EP1648466A1 - Use of cgrp antagonists in treatment and prevention of hot flushes in prostate cancer patients - Google Patents

Use of cgrp antagonists in treatment and prevention of hot flushes in prostate cancer patients

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Publication number
EP1648466A1
EP1648466A1 EP04763078A EP04763078A EP1648466A1 EP 1648466 A1 EP1648466 A1 EP 1648466A1 EP 04763078 A EP04763078 A EP 04763078A EP 04763078 A EP04763078 A EP 04763078A EP 1648466 A1 EP1648466 A1 EP 1648466A1
Authority
EP
European Patent Office
Prior art keywords
piperidinyl
dihydro
dibromo
carbonyl
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04763078A
Other languages
German (de)
French (fr)
Inventor
Henri Doods
Klaus Rudolf
Wolfgang Eberlein
Wolfhard Engel
Mats Hammar
Anna-Clara Spetz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP04763078A priority Critical patent/EP1648466A1/en
Publication of EP1648466A1 publication Critical patent/EP1648466A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/55—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
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system

Definitions

  • the present invention relates to a method of treatment or prevention of hot flushes in men who underwent castration, e.g. due to androgen ablation treatment in prostate cancer therapy (orchiectomy), comprising administration of an effective amount of a CGRP antagonist and/or of a CGRP release inhibitor to a person in need of such treatment.
  • the method 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.
  • the invention relates to the use of a CGRP antagonist and/or of a CGRP release inhibitor for manufacture of a pharmaceutical composition for prevention or treatment of hot flushes in men who underwent castration.
  • Hot flushes and sweating that is vasomotor symptoms, are reported by 43 to 77% of prostate cancer patients after medical or surgical castration, usually persisting for many years, possibly impairing quality of life (Arch. Surg. 43: 209, 1941 ; J. Urol. 152: 1170, 1994). Furthermore, hot flushes occur in 75% of women after menopause.
  • CGRP antagonists CGRP antagonists
  • CGRP release inhibitors CGRP release inhibitors
  • a second object of the invention is the use of a CGRP antagonist and/or of a CGRP release inhibitor for manufacture of a pharmaceutical composition for prevention or treatment of hot flushes in men who underwent castration.
  • the present invention thus relates to the use of CGRP antagonists and/or CGRP release inhibitors for combating hot flushes in men who underwent castration, 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.
  • the treatment according to the invention may be carried out in addition to conventional therapy, thus any aspect of the invention includes combination with conventional therapy or those drugs used in conventional therapy.
  • hormonal therapies comprising oral and topical administration (although especially oral hormonal therapies are known to cause side effects), e.g. oral diethylstilbestrol, topical estrogens such as estrogen patches, oral medroxyprogesterone acetate, megestrol acetate and cyproterone acetate,
  • oral central ⁇ 2-agonists e.g. oral clonidine
  • selective 5-hydroxytryptamine (5-HT) reuptake inhibitors e.g. sertraline (Zoloft ® ) and venlafaxine (Effexor ® ), and
  • acupuncture preferably electrostimulated acupuncture.
  • First-line treatments estrogen patches 0.05 mg/24 hours or 0.10 mg/24 hours (e.g. twice weekly for 4 weeks), transdermal estradiol 0.05 mg/24 hours or oral diethylstilboestrol (DES) 1 mg/day.
  • estrogen patches 0.05 mg/24 hours or 0.10 mg/24 hours (e.g. twice weekly for 4 weeks), transdermal estradiol 0.05 mg/24 hours or oral diethylstilboestrol (DES) 1 mg/day.
  • DES diethylstilboestrol
  • Oral progestagens e.g. megestrol acetate 40 mg/day or oral cyproterone acetate 50 to 300 mg/day, e.g. 50 mg orally twice a day or 300 mg intramuscularly once every 2 weeks, preferably 150 mg/day.
