DE3623437C2 - Ergolinyl urea derivatives labeled in the 2-position with radioactive bromine, process for their preparation and their use as diagnostics - Google Patents

Ergolinyl urea derivatives labeled in the 2-position with radioactive bromine, process for their preparation and their use as diagnostics

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Publication number
DE3623437C2
DE3623437C2 DE19863623437 DE3623437A DE3623437C2 DE 3623437 C2 DE3623437 C2 DE 3623437C2 DE 19863623437 DE19863623437 DE 19863623437 DE 3623437 A DE3623437 A DE 3623437A DE 3623437 C2 DE3623437 C2 DE 3623437C2
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preparation
urea derivatives
diagnostics
labeled
compounds according
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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.)
Expired - Fee Related
Application number
DE19863623437
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German (de)
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DE3623437A1 (en
Inventor
Helmut Dr Wachtel
Peter Andreas Loeschmann
Rainer Dorow
Bernard Dr Acksteiner
Dominique Comar
Bernard Maziere
Christian Loch
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Bayer Pharma AG
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Schering AG
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Priority to DE19863623437 priority Critical patent/DE3623437C2/en
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Priority to US07/371,134 priority patent/US5242678A/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G01N33/9406—Neurotransmitters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
    • C07D457/12—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

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  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Pharmacology & Pharmacy (AREA)
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Description

Die Erfindung betrifft in 2-Stellung mit radioaktivem Brom markierte Ergolinyl­ harnstoffderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Diagnostika.The invention relates to ergolinyl labeled with radioactive bromine in the 2-position Urea derivatives, processes for their preparation and their use as diagnostics.

Die erfindungsgemäßen Verbindungen haben die allgemeine Formel IThe compounds of the invention have the general Formula I.

worin
R⁶ einen C₁- bis C₆-Kohlenwasserstoffrest darstellt
und
C₉-  -  -C₁₀ eine Einfach- oder Doppelbindung ist sowie deren Säureadditionssalze.wherein
R⁶ represents a C₁ to C₆ hydrocarbon radical
and
C₉ - - - C₁₀ is a single or double bond and their acid addition salts.

Der Kohlenwasserstoffrest R⁶ kann gesättigt, ungesättigt oder cycloaliphatisch mit 1-6 Kohlenstoffatomen sein. Bevorzugt ist ein Kohlenwasserstoffrest mit 1-4 Kohlenstoffatomen wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Cyclo­ propylmethyl, 2-Propenyl und Allyl.The hydrocarbon radical R⁶ can be saturated, unsaturated or be cycloaliphatic with 1-6 carbon atoms. Is preferred a hydrocarbon residue with 1-4 carbon atoms such as for example methyl, ethyl, propyl, isopropyl, butyl, cyclo propylmethyl, 2-propenyl and allyl.

Bedeutet C₉-  -  -C₁₀ eine Einfachbindung, so steht das Wasserstoffatom in 10-Stellung α-ständig.C₉ - - - C₁₀ means a single bond, the hydrogen atom is in the 10-position α-constantly.

Zur Bildung der physiologisch verträglichen Säureadditionssalze sind die in der EP-A 82730003.9 genannten Säuren geeignet. For the formation of the physiologically compatible acid addition salts the acids mentioned in EP-A 82730003.9 are suitable.  

Geeignete radioaktive Bromisotope Br* sind beispielsweise das ⁷⁵Br-, ⁷⁶Br-, ⁷⁷Br-, 80mBr- und ⁸⁰Br-Isotop.Suitable radioactive bromine isotopes Br * are, for example, the ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, 80m Br and ⁸⁰Br isotope.

