CA2206519A1 - Dibenz¬cd,f|indole derivatives - Google Patents
Dibenz¬cd,f|indole derivativesInfo
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- CA2206519A1 CA2206519A1 CA002206519A CA2206519A CA2206519A1 CA 2206519 A1 CA2206519 A1 CA 2206519A1 CA 002206519 A CA002206519 A CA 002206519A CA 2206519 A CA2206519 A CA 2206519A CA 2206519 A1 CA2206519 A1 CA 2206519A1
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- Prior art keywords
- compound
- addition salt
- acid addition
- dibenz
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- 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
Abstract
1-Alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz¢cd,f!indoles of formula (I) may be used in the treatment of Morbus Parkinson, alcohol abuse and drug dependency. In said formula, R1, R2 and R3 are independently (C1-4)alkyl, in free or acid addition salt form.
Description
WO 96/20927 PCT/lEP9S/05167 DIB~.NZrcd~flINDOT,E D~,R~VATIVF~
The present invention relates to dibenz[cd,f~indole derivatives, their preparation and ph~ ceutical compositions co"li~it~ g them.
In accordance with the invention, there are provided l-alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indoles and acid addition salts thereof hereinafter referred to as "the compounds of the invention".
The compounds of the invention are preferably substituted in the 4 and 5 positions of the dibenz[cd,f~indole nucleus, preferably by alkyl groups. Any alkyl group in a compound of the invention, particularly the alkyl group in position 1, is preferably (Cl 1)alkyl. When a compound of the invention is substit-~ted in position 4, the configuration 4S,5aR is preferred.
More particularly the present invention provides a (4R*,5aS*) compound of formula I
OH~R2 (I) wherein R" R2 and R3 are independently (C, 4)alkyl, in free or acid addition salt forrn.
The term (4R*,5aS*) according to the usual convention in~ tes 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 pl~rel,~d.
Any alkyl r~rlic~l.c preferably are straight chain radicals.
SUBSTITUTE SHEET (RULE 263 CA 02206~19 1997-0~-30 WO 96/20927 . PCT/EP95/05167 R, is preferably methyl.
R2 is preferably methyl, ethyl or n-propyl.
R3 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-dihydroxy4,5,5a,6-tet~hydro-dibenz[cd,f]indole or an acid addition salt thereof, by splitting the ether groups in a coll~;,ponding l-alkyl4,5,5a,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.
More particularly, the invention provides a process for the production of a (4R*,SaS*) compound of formula I as ~1efine~ above, or an acid addition salt of the compound, which comprises splitting the ether groups in a (4R*,SaS*) compound of formula I[
Rl~
~ Z~R~ (Il) wherein R, to R3 are as defined above, and the Z radicals are the same or different and are splittable ether ~roups, or a precursor thereof, and recovering the (4R*,Sas*) colllpoulld 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. ,, For example the reaction may be carried out by treatment with a strong mineral acid, e.g.
aqueous hydrobromic or hydroiodic acid. Suitable lempeldtures may be from 100 ~C or SUBSTITUTE SHEE~ tRULE 26) CA 02206~19 1997-0~-30 WO 96/20927 . PCTI~EP9S/0~;167 higher, preferably from 100 ~C to the boiling point of the reaction rnixture, especially at about 130 ~C.
The ether group Z is preferably (Cl 4)alkoxy, more preferably a methoxy group.
As used herein the term precursor refers to compounds which are capable of beingconverted into the starting m~tt~.ri~l~ in conventional manner, e.g. temporarily protected compounds.
The resulting compounds of the invention may be recovered from the reaction mixture and purifled 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 forrnation include, for example, hydrochloric acid and meth~nesulfonic acid.
R~ce-mic compounds of the invention may be obtained from racemic starting materials.
Optically active isomers may be obtained from optically active precursors or from the r~em~te The enantiomers may be obtained from the racemate by known methods, for example by fractional cryst~lli7~tion 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. Racernic resolution into the optically active isomers may be effected before splitting of the ether groups, e.g. in a co.l.pound of formula II.
~ .
The 1-alkyl-4,5,5a,6-tetrahydro-dibenzo[cd,f~ indoles cont~ining splittable ether groups in the 9 and 10 positions, may be produced by reducing an applopliate 1-alkyl-4-hydroxy-4,5-dihydro-dibenz[cd,f]indole having splittable ether groups in the 9 and 10 positions.
In particular the (4R*,5aS*) coll,pou,lds of formula II may be prepared by recl~lcing in conventional manner, conveniently under acidic conditions suitable for the acidic reduction of en~mincs or imines, a compound of formula m SUBSTITIJTE S~{EEr (RUL~ 2~) WO 96/20927 . PCT/EP95/05167 ~ N~
,.
wll~lGi-l Z, R~, R2 and R3 are as defined above.
The starting materials l-alkyl4-hydroxy4,5-dihydro-dibenz[cd,f~indoles having splittable ether groups in the 9 and 10 positions may be pl~pa~,d according to known methods, for example as described in UK Patent 2,024,818.
For example starting materials of formula m may be ylc~-,d according to the following reaction sçllpm~: -SUBSTITUTE SHEE~ (RULE 26) WO 96/Z0927 . PCT/EP95/05167 S
N~N3 z~l (V) (IV) ~3NHz 1 HcooH/co(Imidazolyl)2 or C2H50-C2H40H R'3COHal Z~[3 DIBAH z~l (VI) ~NH-R NH--CO--R'3 (VII) n-Butyllithium --Li CO~/Na~iO4~ ~N R3 / R2-MgBr or Rz-Li R ~
Z~H
In the reaction scheme the radicals Rl, R2, R3 and Z are as defined above, R3' 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.
SUBSTITUTE S~EET (RULE 2 WO 96/20927 . PCT/EP95/0!;167 In the above intt~ tes the ether groups Z are preferably methoxy.
Insofar the preparation or any particular starting material is not particularly described, this may be effected in conventional manner or in analogous manner to that described hereinafter for analogous compounds.
In the following Examples all te.llpel~tures are given in degrees Celsius and are uncoll~,cL~d.