  • the invention also includes the use of an active substance selected from CGRP antagonists and CGRP release inhibitors for the preparation of a pharmaceutical composition for treatment or prevention of hot flushes jn men who underwent castration wherein the pharmaceutical composition comprises an active compound used in conventional therapy selected from the group consisting of
  • hormonal drugs e.g. oral diethylstilbestrol, an estrogen, medroxyprogesterone acetate, megestrol acetate and cyproterone acetate, including other salt forms of these drugs,
  • oral central 2-agonists e.g. oral clonidine
  • selective 5-hydroxytryptamine (5-HT) reuptake inhibitors e.g. sertraline (Zoloft .® ) ⁇ and venlafaxine (Effexor ® ).
  • 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.
  • CGRP antagonists include the amino acid derivatives described in WO 98/11128, WO 00/55154, WO 01/32648, WO 01/32649 and WO 01/49676 as well as the non-peptidic active substances described in WO 98/56779, WO 98/09630 aand WO 97/09046.
  • CGRP release inhibitors include serotonin 5-HT-i B/ i D -agonists such as almotriptan, avitnptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan, as well as 5-HTi F -agonists or NPY-agonists.
  • 5-HTi F -agonists or NPY-agonists 5-HTi F -agonists or NPY-agonists.
  • (AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-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-piperi- dinyl]carbonyl]-D-tyrosyl]-N 6 ,N 6 -dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine,
  • (AV) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyi]car- bonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine
  • (AW) 1-[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine,
  • 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 0.0001 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.
  • the dosage may range from 1/5 of the lower limits specified above up to 1/1 of the upper limits specified above.
  • the CGRP antagonists and/or CGRP release inhibitors may be formulated with one or more conventional inert carriers and/or diluents, e.g. with com 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.
  • conventional inert carriers and/or diluents e.g. with com starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol
  • 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),
  • 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).
  • active substance (A) may also be used in form of a physiologically acceptable salt, preferably in form of the hydrochloride salt which is available by reaction of the free base with hydrochloric acid by conventional methods. Amounts are given based on the free base.
  • 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,).
  • (A) 1-[N 2 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidi- nyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
  • (B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1 ,3-benzodiaze- pin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
  • (AC) (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-di- bromo-4-methylphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine,
  • (AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-pi- peridinyl]carbonyl]-D-phenylalanyI]-4-(1-piperidinyl)-piperidine,
  • Marmosets of both sexes are anaesthetised with pentobarbital (initially with 30 mg/kg, i.p., followed by infusion of 6mg/kg/h, i.m.).
  • 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.
  • Rhodes SNES 100 bipolar electrode
  • 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:
  • 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.
  • CGRP antagonist or CGRP release inhibitor for use according to the invention, preferably one of the amino acid derivatives described in WO 98/11128, WO 00/55154, WO 01/32648, WO 01/32649 or WO 01/49676 , for example one of the abovementioned active substances (A) or (B), most preferred is substance (A) hydrochloride.
  • 1 capsule for powder inhalation contains: active substance (A) or (B) 01.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mg
  • 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.
  • 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 ⁇ l
  • the active substance and benzalkonium chloride are dissolved in water and packed in Respimat ® cartridges.
  • 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
  • Active substance sodium chloride and benzalkonium chloride are dissolved in water.
  • Composition 1 spray contains: active substance (A) or (B) 1.0 mg lecithin 0.1 % propellant gas ad 50.0 ⁇ l
  • 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.
  • 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
  • the active substance and the excipients are dissolved in water and transferred into a suitable container.
  • 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.
  • Injectable solution for subcutaneous administration containing 5 mg of active substance (A) or (B) per 1 ml
  • active substance (A) or (B) 5 mg glucose 50 mg polysorbate 80 Tween 80 2 mg water for injections ad 1 ml
  • 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.
  • 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
  • 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 viais; freeze-dry.
  • 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
  • composition active substance (A) or (B) 20 mg lactose 120 mg maize starch 40 mg magnesium stearate 2 mg Povidone K 25 18 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
  • composition active substance (A) or (B) 50 mg hard fat (Adeps solidus) q.s. ad 1700 mg
  • 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.
