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WO1996020927A1 - DERIVES DE DIBENZ[cd,f]INDOLE - Google Patents

DERIVES DE DIBENZ[cd,f]INDOLE Download PDF

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Publication number
WO1996020927A1
WO1996020927A1 PCT/EP1995/005167 EP9505167W WO9620927A1 WO 1996020927 A1 WO1996020927 A1 WO 1996020927A1 EP 9505167 W EP9505167 W EP 9505167W WO 9620927 A1 WO9620927 A1 WO 9620927A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
acid addition
addition salt
dibenz
treatment
Prior art date
Application number
PCT/EP1995/005167
Other languages
English (en)
Inventor
Rudolf Karl Andreas Giger
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
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 Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Novartis Ag
Priority to AU44358/96A priority Critical patent/AU4435896A/en
Priority to EP95943231A priority patent/EP0800515A1/fr
Priority to JP8520725A priority patent/JPH11504616A/ja
Publication of WO1996020927A1 publication Critical patent/WO1996020927A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the present invention relates to dibenz[cd,f]indole derivatives, their preparation and pharmaceutical compositions containing them.
  • the compounds of the invention are preferably substituted in the 4 and 5 positions of the dibenz[cd,fJindole nucleus, preferably by alkyl groups.
  • Any alkyl group in a compound of the invention, particularly the alkyl group in position 1, is preferably (C M )alkyl.
  • the configuration 4S,5aR is preferred.
  • R,, R 2 and R 3 are independently (C M )alkyl, in free or acid addition salt form.
  • (4R*,5aS*) indicates that the compound may be in the form of the racemate or of an optically active isomer, wherein the hydrogen atoms in positions 4 and 5a of the dibenz[cd,f]indole nucleus are syn to each other.
  • the optical isomers having the absolute configuration 4S,5aR are preferred.
  • Any alkyl radicals preferably are straight chain radicals.
  • R is preferably methyl.
  • R 2 is preferably methyl, ethyl or n-propyl.
  • R 3 has preferably 1, 2 or 3 carbon atoms, and is especially methyl, ethyl or n-propyl.
  • the present invention also provides a process for the production of a compound of the invention, which includes the steps of obtaining a l-alkyl-9,10-dihydroxy-4,5,5a,6- tetrahydro-dibenz[cd,f]indole or an acid addition salt thereof, by splitting the ether groups in a corresponding l-alkyl-4,5,5a,6-tetrahydro-dibenz[cd,f]indole having splittable ether groups in the 9 and 10 positions, or a precursor thereof, and recovering the desired l-alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indole as such or as an acid addition salt thereof.
  • the invention provides a process for the production of a (4R*,5aS*) compound of formula I as defined above, or an acid addition salt of the compound, which comprises splitting the ether groups in a (4R*,5aS*) compound of formula II
  • R, to R 3 are as defined above, and the Z radicals are the same or different and are splittable ether groups, or a precursor thereof, and recovering the (4R*,Sas*) compound of formula I as such or as an acid addition salt.
  • the ether splitting process may be effected in conventional manner for splitting ether groups.
  • reaction may be carried out by treatment with a strong mineral acid, e.g. aqueous hydrobromic or hydroiodic acid.
  • a strong mineral acid e.g. aqueous hydrobromic or hydroiodic acid.
  • Suitable temperatures may be from 100 °C or higher, preferably from 100 °C to the boiling point of the reaction mixture, especially at about 130 °C.
  • the ether group Z is preferably (C )alkoxy, more preferably a methoxy group.
  • precursor refers to compounds which are capable of being converted into the starting materials in conventional manner, e.g. temporarily protected compounds.
  • the resulting compounds of the invention may be recovered from the reaction mixture and purified in known manner.
  • the free base forms of the compounds of the invention may be converted into acid addition salt forms in conventional manner and vice versa .
  • Suitable acids for salt formation include, for example, hydrochloric acid and methanesulfonic acid.
  • Racemic compounds of the invention may be obtained from racemic starting materials.
  • Optically active isomers may be obtained from optically active precursors or from the racemate.
  • the enantiomers may be obtained from the racemate by known methods, for example by fractional crystallization of diastereoisomeric salts, e.g. their salts with (+)-di-O,O'-p-toluoyl-D-tartaric acid or (-)-di-O.O'-p-toluoyl-L-tartaric acid.
