal formulation for intravenous injection containing 7.5 mcf 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 Wfl and homogenised by high pressure homogenisation or by the Microfluidizer technique; the liposomal formulation obtained is transferred into a suitable container under aseptic conditions.
Example XVIII Suspension for nasal administration containing 20 mg of act substance (A) or (B) Composition: Ί active substance (A) or (B) carboxymethylcellulose (CMC) sodium monohydrogen phosphate/sodium dihydrogen phosphate buffer pH 6.8 sodium chloride methyl parahydroxybenzoate propyl parahydroxybenzoate purified water ad 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 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 ma 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 μιτι using a suitable dispersing technique (e.g. wet grinding, high pressure homogenisa ion, microfluidisation, etc.). The suspension is transferred into a corresponding container under aseptic conditions.
Passages of the description which are not within the scope of the claims do not constitute part of the invention.

Claims (3)

1. 30 148057/2 a CGRP antagonist for preparing a pharmaceutical composition for treating menopausal hot flushes, characterised in that the CGRP antagonist is selected from among: (A) l -[N2[3,5-dibromo-N-[[4-(3.4-dihydro-2(lH)-oxoquinazolin-3-yl)-l -piperidinyl] cai-bonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (B) I - 4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(l H)-oxo-l,3- benzodiazepin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)- piperidine, (C) l -[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(ll-I)-oxoquinazolin-3-yl)- t- piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (D) l-[ 2-[4-amino-3, 5-dibromo-N-[[4-(3, 4-dihydro-2(l H)-oxoquinazolin-3-yl)-l- piperidinyl]cai-bonyl]-D-phenylalanyl]-L-Iysyl]-4-(4rpyridinyl)-piperidine, (E) l -[N2-[3,5-dibromo-N-[[4-(l ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l- piperidinyl]carbonyl]-D-t)Tosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (F) 1 - [N2- [4-amino-3 ,5-dibromo-N-[[4-( 1 ,3 -di hydro-4-phenyl-2(2H)-oxoimidazo l- 1- yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (G) 1 -[3 ,5-dibromo-N-[[4-(3 ,4-dihydro-2( 1 H)-oxothieno[3,4-d]pyrimidin-3 -yl)- 1 - piperidinyl]carbonyl]-D-tyrosyl]-4-(l-piperidinyl)-piperidine, (H) l-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-l ,2,4-triazol-2- yl)-l -piperidinyl]carbonyl]-D-phenylalanyl]-4-(l -methyl-4-piperidinyl)-piperidine, (I) l-[4-an ino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-l ,2,4-triazol- 2- yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine, (J) l-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-l ,2,4-triazol- 2-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-methyl-4-piperidinyl)-piperazine, (K) 1 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(l H)-oxothieno[3,2-d]pyrimidin-3- yl)-l -piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine, (L) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)- oxoimidazol- 1 -yl]- 1 -piperidin-yl]carbonyl]-D-phenylalanyl]-4-(l -ethyl-4-piperidinyl)- piperidine, 31 148057/2 (M) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yI]-l -piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-hexyl-4-piperidinyl)-piperidine, (N) l -[4-amino-3.5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-cyclopi pylmethyl-4-piperidinyl)-piperidine, (O) l-[N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl]carbonyl]-3-etheny l-D,L-phenylalany 1] -4-(hexahydro- 1 H- 1 -azepinyl)-piperidine, (P) (R3)-l-[4-[4-(3,4-dihydro-2(1 H)-oxoq hydroxy-3, 