  • composition active substance (A) or (B) 5 mg
  • 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 Agueous solution for intravenous administration containing 5 mg of active substance (A) or (B)
  • composition active substance (A) or (B) 5 mg
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • composition active substance (A) or (B) 5.0 mg polysorbate 80 0.5 mg water for injections 0.5 ml
  • the active substance is suspended in the polysorbate 80 solution and comminuted to a particle size of about 1 ⁇ m using a suitable dispersing technique (e.g. wet grinding, high pressure homogenisation, microfluidisation, etc.).
  • a suitable dispersing technique e.g. wet grinding, high pressure homogenisation, microfluidisation, etc.
  • the suspension is transferred into a corresponding container under aseptic conditions.

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Abstract

The invention relates to a method of treatment or prevention of hot flushes in men who underwent castration, e.g. due to androgen ablation treatment in prostate cancer therapy, comprising administration of an effective amount of a CGRP antagonist and/or of a CGRP release inhibitor to the patient, and to the use of said active compounds for the manufacture of a pharmaceutical composition intended to be used in this method.

Description

USE OF CGRP ANTAGONISTS IN TREATMENT AND PREVENTION OF HOT FLUSHES IN PROSTATE CANCER PATIENTS
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method of treatment or prevention of hot flushes in men who underwent castration, e.g. due to androgen ablation treatment in prostate cancer therapy (orchiectomy), comprising administration of an effective amount of a CGRP antagonist and/or of a CGRP release inhibitor to a person in need of such treatment. The method 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.
In a second aspect, the invention relates to the use of a CGRP antagonist and/or of a CGRP release inhibitor for manufacture of a pharmaceutical composition for prevention or treatment of hot flushes in men who underwent castration.
BACKGROUND OF THE INVENTION
Hot flushes and sweating, that is vasomotor symptoms, are reported by 43 to 77% of prostate cancer patients after medical or surgical castration, usually persisting for many years, possibly impairing quality of life (Arch. Surg. 43: 209, 1941 ; J. Urol. 152: 1170, 1994). Furthermore, hot flushes occur in 75% of women after menopause. In WO 01/10425 it has been proposed 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.
Although it has been already reported that plasma calcitonin gene-related peptide was increased during hot flushes in six men who underwent castration therapy, the mechanism of hot flushes in men is not well known. For instance, it is unclear up to now why some men have vasomotor symptoms whereas some do not and it was suggested to discover more about the mechanism of these symptoms to develop new treatment alternatives (J. Urol. 166: 1720-1723, 2001).
BRIEF SUMMARY OF THE INVENTION
There is a clear need for alternative approaches and improvement in the treatment and prevention of hot flushes in men who underwent castration.
It is therefore an object of the invention to provide a method of treatment and prevention of hot flushes in men who underwent castration, comprising administering to a patient in need of such treatment an effective amount of a CGRP antagonist and/or of a CGRP release inhibitor. .
A second object of the invention is the use of a CGRP antagonist and/or of a CGRP release inhibitor for manufacture of a pharmaceutical composition for prevention or treatment of hot flushes in men who underwent castration.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that the symptoms of hot flushes in men who underwent castration 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 conventional therapy.
The present invention thus relates to the use of CGRP antagonists and/or CGRP release inhibitors for combating hot flushes in men who underwent castration, 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 therapy, thus any aspect of the invention includes combination with conventional therapy or those drugs used in conventional therapy.
The expression "conventional treatment" is meant to comprise
hormonal therapies comprising oral and topical administration (although especially oral hormonal therapies are known to cause side effects), e.g. oral diethylstilbestrol, topical estrogens such as estrogen patches, oral medroxyprogesterone acetate, megestrol acetate and cyproterone acetate,
oral central α2-agonists, e.g. oral clonidine,
selective 5-hydroxytryptamine (5-HT) reuptake inhibitors, e.g. sertraline (Zoloft®) and venlafaxine (Effexor®), and
acupuncture, preferably electrostimulated acupuncture.
Suggested recommendations for conventional treatment of hot flushes in men with prostate cancer treated by castration are:
First-line treatments: estrogen patches 0.05 mg/24 hours or 0.10 mg/24 hours (e.g. twice weekly for 4 weeks), transdermal estradiol 0.05 mg/24 hours or oral diethylstilboestrol (DES) 1 mg/day.