  • Racemic resolution into the optically active isomers may be effected before splitting of the ether groups, e.g. in a compound of formula U.
  • the l-alkyl-4,5,5a,6-tetrahydro-dibenzo[cd,f] indoles containing splittable ether groups in the 9 and 10 positions may be produced by reducing an appropriate 1 -alkyl-4-hydroxy- 4,5-dihydro-dibenz[cd,f]indole having splittable ether groups in the 9 and 10 positions.
  • (4R*,5aS*) compounds of formula II may be prepared by reducing in conventional manner, conveniently under acidic conditions suitable for the acidic reduction of enamines or imines, a compound of formula HI
  • the starting materials l-alkyl-4-hydroxy-4,5-dihydro-dibenz[cd,f]indoles having splittable ether groups in the 9 and 10 positions may be prepared according to known methods, for example as described in UK Patent 2,024,818.
  • Rute R 2 , R 3 and Z are as defined above, R 3 ' is hydrogen, methyl or ethyl and Hal is chlorine or bromine.
  • the reactions may be carried out in conventional manner and the products of the above reactions may be isolated and purified in known manner.
  • the ether groups Z are preferably methoxy.
  • a mixture of 400 ml (2.87 M) of trifluoro-acetic anhydride and 400 ml (5.22 M) of trifluoro-acetic acid is added at room temperature under a nitrogen atmosphere to 61.1 g (0.206 M) of 3,4-dimethoxy-5-methyl-phenanthrene-9-carboxylic acid and the mixture is stirred for 10 minutes. After cooling to -5°, 16.08 g (0.247 M) sodium azide are carefully added in solid form and stirred for 2 hours at 0°, then poured onto ice, extracted three times with methylene chloride and washed with a solution IN of sodium hydroxide.The aqueous phases are extracted twice with methylene chloride 2-propanol 8:2.
  • the acid solution is made alkaline to pH 10 by addition at 0° of 3 litres 2N sodium hydroxide and the mixture is extracted three times with methylene chloride / 2-propanol 7:3. The organic phases are combined, washed, dried and evaporated to give the title compound as a brown oil.
  • a suspension of 100 g (0.273 M) of 5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy -l-methyl-4-n-propyl-dibenz[cd,fjindole in 2000 ml ethanol is added with stirring to a suspension of 322g (4.928 M) of zinc dust and 74.3 g (0.273 M) of mercury (II) chloride in 2000 ml distilled water.
  • the reaction mixture is refluxed, 450 ml of 18% hydrochloric acid are added dropwise over a period of 15 minutes and the mixture is refluxed overnight with stirring.
  • the mixture is then cooled to room temperature, filtered and the zinc amalgam is washed with 500 ml methylene chloride.
  • EXAMPLE 2 M-.4S.5aRV5-ethyl-4.5.5a.6-tetrahvdro-9.10-dihvdroxy- l-methvl-4-n- ⁇ ropvl-dibenzrcd.flindole
  • 9-amino-3,4-dimethoxy-5-methyl-phenanthrene may be converted directly into 9-emylamino-3,4-dimethyloxy-5-methyl-phenanthrene by heating with ethylamine in 2-ethoxyethanol.
  • the l-alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indoles, in particular the compounds of formula I, and their pharmaceutically acceptable acid addition salts, hereinafter referred to as "the agents of the invention" exhibit pharmacological activity in animals and are therefore useful as pharmaceuticals.
  • the agents of the invention are useful as central dopaminergic stimulant agents, as indicated by standard tests, for example according to the method of U. Ungerstedt et al. [Acta Physiol. Scand. Suppl. (1971), 2g7__Su ⁇ pl. 66-93], by induction of contralateral turning of notable duration in rats (whose substantia nigra has been lesioned by a microinjection of 6-hydroxy-dopamine one week previously) after p.o. administration in an amount of about 0.03 to about 10 mg/kg animal body weight. The activity is confirmed by induction of dose dependent stereotyped sniffing, licking and biting behaviour in the rat according to the following test, after i.p. administration in an amount of about 1 to about 30 mg/kg animal body weight.
  • Rats, 180-222 g are placed in perspex cylinders of 30 cm diameter on a wire grid floor. After 30 minutes to allow acclimatisation to the cage, the rats are injected with the compound under investigation. The behaviour of the rats is observed for 2 minutes at 30 minutes intervals for 2 hours and then at 60 minutes intervals for a total of up to 7 hours. The degree of stereotyped behaviour observed is assessed using a scoring system based on that described by Costall, Naylor and Olley [Europ. J. Pharmac. 1£, 83-94, (1972)].
  • the agents of the invention are therefore useful as central dopaminergic stimulant agents, for example for treating Mobus Parkinson.