SUBSTITUTE S~tEET (RUL~ 2~i) WO 96120927 PCT/:E;P95/(15167 EXAMPLE 1: (+~(4R*.SaS*)-5-ethyl-4.5.5a.6-tetrahydro-9.10-dihydroxy-1-methyl-4-n-propyl-dibenz Icd.flindole a) 9-~mino-3.4-dimethoxy-5-methyl-phenanthrene (compound of formula V) 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 tel-Ipelature under a nitrogen atmosphere to 61.1 g (0.206 M) of 3,4-~im~thoxy-5-methyl-phenanthrene-9-carboxylic acid and the ll~i~lu.~ is stirred for 10 minllte~. 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 organic phases are combined, dried and evaporated, to give white crystals. 86 g of the resultant mixed anhydride are warmed for 2 hours under reflux in 800 ml of a solution 2N of sodium hydroxide and 800 ml ethanol and evaporated. The residue is washed with water /ice and extracted three times with methylene chloride. The organic phases are combined, dried and evapol~ted to give the title compound as a yellow powder. M.p. 130-133~.
b) 9-acetyl~mino-3~4-dimethoxy-5-methyl-phenanthrene (connpound of formula VI) 105.7 ml (0.750 M) of N-ethyl-N,N-diisopropylamine are added to a solution of 100.2 g (0.375 M) of 9-arnino-3,4-dimethoxy-5-methyl-ph~on~nthrene in 1000 ml methylene chloride. To the resulting mixture is added dropwise over 30 minlltes a solution of 34,5 ml (0.450 M) of acetyl chloride in 250 ml methylene chloride. During the addition, the Lc~ ature of the reaction mixture is m~int~inP-i at 20~ by cooling with ice. The reaction Lulc is stirred for 2 hours at room lelllp~ldLulc and extracted with methylene chloride.
The organic phases are washed with ice cooled 2N hydrochloric acid, water and 2Nsodium bicarbonate, dried over sodium sulfate and evaporated, to give the title compound.
M.p. 218-219~ after crystallisation from ethanol.
SUBSTITUTE St~EET (RUI ~ 26) CA 02206~19 1997-0~-30 WO 96t20927 PCT/EP9SIOS167 c) 9-etll,vlamino-3.4-dimethoxy-5-methyl-phenanthrene (compound of formula VII) 1700 ml (2.05 M) of a 20% solution of diisobutylaluminium hydride in toluene are added at room temperature over a period of 45 ~ninuteS to a suspension of 105.7 g (0.342 M) of 9-acetylamino-3,4-dimethoxy-6-methyl-ph~,n~nthrene in 1500 ml anhydrous tetrahydrofuran. The mixture is then warmed with stirring under a nitrogen atmosphere for 2 hours at 80~. The reaction mixture is then cooled at 0~ and under nitrogen atmosphere and a mixture of 2500 ml 2N hydrochloric acid / ice, cooled at -10~, is added by portions at such a rate that the gas evolution is m~int~ined. The acid solution is made ~lk~lin~, 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.
d) 5-et'n,yl~.5-dihydro-9.10-dimethoxy-1-methyl4-oxo-dibenzrcd.flindole (compound of formula IX) 661.4 ml (1.084 M) of a 15% solution of n-butyl-lithium in hexane are added at 0~, over a period of 20 min~ltes and under a nitrogen atmosphere, to a solution of 97 g (0.328 M) of 9-ethylamino-3,4-dimethoxy-5-methyl-phPn~nthrene in 1000 ml anhydrous tetrahydrofuran; the reaction mixture becomes dark red. After stirring for 30 minllt~s at 0~, the mixture is ltransferred in portions with a teflon tub with nitrogen ~I-,S~.Ul~ at -50~ into a lllixLult; of 500 g sodium sulfate and 500 g dry ice in 15.00 ml tetrahydrofuran. After the temperature of the mixture has reached room lell.~e.~lul~, the mixture is poured onto water / ice and extracted three times witn methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated to give the title compound. M.p.
148-149~ after cryst~llic~tion from ethyl acetate / hexane.
SU~3ST~TUTE S~EET (RULE 26) CA 02206~l9 l997-0~-30 WO 96/20927 . PCT/EP9S/05167 e) 5-ethyl~.5-dihydro4-hydroxy-9.10-dimethoxy-1-methyl-4-n-pro~yl-dibenzrcd.flindole (compound of formula m) .
A solution of 377 ml (4.1 M) of n-propyl-bromide in 4 litres tetrahydrofuran is added over a period of 90 ~--;--u~es at reflux to 99.8 g (4.1 M) of m~gn~cium tllrnin~ and the mixture is stirred for one hour at reflux. To the resultant mixture is added dropwise over 30 min~lt~c and under a nitrogen atmosphere a solution of 880 g (2.73 M) of S-ethyl~,5-dihydro-9,10-dimethoxy-1-methyl4-oxo-dibenz[cd,f]indole in 6 litres tetrahydrofuran. The reaction mixture is warmed for 2 hours at reflux and then extracted with methylene chloride. The organic phase is washed with a saturated solution of potassium bicarbonate and with water, dried over sodium sulfate and evaporated to give the title co...~ound in the form of a red-brown oil [IR Spectrum (CH2Cl2): 3540 cm~~
(OH)]. The crude product is directly used for the next step.
f~ (+)-(4R*.5aS*)-S-ethyl-4.5.5a.6-tetrahydro-9.10-dimethoxy-1-methyl 4-n-propyl-dibenzrcd.flindole (compound of formula II) A suspension of 100 g (0.273 M) of 5-ethyl-4,5-dihydro~-hydroxy-9,10-dimethoxy -1-methyl~-n-propyl-dibenz[cd,flindole 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 1~ minutes and the mixture is refluxed overnight with stirring. The mixture is then cooled to room te..,pe.~ture, filtered and the zinc ~m~ m iS washed with 500 ml methylene chloride. The filtrate is made ~lk~line with 1 litre of concentrated NH40H and extracted three times with methylene chloride (700 ml each time). The combined organic phases are washed with water, dried and evaporated.
The resultant oil is chromatographed on silica gel using methylene chloride with 25'o methanol to give the title compound as an oil.
SUBSTITUTE SHEET (RUL~ 2~) CA 02206~19 1997-0~-30 WO 96/20927 . PCT/EP95/0~i167 g) ( l )-(4R*.Sas*)-5-ethyl4.5.5a.6-tetrahydro-9~ 1 0-dihydroxy-1-methyl-4-~-~ropyl-dibenzrc-l flindole .
100 g of (+)-(4R*,SaS*)-5-ethyl~,5,Sa,6-tetrahydro-9,10-dimethoxy-1-methyl-4-n-propyl-dibenz[cd,f]indole in 1 litre of a 47% aqueous solution of hydrobromic acid are warmed for 6 hours at reflux at a bath temperature of 150~. After evaporation of the mixture to dryness, the crystalline residue is stirred in acetone and filtered. The precipitate is washed with acetone, then with ether and dried under high vacuum, to give thehydrobromide of the title compound. M.p. of the hydrochloride: >250~ with decomposition.