Second-line treatments:
Oral progestagens, e.g. megestrol acetate 40 mg/day or oral cyproterone acetate 50 to 300 mg/day, e.g. 50 mg orally twice a day or 300 mg intramuscularly once every 2 weeks, preferably 150 mg/day.
Third-line treatments:
Oral clonidine 0.1 mg/day or oral sertraline; start on 25 mg/day, titrate individually (to approximately 75-100 mg daily) or oral venlafaxine 12.5 mg twice daily or acupuncture.
The invention also includes the use of an active substance selected from CGRP antagonists and CGRP release inhibitors for the preparation of a pharmaceutical composition for treatment or prevention of hot flushes jn men who underwent castration wherein the pharmaceutical composition comprises an active compound used in conventional therapy selected from the group consisting of
hormonal drugs, e.g. oral diethylstilbestrol, an estrogen, medroxyprogesterone acetate, megestrol acetate and cyproterone acetate, including other salt forms of these drugs,
oral central 2-agonists, e.g. oral clonidine, and
selective 5-hydroxytryptamine (5-HT) reuptake inhibitors, e.g. sertraline (Zoloft .® )\ and venlafaxine (Effexor®).
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, WO 00/55154, WO 01/32648, WO 01/32649 and WO 01/49676 as well as the non-peptidic active substances described in WO 98/56779, WO 98/09630 aand WO 97/09046.
Examples of CGRP release inhibitors include serotonin 5-HT-iB/iD-agonists such as almotriptan, avitnptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan, as well as 5-HTiF-agonists or NPY-agonists. Of the CGRP antagonists described in WO 98/11128, the following compounds, for example, may be used for the treatment and/or prevention of hot flushes in men who underwent castration, or for the preparation of a corresponding pharmaceutical composition:
(A) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidi- nyl]carbonyI]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(B) 1 -[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1 ,3-benzodi- azepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(C) 1-[N -[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)-piperazine,
(D) 1 -[N -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-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)-oxoimidazol-1 -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- 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(1 H)-oxothieno[3,4-d]pyrimidin-3-yl)- 1-piperidinyl]carbonyl]-D-tyrosyI]-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]carbonyI]-D-phenyl-alanyl]-4-(1-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-phenyl-alanyI]-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]carbonyI]-D-phenyl-alanyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(K) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxothieno[3,2-d]pyrimidin-3- yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(L) 1-[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(tri-fluoromethyl)phenyl]- 2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperi- dinyl)-piperidine,
(M) 1 -[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-ylj-1 - piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine,
(N) 1-[4-amino-3,5-dibromo-N-[[4-[3I4-dihydro-2(1 H)-oxoquinazolin-3-yl]- 1-piperidinyl]carbonyI]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)- piperidine,
(O) 1-[N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]- 3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine,
(P) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2- [(4-hydroxy-3,5-dimethylphenyl)methyl]-1 l4-dioxobutyl]-4-(1-piperidinyl)-piperidine,
(Q) 1-[4-amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-pi- peridinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(R) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-pi- peridinyl]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-piperidinyI)-piperidine,
(U) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-pi- peridinyl]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-pi- peridinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(W) 1 -[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1 -pi- peridinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-piperazine,
(X) 1 -[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1 -pi- peridinyl]carbonyl]-D-phenylalanyl]-4-[(1 -methyl-4-piperazinyI)carbonyl]-piperazine,
(Y) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-pi- peridinyl]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-pi- peridinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine,
(AA) 1-[N2-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbo- nyl]-N'-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AB) 1-[N2-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbo- nyl]-N'-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(AC) (R,S)-1 -[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1 -piperidinyl]-2-[(3,5-di- bromo-4-methylphenyl)methyI]-1 ,4-dioxobutyl]-4-(4-methyI-1 -piperazinyl)-piperidine, (AD) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-di- bromo-4-methoxyphenyl)methyl]-1 ,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(AE) (R,S)-1-[4-[4-(3I4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-di- bromphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AF). 1-[N2-[N-[[4-(1 ,3-dihydro-2(2H)-oxobenzimidazoI-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)-oxobenzimida- zol-1-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)-oxobenzimidazol-1-yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-pipera- zine,
(Al) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazoIin-3-yl)-1- piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-pipera- zine,
(AJ) (R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1 H)-oxoquina- zolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine,
(AK) 1 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2, 1 ,3-benzothiadiazin- 3-yl)-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -piperidinyl)-piperidine,