5-dimethylphenyl)mediyl]-l,4-dioxobutyl]-4-(l-piperidinyl)-piperidine, (Q) l-[4-amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-l-piperidinyl] carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine, (R) l-[4-amino-3,5-dibromo-N-[[4-(3,4-diIiydro-2(l H)-oxoquinazolin-3-yl)- l-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)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine, (T) l-[4-amino-3,5-dibromo-N-[[4-[2(lH)-oxoquinolin-3-yl]-l -piperidinyl]carbonyl]- D-phenylalanyl]-4-(l -piperidinyl)-piperidine, (U) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimetliylamino)propyl]-piperazine, (V) 1 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l -piperidinyl]carbonyl]-D-phenylalan)'l]-4-(4-methyl-l-piperazinyl)-piperidine, (W) l-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2( l H)-oxoquinazolin-3-yl]-l -piperidinyl]carbonyl]-D-phenylalanyl]-4-[(l-methyl-4-piperidinyl)carbonyl]-piperazine, (X) l -[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(l-methyl-4-piperazinyl)carbony]]-piperazine, (Y) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(l H)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]plieny!]-piperazine, (Z) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-l-piperidinyl]-piperidine, (AA) 1 -[N2-[[4-( 1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol- 1 -yl)- 1 -piperidinyl]carbonyl]-N'-methyl-D-tryptyl]-4-(4-methyl-l -piperazinyl)-piperidine, 32 148057/2 (AB) l -[N2-[[4-(L3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-\'l)-l-piperidinyl] carbonyl]-N'-(l , l -dimethylet]ioxycarbonyl)-D-ti7ptyl]-4-(l -methyl-4-piperidinyl)-piperidine, (AC) (R, S)-l-[4-[4-(3, 4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methy 1 ]- 1 ,4-dioxobuty 1] -4-(4-methyl- 1 -pi perazi nyl)-piperidi ne, (AD) (R,S)-l -[4-[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(3,5-dibromo-4-methoxyphenyl)methyl]-l ,4-dioxobutyl]-4-(l -methyl-4-piperidinyl)-piperidine, (AE) (R,S)-l-[4-[4^3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-2-[(3,4-dibromophenyl)methyl]-l,4-dioxobutyl]-4-(4-methyl-l-piperazinyl)-piperidine, (AF) l -[N2-[N-[[4-(l,3-dihydro-2(2H.)-oxobenzimidazol-l-yl)-l-piperidinyl]cai-bonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (AG) l-[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-6-hydroxy-2(2H)-oxobenzimidazol-l-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l -piperidinyl)-piperidine, (AH) l -( J2 4-amino-3,5-dibromo-N-[[4-(l ,3-dihydro-2(2H)-oxobenzimidazol-l -yl)- l ^ piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (AI) l-[N2-4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (AJ) (R, S)-l -(2-(4-amino-3, 5-dibromobenzoyl)-4 [4-(3, 4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]-4-oxobutyl]-4-(l-pipcridinyl)-piperidine, (AK) 1 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2, 1 , 3-benzothiadiazin- 3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l -piperidinyl)-piperidine, (AL) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin- 3-yl]-l -piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)carbonyl]-piperidine, (AM) l-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydi -2(l H)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine, (AN) l-| I2-[3,5-dibiOmo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyiOsyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine, (AO) l -[4-amino-N-[[4-[4-(3-bromophenyl)-l ,3-dihydro-2(2H)-oxoimidazol-l -yl]-l-piperidinyl]carbonyl]-3,5-dibrorao-D-phenylalanyl]-4-( l -metliyl-4-piperidinyl) piperidine, (AP) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl]- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl- 1 -piperazinyl)-piperidine, 148057/2 (AQ) l-[4-an ino-3,5-dibromo-N-[[4-[l ,3-dihydro-4-[3-(trifluoromethy])phenyl]- 2(2H)-oxoimidazol-l -yl]-l -piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-pipendinyi)-piperidine, (AR) l-[4-amino-3, 