Zum Nachweis von funktionellen und strukturellen cerebralen Veränderungen sind die Autoradiographie und insbesondere die Positronen-Emissions-Tomographie (PET) und die Single-Photonen- Emissions-Computer-Tomographie (SPECT) geeignet. Da Funktionen des Gehirns topographisch organisiert sind und man nicht vom Funktionszustand einer Zelle oder eines Zellverbandes - wie etwa im Falle der Leber - auf die Funktion des gesamten Organes schließen kann, bedeutet die Visualisierung und Quanti­ fizierung der räumlichen und zeitlichen Verteilung von morpho­ logischen und funktionellen Gewebsparametern eine Verbesserung der Diagnostik.For the detection of functional and structural cerebral Changes are autoradiography and especially that Positron Emission Tomography (PET) and the Single Photon Emission computer tomography (SPECT) suitable. Because functions of the brain are topographically organized and not from the Functional state of a cell or cell cluster - as in the case of the liver - on the function of the whole Can close organs means visualization and quanti Creation of the spatial and temporal distribution of morpho logical and functional tissue parameters an improvement diagnostics.

Es ist bekannt, daß Ergolinylharnstoffderivate noradrenerge dopaminerge und serotoninerge Neurone beeinflussen, wobei durch Bindung an die präsynaptischen oder postsynaptischen neuronalen Rezeptoren die Wirkung des natürlichen Neurotransmitters­ imitiert (Agonist) oder der Wirkung des natürlichen Neurotrans­ mitters entgegengewirkt wird (Antagonist).Ergolinyl urea derivatives are known to be noradrenergic influence dopaminergic and serotoninergic neurons, whereby by Binding to the presynaptic or post-synaptic neuronal Receptors the effect of the natural neurotransmitter imitates (agonist) or the effect of natural neurotrans is counteracted in the middle (antagonist).

Ferner ist bekannt, daß mit Positronen emittierenden Dopamin­ antagonisten durch PET Dopaminrezeptoren darstellbar sind (Maziere B., et al., Life Sci., 35 : 1349-1356).It is also known that with positron emitting dopamine antagonists can be represented by PET dopamine receptors (Maziere B., et al., Life Sci., 35: 1349-1356).

Es wurde nun gefunden, daß die erfindungsgemäßen Verbindungen infolge ihrer Affinität zu Monoamin-Rezeptoren für diagnosti­ sche Zwecke besonders geeignet sind. Sie können zur in-vivo und in-vitro Darstellung dopaminerger und anderer monoaminerger Rezeptoren eingesetzt werden und eignen sich daher zur Visua­ lisierung von Struktur und Funktion dopaminerger und anderer monoaminerger Systeme in Organismen oder Teilen davon wie beispielsweise Gesamthirn, Basalganlien und Frontalhirn. It has now been found that the compounds according to the invention due to their affinity for monoamine receptors for diagnosti cal purposes are particularly suitable. You can go to in vivo and in vitro presentation of dopaminergic and other monoaminergic Receptors are used and are therefore suitable for visua lization of structure and function of dopaminergic and others monoaminergic systems in organisms or parts thereof such as for example whole brain, basal organs and frontal brain.  

Diagnostisch ist durch die geringere Anreicherung der markier­ ten Dopaminrezeptorantagonisten wie beispielsweise von radioak­ tiv markiertem 2-Brom-Lisurid in den Basalganglien die Erken­ nung von frühen oder fortgeschrittenen Fällen von Morbus Par­ kinson möglich wobei durch vorherige Gabe von D-2-Antagonisten die bildliche Darstellung verhindert wird.Diagnostic is due to the lower enrichment of the markier dopamine receptor antagonists such as from radioak Marked 2-bromo-lisuride in the basal ganglia early or advanced cases of Par's disease kinson possible with previous administration of D-2 antagonists the visual representation is prevented.

Da keine Bindung an Serotoninrezeptoren eintritt und die An­ reicherung in sehr kurzer Zeit erfolgt so daß die Strahlen­ belastung gering ist, sind die erfindungsgemäßen Verbindungen insbesondere radioaktiv markiertes Brom-Lisurid, besonders ge­ eignet zur selektiven Darstellung von zentralen Dopaminrezepto­ ren.Since there is no binding to serotonin receptors and the An Enrichment takes place in a very short time so that the rays is low, the compounds of the invention in particular radio-labeled bromine lisuride, especially ge is suitable for the selective display of central dopamine receptors ren.