(AL) 1 -[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3- yl]-1-piperidinyI]carbonyl]-D-phenyl-alanyl]-4-(1-piperidinyl)carbonyl]-piperidine
(AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1- 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-piperi- dinyl]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-1-yl]-1- piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyI-4-piperidinyl)-piperi- dine,
(AP) 1 -[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazoi-1 -yl]- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AQ) 1-[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]- 2(2H)-oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -piperidinyl)- piperidine,
(AR) 1-[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]- 2(2H)-oxoimidazol-1-yl]-1-piperidinyI]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8- azabicyclo[3,2,1]oct-3-yl)-piperazine,
(AS) 1-[3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-pi- peridinyl]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-pi- peridinyl)-piperazine,
(AU) 1 -[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl]- 1 -piperidinyl]carbonyl]-D-phenyIalanyl]-4-(hexahydro-4-methyl-1 H-1 ,4-diazepin- 1-yl)piperidine,
(AV) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyi]car- bonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine, (AW) 1-[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(AX) 1-[3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1-azepinyl)-pipe- ridine,
(AY) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]car- bonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(AZ) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-pipera- zine,
(BA) 1-[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazόl-1-yl)- 1 -piperidinyl]carbonyl]-D-pheny!aIanyl]-4-(1 -methyl-4-piperidinyl)-piperazine,
(BB) 1 -[3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine,
(BC) 1-[N6-acetyl-N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(BD) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperi- dinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1 -azepinyl)-piperidine,
(BE) 1-[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1- yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-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-phenylaIanyl]-4-(1-methyl-4-pi- peridinyl)-piperidine, (BG) 1-[3,5-dibromo-N-[[4-(3J4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidi- nyl]carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine,
(BH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-pi- peridinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine,
(Bl) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidi- nyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine,
(BJ) 1-[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)- 1 -piperidinyl]carbonyl]-D-phenylalanyl]-4-(1 -et yl-4-pi perid i nyl)-pi perid ine ,
(BK) 1 -[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-(3-hydroxyphenyl)-2(2H)- oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidine,
(BL) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yI)-1-piperidinyl]car- bonyl]-D-tyrbsyl]-4-(hexahydro-1 H-1 -azepinyl)-piperidine,
(BM) 1 -[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(BN) 1-[4-amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-1 ,3-dihydro-2(2H)-oxoimi- dazol-1-yl]-1-piperidinyl]carbonyI]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicy- clo[3,2, 1 ]oct-3-yl)-piperazine,
(BO) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine,
(BP) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazoIin-3-yl)-1- piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine, (BQ) 1 -[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-(3-methoxyphenyl)-2(2H)- oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabi- cyclo[3,2,1]oct-3-yl)-piperazine,
(BR) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidi- nyl]carbonyl]-D-tyrosyl]-4-[1-(cyclopropyl-methyl)-4-pipehdinyl]-piperidine,
(BS) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 H-1 -azepinyl)-piperidine,
(BT) 1 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine,
(BU) 1-[3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-pi- perid inyl]carbonyl]-D-tyrosyl]-4-(4-pyrid inyl)-pi perid i ne ,
(BV) 1 -[3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(BW) 1 -[N2-[3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trif luoromethyl)phenyl]-2(2H)- oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(BX) 1-[3,5-dibromo-N-[[4-(1 ,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1- piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine,
(BY) 1-[4-amino-N-[[4-[4-(3-chlorophenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1-yl]-1- piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyI)-piperi- dine,
(BZ) 1 -[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trif luoromethyl)phenyl]- 2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 H- 1 -azepinyl)-piperidine,
(CA) 1-[4-amino-3,5-dibromo-N-i[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-[[4-[4-(3-chlorophenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1-yl]-1- piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(hexahydro-1 H-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)-oxoimidazoI-1-yl)-1-pi- peridinyl]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-[3J4-dihydro-2(1H)-oxoquinazolin-3-yI3-1-piperidinyl]car- bonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(CG) 1 -[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimi- dazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperi- dine,
(CH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-pi- peridinyl]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-1 H-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-piperidinyI]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