EXAMPLE 2: (-)-(4S,5aR)-5-ethyl-4,5.5a,6-tetrahydro-9. 1 0-dihydroxy-1 -met~yl-4-n-propyl-dibenzrcd,flindole a) (-)-(4S.SaR)-5-ethyl4.5 .5a.6-tetrahydro-9. 1 0-dimethoxy- 1-rn~thyl~-n-propyl-dibenzrcd.flindole 74.3 g (211 rnM) of (~)-(4R*,5aS*)-5-ethyl-4,5,5a,6-tetrahydro-9.10-dimethoxy-1-methyl-4-n-propyl-dibenz[cd,f~indole are dissolved in 600 ml acetone and a solution of 81.67 g (211 rnM) of (-)-di-O,O'-p-toluoyl-L-tartaric acid monohydrate in 300 ml acetone is added with stirring. The mixture is further stirred for one hour at room telllp~,ldture, a total of 1 litre ether being added in portions during this period. The resultant precipitate is filtered off, washed with ethyl acetate until it remains light yellow, and dried.
114.7 g of the crystals obtained from the first cryst~ tion are dissolved in 1 litre CH2Cl2/methanol 7:3 at reflux and the solution is filtered and conce~lrdted until a major part of the product crystallizes out. The nli~lUlc iS stirred for about 15 minutes the product is filtered off, washed with ethyl acetate until it remains colourless and dried.
48 g of the resulting product is recryst~ ed in the same manner by using 700 ml CH2Cl2 / methanol 50:50 to give colourless crystals.
SU8STITUTE SHEET (RULE 2~i~
WO 96~20927 . PCT/EP9!jlOS167 The resulting crystals are recryst~llice~l in the same manner by using 1.2 litres acetone and 60 ml methanol. There is thus obtained (-)-(4S,SaR)-5-ethyl4,5,5a,6-tetrahydro -9,1 0-dimethoxy- 1 -methyl4-n-propyl-dibenz[cd,~indole (-)-di-O.O'-p-toluoyl-L-tartrate in form'of colourless crystals which melt at 185-198~;
[a]D20 = -175.4~ (c - 2 in dimethylform~mi(l~). [a]D20 of the base (oil) = -197~ (c = 1, EtOH);
b) (-)-(4S.SaR)-5-ethyl4.5.5a.6-tetrahydro-9. l 0-dihydroxy-l-methyl~-n-propyl-dibenzrcd.flindole ProceP-lin~ as described in Example lg), (-)-(4S,5aR)-5-ethyl4,5,5a,6-tetrahydro-9,10-dihydroxy-1-methyl-4-n-propyl-dibenz[cd,f~indole is obtained; the methanesulfonate melts at 212-214~ with decomposition; [a]D20 = -159.2~ (c = 0.75 in m~th~nol).
EXAMPLE 3:
Procee~ing as described in Examples 1 and 2, the following compounds are obtained:
a) (+)-(4R*,5aS*)~,5,5a,6-tetrahydro-9,10-dimethoxy-1,5-di~wlllyl-4-n-propyl-dibenz[cd,f]indole b) (+)-(4R*,5aS *)-4,5,5a,6-tetrahydro-9, 1 0-dihydroxy- 1 ,5-dimethyl-4-n-propyl-dibenz[cd,f]indole. M.p. 215-217Cwith decomposition c) (-)-(4S,SaR)4,5,5a,6-tetrahydro-9, 1 0-dimethoxy- 1 ,5-dimethyl4-n-propyl-dibenz[cd,f]indole. [a]D20 of the (-)-di-O,O'-p-toluoyl-L-tartrate = -177~
(c =1, dimethylformamide). [a]D20 of the base = -218~ (c = 0,7, EtOH) d) (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9, 1 0-dihydroxy- 1 ,5-dimethyl-4-n-propyl-dibenz[cd,f]indole. The mPth~n~sulfonate melts at 201-203~ with decomposition, [a]D20 = -189~ (c = 0.5, MeOH). - ' It is also to be appreciated that 9-amino-3,4-dimethoxy-5-methyl-phPn~nthrene may be converted directly into 9-ethylamino-3,4-dhl.elllyloxy-5-methyl-phto-n~nthrene by heating with ethylamine in 2-ethoxyethanol.
SUBSTI~UTE SHEET (RUL~ 26) CA 02206~19 1997-0~-30 WO 96/20927 . PCTIEP9~105167 The 1 -alkyl-9, 1 0-dihydroxy -4,5 ,5a,6-tetrahydro-dibenz[cd,f~ indoles, in particular the compounds of formula I, and their ph~rm:lceutically acceptable acid addition salts, hereinafter referred to as "the agents of the invention", exhibit pharmacological activity in anim~lc and are therefore useful as ph~rm~euticals.
In particular, the agents of the invention are useful as central dopaminergic stim~ nt agents, as inllic~t~cl by standard tests, for example according to the method of U.
Ungerstedt et al. [Acta Physiol. Scand. Suppl. (1971), ~LSuppl. 66-9~], by induction of contralateral turning of notable duration in rats (whose substantia nigra has been lesioned by a microinjection of 6-hydroxy-doparnine one week previously) after p.o. ~riminictration in an amount of about 0.03 to about 10 mg/kg animal body weight. The activity isco.-ri..l-P~i by induction of dose dependent stereotyped cniffing, licking and biting behaviour in the rat according to the following test, after i.p. ~-iminictration 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 rli~m~ter on a wire grid floor.
After 30 n~illuL~s to allow acclim~tic~tion to the cage, the rats are injected with the compound under investigation. The behaviour of the rats is observed for 2 ..-i~ es 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 accesce~l using a scoring system based on that described by Costall, Naylor and Olley [Europ. J. Ph~ c 18, 83-94, (1972)].
The agents of the invention are therefore useful as central dopaminergic stim~ nt agents, for example for treating Mobus Parkinson.
For the above mentioned indication the ap~ liate dosage will, of course, vary depending upon, for example, the host, the mode of ~lminictration, and the severity of the condition being treated. However, in general, satisfactory results in ~nim~ls are indicated to be obtained when ~lministered at a daily dosage of from about 0.1 mg to 10 mg per kg animal body weight. In larger m~mm~c, for example hl~m~ncl an inrli~t.q~ daily dosage is in the range from about 4 to about 30 mg, conveniently given in divided doses 2 to 4 SUBS~ITUTE S~{EET (RULE 26~
CA 02206~19 1997-05-30 WO 96120927 . PCTIEP95/05167 times a day or in sust~inP~ release form. Dosage forms suitable for oral a~lminictration ' comp;ise from about 1 to about 15 mg of the agents.