Aber auch Dopaminmangelkrankheiten oder Störungen des Dopamin-Systems wie beispielsweise bei seniler Demenz, motorischer Hypo-, Dys- oder Hyperfunktion einschließlich der Spätfolgen von Medikamenteneinnahme sind erkennbar.But also dopamine deficiency diseases or disorders of the dopamine system such as senile dementia, motor Hypo, dys, or hyperfunction including the late effects from taking medication are recognizable.

Ferner ist auch eine Störung limbischer und cortikaler dopamin­ erger Systeme wie sie beispielsweise im Bereich der Psychosen und besonders bei Schizophrenien vorliegt, nach Formen und Symptomen differenzierbar und somit einer differenzierten Therapie und Therapiekontrolle zugänglich.It is also a disorder of limbic and cortical dopamine erger systems such as those in the field of psychoses and especially with schizophrenia, by forms and Symptoms differentiable and thus a differentiated Therapy and therapy control accessible.

Dopaminrezeptoren finden sich auch in der Hypophyse, so daß eine Darstellung von Prolactinomen und deren Metastasen möglich ist.Dopamine receptors are also found in the pituitary gland, so that a representation of prolactinomas and their metastases possible is.

Die erfindungsgemäßen Verbindungen können so auch zur Auf­ findung von Tumoren und Metastasen eingesetzt werden.The compounds according to the invention can also be used for tumor and metastasis.

Ein weiterer Vorteil der erfindungsgemäßen Verbindungen liegt darin, daß die Markierung durch Substitution mit radioaktivem Brom an Therapeutika vorgenommen werden kann, wobei in sehr guten Ausbeuten Verbindungen mit einer sehr hohen spezifischen Aktivität erhalten werden, die auch unmarkiert als Therapeutika bekannt sind. Another advantage of the compounds according to the invention is in that the labeling by substitution with radioactive Bromine can be made to therapeutics, being in a lot good yields compounds with a very high specific Activity can be obtained that is also unlabeled as a therapeutic are known.  

Beispielsweise können die Verbindungen der allgemeinen Formel I durch Umsetzung der nicht bromierten Verbindungen mit radioaktiv markiertem Natrium-[CBr*]-bromid in Gegenwart eines Oxidationsmittels hergestellt werden.For example, the compounds of the general Formula I by reacting the non-brominated compounds with radiolabelled sodium [CBr *] bromide in the presence of a Oxidizing agent are produced.

Als Oxidationsmittel ist beispielsweise Chloramin T oder H₂O₂/ Eisessig geeignet. Die Reaktion wird in aprotischen oder protischen Lösungsmitteln wie beispielsweise chlorierten Kohlenwasserstoffen wie Dichlormethan, Dichlorethan, Chloroform oder niederen aliphatischen Carbonsäuren wie Essigsäure oder Propionsäure bei Raumtemperatur in 1-30 Minuten vorge­ nommen.The oxidizing agent is, for example, chloramine T or H₂O₂ / Suitable for glacial acetic acid. The reaction is in aprotic or protic solvents such as chlorinated Hydrocarbons such as dichloromethane, dichloroethane, chloroform or lower aliphatic carboxylic acids such as acetic acid or Propionic acid at room temperature in 1-30 minutes taken.

Die Umsetzung kann unter Inertgas wie zum Beispiel Stickstoff oder Argon vorgenommen werden.The reaction can be carried out under an inert gas such as nitrogen or argon.

Die Reinigung der Verbindungen erfolgt nach den üblichen Metho­ den beispielsweise durch HPL-Chromatographie.The compounds are cleaned in accordance with the customary method for example by HPL chromatography.

Die erfindungsgemäßen Verbindungen werden in Form ihrer wasser­ löslichen Salze oder in einer üblichen Pufferlösung parenteral appliziert.The compounds of the invention are in the form of their water soluble salts or parenterally in a conventional buffer solution applied.

Die Ausgangsstoffe sind bekannt oder können in Analogie zu be­ kannten Methoden hergestellt werden.The starting materials are known or can be in analogy to known methods can be produced.

Das nachfolgende Beispiel soll das erfindungsgemäße Ver­ fahren erläutern.The following example is the Ver explain driving.