(A) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi- dinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3l4,5-tetrahydro-2(1 H)-oxo-1 ,3-benzodi- azepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(I) 1 -[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1 ,2,4-triazol-
2-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-piperidinyl)-piperidine,
(J) 1-[4-amino-3J5-dibromo-N-[[4-(2,4-dihydro-5-phenyI-3(3H)-oxo-1 ,2,4-triazol- 2-yl)-1-piperidinyl]carbonyl]-D-phenyI-alanyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(AC) (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5- dibromo-4-methylphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AF) 1-[N2-[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(1 H)-oxoquinazolin-3-yl)-1-pi- peridinyl]carbonyI]-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 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidi- nyl]carbonyI]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine and (B) 1-[4-amino-3,5-dibromo-N-[[4-(2I3,4,5-tetrahydro-2(1 H)-oxo-1 ,3-benzodi- azepin-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 are particularly preferred.
The dosage required to produce the desired effect is appropriately 0.0001 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 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 com 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 the method of treatment or prevention according to the invention 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-piperidi- nyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, (B) 1 -[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1 ,3-benzodiaze- pin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(I) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(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]carbonyl]-D-phenyl-alanyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(AC) (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-di- bromo-4-methylphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AF) 1 -[N2-[N-[[4-(1 ,3-dihydro-2(2H)-oxobenzimidazol-1 -yl)-1 -piperidinyljcarbonyl]- 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-piperi- dinyl]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).
In the method according to the invention and in any of the formulations given above active substance (A) may also be used in form of a physiologically acceptable salt, preferably in form of the hydrochloride salt which is available by reaction of the free base with hydrochloric acid by conventional methods. Amounts are given based on the free base.
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 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(1 H)-oxoquinazolin-3-yl)-1-piperidi- nyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(B) = 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1 ,3-benzodiaze- pin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(AC) = (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-di- bromo-4-methylphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AM) = 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-pi- peridinyl]carbonyl]-D-phenylalanyI]-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:
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
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, WO 00/55154, WO 01/32648, WO 01/32649 or WO 01/49676 , for example one of the abovementioned active substances (A) or (B), most preferred is substance (A) hydrochloride.
Example
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) 01.0 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 μl
Method of preparation:
The active substance and benzalkonium chloride are dissolved in water and packed in Respimat® cartridges.
Example
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 μl
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 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 injections 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 == KH2PO4 12 mg disodium hydrogen phosphate
= Na2HPO4-2H2O 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/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 (Wfl); add salt-forming agent; dissolve active substance with heating; make up to specified volume with Wfl; transfer into viais; freeze-dry.
Solvent for lvophilisate: 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
Lvophilisate 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 lvophilisate: 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 (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
Agueous solution for nasal administration containing 10 mg of active substance (A) S iBl 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
Agueous solution for nasal administration containing 5 mg of active substance (A) or '
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 Agueous 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 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 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 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
Agueous solution for subcutaneous administration with 10 mg of active substance (A) or 3>
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
Agueous 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 μm 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

Patent Claims
1. A method of treatment or prevention of hot flushes in men who underwent castration comprising administration of an effective amount of a CGRP antagonist and/or of a CGRP release inhibitor to a person jn need of such treatment.
2. The method of claim 1 , characterised in that it is effected as a monotherapy with a single active substance.
3. The method of claim 1 , characterised in that it is effected as a supplement to conventional therapy.
4. The method of claim 1 , characterised in that the active substance is a CGRP antagonist.
5. The method of claim 1, characterised in that the active substance is a CGRP release inhibitor selected from the group consisting of serotonin 5-HT1B/iD-agonists, 5-HTiF-agonists and NPY-agonists.