5-dibromo-N-[[4-[l ,3-dihydro-4-[3-(trifl^ 2(2H)-oxoimidazol-l -yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methy^ azabicyclo[3,2,l]oct-3-yl)-piperazine, (AS) l -[3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l -piperidinyl]carbonyl]-D-tyrosyl]-4-(l -piperidinyl)-piperidine, (AT) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-l-yl]-l-piperidinyl]carbonyl]-D-phetiylalanyl]-4-(l-ethyl-4-piperidinyl)-piperazine, (AU) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl]-1 -piperidinyncai-bonylJ-D-phenylalanj'lj^-^iexaliydro^-methyl- 1 H- 1 ,4-diazepin- 1 -yl)piperidine, (AV) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l -piperidinyl] carbonyl]-D-tyrosyl]-4-[l-(methylsulphonyl)-4-piperidinyl]-piperidine, (AW) 1 -[4-amino-3,5-dibromo-N-[[4-(l ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l -methyl-4-piperidinyl)-piperidine, (AX) l-[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-l-yi]-l -piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-lH-l-azepinyl)-piperidine, (AY) l -[3,5-dibromo-N-[[4-(3,4-diliydro-2(lH)-oxoquinazolin-3-yl)-l -piperidinyl] carbonyl]-D-tyrosyl]-4-(l-methyl-4-piperidinyl)-piperidine, (AZ) l -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,l ]oct-3-yl)-piperazine, (BA) l -[4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l -piperidinyl]cai-bonyl]-D-phenyl-alanyl]-4-(l -methyl-4-piperidinyl)-piperazinc, (BB) · 1 3,5-dibromo-N-[[4-[l ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-l -yl]-l-piperidinyl]carbonyl]-D-tyrosyl]-4-(l -piperidinyl)-piperidine, ~(BC) l -[N6-acetyl- 2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(l H)-oxoquinazolin-3-yl)-l-pipendinyl]carbonyl]-D-t}Tosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 34 148057/2 (BD) 1 -[3,5-dibromo-N-[[4-( 1 ,3 -dihydro-4-phenyl-2(2H)-oxoimidazol- 1 -yl)- 1 -piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-lH-l (BE) 1 4-amino-3,5-dibromo-N-[[4-(l,3-dihydro-4-(3-thieiiyl)-2(2H)-oxoimidazol-l -yl)-l-piperidinyl]cai-bonyl]-D-phenylalanyl]-4-(3-methyl-4-piperidinyl)-piperidine (BF) l-[4-amino-3,5-dibromo-N-[[4-[l ,3-dihydro-4-[3-(trifluorom tliy])phenyl]-2 oxoimidazol-l -yl]-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-methyl-4-piperid piperidine, (BG) 1 3,5-dibromo-N-[[4-(3?4-dihydro-2(l H)-oxoquinazolin-3-yl)-l -piperidinyl] carbonyl]-D-tyrosyl]-4-[l-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine, (BH) l-[4-amino-3,5-dibronio-N-[[4-[3,4-dihydro-2(lH)-oxoquinazolin-3-yl]-l-piperidinyl]carbonyl]-D-phenyla]anyl]-4-(l-rnethyIsulphonyl-4-piperidinyl)-piperidine, (BI) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l -piperidinyl] carbonylj-D-tyrosyl]-4-(4-piperidinyl)-piperidine, (BJ) l-[4-amino-3,5-dibromo-N-[[4-(l ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l -ethj'l-4-piperidinyl)-piperidine, (B ) l-[4-amino-3,5-dibromo-N-[[4-(l ,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxoimidazol-l -yl)- l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-methyl-4-piperidinyl)-piperidine, (BL) l-[3,5-dibromo-N-[[4-(3,4-dihydro-2(l H)-oxoquinazolin-3-yl)-l-piperidinyl] carbonyl]-D-tyrosyl]-4-(hexahydro-l H-l -azepinyl)-pip ridine, (BM) l-[4-amino-3,5-dibromo-N-[[4-(l ,3-dihydro-4-phenyl-2(2H)-oxoimidazol- l-yl)- l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-piperidinyl)-piperidine, (BN) l-[4-amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-l,3-dihydro-2(2H)-oxoiniidazol-1 -yl]- -piperidinyl]carbonyI]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicycIo[3 ,2, 1 ]oct-3 -yl)-piperazine, (BO) l-[4-amino-3,5-dibiOmo-N-[[4-(3,4-diliydro-2(l H)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-ethyl-4-piperidinyl)-piperidine, (BP) l-[4-amino-3,5-dibi