  • the appropriate dosage will, of course, vary depending upon, for example, the host, the mode of administration, and the severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained when administered at a daily dosage of from about 0.1 mg to 10 mg per kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 4 to about 30 mg, conveniently given in divided doses 2 to 4 times a day or in sustained release form. Dosage forms suitable for oral administration comprise from about 1 to about 15 mg of the agents.
  • agents of the invention are furthermore useful for preventing alcohol abuse, as indicated by the reduction of alcohol consumption in alcohol preferring rats on p.o. administration of about 0.5 to 2 mg/kg of the compounds.
  • the compounds are administered p.o. in aqueous solution and the consumption of food, water and alcohol is recorded during 12 hours and compared with the average consumption within a period of 3 days before the administration.
  • agents of the invention are also useful for the treatment, especially the preventive treatment, of drug withdrawal symptoms in patients undergoing drug withdrawal from dependence-producing drugs, and for suppression of dependence, habituation or addiction on dependence-producing drugs.
  • rats display an abstinence syndrome manifest as a reduction in social interaction, which is reversed by administration of the agents of the invention at about 0.05 to about 1 mg/kg animal body weight i.p.
  • rats which can self-administer themselves with cocaine over several weeks are tested for their physical dependence liability according to the method described by N.E. Goeders et al. in Pharmacol. Biochem. Behaviour 22, 859-866 (1989).
  • the agents of the invention cause a significant decrease in the intake of cocaine at about 0.05 to about 1 mg kg animal body weight i.p..
  • the appropriate dosage will, of course, vary depending upon, for example, the host, the mode of administration, and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained when administered at a daily dosage of from about 0.1 mg to about 2 mg per kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 0.5 to about 30 mg conveniently given in divided doses 2 to 4 times a day or in sustained release form. Dosage forms suitable for oral administration comprise from about 0.1 to about 15 mg of the agents.
  • the preferred compound is the compound of example 1. It has, for example, been determined that in the above mentioned Ungerstedt model, this compound induces within 7 hours 2200 contralateral turns on administration of 0.3 mg/kg p.o. or 0.1 mg/s.c, as compared to bromocriptine which induces within 7 hours 1720 contralateral turns on administration of 1 mg/kg s.c.
  • the alcohol intake is reduced by 60 % on administration of 0.5 mg/kg p.o. of the compound of example 1, as compared to bromocriptine which reduces the intake by 70 % on administration of 4.0 mg/kg p.o..
  • the cocaine intake is reduced by 30 % on administration of 0.1 mg/kg i.p. of the compound of example 1.
  • the agents of the invention in pharmaceutically acceptable acid addition salt form exhibit the same order of activity as the agents of the invention in free base form.
  • agents of the invention can be administered by any conventional route, preferably orally, for example in the form of tablets or capsules, or parenterably, for example in the form of injectable solutions or suspensions.
  • the present invention also provides an agent of the invention, for use as a pharmaceutical, in the treatment of Morbus Parkinson, in the prevention of alcohol abuse or in the treatment of drug withdrawal symptoms and suppression of dependence, habituation or addiction on dependence-producing drugs.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the invention in association with a pharmaceutical carrier or diluent.
  • Such compositions may be manufactured in conventional manner.
  • Unit dosage forms contain, for example, from about 0.01 mg to 15 mg of the active agent.
  • the present invention furthermore provides the use of the agents of the invention for the manufacture of a medicament for the treatment of Morbus Parkinson, in the prevention of alcohol abuse or in the treatment of drug withdrawal symptoms and suppression of dependence, habituation or addiction on dependence-producing drugs.
  • the present invention provides a method for the treatment of Morbus Parkinson, for the prevention of alcohol abuse or for the treatment of drug withdrawal symptoms and suppression of dependence, habituation or addiction on dependence-producing drugs, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of the active agent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