6. The method of claim 1 , characterised in that the active substance is a CGRP release inhibitor selected from the group consisting of almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.
7. The method of claim 4, characterised in that the CGRP antagonist is selected from the group consisting of:
(A) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperi- dinyl]carbonyI]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1 ,3-benzodi- azepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyI]-4-(1-piperidinyl)-piperidine, (C) 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)-piperazine,
(D) 1-[N2-t4-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)-oxoimidazol-1-yl)-1- piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(F) 1-[N -[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-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)-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-phenyl-alanyl]-4-(1-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-phenyl-alanyl]-4-(1-piperidinyI)-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-(1-methyl-4-piperidinyl)-piperazine,
(K) l-μ-amino-S.δ-dibromo-N-^^S^-dihydro^l H)-oxothieno[3,2-d]pyrimidin-3- yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(L) 1 -[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(tri-fluoromethyl)phenyl]- 2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperi- dinyl)-piperidine, (M) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1- piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine,
(N) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1- piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-piperidine,
(O) 1-[N-[[4-[3,4-dihydro-2(1H)~oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3- ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine,
(P) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4- hydroxy-3,5-dimethylphenyl)methyl]-1 ,4-dioxobutyl]-4-(1-piperidinyl)-piperidine,
(Q) 1 -[4-amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1 -piperi- dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(R) 1 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1 -piperi- dinyl]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-piperidinyljcarbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(T) 1-[4-amino-3,5-dibromo-N-[[4-[2(1 H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]- D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(U) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyI]-piperazine,
(V) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-piperi- dinyl]carbonyI]-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]-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-piperazine, (X) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-piperi- dinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine,
(Y) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-pi- peridinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyljphenyl]-piperazine,
(Z) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-pi- peridinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine,
(AA) 1 -[N2-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)-1 -piperidinyljcar- bonyl]-N'-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AB) 1-[N -[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]car- bonyl]-N'-(1 , 1 -dimethylethoxycarbonyl)-D-tryptyl]-4-(1 -methyl-4-piperidinyl)-piperi- dine,
(AC) (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3)5-di- bromo-4-methylphenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AD) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-di- bromo-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-di- bromophenyl)methyl]-1 ,4-dioxobutyl]-4-(4-methyl-1 -piperazinyl)-piperidine,
(AF) 1-[N2-[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)-oxobenzimida- zol-1-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)-oxobenzimidazol-1-yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-pipera- zine,
(Al) 1-[N2-[4-άmino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-pipera- zine,
(AJ) (R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxoquina- zolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine,
(AK) 1 -[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2, 1 ,3-benzothiadiazin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(AL) 1-[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3- yl]-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-piperidinyI)carbonyl]-piperidine,
(AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-pi- peridinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(AN) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidi- nyl]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-1-yl]-1- piperidinyl]carbonyl]-3,5-dibromo-D-phenyIalanyl]-4-(1-methyl-4-piperidinyl)-piperi- dine,
(AP) 1-[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazoI-1-yl]- 1-piperidinyl]carbonyI]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine, (AQ) 1 -[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trif luoromethyl)phenyl]-
2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)- piperidine,
(AR) 1-[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]- 2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8- azabicyclo[3,2,1]oct-3-yl)-piperazine,
(AS) 1-[3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-pi- peridinyl]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-pi- peridinyl)-piperazine,
(AU) 1 -[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl]- 1 -piperidinyl]carbonyl]-D-phenylaIanyl]-4-(hexahydro-4-methyl-1 H-1 ,4-diazepin-1- yl)piperidine,
(AV) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]car- bonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine,
(AW) 1-[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(AX) 1-[3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyI]-4-(hexahydro-1 H-1-azepinyl)-piperi- dine,
