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WO1992011013A1 - 5-cyanomethylen-10-(piperazin-1-yl)-dibenzo[a,d]cycloheptenes de traitement de la migraine - Google Patents

5-cyanomethylen-10-(piperazin-1-yl)-dibenzo[a,d]cycloheptenes de traitement de la migraine Download PDF

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Publication number
WO1992011013A1
WO1992011013A1 PCT/EP1991/002379 EP9102379W WO9211013A1 WO 1992011013 A1 WO1992011013 A1 WO 1992011013A1 EP 9102379 W EP9102379 W EP 9102379W WO 9211013 A1 WO9211013 A1 WO 9211013A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyanomethylene
dibenzo
cycloheptenes
piperazine
cells
Prior art date
Application number
PCT/EP1991/002379
Other languages
German (de)
English (en)
Inventor
Gerd Steiner
Alfred Bach
Liliane Unger
Manfred Raschack
Original Assignee
Basf Aktiengesellschaft
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 Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Publication of WO1992011013A1 publication Critical patent/WO1992011013A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the present invention relates to a new use of 5-cyanomethylene-10- (piperazin-1-yl) dibenzo [a, d] cycloheptenes.
  • 5-cyanomethylene-10- (piperazin-1-yl) -dibenzo [a, d] cycloheptenes are already known from EP-PS 35,711. Neuroleptic, sedative, hypnotic and tranquilizing effects have been described for these compounds.
  • R 1 is a hydrogen atom or a C 1-3 alkyl radical
  • R 2 and R 3 are hydrogen atoms or one of the radicals R 2 and R 3 can also represent a fluorine or chlorine atom, and their salts with physiologically compatible acids also have a good action against migraines.
  • the homogenate was diluted with incubation buffer (50 mM Tris-HCl, 10 ⁇ M pargylin, 4 mM CaCl 2 ; 0.1% ascorbic acid, pH 7.7).
  • test batches (1 ml) were composed of: 600 ⁇ g homogenate, 3 nM - 3 H-serotonin (NEN, Dreeich; specific radioactivity 23.2 Ci / mmol).
  • NNN 3 nM - 3 H-serotonin
  • 100 nM 8-hydroxydipropylaminotetralin and 10 nM mianserin were added to the batches.
  • the non-specific binding was determined with 1 ⁇ M serotonin; it was 65% of the total binding.
  • the cDNA coding for the 5HT 1D- like receptor was isolated from the vector mp18 with the aid of the restriction enzymes HindIII and EcoRI and was commercially available from the
  • Luvitrogen integrates commercially available cloning vector pCDM8.
  • the vector was restricted with the enzyme BstXI and the so-called stuffer fragment was separated from the vector by gel electrophoresis.
  • After the gel elution for the stuffer fragment shortened pCDM ⁇ vector was ligated provided with BstXI linkers encoding the 5HT1 D receptor -like DNA in the pre-treated as described above pCDM8. The ligation took place at 12 ° C and lasted 14 h. The methods used are described in "Current Protocols in Molecular Biology" Volumes I and II, published by Greene Publishing Associates and Wiley Interscience ISBN 0-471-50338-X.
  • 293 cells were cultivated under standard conditions in a 10 cm cell culture dish up to a cell number of 7 to 8 ⁇ 106 cells. After trypsinization, the cells were diluted 1: 3 in MEM medium (Gibco 041 to 1090 M), which contained 2.2 g / l NaHCO 3 , and sown again in 10 cm petri dishes. The cells were then cultured at 37 ° C. for 40 to 48 h.
  • the DNA to be transfected was prepared as follows: 20 ⁇ g of the DNA solution (1 mg / ml), purified via
  • the solution was placed on a 10 cm cell culture dish containing the 293 cells cultured as described above. After thorough mixing, the cells were cultured in a 3% CO 2 incubator at 37 ° C. for 15 to 20 h. 5 ml of serum-free medium were then carefully added. After removing all of the medium and repeating the washing process with 5 ml of serum-free medium, 10 ml of complete medium were added to the cells. After 48 h of incubation in a 5% CO 2 incubator, the cells could be used for pharmacological and electrophysiological studies. 2.5 ml of cold PBS was added to the transfected and cultured cells.
  • test batch of 1 ml was composed of 35 ⁇ g of the homogenate obtained, 3 nM 3 ⁇ -serotonin (NEN, Dreeich; specific radioactivity 23.2 Ci / mmol). Non-specific binding was carried out with serotonin and was 15% of the total binding.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On utilise pour traiter la migraine des 5-cyanométhylen-10-(piperazin-1-yl)-dibenzo[a,d]cycloheptènes répondant à la formule (I), dans laquelle R?1, R2 et R3¿ ont la signification donnée dans la description.
PCT/EP1991/002379 1990-12-22 1991-12-12 5-cyanomethylen-10-(piperazin-1-yl)-dibenzo[a,d]cycloheptenes de traitement de la migraine WO1992011013A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19904041463 DE4041463A1 (de) 1990-12-22 1990-12-22 5-cyanmethylen-10-(piperazin-1-yl)-dibenzo(a,d)cycloheptene zur bekaempfung der migraene
DEP4041463.9 1990-12-22