The agents of the invention, in particular the compounds of formula I, are furthermore useful for preventing alcohol abuse, as indicated by the reduction of alcohol consumption in alcohol preferring rats on p.o. a~iminictration of about 0.5 to 2 mg/kg of the compounds.
.
Male and female rats of an alcohol ple~,ling strain are placed in individual cages each cont~ining an eatometer according to Fallon [Science l48, 977-8 (1965)] and two bottles fitted with double sphere valves, allowing a gravimetric determination of the quantities of food and beverage actually taken. The ~nim~lc receive a vitamin rich standard chow, ~lictille~ water in one bottle and an aqueous ethanol solution (10 % per volume) in the other. Under these conditions 50 to 97 % of the absorbed liquid is taken from the bottle cont~inin~ the ethanol solution, which cGll~,sponds to a daily coll~ Lion of 4 to 6 g pure ethanol by kg animal body weight, al1d the rats develop an ethanol addiction which appears from their increasing startle behaviour when c~l~king the cages during the abstinence periods.
The compounds are ~-iminictered p.o. in aqueous solution and the consumption of food, water and alcohol is recorded during 12 hours and colllpal~d with the average consumption within a period of 3 days before the ~iminictration.
In this test, the alcohol consumption is significantly reduced by the ~llminictration of the agents of the invention without .cignifi~nt reduction of food and liquid ingestion.
The agents of the invention, in particular the compounds of formula I, are also useful for the tre~tmPnt, especially the preventive treatment, of drug withdrawal symptoms in patients undergoing drug withdrawal from dependence-producing drugs, and for ~.upp~ssion of depen~enre habituation or addiction on dependence-producing drugs.
In one test based on the method described by S.E. File in Neurosci. Meth., 1980, 2, SUBSTITUTE S~tEE~ (RULE 2f;) _ CA 02206~19 1997-0~-30 WO 96/20927 . PCT/EP9S/~)5167 219-238, rat~C display an abstinence syndrome manifest ac a reduction in social interaction, which is reversed by ~-imini.ctration of the agents of the invention at about 0.05 to about 1 mg/kg animal body weight i.p.
In another test, rats which can self-~-lminict.~r 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 ~3, 859-866 (1989). In this test, 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..
For the above mentioned indications the a~.u~liate dosage will, of course, valy depending upon, for example, the host, the mode of ~lmini.ctration, and the nature and severity of the condition being treated. However, in general, satisfactory results in ~nim~lc are indicated to be obtained when ~fimini.ctP.red at a daily dosage of from about 0.1 mg to about 2 mg per kg animal body weight. In larger m~mm~lc, for example humans, an inllic~ted 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 suct~in~l release form. Dosage forms suitable for oral ~iminictration comprise from about 0.1 to about 15 mg of the agents.
For all these indications the prefe,l~d compound is the compound of example 1. It has, for example, been cletermined that in the above mentioned Ungerstedt model, this compound in~ e,c within 7 hours 2200 contralateral turns on ~riminictration 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 ~(lminicfration of 1 mg/lcg s.c.. In the above mentioned alcohol consurnption model, the alcohol intake is reduced by 60 % on ~-imini.ctration of 0.5 mg/kg p.o. of the compound of example 1, as cOlllpal~d to bromocriptine which reduces the intake by 70 %
on ~-lminictration of 4.0 mg/kg p.o.. In the above mentioned cocaine intake model, the cocaine intake is reduced by 30 % on ~minictration of 0.1 mg/kg i.p. of the compound of example 1.
The agents of the invention in pharm~eutically acceptable acid addition salt form exhibit SUBSTITUTE SHE~ (RUL~ 2~
CA 02206~19 1997-0~-30 WC~ 96120927 PCT/EP9~i/05167 the same order of activity as the agents of the invention in free base form.
The agents of the invention can be ~lminictPred 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.
In accordance with the foregoing, the present invention also provides an agent of the invention, for use as a ph~rm~eutical, in the treatment of Morbus Parkinson, in the el~Lion of alcohol abuse or in the tre~mPnt of drug withdrawal symptoms and ~up~l~ssion of dependence, habituation or addiction on dependence-producing drugs.
The present invention also provides a ph~rm~eutical composition comprising an agent of the invention in association with a ph~rm~cell~ical carrier or diluent. Such compositions may be manufactured in co~ ,nlional 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 ofdepe~cle~e7 habituation or addiction on dependence-producing drugs.
Moreover 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 depencl~nce, habituation or addiction on depen-len~e-producing drugs, in a subject in need of such treatment, which comprises ~rlminictering to such subject a ther~reutic~lly effective amount of the active agent.
SUBSTITUTE St~EET (RULE 2~)
The present invention relates to dibenz[cd,f~indole derivatives, their preparation and ph~ ceutical compositions co"li~it~ g them.
In accordance with the invention, there are provided l-alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indoles and acid addition salts thereof hereinafter referred to as "the compounds of the invention".
The compounds of the invention are preferably substituted in the 4 and 5 positions of the dibenz[cd,f~indole nucleus, preferably by alkyl groups. Any alkyl group in a compound of the invention, particularly the alkyl group in position 1, is preferably (Cl 1)alkyl. When a compound of the invention is substit-~ted in position 4, the configuration 4S,5aR is preferred.
More particularly the present invention provides a (4R*,5aS*) compound of formula I
OH~R2 (I) wherein R" R2 and R3 are independently (C, 4)alkyl, in free or acid addition salt forrn.
The term (4R*,5aS*) according to the usual convention in~ tes 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 pl~rel,~d.
Any alkyl r~rlic~l.c preferably are straight chain radicals.
SUBSTITUTE SHEET (RULE 263 CA 02206~19 1997-0~-30 WO 96/20927 . PCT/EP95/05167 R, is preferably methyl.
R2 is preferably methyl, ethyl or n-propyl.
R3 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-dihydroxy4,5,5a,6-tet~hydro-dibenz[cd,f]indole or an acid addition salt thereof, by splitting the ether groups in a coll~;,ponding l-alkyl4,5,5a,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.
More particularly, the invention provides a process for the production of a (4R*,SaS*) compound of formula I as ~1efine~ above, or an acid addition salt of the compound, which comprises splitting the ether groups in a (4R*,SaS*) compound of formula I[
Rl~
~ Z~R~ (Il) wherein R, to R3 are as defined above, and the Z radicals are the same or different and are splittable ether ~roups, or a precursor thereof, and recovering the (4R*,Sas*) colllpoulld 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. ,, For example the reaction may be carried out by treatment with a strong mineral acid, e.g.
aqueous hydrobromic or hydroiodic acid. Suitable lempeldtures may be from 100 ~C or SUBSTITUTE SHEE~ tRULE 26) CA 02206~19 1997-0~-30 WO 96/20927 . PCTI~EP9S/0~;167 higher, preferably from 100 ~C to the boiling point of the reaction rnixture, especially at about 130 ~C.