Des 1-alkyl-9,10-dihydroxy-4,5,5a,6-tétrahydro-dibenz[cd,f]indoles peuvent être utilisés dans le traitement de la maladie de Parkinson, l'abus d'alcool et la pharmacodépendance. Dans la formule, R1, R2 et R3 représentent, indépendamment l'un de l'autre, alkyle en C1-4 sous forme libre ou de sel d'addition d'acide.
PCT/EP1995/005167 1994-12-30 1995-12-29 DERIVES DE DIBENZ[cd,f]INDOLE WO1996020927A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU44358/96A AU4435896A (en) 1994-12-30 1995-12-29 Dibenz{cd,f}indole derivatives
EP95943231A EP0800515A1 (fr) 1994-12-30 1995-12-29 DERIVES DE DIBENZ cd,f]INDOLE
JP8520725A JPH11504616A (ja) 1994-12-30 1995-12-29 ジベンズ［ｃｄ，ｆ］インドール誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9426407.4 1994-12-30
GBGB9426407.4A GB9426407D0 (en) 1994-12-30 1994-12-30 Improvements in or relating to organic compounds

Publications (1)

Publication Number Publication Date
WO1996020927A1 true WO1996020927A1 (fr) 1996-07-11

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ID=10766712

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/005167 WO1996020927A1 (fr) 1994-12-30 1995-12-29 DERIVES DE DIBENZ[cd,f]INDOLE

Country Status (8)

Country Link
EP (1) EP0800515A1 (fr)
JP (1) JPH11504616A (fr)
AU (1) AU4435896A (fr)
CA (1) CA2206519A1 (fr)
GB (1) GB9426407D0 (fr)
IL (1) IL116606A0 (fr)
WO (1) WO1996020927A1 (fr)
ZA (1) ZA9511036B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7276250B2 (en) 2001-07-06 2007-10-02 Penwest Pharmaceuticals Company Sustained release formulations of oxymorphone
US8309122B2 (en) 2001-07-06 2012-11-13 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2024818A (en) * 1978-06-23 1980-01-16 Sandoz Ltd Phenanthrene derivatives, their preparation and pharmaceutical compositions containing them
GB2078225A (en) * 1980-06-27 1982-01-06 Sandoz Ltd 4,5,5a,6-tetrahydro-dibenz[cd,f]indoles
CH660187A5 (en) * 1983-04-06 1987-03-31 Sandoz Ag Dibenz[cd,f]indole derivatives, their preparation and the pharmaceutical compositions containing them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2024818A (en) * 1978-06-23 1980-01-16 Sandoz Ltd Phenanthrene derivatives, their preparation and pharmaceutical compositions containing them
GB2078225A (en) * 1980-06-27 1982-01-06 Sandoz Ltd 4,5,5a,6-tetrahydro-dibenz[cd,f]indoles
CH660187A5 (en) * 1983-04-06 1987-03-31 Sandoz Ag Dibenz[cd,f]indole derivatives, their preparation and the pharmaceutical compositions containing them

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7276250B2 (en) 2001-07-06 2007-10-02 Penwest Pharmaceuticals Company Sustained release formulations of oxymorphone
US8309122B2 (en) 2001-07-06 2012-11-13 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations

Also Published As

Publication number Publication date
AU4435896A (en) 1996-07-24
IL116606A0 (en) 1996-03-31
EP0800515A1 (fr) 1997-10-15
CA2206519A1 (fr) 1996-07-11
GB9426407D0 (en) 1995-03-01
JPH11504616A (ja) 1999-04-27
ZA9511036B (en) 1997-06-30

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