(AY) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazoIin-3-yl)-1-piperidi- nyl]carbonyl]-D-tyrosyI]-4-(1-methyI-4-piperidinyl)-piperidine, (AZ) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)- piperazine,
(BA) 1 -[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1 -yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(BB) 1 -[3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine,
(BC) 1 -[N6-Acetyl-N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)- 1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(BD) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-pi- peridinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine,
(BE) 1 -[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-(3-thienyI)-2(2H)-oxoimidazol-1 - yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-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 -methyI-4- piperidinyl)-piperidine,
(BG) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidi- nyl]carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine,
(BH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1- piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine,
(Bl) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]car- bonyl]-D-tyrosyI]-4-(4-piperidinyI)-piperidine, (BJ) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine,
(BK) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)- oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)- piperidine,
(BL) 1 -[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1 -piperidi- nyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine,
(BM) 1-[4-amino-3,5-dibromo-N-[[4-(1 ,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(BN) 1-[4-amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-1 ,3-dihydro-2(2H)-oxo- imidazol-1 -yl]-1 -piperidinyl]carbonyI]-D-phenylaianyl]-4-(exo-8-methyl-8-azabi- cyclo[3,2,1]oct-3-yl)-piperazine,
(BO) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyI)-piperidine,
(BP) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine,
(BQ) 1-[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-(3-methoxyphenyl)-2(2H)- oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabi- cyclo[3,2,1]oct-3-yl)-piperazine,
(BR) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidi- nyl]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-pi- peridinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, (BT) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-pi- peridinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine,
(BU) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-pi- peridinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine,
(BV) 1-[3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo- imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(BW) 1-[N2-[3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)- oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(BX) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-pi- peridinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine,
(BY) 1-[4-amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1- piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-pi- peridine,
(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-1 H-1 -azepinyl)- piperidine,
(CA) 1-[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)- oxoimidazol-1 -yl]-1 -piperidinyl]carbonyl]-D-phenylalanylj-4-(1 -methyl-4-piperidinyl)- piperazine,
(CB) 1-[4-amino-N-[[4-[4-(3-chlorophenyl)-1 ,3-dihydro-2(2H)-oxoimidazol-1-yl]-1- piperidinyl]carbonyI]-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)-oxoimidazol-1-yl)-1-piperi- dinyl]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)-oxoimidazo!-1 -yl]- 1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazine,
(CF) 1-[3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-piperidi- nyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(CG) 1 -[4-amino-3,5-dibromo-N-[[4-[1 ,3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimi- dazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperi- dine,
(CH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-pi- peridinyl]carbonyl]-D-phenylalanyI]-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-phenyIalanyl]-4-(hexahydro-1 H-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.
8. The method of claim 7, characterised in that the CGRP antagonist is
(A) 1-[N -[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidi- nyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine hydrochloride.
9. Use of an active substance selected from CGRP antagonists and CGRP release inhibitors for the preparation of a pharmaceutical composition for treatment or prevention of hot flushes in men who underwent castration, wherein the pharmaceutical composition optionally comprises an active compound used in conventional therapy selected from the group consisting of hormonal drugs, oral central α2-agonists, and selective 5-hydroxytryptamine (5-HT) reuptake inhibitors.
10. Use according to claim 9, characterised in that the pharmaceutical composition contains only one active substance.
11. Use according to claim 9, characterised in that the active substance is a CGRP antagonist.
12. The use of claim 9, characterised in that the active substance is a CGRP release inhibitor selected from the group consisting of serotonin 5-HT-iB/iD-agonists, 5-HT-IF- agonists and NPY-agonists.
13. The use of claim 9, characterised in that the active substance is a CGRP release inhibitor selected from the group consisting of almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.
14. The use of claim 9, characterised in that the CGRP antagonist is selected from the group defined in claim 7.
15. The use of claim 14, characterised in that the CGRP antagonist is
(A) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazoIin-3-yl)-1-piperidi- nyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine hydrochloride.
EP04763078A 2003-07-07 2004-07-02 Use of cgrp antagonists in treatment and prevention of hot flushes in prostate cancer patients Withdrawn EP1648466A1 (en)

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