The ether group Z is preferably (Cl 4)alkoxy, more preferably a methoxy group.
As used herein the term precursor refers to compounds which are capable of beingconverted into the starting m~tt~.ri~l~ in conventional manner, e.g. temporarily protected compounds.
The resulting compounds of the invention may be recovered from the reaction mixture and purifled 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 forrnation include, for example, hydrochloric acid and meth~nesulfonic acid.
R~ce-mic compounds of the invention may be obtained from racemic starting materials.
Optically active isomers may be obtained from optically active precursors or from the r~em~te The enantiomers may be obtained from the racemate by known methods, for example by fractional cryst~lli7~tion 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. Racernic resolution into the optically active isomers may be effected before splitting of the ether groups, e.g. in a co.l.pound of formula II.
~ .
The 1-alkyl-4,5,5a,6-tetrahydro-dibenzo[cd,f~ indoles cont~ining splittable ether groups in the 9 and 10 positions, may be produced by reducing an applopliate 1-alkyl-4-hydroxy-4,5-dihydro-dibenz[cd,f]indole having splittable ether groups in the 9 and 10 positions.
In particular the (4R*,5aS*) coll,pou,lds of formula II may be prepared by recl~lcing in conventional manner, conveniently under acidic conditions suitable for the acidic reduction of en~mincs or imines, a compound of formula m SUBSTITIJTE S~{EEr (RUL~ 2~) WO 96/20927 . PCT/EP95/05167 ~ N~
,.
wll~lGi-l Z, R~, R2 and R3 are as defined above.
The starting materials l-alkyl4-hydroxy4,5-dihydro-dibenz[cd,f~indoles having splittable ether groups in the 9 and 10 positions may be pl~pa~,d according to known methods, for example as described in UK Patent 2,024,818.
For example starting materials of formula m may be ylc~-,d according to the following reaction sçllpm~: -SUBSTITUTE SHEE~ (RULE 26) WO 96/Z0927 . PCT/EP95/05167 S
N~N3 z~l (V) (IV) ~3NHz 1 HcooH/co(Imidazolyl)2 or C2H50-C2H40H R'3COHal Z~[3 DIBAH z~l (VI) ~NH-R NH--CO--R'3 (VII) n-Butyllithium --Li CO~/Na~iO4~ ~N R3 / R2-MgBr or Rz-Li R ~
Z~H
In the reaction scheme the radicals Rl, R2, R3 and Z are as defined above, R3' 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.
SUBSTITUTE S~EET (RULE 2 WO 96/20927 . PCT/EP95/0!;167 In the above intt~ tes the ether groups Z are preferably methoxy.
Insofar the preparation or any particular starting material is not particularly described, this may be effected in conventional manner or in analogous manner to that described hereinafter for analogous compounds.
In the following Examples all te.llpel~tures are given in degrees Celsius and are uncoll~,cL~d.
SUBSTITUTE S~tEET (RUL~ 2~i) WO 96120927 PCT/:E;P95/(15167 EXAMPLE 1: (+~(4R*.SaS*)-5-ethyl-4.5.5a.6-tetrahydro-9.10-dihydroxy-1-methyl-4-n-propyl-dibenz Icd.flindole a) 9-~mino-3.4-dimethoxy-5-methyl-phenanthrene (compound of formula V) 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 tel-Ipelature under a nitrogen atmosphere to 61.1 g (0.206 M) of 3,4-~im~thoxy-5-methyl-phenanthrene-9-carboxylic acid and the ll~i~lu.~ is stirred for 10 minllte~. 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 organic phases are combined, dried and evaporated, to give white crystals. 86 g of the resultant mixed anhydride are warmed for 2 hours under reflux in 800 ml of a solution 2N of sodium hydroxide and 800 ml ethanol and evaporated. The residue is washed with water /ice and extracted three times with methylene chloride. The organic phases are combined, dried and evapol~ted to give the title compound as a yellow powder. M.p. 130-133~.
b) 9-acetyl~mino-3~4-dimethoxy-5-methyl-phenanthrene (connpound of formula VI) 105.7 ml (0.750 M) of N-ethyl-N,N-diisopropylamine are added to a solution of 100.2 g (0.375 M) of 9-arnino-3,4-dimethoxy-5-methyl-ph~on~nthrene in 1000 ml methylene chloride. To the resulting mixture is added dropwise over 30 minlltes a solution of 34,5 ml (0.450 M) of acetyl chloride in 250 ml methylene chloride. During the addition, the Lc~ ature of the reaction mixture is m~int~inP-i at 20~ by cooling with ice. The reaction Lulc is stirred for 2 hours at room lelllp~ldLulc and extracted with methylene chloride.
The organic phases are washed with ice cooled 2N hydrochloric acid, water and 2Nsodium bicarbonate, dried over sodium sulfate and evaporated, to give the title compound.
M.p. 218-219~ after crystallisation from ethanol.
SUBSTITUTE St~EET (RUI ~ 26) CA 02206~19 1997-0~-30 WO 96t20927 PCT/EP9SIOS167 c) 9-etll,vlamino-3.4-dimethoxy-5-methyl-phenanthrene (compound of formula VII) 1700 ml (2.05 M) of a 20% solution of diisobutylaluminium hydride in toluene are added at room temperature over a period of 45 ~ninuteS to a suspension of 105.7 g (0.342 M) of 9-acetylamino-3,4-dimethoxy-6-methyl-ph~,n~nthrene in 1500 ml anhydrous tetrahydrofuran. The mixture is then warmed with stirring under a nitrogen atmosphere for 2 hours at 80~. The reaction mixture is then cooled at 0~ and under nitrogen atmosphere and a mixture of 2500 ml 2N hydrochloric acid / ice, cooled at -10~, is added by portions at such a rate that the gas evolution is m~int~ined. The acid solution is made ~lk~lin~, 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.
d) 5-et'n,yl~.5-dihydro-9.10-dimethoxy-1-methyl4-oxo-dibenzrcd.flindole (compound of formula IX) 661.4 ml (1.084 M) of a 15% solution of n-butyl-lithium in hexane are added at 0~, over a period of 20 min~ltes and under a nitrogen atmosphere, to a solution of 97 g (0.328 M) of 9-ethylamino-3,4-dimethoxy-5-methyl-phPn~nthrene in 1000 ml anhydrous tetrahydrofuran; the reaction mixture becomes dark red. After stirring for 30 minllt~s at 0~, the mixture is ltransferred in portions with a teflon tub with nitrogen ~I-,S~.Ul~ at -50~ into a lllixLult; of 500 g sodium sulfate and 500 g dry ice in 15.00 ml tetrahydrofuran. After the temperature of the mixture has reached room lell.~e.~lul~, the mixture is poured onto water / ice and extracted three times witn methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated to give the title compound. M.p.