Publications (1)

Publication Number Publication Date
WO1992011013A1 true WO1992011013A1 (fr) 1992-07-09

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/002379 WO1992011013A1 (fr) 1990-12-22 1991-12-12 5-cyanomethylen-10-(piperazin-1-yl)-dibenzo[a,d]cycloheptenes de traitement de la migraine

Country Status (2)

Country Link
DE (1) DE4041463A1 (fr)
WO (1) WO1992011013A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024116A1 (fr) 1992-05-28 1993-12-09 Glaxo Canada Inc. Compositions pharmaceutiques comprenant des agonistes des recepteurs 5-ht1 et des stimulateurs d'absorption
US7189753B1 (en) 1997-11-06 2007-03-13 Cady Roger K Preemptive prophylaxis of migraine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3457264A (en) * 1965-07-06 1969-07-22 Farmochimica Cutolo Calosi Spa N-(5h-dibenzo-(a,d)-cyclohepten - 5 - one-11-yl)-piperazines and method of preparing the same
US3462436A (en) * 1965-01-27 1969-08-19 Rhone Poulenc Sa 11-piperazino-dibenzocycloheptadiene derivatives
EP0035714A2 (fr) * 1980-03-08 1981-09-16 BASF Aktiengesellschaft 5-Cyanométhylène-10,11-dihydro-dibenzo-(a,d)-cycloheptènes-10-substitués, procédé pour leur préparation, et compositions pharmaceutiques les contenant
EP0035711A2 (fr) * 1980-03-08 1981-09-16 BASF Aktiengesellschaft 5-Cyanométhylène-dibenzo (a,d)-cycloheptènes-10-substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3462436A (en) * 1965-01-27 1969-08-19 Rhone Poulenc Sa 11-piperazino-dibenzocycloheptadiene derivatives
US3457264A (en) * 1965-07-06 1969-07-22 Farmochimica Cutolo Calosi Spa N-(5h-dibenzo-(a,d)-cyclohepten - 5 - one-11-yl)-piperazines and method of preparing the same
EP0035714A2 (fr) * 1980-03-08 1981-09-16 BASF Aktiengesellschaft 5-Cyanométhylène-10,11-dihydro-dibenzo-(a,d)-cycloheptènes-10-substitués, procédé pour leur préparation, et compositions pharmaceutiques les contenant
EP0035711A2 (fr) * 1980-03-08 1981-09-16 BASF Aktiengesellschaft 5-Cyanométhylène-dibenzo (a,d)-cycloheptènes-10-substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024116A1 (fr) 1992-05-28 1993-12-09 Glaxo Canada Inc. Compositions pharmaceutiques comprenant des agonistes des recepteurs 5-ht1 et des stimulateurs d'absorption
US7189753B1 (en) 1997-11-06 2007-03-13 Cady Roger K Preemptive prophylaxis of migraine

Also Published As

Publication number Publication date
DE4041463A1 (de) 1992-06-25

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