mo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-j'l)-l-piperidinyl]carbonyl]-D-phen}'lalanyl]-4-(l-ethyl-4-piperidinyl)-piperazine, (BQ) l-[4-amino-3, 5-dibromo-N-[[4-[l ,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-l-yl]-l-piperidinyl]carbonyI]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,l ]oct-3-yl)-piperazine, 35 148057/2 (BR) l-[3.5-dibromo-N-[[4-(3,4-dihydro-2(lH)-oxoquinazolin-3-yl)-l -piperidinyl] carbonyl]-D-tyrosyl]-4-[l-(cycloprop\'lmethyl)-4-piperidinyl]-piperidine, (BS) l -[4-amino-3,5-dibromo-N-[[4-(3.4-dihydro-2(l H)-oxoquinazolin-3-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-lH-l-azepinyl)-piperidine, (BT) l-[4-amino-3,5-dibromo-N-[[4-(3;4-dihydro-2(l H)-oxoquinazolin-3-yl)-l -piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine, (BU) l-[3,5-dibromo-N-[[4-(l ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-2-yl)-l-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine, (BV) l-[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol- 1 -yl]- 1 -pi peridi ny 1 ] carbony 1] -D-tyrosyl] -4-( 1 -methy 1-4-piperidinyl)-piperazine, (BW) l-[N2-[3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyI)phenyl]-2(2H)-oxoimidazol-l-yl]-l-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (BX) l-[3,5-dibromo-N-[[4-(l ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-l -yl)-l -piperidinyl]carbonyl]-D-tyrosyl]-4-(l -piperidinyl)-piperidine, (BY) 1 -[4-amino-N-[[4-[4-(3-chlorophenyl)- 1 ,3-diliydro-2(2H)-oxoimidazol- 1 -yl]- 1 -piperidinyl]carbonyl]-3,5-dibromo-D-phenylal^ (BZ) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(triiluoromethyl)phenyl]-2(2H)-oxoimidazol- 1 -yl]- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro- 1 H- 1 -azepinyl)-piperidine, (CA) l-[4-amino-3,5-dibromo-N-[[4-[l,3-dihydro-4-[3-(trifluoromethyI)phenyl]-2(2H)-oxoimidazol-l-yl]-l-piperidinyl]carbom'l]-D-phenylalanyl]-4-(l -methyl -4-piperidinyl)-piperazine, (CB) l-[4-amino-N-[[4-[4-(3-chlorophenyl)-l ,3-dihydro-2(2H)-oxoimidazol-l -yl]-l-piperidinyl]carbon'yl]-3,5-dibromo-D-phenylalanyl]-4-(hexahydro-l H-l-azepinyl)-piperidine, (CC) 1 -[4-amino-3,5-dibromo-N-[[4-(l ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine, (CD) l-[3,5-dibromo-N-[[4-(l ,3-dihydro-4-plienyl-2(2H)-oxoimidazol-l-yl)-l-piperidinyl]carbonyl]-D-tyrosyl]-4-(l -rneth}'l-4-piperidinyl)-piperidine, (CE) l-[4-amino-3,5-dibromo-N-[[4-[l ,3-di]iydro-4-phenyl-2(2H)-oxoimidazol-l -yl]-l -piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(l -oxoethyl)phenyl]-piperazine, 36 148057/2 (CF) 1 - [3 ,5-dibromo-N-[[4-[3 ,4-dihydro-2( 1 H)-oxoquinazolin-3 -yl] - 1 -piperidinyl] carbonyl]-D-t}TOsyl]-4-(l-methyl-4-piperidinyl)-piperazine, (CG) l-[4-amino-3,5-dibromo-N-[[4-[l J3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimidazol-l -yl]-l -piperidinyl]carbonyl]-D-phenylalanyl]-4-(l -methyl-4-piperidinyl)-piperidine, (CH) 1 - [4-amino-3 , 5 -dibromo-N- [[4- [3 ,4-dihydro-2( 1 H)-oxoquinazol in-3 -yl] - 1 -piperidinyl]carbonyI]-D-phenyIalanyl]-4-(l-pyrrolidinyl)-piperidine, (CI) l -[4-aj-nino-3,5-dibromo-N-[[4-(l ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-l -yl)-l -piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-l H-l-azepinyl)-piperidine and (CJ) l-[4-ainino-3,5-dibromo-N-[[4-(l,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-^ yl)-l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(l-methyl-4-piperidinyl)-piperazine, the tautomers, the diastereomcrs, the enantiomers, the mixtures thereof and the physiologically acceptable salts thereof.
2. Use according to claim 1 , characterised in that it is done as a supplement to hormone replacement therapy.
3. Use according to claim 1, characterised in that the pharmaceutical composition contains only one active substance. For the Applicants, REINHOLD COHN AND PARTNERS
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