148-149~ after cryst~llic~tion from ethyl acetate / hexane.
SU~3ST~TUTE S~EET (RULE 26) CA 02206~l9 l997-0~-30 WO 96/20927 . PCT/EP9S/05167 e) 5-ethyl~.5-dihydro4-hydroxy-9.10-dimethoxy-1-methyl-4-n-pro~yl-dibenzrcd.flindole (compound of formula m) .
A solution of 377 ml (4.1 M) of n-propyl-bromide in 4 litres tetrahydrofuran is added over a period of 90 ~--;--u~es at reflux to 99.8 g (4.1 M) of m~gn~cium tllrnin~ and the mixture is stirred for one hour at reflux. To the resultant mixture is added dropwise over 30 min~lt~c and under a nitrogen atmosphere a solution of 880 g (2.73 M) of S-ethyl~,5-dihydro-9,10-dimethoxy-1-methyl4-oxo-dibenz[cd,f]indole in 6 litres tetrahydrofuran. The reaction mixture is warmed for 2 hours at reflux and then extracted with methylene chloride. The organic phase is washed with a saturated solution of potassium bicarbonate and with water, dried over sodium sulfate and evaporated to give the title co...~ound in the form of a red-brown oil [IR Spectrum (CH2Cl2): 3540 cm~~
(OH)]. The crude product is directly used for the next step.
f~ (+)-(4R*.5aS*)-S-ethyl-4.5.5a.6-tetrahydro-9.10-dimethoxy-1-methyl 4-n-propyl-dibenzrcd.flindole (compound of formula II) A suspension of 100 g (0.273 M) of 5-ethyl-4,5-dihydro~-hydroxy-9,10-dimethoxy -1-methyl~-n-propyl-dibenz[cd,flindole 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 1~ minutes and the mixture is refluxed overnight with stirring. The mixture is then cooled to room te..,pe.~ture, filtered and the zinc ~m~ m iS washed with 500 ml methylene chloride. The filtrate is made ~lk~line with 1 litre of concentrated NH40H and extracted three times with methylene chloride (700 ml each time). The combined organic phases are washed with water, dried and evaporated.
The resultant oil is chromatographed on silica gel using methylene chloride with 25'o methanol to give the title compound as an oil.
SUBSTITUTE SHEET (RUL~ 2~) CA 02206~19 1997-0~-30 WO 96/20927 . PCT/EP95/0~i167 g) ( l )-(4R*.Sas*)-5-ethyl4.5.5a.6-tetrahydro-9~ 1 0-dihydroxy-1-methyl-4-~-~ropyl-dibenzrc-l flindole .
100 g of (+)-(4R*,SaS*)-5-ethyl~,5,Sa,6-tetrahydro-9,10-dimethoxy-1-methyl-4-n-propyl-dibenz[cd,f]indole in 1 litre of a 47% aqueous solution of hydrobromic acid are warmed for 6 hours at reflux at a bath temperature of 150~. After evaporation of the mixture to dryness, the crystalline residue is stirred in acetone and filtered. The precipitate is washed with acetone, then with ether and dried under high vacuum, to give thehydrobromide of the title compound. M.p. of the hydrochloride: >250~ with decomposition.
EXAMPLE 2: (-)-(4S,5aR)-5-ethyl-4,5.5a,6-tetrahydro-9. 1 0-dihydroxy-1 -met~yl-4-n-propyl-dibenzrcd,flindole a) (-)-(4S.SaR)-5-ethyl4.5 .5a.6-tetrahydro-9. 1 0-dimethoxy- 1-rn~thyl~-n-propyl-dibenzrcd.flindole 74.3 g (211 rnM) of (~)-(4R*,5aS*)-5-ethyl-4,5,5a,6-tetrahydro-9.10-dimethoxy-1-methyl-4-n-propyl-dibenz[cd,f~indole are dissolved in 600 ml acetone and a solution of 81.67 g (211 rnM) of (-)-di-O,O'-p-toluoyl-L-tartaric acid monohydrate in 300 ml acetone is added with stirring. The mixture is further stirred for one hour at room telllp~,ldture, a total of 1 litre ether being added in portions during this period. The resultant precipitate is filtered off, washed with ethyl acetate until it remains light yellow, and dried.
114.7 g of the crystals obtained from the first cryst~ tion are dissolved in 1 litre CH2Cl2/methanol 7:3 at reflux and the solution is filtered and conce~lrdted until a major part of the product crystallizes out. The nli~lUlc iS stirred for about 15 minutes the product is filtered off, washed with ethyl acetate until it remains colourless and dried.
48 g of the resulting product is recryst~ ed in the same manner by using 700 ml CH2Cl2 / methanol 50:50 to give colourless crystals.
SU8STITUTE SHEET (RULE 2~i~
WO 96~20927 . PCT/EP9!jlOS167 The resulting crystals are recryst~llice~l in the same manner by using 1.2 litres acetone and 60 ml methanol. There is thus obtained (-)-(4S,SaR)-5-ethyl4,5,5a,6-tetrahydro -9,1 0-dimethoxy- 1 -methyl4-n-propyl-dibenz[cd,~indole (-)-di-O.O'-p-toluoyl-L-tartrate in form'of colourless crystals which melt at 185-198~;
[a]D20 = -175.4~ (c - 2 in dimethylform~mi(l~). [a]D20 of the base (oil) = -197~ (c = 1, EtOH);
b) (-)-(4S.SaR)-5-ethyl4.5.5a.6-tetrahydro-9. l 0-dihydroxy-l-methyl~-n-propyl-dibenzrcd.flindole ProceP-lin~ as described in Example lg), (-)-(4S,5aR)-5-ethyl4,5,5a,6-tetrahydro-9,10-dihydroxy-1-methyl-4-n-propyl-dibenz[cd,f~indole is obtained; the methanesulfonate melts at 212-214~ with decomposition; [a]D20 = -159.2~ (c = 0.75 in m~th~nol).