Beispiel 1example 1

0,01 µMol Lisurid werden in 200 µl Essigsäure suspendiert, 1.850 - 3.700 MBq Na⁷⁶ Br (wäßrige Lösung) und eine Oxidations­ lösung (200 µl) aus 30% H₂O₂/ Eisessig (2:1) zugegeben. Man läßt drei Minuten reagieren und trennt über eine halbpräpara­ tive HPLC-Säule. Man erhält 2-[⁷⁶Br]-Bromlisurid.0.01 µMol lisuride are suspended in 200 µl acetic acid, 1,850 - 3,700 MBq Na⁷⁶ Br (aqueous solution) and an oxidation solution (200 µl) of 30% H₂O₂ / glacial acetic acid (2: 1) added. Man allows to react for three minutes and separates via a semi-preparation tive HPLC column. 2- [⁷⁶Br] -bromlisuride is obtained.

Analog erhält man mit ⁷⁵Br, ⁷⁷Br, 80mBr und ⁸⁰Br die entsprechend markierten Verbindungen.Similarly, with ⁷⁵Br, ⁷⁷Br, 80m Br and ⁸⁰Br the correspondingly labeled compounds are obtained.

Claims (5)

1. In 2-Stellung mit ⁷⁵Br-, ⁷⁶Br-, ⁷⁷Br-, 80mBr-, ⁸⁰Br-Isotopen markierte Ergolinyl­ harnstoffderivate der allgemeinen Formel I worin
R⁶ einen C₁-bis C₆-Kohlenwasserstoffrest darstellt
und
C₉-  -  -C₁₀ eine Einfach- oder Doppelbindung ist sowie deren Säureadditionssalze.1. Ergolinyl urea derivatives of the general formula I labeled in the 2-position with ⁷⁵Br-, ⁷⁶Br-, ⁷⁷Br-, 80m Br-, ⁸⁰Br-isotopes wherein
R⁶ represents a C₁ to C₆ hydrocarbon radical
and
C₉ - - - C₁₀ is a single or double bond and their acid addition salts. 2. Verfahren zur Herstellung der Verbindungen gemäß Anspruch 1 dadurch gekennzeichnet, daß man die in 2-Stellung nicht bromierte Ver­ bindung der allgemeinen Formel I in Gegenwart eines Oxi­ dationsmittels mit Na-[⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁸⁰Br oder 80mBr]- Bromid* umsetzt.2. A process for the preparation of the compounds according to claim 1, characterized in that the 2-position not brominated Ver compound of the general formula I in the presence of an oxidizing agent with Na- [⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁸⁰Br or 80m Br] - bromide * implements. 3. Verwendung der Verbindungen gemäß Anspruch 1 als Diag­ nostika.3. Use of the compounds according to claim 1 as a diag nostika. 4. Verwendung der Verbindungen gemäß Anspruch 1 zur Darstellung von Monoamin-Rezeptoren.4. Use of the compounds according to claim 1 for illustration of monoamine receptors. 5. Verwendung von radioaktiv markiertem 2-Brom-Lisurid gemäß Anspruch 3 und 4.5. Use of radioactively labeled 2-bromo-lisuride according to Claims 3 and 4.
DE19863623437 1986-07-10 1986-07-10 Ergolinyl urea derivatives labeled in the 2-position with radioactive bromine, process for their preparation and their use as diagnostics Expired - Fee Related DE3623437C2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE19863623437 DE3623437C2 (en) 1986-07-10 1986-07-10 Ergolinyl urea derivatives labeled in the 2-position with radioactive bromine, process for their preparation and their use as diagnostics
US07/371,134 US5242678A (en) 1986-07-10 1989-06-26 BR*-diagnostics for monoamine receptors

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DE3623437C2 true DE3623437C2 (en) 1998-04-09

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Publication number Priority date Publication date Assignee Title
DK338789A (en) * 1988-07-15 1990-01-16 Schering Ag 2-SUBSTITUTED ERGOLINYLURINE DERIVATIVES AND PROCEDURES FOR THE PRODUCTION THEREOF, THEIR USE AS MEDICINES AND INTERMEDIATES FOR THE PRODUCTION THEREOF

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
US-Z.: LIFE SCIENCES 35 (1984), S.1349-1356 *

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