EXAMPLE 3:
Procee~ing as described in Examples 1 and 2, the following compounds are obtained:
a) (+)-(4R*,5aS*)~,5,5a,6-tetrahydro-9,10-dimethoxy-1,5-di~wlllyl-4-n-propyl-dibenz[cd,f]indole b) (+)-(4R*,5aS *)-4,5,5a,6-tetrahydro-9, 1 0-dihydroxy- 1 ,5-dimethyl-4-n-propyl-dibenz[cd,f]indole. M.p. 215-217Cwith decomposition c) (-)-(4S,SaR)4,5,5a,6-tetrahydro-9, 1 0-dimethoxy- 1 ,5-dimethyl4-n-propyl-dibenz[cd,f]indole. [a]D20 of the (-)-di-O,O'-p-toluoyl-L-tartrate = -177~
(c =1, dimethylformamide). [a]D20 of the base = -218~ (c = 0,7, EtOH) d) (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9, 1 0-dihydroxy- 1 ,5-dimethyl-4-n-propyl-dibenz[cd,f]indole. The mPth~n~sulfonate melts at 201-203~ with decomposition, [a]D20 = -189~ (c = 0.5, MeOH). - ' It is also to be appreciated that 9-amino-3,4-dimethoxy-5-methyl-phPn~nthrene may be converted directly into 9-ethylamino-3,4-dhl.elllyloxy-5-methyl-phto-n~nthrene by heating with ethylamine in 2-ethoxyethanol.
SUBSTI~UTE SHEET (RUL~ 26) CA 02206~19 1997-0~-30 WO 96/20927 . PCTIEP9~105167 The 1 -alkyl-9, 1 0-dihydroxy -4,5 ,5a,6-tetrahydro-dibenz[cd,f~ indoles, in particular the compounds of formula I, and their ph~rm:lceutically acceptable acid addition salts, hereinafter referred to as "the agents of the invention", exhibit pharmacological activity in anim~lc and are therefore useful as ph~rm~euticals.
In particular, the agents of the invention are useful as central dopaminergic stim~ nt agents, as inllic~t~cl by standard tests, for example according to the method of U.
Ungerstedt et al. [Acta Physiol. Scand. Suppl. (1971), ~LSuppl. 66-9~], by induction of contralateral turning of notable duration in rats (whose substantia nigra has been lesioned by a microinjection of 6-hydroxy-doparnine one week previously) after p.o. ~riminictration in an amount of about 0.03 to about 10 mg/kg animal body weight. The activity isco.-ri..l-P~i by induction of dose dependent stereotyped cniffing, licking and biting behaviour in the rat according to the following test, after i.p. ~-iminictration 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 rli~m~ter on a wire grid floor.
After 30 n~illuL~s to allow acclim~tic~tion to the cage, the rats are injected with the compound under investigation. The behaviour of the rats is observed for 2 ..-i~ es 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 accesce~l using a scoring system based on that described by Costall, Naylor and Olley [Europ. J. Ph~ c 18, 83-94, (1972)].
The agents of the invention are therefore useful as central dopaminergic stim~ nt agents, for example for treating Mobus Parkinson.
For the above mentioned indication the ap~ liate dosage will, of course, vary depending upon, for example, the host, the mode of ~lminictration, and the severity of the condition being treated. However, in general, satisfactory results in ~nim~ls are indicated to be obtained when ~lministered at a daily dosage of from about 0.1 mg to 10 mg per kg animal body weight. In larger m~mm~c, for example hl~m~ncl an inrli~t.q~ daily dosage is in the range from about 4 to about 30 mg, conveniently given in divided doses 2 to 4 SUBS~ITUTE S~{EET (RULE 26~
CA 02206~19 1997-05-30 WO 96120927 . PCTIEP95/05167 times a day or in sust~inP~ release form. Dosage forms suitable for oral a~lminictration ' comp;ise from about 1 to about 15 mg of the agents.
The agents of the invention, in particular the compounds of formula I, are furthermore useful for preventing alcohol abuse, as indicated by the reduction of alcohol consumption in alcohol preferring rats on p.o. a~iminictration of about 0.5 to 2 mg/kg of the compounds.
.
Male and female rats of an alcohol ple~,ling strain are placed in individual cages each cont~ining an eatometer according to Fallon [Science l48, 977-8 (1965)] and two bottles fitted with double sphere valves, allowing a gravimetric determination of the quantities of food and beverage actually taken. The ~nim~lc receive a vitamin rich standard chow, ~lictille~ water in one bottle and an aqueous ethanol solution (10 % per volume) in the other. Under these conditions 50 to 97 % of the absorbed liquid is taken from the bottle cont~inin~ the ethanol solution, which cGll~,sponds to a daily coll~ Lion of 4 to 6 g pure ethanol by kg animal body weight, al1d the rats develop an ethanol addiction which appears from their increasing startle behaviour when c~l~king the cages during the abstinence periods.
The compounds are ~-iminictered p.o. in aqueous solution and the consumption of food, water and alcohol is recorded during 12 hours and colllpal~d with the average consumption within a period of 3 days before the ~iminictration.
In this test, the alcohol consumption is significantly reduced by the ~llminictration of the agents of the invention without .cignifi~nt reduction of food and liquid ingestion.
The agents of the invention, in particular the compounds of formula I, are also useful for the tre~tmPnt, especially the preventive treatment, of drug withdrawal symptoms in patients undergoing drug withdrawal from dependence-producing drugs, and for ~.upp~ssion of depen~enre habituation or addiction on dependence-producing drugs.
In one test based on the method described by S.E. File in Neurosci. Meth., 1980, 2, SUBSTITUTE S~tEE~ (RULE 2f;) _ CA 02206~19 1997-0~-30 WO 96/20927 . PCT/EP9S/~)5167 219-238, rat~C display an abstinence syndrome manifest ac a reduction in social interaction, which is reversed by ~-imini.ctration of the agents of the invention at about 0.05 to about 1 mg/kg animal body weight i.p.
In another test, rats which can self-~-lminict.~r 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 ~3, 859-866 (1989). In this test, 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..
For the above mentioned indications the a~.u~liate dosage will, of course, valy depending upon, for example, the host, the mode of ~lmini.ctration, and the nature and severity of the condition being treated. However, in general, satisfactory results in ~nim~lc are indicated to be obtained when ~fimini.ctP.red at a daily dosage of from about 0.1 mg to about 2 mg per kg animal body weight. In larger m~mm~lc, for example humans, an inllic~ted 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 suct~in~l release form. Dosage forms suitable for oral ~iminictration comprise from about 0.1 to about 15 mg of the agents.
For all these indications the prefe,l~d compound is the compound of example 1. It has, for example, been cletermined that in the above mentioned Ungerstedt model, this compound in~ e,c within 7 hours 2200 contralateral turns on ~riminictration 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 ~(lminicfration of 1 mg/lcg s.c.. In the above mentioned alcohol consurnption model, the alcohol intake is reduced by 60 % on ~-imini.ctration of 0.5 mg/kg p.o. of the compound of example 1, as cOlllpal~d to bromocriptine which reduces the intake by 70 %
on ~-lminictration of 4.0 mg/kg p.o.. In the above mentioned cocaine intake model, the cocaine intake is reduced by 30 % on ~minictration of 0.1 mg/kg i.p. of the compound of example 1.
The agents of the invention in pharm~eutically acceptable acid addition salt form exhibit SUBSTITUTE SHE~ (RUL~ 2~
CA 02206~19 1997-0~-30 WC~ 96120927 PCT/EP9~i/05167 the same order of activity as the agents of the invention in free base form.
The agents of the invention can be ~lminictPred 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.
In accordance with the foregoing, the present invention also provides an agent of the invention, for use as a ph~rm~eutical, in the treatment of Morbus Parkinson, in the el~Lion of alcohol abuse or in the tre~mPnt of drug withdrawal symptoms and ~up~l~ssion of dependence, habituation or addiction on dependence-producing drugs.
The present invention also provides a ph~rm~eutical composition comprising an agent of the invention in association with a ph~rm~cell~ical carrier or diluent. Such compositions may be manufactured in co~ ,nlional 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 ofdepe~cle~e7 habituation or addiction on dependence-producing drugs.
Moreover 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 depencl~nce, habituation or addiction on depen-len~e-producing drugs, in a subject in need of such treatment, which comprises ~rlminictering to such subject a ther~reutic~lly effective amount of the active agent.
SUBSTITUTE St~EET (RULE 2~)
Claims (10)
1. A 1-alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indole or an acid addition salt thereof.
2. A (4R*,5aS*) compound of claim 1 of formula I
(I) wherein R1, R2 and R3 are independently (C1-4)alkyl, in free or acid addition salt form.
(I) wherein R1, R2 and R3 are independently (C1-4)alkyl, in free or acid addition salt form.
3. A compound of claim 1 which is (4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy-1-methyl-4-n-propyl-dibenz[cd,f]indole, in free or acid addition salt form.
4. A process for the production of a compound according to claim 1, or an acid addition salt thereof, which comprises the steps of obtaining a 1-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 1-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 1-alkyl-9,10-dihydroxy-4,5,5a,6-tetrahydro-dibenz[cd,f]indole as such or as an acid addition salt thereof.
5. A process for the production of a (4R*,5aS*)compound of formula I according to claim 2, in free or acid addition salt form, which comprises splitting the ether groups in a (4R*,5aS*) compound of formula II
(II) wherein R1 to R3 are as defined in claim 2, and the Z radicals are the same or different and are splittable ether groups, or a precursor thereof, and recovering the (4R*,5as*) compound of formula I as such or as an acid addition salt.
(II) wherein R1 to R3 are as defined in claim 2, and the Z radicals are the same or different and are splittable ether groups, or a precursor thereof, and recovering the (4R*,5as*) compound of formula I as such or as an acid addition salt.
6. A compound of any one of claims 1 to 3 in free or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical.
7. A compound of any one of claims I to 3 in free or pharmaceutically acceptableacid addition salt form, for use 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.
8. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 in free or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
.
.
9. The use of a compound of any one of claims 1 to 3 in free or pharmaceuticallyacceptable acid addition salt form, in 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, habituationor addiction on dependence-producing drugs.
10. 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 subjectin need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of any one of claims 1 to 3 in free or pharmaceutically acceptable acid addition salt form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9426407.4A GB9426407D0 (en) | 1994-12-30 | 1994-12-30 | Improvements in or relating to organic compounds |
| GB9426407.4 | 1994-12-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2206519A1 true CA2206519A1 (en) | 1996-07-11 |
Family
ID=10766712
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002206519A Abandoned CA2206519A1 (en) | 1994-12-30 | 1995-12-29 | Dibenz¬cd,f|indole derivatives |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0800515A1 (en) |
| JP (1) | JPH11504616A (en) |
| AU (1) | AU4435896A (en) |
| CA (1) | CA2206519A1 (en) |
| GB (1) | GB9426407D0 (en) |
| IL (1) | IL116606A0 (en) |
| WO (1) | WO1996020927A1 (en) |
| ZA (1) | ZA9511036B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1406630A1 (en) | 2001-07-06 | 2004-04-14 | Endo Pharmaceuticals Inc. | Parenteral administration of 6-hydroxy-oxymorphone for use as an analgesic |
| US8329216B2 (en) | 2001-07-06 | 2012-12-11 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI70407C (en) * | 1978-06-23 | 1986-09-19 | Sandoz Ag | FREQUENCY REFRIGERATION FOR THERAPEUTIC THERAPEUTIC ANALYZLE 4,5,5A, 6-TETRA-HYDRO-DIBENS / CD F / INDOL DERIVAT |
| BE889324A (en) * | 1980-06-27 | 1981-12-22 | Sandoz Sa | NOVEL DIBENZ (CD, F) INDOLE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
| CH660187A5 (en) * | 1983-04-06 | 1987-03-31 | Sandoz Ag | Dibenz[cd,f]indole derivatives, their preparation and the pharmaceutical compositions containing them |
-
1994
- 1994-12-30 GB GBGB9426407.4A patent/GB9426407D0/en active Pending
-
1995
- 1995-12-28 ZA ZA9511036A patent/ZA9511036B/en unknown
- 1995-12-28 IL IL11660695A patent/IL116606A0/en unknown
- 1995-12-29 CA CA002206519A patent/CA2206519A1/en not_active Abandoned
- 1995-12-29 JP JP8520725A patent/JPH11504616A/en active Pending
- 1995-12-29 WO PCT/EP1995/005167 patent/WO1996020927A1/en not_active Application Discontinuation
- 1995-12-29 AU AU44358/96A patent/AU4435896A/en not_active Abandoned
- 1995-12-29 EP EP95943231A patent/EP0800515A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| WO1996020927A1 (en) | 1996-07-11 |
| GB9426407D0 (en) | 1995-03-01 |
| JPH11504616A (en) | 1999-04-27 |
| IL116606A0 (en) | 1996-03-31 |
| ZA9511036B (en) | 1997-06-30 |
| AU4435896A (en) | 1996-07-24 |
| EP0800515A1 (en) | 1997-10-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |