CA2025003A1 - Use of dopamine-autoreceptor agonists in the treatment of drug dependency - Google Patents

Abstract

Abstract The invention related to the use of dopamine-autoreceptor agonists, particularly 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine (BHT 920) and (S)-2-amino-4,5,6,7-tetrahydro-6-n-propylamino-benzo-thiazole in the treatment of drug dependency.

Description

l)6~ ;10 1~:07 ~1~73 204~'72 FB~)EIIN BRICHTON 1~ o4 2~ 3 ThQ present inven~ion rela~s to th~ uae of dopamine-autoreceptor agonists, parti~ularly 6-Allyl-2-amino-s~
6,7,8-tetrahydro-4H-thiazo10[4,s-d~-azeplne (BHT 920) and (s)-2-amino-4~s~6~7-tetrahydro~6-n-propylamin benzothi~zole in th~ tre~tm~nt Or drug dopendenoy.

~clc~ian Patenta ~84 41S nnd ?71 330 ds~ribe inter a~
thinzo~o ~nd oxAzolo-dorivativQs o~ gene~l fermula Rl-N ~

~C112 )n NH2 wherein R~ ropresent~ a hydrogen Atom, a ~ Alk~l ~roup optlonally ~ubsti~uted by ~ hydroxyl ~roup, a benzyl g~oup optlon~lly sub~tituted by halogQn, methyl or m4thoxy, or ~n ~llyl ~roup, n represont~ the numb~r 2 or ~loo 1, i~ X i5 a sulphur atom, and ~, X rQprenents an oxygen or ~ulphur atom, nnd th~
as physiologic~lly acc~ptable acld s~lta theroo~ with orqanla or lnorgania acid~.

It i~ ~nown from Bel~i~n Paten~ 684 415 and ?71 330 ~hat the compounds o~ general ~ormula ~ and the phys~ologic~lly accoptnble acid ~ddition salts thereof have valu~lo ph~rmacolog$c~1 propertie~. ~hua, the ¢ompo~nds doscrlbed ln Bolg~on pat~nt~ 684 415 have ln partiaular ~nalgeaio, aedntiv~, ~nd Anti-tuaaive, ~nti-pyre~lo and anti-phloyi~tio ~ctlvlty And the a~mp~unda desc~ibed in Belglan P~tent 771 330 have, dependlng on thelr aubstitu~ion, hyp~tensive, sed~tive, anti-tusslve ~nd/or ~nti-ph~ogl~tic aativity.

O5/~J ' 111 1~ 273 2~4~72 FB[)EHN B~ICHTON 1~(35 202~0a3 .
'l`he above mentioned patents also show that the thiaYGlo~
derivate~ o~ ~eneral ~ormula I, wherein ~1 represents a ~l,4-alkyl group or an allyl group, n represents the number 2 and X represents a ~ulphur atom have, m~re p~rticul~rly, n hypoten~ive ef~ect and ~he oxazolo-derivstes of general Formula I wher~in Rl represents a .-hydrogen stom, nnd optionAlly a hydroxy-~ub~tituted C14~
alkyl group or ~n allyl group, n repr~ents the number 2 and X repre~ent~ an oxygon ~tom, havo in partioular antl-tus3ive properties.

It is known ~rom EP-Al-OOOS 732 th~t th~ compound~ o :-:
~eneral ~ormu.la 1 wh~rein n repre~nt~ the number ~ Also havo an ~ntl-angin~ activity.
It i~ also known from U~ PA~ent No.4 400 378 th~t th~
eompounds of qoner~l ~ormula I hAv~ an anti-~aucoma ~ffqct.

According to ehe sc~enti~ie pu~ tion~ available hlthqrto, the compound 2-amino-6-allyl-5,6,7,8 tetrahydro-4H-thiAzolot4,5-d]nzepine dlhydrochlorido (BHT 920~ wAa al~o pereoivod to be An agoni~t a~t~ng se~eatively on pr~-synaptic dopaminer~lc receptor~ (e.g.
2S Anden et al., Aeta PhArmacol. et Toxlaol., ~2, 51-56 (1983) and 3. Neural tr~n~mission ~, 129-137 (1983). ~ ~:

It is known ~rom EP-Al 192 098 that BH~ ~20 also h~`s An AgOlliBtiC e~eot on postsynaptic dopaminergic ~tructure~ oP th~ braln, but only wh~n thcre iB a dop~mine doflciency ca~ed by d~n~rvatlon o~ :
de~ener~tion, This dlscovery marks th~ compound out partlcula~ly ~or the t~e~tm~nt ~ PQrkin~ons di~eAse or P~rkin~onl~m.

~6/09 ' t~ 3273 2~4l~72 FBDEHN BRl(iHTON 1~
, ~ 2025~03 German Patent No. 34 47 075.l descrlbe~
tetrahydrobenzthi~zoles of g~neral fermul.a I, ~ N ~ ~ ~ R2 (I) the ~nantiomer~ ~nd the na~d ~ddltion ~alts thereo~, pArtloularly the phy~loloq~cally ~cceptable acid addltlon ~alts thereof with inorgAnic or or0~nic acids, and proco~se~ rOr prep~rlng tho~.

If in qeneral ~ormula I, one of the groups R1 or R~ or both groups ~ nd ~ repre~ent ~n acyl group, the~
aompounds Or qeneral ~or~uln I nre valuabl~ ~ .
lnterm~dlAtea ~or the proparatlon of t~le othex compounds ot general tormula 1 whioh h~ve valuAble phArmaoological !~ prop-rtlos, more partlaulary, An ~f~eot on the centrAl nervous oy~t-m ~nd/or the clrcul~tlon. .

0 ~he preeent invontion r-late~ to the u~e of dopAmin~-~ autore~ptor-agonl~t~, p~rtlcul~rly 6-allyl-2-~mlno~5, 3~ 6~7,~-~N~ zolot4,5-d~ p~n~ ~aHT 920) ~nd ~8)-2-amino-~,5,6,7-t~trahydro-6-n-propylamino-bonzoth~ole (SNO ~l~) a~nd the phar~ac~utlcally ~cceptablo aold ~:
~ddltian~ ~alte ther~of ln tho treatment o~ drug dep~ndenoy. Tbe d~pAmln~-autoreceptor-~gonl~ti~ are dm~nlster~d ovor ~ ~irly long p~riod (weok~ to month~
rom the withdr~wal o~ the drug). I~ t~e pat~nt ; : -rël~pses in~o druq taklng, the p~ychic dependency of th~
, ~f 30 Ipatient on the drug i~ broken slnc~ the ouphoric reward . ;
expeated ~ra~ dru~ t~klng i~ not ~ahieved.

Som~ oompo~nd~ whioh are dopAmlne-Autoreoeptor~agoniets, ~ .
!; p~rticularly ~H~` 9~0 And ~ 2-amin~-4,5,6,~-tetrahydro-6n-propylamino-bonzothiA~ole~ ~ro known ~om ~h~ p~ent~
and patent applications de~cribed ~bove.

~`'`'' ~ ' "-'' '';,', ~ 73 2~J4072 FB~E~N ~R I (~HTON ~ 0(:)7 , ` ~02~003 ':
The invention further relates to the use of said compounds for preparing from pharmaceutical compound~ -compositions ~u~table ~or tre~ting drug dependency.

~`or tr~Atinq drug dQp4ndency the compounds and ~uitable aald a~dition ~alts thereo~ ~ay be incorporated in the conv~nt~onAl g~l~nic preparation~ for oral, p~renteral, rect~l, or tran~dermAl appll~atlons.

The singlo do~e ~y or~l route in human~ is nor~ally betw~en 2.5 ~g and 350 ~g, pre~erAbly between 100 ~g and 250 ~g~ ~or multlple appllc~tion (e.g. thre~ time~ a day) th~ dall~ dose io pro~erably b~tween 15 and g~O ~g, pr~ferably between 30 and 75~ ~g.
lS ~he par~ntcr~l ~nd reCtAl do~es may b~ in the s~me rAnge :~
A~ the quantitl-~ Or subst~nce for oral ndministrat~on.

Th~ ~ollowing i~ An explAnation o~ some of the te~ms aonvontionally used ln thc l~torature:
~20 R~w~rd ~lnner reward): feeling o~ euphorla, p~e~ure gain, ~rlg~ered by tn~ t~klng of drug~.

Rein~orcement (po~itlve r~in~orcHment): in ~nlmal trials~ repet~tion of an nctlon which ha~ been l~arncd, trigger~d by a reward.

Drug craving: need or a 3trong desiro ~or a drug ~.g. a~ -u~uAlly occur~ aft~r wlthdr~wal of A drug.
'Animal trial~ hnve shown th~t drugs wh~4h have th~
potentlal ~or mi~use, suah ~s cocalno, opin~s and ~lcohol, rQsult ln the r~l~A6e o~ dopamine tDA) in v~rious ~ones o~ the br~in ~S, 13, 24). It has also b~n ~hown (2B) t.hat intracranial electrlcal ~timul.ation o~ DA-rich ~ones o~ the brAin, bring ~bou~ high rate3 o~
~el~-stimulAti.on. I~ }1~5 ~een concluded ~rom thefi~

~` 2~2~03 rindings th~t the releas~ o~ ~A brings about a reward and thus resul~s in posltive rein~orcement. ~hi~ would provid~ t~e basis ~or psychlc dep~ndency.

~y aontrast, ~he chronic ad~lnistr~tion of, ~.g.
psycho~oto~ s~imul~nts And opiAtcs ~e~ult~ ln dopl~tion oP DA in the braln, ~nd th~re~ore ro~ults in superaensltlvity o~ po~tJyn~ptic DA-receptors; this observatlon expl~ln~ the de~elopm~nt o~ tol-rance and druq cravlng a~t~r wlthdraw~l (1,5,14,16,17,27). ~ . ..

Th~re have nlno been r~ports (~,20,B,11,15,~,10,27,23) of allnical trlals Or DA-ngonlats (am~nt~dine, bromocrlptlno and ~-dopa) whloh ~ere u~d during drug withdrawal (p~rticulArly cocalne). In the ma~ority of t~o~e o~se~ the report~ ind~cated that ~h~
admlnlstration Or the DA-agohi~ts reduced the drug-cr~vin~. Howover, the problem ~coompanying this posltiv4 reoult i9 that DA-aqonlst~ h~ve ~ potonti~l ~or ~ .
mlsu~e ~19~21,25). ~his potential for mlsu~e ls A~80 ~ unde~tandable ~or ~he above mentloned DA-Ago~i6tc `:~ a~antad~nè, bromooript~lne and L-dopa, since these ~ub~tan~o are po~taynaptlc DA-aqoni~to whlch ~ring : abou~ a reward by ~helr ~A-liko e~ect. .:
~ as : ~
~he above mentioned clinlc~l triAl~ wore conduct~d on ~;: chronlc add~cts in wbom ther~ wa6 DA depletion and ~uporff3en~s~tiv1ty of postfff3ynAptic reaeptor3. If th~
8upor s~nff3itivity if~ refff3tricted to aome o~ th~
30 postsynatic ~eoeptors~ the D~-like activ~ty o~ th~
subfff~tAnce~s on tb~ nor~sl syot~m m~y c~w~e the potential ; for m~ff3u~ ~o oome into pl~y. Th1ff3 po~enti~l ~or misuse .. ; . -may a1BO ~riff~o if deff3ensltioatlon o~ the pofff3t~ynaptlo ~ ~
roceptors oacur~ ~ff~ome tlme a~te~ wlthdrAwal.
;, .~,., In vl~w o~ the findin~ff3 desoribed ~pot~ntial for mi~use) it. mus~. ~e conclud¢d that dopam~ne-~eaRptor agoni~ts are ~5~ ) 16:11 ~0~73 2~4~72 FB~EHN BRICHTON ~0 .~ ~
?~.25~03 not suitable for treatment for psychic dependency in continuing drug abuse and are of only very limited value ln the ~reatmen~ o~ druq craving durlng with~rawal.

It ha~ now be~n found th~t, by COhtraS~ with the dopamlno-r~oeptor agoni~ts, the DA-autoreceptor agonist~
with tho act$vlty pro~lle of BHT 920 ~or example, and (S)-~-a~lno-4,5,6,7-t~trahydro-6-n-p~opylamlno-b0nzo-thiazol~ (~ND 919) ~re very well ~uit~d to the treatment of drug abuse.

US pAtonts 4,426,3~6 ~nd 4,612,3~ d~cribe ~ubotitu~d phen~lplporidines or triayclic Amine~ a~ dopamine autoreceptor Agonist~. The p~tent ap~ciflc~tions aontaih a referenoe to the use o~ these compounds in druq abu~e. The dopamlne autoreceptor agoni~ts u~ed According to tbQ invention dif~er ~rom the dopamlne ~utorocoptor ~onl~t~ de~lt with ln the above m~ntioned US p~tent~ ln theix 5pecial ~ctlvlty pro~ile. Thls nativlty profile, wh~oh i9 doacrlbed in mor~ detail herelna~tor, shows that they ~re partioul~rly ~u~t~ble for trea~lng all aomponents o~ drug abu~e.
. ....................................... . .
D~-Autoreaept4r agonl~ts rcduoe the ~eleAse nnd 25 ~ynthe~l~ o~ dopamlno from the cells of the m~soli~bic and nigro-striatal sy~te~ ~2~ his ~eduction ;. ooun~racts the ~ncrea~e in the r~le~se o~ DA brought about by drugs ~e.~. cocAine). I~, during the treatment of druq dependency, the patient ta~es a DA aUtorQCeptor .aqonist o~ this klnd, preferably regul~rly, and should ~e r~lApse in~o drug ~buse, the expec~ed rew~rd wlll not oacUr, ~lnce thore wlll not be n ~u~fic~ent incre~b in the rélea~e o~ DA~ The need ror repe~ition or the reward wlll therefore not be rc-~wa~ened and the p~ychlc 3S d~p~ndency wlll ~e broken. Thus it 1~ m~de ea61~r ~o giv~ up the drug and in thl~ way the danger o~ rQlapse ~tQr drug wit11draw~1 can be reduoed. Therefor~, for the ()5~C~ 3 12 ~273 2~4~72 FB[)EHN BRl(iHTON ~101~
--- 2~2~ao3 first time, therQ $s an opportuhity to trea~ the psychic dependency in oase~ of drug a~use.

Extens1ve animal trial6 have now shown that th~se DA-autoreceptor agonlsts (e.g. BHT 920 ~nd SND ~1~) have no pot~nti~l tor abu~e. Thi~ $~ Or ma~or importana~ in ther~py.

A furth~r ~ctivity o~ the pre~erred DA-au~or~Ceptor agonists Qupporte the therapy d~scribed a~ove~ the oompounds, unlike the postsynaptic DA~Agoni~ts de6cribed ~- :
above, do not stimulate All the post synaptic DA- .: .:
recept~r~ in gen¢rAl ~nd thu~ do n~t stimulate tlle dopamlnergi~Ally innervated brAin oell~, but stimulate 1~ only tho DA-r~cQptor~ w~ich ~re ~per 6ensltiv~ ~ter :
chronla drug abu~e. Re~erenco i~ made to thi~ in ~30~ -~
in conne~tion with the treat~ent ot Parkinson~ disease.
; ~hlB ~timul~tion 1~ O~ i~port~noe with pat$ent6 with a long hlstory o~ drug abu~e, ~ince some of th~ DA~
receptor~ are hypor-~en~ltlv~ $n these ca~es owlng to ~`!i1 DA-deplet$on o~ ~he ~r~in cel~, and thls i8 looked upon as tho a~use ot the dry~q cravlng durlng w$thdrawal. .

A~ ha~ already b~en mentioned, these DA-autorecep~or ; 2~ agon~t~, act only on t~- receptors whlch h~ve beon m~de uper-~ensitlvo, ~e.g. by ohronic drug ~buse), And thus all-vi~te the drug crnving. How~ver, ~hey do not work : on th~ norm~l sy~te~, nor do they a~ect receptor~ whioh ~ ::
hà~e boen de-sensitised a~ter a oe~t~in period o~
, , 1 30 treAtm-nt. T~e DA-~UtoreCeptor agoni~t~ thus h~ve no :
potential ~or AbUSO. ::~

1` ,. :,. , .. :. -: Another advan~ge o~ u~ln~ ~ number of DA-recep~or gonist~ ~e.q. aHT 920), i~ the f~ct thnt, owing to ~i 3S their O~ntr~l ~lpha^~oni~tlc propertie~, they allevia~e ;:~
~:, thR physical withdraw~l symptoms.

~35/~3~3 ' ~;H:~ 16:12 ~0~!73 ~(~4~72 FBPEHN BRICHTON 1~

!2 ~2 ~ Q ~ ~

~he e~ects described abo~e may be demonstrated by the animal ~rial~; as follows.

Te~t 1 .
Tho experlm~nt was carried out on 3 monkeys who were experiQnoed wtt~ intxAVenoUs sel~-ad~inistra~ion of sodlum mettlohexital and ~aline solution. They were glven the opportunity ~o obtain infu~lons of t~e druq or 10 the snllne solution, and to r~spond ~o them in the cours~ of 2 sessions a day, each la6ting 130 minutes.
At the ~ta~t of eAch session, ~ red light mount~d above one o~ ~hQ 2 leve~ WAg ~witched on in each monkey CAge.
As soon a~ t~e light w~ ~w~tohed on, lo re~ponses to 15 tha rclevant lever r-9ulted in ~n intravenous ln~usion (1 ml) of the solu~lon of the drug or o~ the sal~ne oolution, lnsting ~or 5 s-conds. ~h infusion was followo~ by an interruption l~stlng lO seconds; during infu~ion and interruptlon ~he red lig~t went out.
During the ~nfu~ion a a-ntrnlly mounte~. green li~ht wa8 ~wltohed on. After eAch interruption the red li~ht was swltohed on ag~$n. There was a 200 infusion limit to tho ~esslon, but none o~ th~ monkeys administered the maximum number o$ lnfualon~.
~h~ monkey~ wer~ offered Aodiu~ m~thohoxttal (o.l mg/kg per l~ectionl and sallne solution for approxlmately hal~ tho duration Or the ba~ic se~Qions.
. ,~ .
BcforQ the ~ffect of the ~e~t substance was ~nvostigated, ~ach monkey ~how~d ~ alear and consist~ntly different; reactioh to the sodium methohexital llnd sslin~.

~5 The benzodiazeplno:q diazepam and midazol~m l~eh~ved in r~uc:h the sam~ ~13.y witl~ thls t~;2st c~rrelngement, whlch means th~t the teF. i~ able to det:o~m$ne addictive 2 0 2 ~

~.o ..
potential simllar to t~at of barbiturates and :
bQnzodiazepines. : .

Fou~ dosea of th~ test substanc~s BH~ ~20 were te3ted;
S o~ch do~e was te~ted twiae in each of the monkey~. The . numb-r o~ ln~ections o~ test subst~nce taken was no higher than the number of ln~ection~ oP ~aline solution ta~en ~nd su~stantlally lower ~han the number o~
methohexital in~ectionn. The e~fect Or t~e slze of the dose i~ min~m~l. Th~se result~ ohow ~hat the test sub~tanae doe3 not show any re~n~orcement at the doses :
4sed. ~ ;

l~h~ following averag~ v~lue~ ~ere obtalned f or the test.
lS :. ;,.
ln the oeoslon cArrled 04t lmmediat~ly be~oro the .
ses-ion wlth the ~est substance, ~or 3 animals there :; :
wer~ b-tween 120 nnd 140 ~el~-admlnlst~r~d ln~ections of 0.1 mg/kq por ln~eotioh o~ methyl ~exlt~l and 5 ao selr- ~ ~
~0 adminl~tered $n~eotiono o~ salln~ ~olu~on. In the ~ :
~e~lon~ ln whic~ the tost ~ubseanoe ~HT 920 W~8 used, the Sollowlng reault~wer- obtalned~

25 mg BHT ~20 Nuaber o~ ~elr ka e~r ~eqtlo~ ==~=c~
1,~ ~: `' "' ' 0,0001 21 :~
, 001 19 ,.. ' . ~.

"0,01 10 ' '-`:

It oAn be c~noluded from t~ia that BHT g20 does not ~ave any ~ddiotive potenti~l simllar to that o~ bArbiturat~
~nd ~nsodias~pines.

~e~

~35~ ) 16 14 ~0273 2~l4072 FBl)EHN BRI.HTON 1~ 3 ~2~
~ .

~h~ test substance ~llT 920 was ihve6~igated in a test arra~gement similar to that o$ Test 1, i.n which the . monkeys w~re giving intravenous l~fusions of cocaine.
In this test arrang~ment, 4 doses o~ ooca ine or test sub~tanoe were made available to the mon~eys in each ~e~ion la~tlng 130 mlnutes. Each dose wao available ~or 25 ~inuto~ or untll 20 in~usions had been taken.
The t~e scal- for admini~tering th~ drug~ was a fixed rang4 of 30 ~o 45 second~. Be~w~en the administration lo of the alngle dosAg~ there wa~ a brea~ of lO minutes.
In each o~ the 3 monkeya, cocaine ~intained a dosag~
dependent ~ncr-ase ln th~ frequency o~ the reactlonfi.
BHT ~20 resulted only ln a fr~quenay of r~sponse~ in the rangQ whlch WA~ A180 ob~ervod wlth ~h~ a 9allne ~olutlon. There was no do~age dep~nd~ncy of any klnd.

T~e doses o~ BH~ 920 were 0.001, 0.003 and O.ol mg/kg per in~ectlon.

~0 It osn be conaluded ~rom th~ th~t BH~ 920 doe~ not hnve ~n addiatlve po~ential slmilAr to oooslne.

Test 3 After Test 2 ha~ been cnr~lod o~t, lt was ob~erved ln ttle ~e~slon ~ollowlng the ndmlnistration o~ BHT 920 that ~ :
in a of the 3 exporlment~l ~nlmals the Srequency of reac~ion caused by cocaine, WAS SUbstaht~ y b~low the . ~ :
~req~enay of re~ction~ observed ln T~st 2 ~or cocaine.
In othor anal~gouo experlments (see tbe enclosed graphic `representation~ ~or monkey l, monkey 2 and monkey 3) the drug-depend~nt animal~ wero offered BHT 920 in 2 doses ~0.01 and 0.1 mg/~g per in~ection) at the same tlmç as they wer~ o~ored inarea~lng dose~ of cocaine (2 anlmAls~ or ~l~entanil ~l anlm~l). In all the ani~alF, ~he addltion~l adminlfitration o~ ~HT 920 at thR lower d~A~e, ~a~ul~ed in A fiiqlliflCant deorease in t:~le rate l:~5/0~ ' ~l) 1û 15 ~)273 2l34~72 FBDEHN BRICHTON Qll~14 ....
2 ~

o~ 8elf-adminigtration o~ th~ cocaine or alf~ntanil.
The high dosage caused the rat~ to ~all ~o zero in all oP the animal~. Even VQry h~gh deses of the addicti.ve drug w~r~ unable to oancol out thi~ e~fQCt Or BHT 920. ~ :
on the ba~l8 o~ behavlour~l observations during the ~ests descrlbed ~bove, it ¢an be statod t~at th~
lnhlbltory ~eat of BHT 920 c~nno~ b- explained by g~nor~l ~od~tion. ~t cAn ther~ore b~ concluded that the adm~nlotration o~ B~T 920 r~duoe~ ~h~ craving ~or cocaine And hre~ks tho p~ychi~ dependency on the drug.

The Ad~nt~g~s of t~e use of BHT 920 according to tho lnventlon can bo ~um~Arisod as ~ollows~

lS ~lnc- ~H~ ~20 does not of its~lf lnduc~ ~ny addlctlon, .
thi~ composition c~n b- adminlst-red ~or lengthy p~riods (month~ or ye~rs) wlthout the d~ng~r of the fir~t ~--addlction belng replaced by a new (al~lt les~ harm~ul addlctlon). During wi~hdrnw~l (wh~n t~e drug 18 wlthdrawn ~t~p ~y otcp or totally) the p~tlent suffers ~rom th~ cono~qUences o~ the dopamine de~ici~ncy :~ :
ooourring ln the brAln ~e.g. dopresslon~ ~nd rrom ~ phy~io~l wlthdr~w~l oymptoas BUCh n~ disorders o~ ~ho ,~ cArd~o-aircul~tory ~yatom, di~ordor~ o~ glAnd function, ~: 25 tr~mor, etc. The rogular ad~ini~r~tion o~ BHT Y20 al1evi~tee or doe~ aw~y w~h t~ physloal withdrnwal symptome by it# ~2-ngonistie ~ect. In the situation of dop~mine d~ialency in quest~on, BHT 920 al80 c~uses a r~e in the dopamln~ supply $n the bra~n to ~ lovel ~0 whlch ~orre~ponds to t~at o~ a ~eal~hy sy~tem, by lt~
'po~tsynaptlc dopamine P2-agonintic activity. ~hi~
removes a cause ~ the patient~s depr~oe6~0n wlthout tr~ggering any sens~tlon~ o~ ~uphori~ ~r~w~rd).
untxQAted pa~lont~ wlll oxperience h reward by t~klny the dru~, thereb~ lntensi~y$ng the p~y~hic dependency o~
t~e drug. ~n pat~n~ who wi~h to with~t~w bu~ ~re stl11 taklng drugs or have r~t~rned to t~kinc3 druqs, the ; " :~
,. ' ' :". '', ~ 9~ 15 ~l273 ~9~72 F~EHN BRICHTON ~15 ,~ .
~ 2~2~3 ~3 regular taklng of ~HT 920 l~ads to a reduction in psychic depQndency. Thi~3 oan be pu~ down to the ~act that the dopamine-autoreceptor-agonist~c activity o~ B~T
920 prev~nts the r¢lea~e o~ additional dopamin~. As a rosult, the pAtient will not experiQnce any r~ward when tak~n~ B~ 9~0 regularly, in ~pite Or the ad~lni~ration o~ dru~. The psyahic d~pendency o~ th~ pati~nt on the drug 18 thu~ brok~n.

This summary mAkes it clear ~b~t the u~e of ~NT g20 according to the inv~ntion has ~ubs~antisl advantag~
o~er conventional methods o~ treatment ln drug withdrawal.

8ND 919 l~ an aatlve ~ub~tonce which 18 ana~agou~ to BHT
~20 ln lt~ aativlty pro~ilo. It i8 ~nown that ~NP 919 i~ o dopamine-autor~ceptor-agonl~t with a po~tsynaptic Dz-agoni~tlc ~ect und~r tho cond~tlons of dopa~ln~
d-pletl~n And additionol~y ha~ ~ cen~ral a2-agoni~tic ~0 actlvlty. SND 919 can bo used according to the inVent~on in the some way as BHT 920 ln drug withdrawal.
Tha same applies to dopnmine-autoreceptor-ago~ t~ wlth an anAlogous activity profile.

:~ ... . .
~ :
. .. .

~5 ~6,~3~ ' 90 16 1~ ~273 2~4~72 FBDEHN BRI~;HTON E~16 2~ 3 LitorAtu~ç~

1) AhtQ~ L; Att~ la P~ L~uhAkang~g V; solkinen A;
Sipila~ J, J N~ur~l Tran~m, 68, 63-78 (1987 2) C)aakls CA Gold MS; Davies RK; Sw~n~ay DR, Int J
Psyohiatry Med, 15 12S-35, (1985-86) 7) Dackis CA: Gold MS; ~weeney DR) Byron ~P Jr; C:lim~o R~ Psyabiatry Et~i, 20~ 261-4, (1987) 8) ~xtein IL; Gro6s DA; Gold MS, ~m ~ Psychiatry, 146, 403, ~ 198~) 15 9) G~wln FH: Morgan ~: Ko~ten TR~ K~eber HD, Psyc~hoph~ colo~y, 97, 402-3, ~1~8~) 10) GlAnnini A~ aillQt'C W, J Clin Phannaco~, 27, 549-54, (1987) ; ~ ~ .
11) Handelsman L: Chord~a PL; Escov~r I~ M~rion I~;
Lowlnson JH, A~n J Psychlatry~ 145~ S33, (19Ha) ; ~ ,.. .
13) Kilanmsa K ~abA~off a, Phnrm~col ~ochem ~ehav, la, 383-8, ~ 3) .:
:~ 14) KoltA MG; 8hreve P; De 80uza Vt Uretoky NJ, .~
`~ Neuropharmacology, 24, 823-9, ~1985) ~ . -,~ 30 lS) Xo-qten TR; Schumann B: Wright D, ~n J P~ychlatry, .;' - ~;
145, 3Bl-2, (1983) 16) Xove~o~ GI,; Horv~th Z; 8nrny~i Z~ FAludi M; Telegdy .;
G~ NeurophArmA~o~ogy~ 24, 413-9, (1~85) . ' .
',;
17) Xovacs G~ Telegdy G; H~di X, Ph~rmAaol ~looh~3m ,:
aehav~ 21, ~45-8 (~.~8q) ''" '' ' ' "

6~ )9 ' ~10 1~ 17 ~273 ~f34~72 F~PEHN BRICHTON ~ 17 2~2~3 1~) Nausieda PA, Clin Neurophama~ol, 8, 31~-27, (1~85) 20) Pike RF, Pootgrad Med, 85, 115-6, (1989) 21) Priebe S
Pharmacop~yohiatry, 17, 109-10, (1~4) 23) Rosen ~; Flemen~aU At ~later VL, Am J psychiatry, 143, 14~3, (lsa6) 24) son~hlla PK: Glbb 3W; HAn~on GR, J Pharmacol and EXp ~her, 2~8, 932-37, (1986) 2S) Ta~k Et De Cuyper~ Gt JAnne~ Ct ~mouahamp8 A, ACtA
PsychiAtr 8cnnd, 78, 35~-60, (19B8) a7) ~ennant FS Jrt Sagh~ri~n AA, Ar~h Int Med, 147, 109-12, (1987) 28) Wa~quler A.
In; ~A~n-stimulation R~Ard (A. W~uqu~r, E.T.
Rolls, eds.) North-Hollnnd Publ. CompAny~
as Amaterd~m 1976 a~) Anden N.E. et al., NAunyn-Schm$Qdeb. Arch. Ph~rmacol., 321, 10~, ~ lsaa 30) Hlnzen et al., Eur. J. Pharmaaol., 131, 75-~6, (1986) ~ ho DA-autoreceptor agoni~t cAn be adminstered in the prepara~ion~ known ~ for these compound~. The sub~t~nces ~re pre~erably Admini.st~red at regular interval~, and in oertain CASO~ over long periods o~

~5~ ) 16 17 ~0273 ~134072 FBDEHN BRI~;HTON 1 , 2 0 ~ 3 ~ime.

5 ~xAmpl~.I

Core ~or a coAted tabl~t.

com~ltion:
l tabl~t oore contains:
B~ 920 50 ~g L~¢tose 38.45 mq Corn starch lo.0 mg :
15 Golatine l.0 ~g NAgnesium Bte4rAte - Q~ 5 S0.0 mg ; , Met~a ~ P~t .~
Tho mixture o~ the active subst~nce wlth lactose and m.
corn 6tarch 18 granul~ted with ~ lO~ ~queous gelntine :
~olutlon through a lm~ scr~en~ dried at 40 C and rubbed ,;
through the oame sc~on n~4~n. The grAnules ~hus :~
as obt~ine~ ar~ ~ixed w~th magn-~ium stearate and compr~8~ed into tAble~ core8- ~his proaedure mu~t bo -; :
carr~ed out in a d~kon~d room. ::
~" ' "~:' We~ght o~ ~ore: 50 ~
.Punoh: 5 ~m, aonvex :,, ' " .~
The tablet cores th~ obtalned~ are coated by known me~hod~ With n ~oating consl~tln~ e~sentially of ~ugar and talc. Tho ~lnlshed co~tod table~ ~re poli~hed with :
beesw~x. We~ht of co~ted tablet lO0 mg.

- 06r~;1 "30 1~ 273 2~41~72 FBDEHN BRI~HTON i~Ol~J
?~ 2 ~ ~ ~ 3 : ~
, Exampl~

Supposltorie~
1 ~Upp~itory oonta i ns:
S ~HT ~20 100 ~g Supposltory m~ss ~e.g. witepsol W 45) 1690~0 mg ~Q~hu~ reD~t~n Th~ ~inally powder~d ~ub~tance is stirred, usinq an immorslon homog~nlser, into the molten suppository mas~
which ha~ been cooled to 40~C. At 35'C the mass ls pourod into slight~y ohilled moulds.
X~L~ ' Ampoulo~ cont~ining 200 ~g o~ ~-H~ 920 1 ampoule oontAlr~
20 E~-H~ 920 200 l~g Cl~rlc a¢id ~ . o mg 8Odium pho~pha~ s-c. 2 H20 3 . 0 mg ~odlum pyrosulphl~e 1. 0 ~ng Di~tllloCI water up to 1. 0 ~nl ~ho bu~er ~ub~tnnce~ ~ct~e subfitance and sodium pyrosulphite, are di~solved euccessively in boiled water whl~h hn~ been cooled under C02 ga~. The required volume i~ ~de up wlth boil~d w~tor ~nd ~ilt~red to removo pyrogon~.
Bottl in~ s ln brown smpoules under ~ protect lv~ g~s Sterlls~tion: 20 minu~es a~ 120-C, 35 T~le ampoule solutlon must be p~pAred snd bottled in a darkened room.

V6,~U9 ' 9~ 113 19 ~273 ~J4072FBDEHN BRICHTON I~ 213 .
2~2~;Q~3 18 ; ;~
Rx,ampl~

Coated tablets cont~ining 1 m~ of B~T 920 1 tablet cor4 containa B~HT gao ~actoso 100 ~ig Corn iatarc~h 36 . O mg a~latine 12.4 mg Magnesium stoarate.5 _ma 50. o mg :, Met4~ Of ~E~ar~lon Analogouo to l~xample 1 . .
Welgh~ o~ core 50 mg .
15 Punch 5 mm, convex Weight of coat~d tabl~t 100 mg ao CoAted ~Ablet~ aont~inlng 0.2 mg o~ 8~T 920 . :
1 tablet core contains;
B-HT 9~0 0.~ mg .:~ :
Digoxin 0.25 mg Lacto~e 66.55 m~
Potato 8t~rch 25.00 mg PolyVinylpyrrolidone 2.0 ~g Ma~n~ tearate __1~ Q_ ~ :
120.0 mq ., -: ~ .
~ ~=e=~ . :
' ~:
~he lntonslve mixture of the aotive substances w~th lA¢tose and potato ot~rch 1~ gr~nulatod with a 10%
olutlon o~ th~ polyvinylpyrrolidone ln ethanol, by ~5 rubbing through a ~icreen, 1.5mm, drying at 40 C and rub~i~g througll a l.Omm screen. ~he grallules thus obtalnQd a~e mixed vith magne~:ium s~arate and - 85f88 ' 1t) 18 18 ~0273 2~48~2 FBDEHN BRltAHTON 1~lo~l ~ 2 ~

~1 1!3 . , c4mpresE~ed inta tablet c~ores.
Weight of Core 120 mg Punc:h 7 mm, convQx S Th~ tab1et coreo thu~ produced ~re co~ed in a known manne~ wlth ~ co~ting aon~i~ting o~ augar and talo. The ~ini~od co~ted tablet~ are polish~d w~th beeswax.
Wolght o~ coa~ed table~ 200 mg.

Ex~mple VI

Oblong gel~tine aap~ule~ containin~ 300 ~g Of B-HT~20.
1 aap~ule conta~n~: :
B-HT 920 0. 3 mg 15 Codsino Phoeptlnt~ lo.o m~
T~rt~rio ~cld 3.0 mg Corn Rtarch _n.~-7 mg 100.0 mg .

M~th~ Qf pr~arAtion : Th~ ~ubst~nosa are ln~ensivoly mixed And pack~d into opaqus cap~u1~ of ~uitable ol~ ap~ule content~: 100 ~ . .
: mg.
2S ~he px~pArAtions ~or ths trAn~d~rmal adminlatrAtion of th~ tancss can bo found, ~or ex~mple, in EP A-227~ .
988.

.:

q.5 ~.?-tstr~hYdro-b~nzthiazole-dih,Ydrochloride 1 tablQt ~or~ contains:
35 ~ctlve ~ub~tan~e 5.0 mg LActose 33.5 ~g ~orn Qtarch 10.0 m~

",'':' ' " '' ~5 ~ 3 ~273 2~41372 FBD~HN BR I CHTON ~ ~3~2 ,., ~
~ ~ 2 ~ ~ ~ .3 2 0 ~ r Gelatlne 1. 0 m~
Magnesium steArate _Ø 5 n!g 50.0 mg . ~.
M~tl~Q~ and Dr~aration . . . ..
The mixture of 'che llctive au~stance wlth lactoae and . ~
corn ~t8~ch 1~ granulAted with a 10% aqueous gel~tine ~ .:
solutlon through a screen with a lmm mesh, dried at 40'C .-:
10 and rubb~d throu~h the fiam~ ~3cr~en again. The granules . ..
thus obtained ar~ mixed with ma~n~:;ium stearat~ and compre~sod w~ ~h into tablot co~es. ~he opera~ion ~u~t be carrl-d out ln A darkened room.

15 Weiqht P~ cor~ 50 mg.

Punch 5 mm, conv~3x . ~ :

Tt~e tAblet c~re thus obtain~d ~re coat~d in ~ known 20 m~nner with a coatlng consl5ting of ea~,entially ~ugar and talc. Th~ ~lnished coAted taS~l~ts ~re polish~d wlth BW~X

W~lght c~ coat~d t~ble'c: 10~ mq Su~20ai~1 ori~s S~ontaininq 10 m Q~! 2-A~n1no-6-n-3~ dillydro~ de , l auppo~itory contA~nl~;
Aative aubs~Anoe 10.0 mg Suppo~ito~y mABB ~o-g. Witeptol ~5 W45) 1,6~0tO m~ ;
1,700.0 ~g . .

-~ ~6;~ lB ~ 273 204~72 FBDEIIN BRICHTON ~0~3 ~ ,, ` 202~3 Metho~_~f REe~a~a~ion The ~inely pow~er~d s~stance is ~tirred using an lmmQrslon homogenlser into the mol~en ~uppository masa cool~d to 40~. A~ 35~c thQ m~s l~ poured into 81lghtly chllled mould~.

Welqht o~ ~uppository; 1.7 g 10 Ex~m~ ' ' 4~5~6~7-tre3i~hvdrobenzthia~olQ-glhydrochloride lS 1 nmpoule contnin~:
Aatlve ~ub~tance 5.0 mg Cltria ~cld 7,0 ~g Sodlum pho~ph~te ~ec. x 2 H20 3.0 mg ~odlum pyrosulphlt- l.O mq : 20 Dlstllled waterup to ~.0 ml ~ethod ~lp~aratlon ~' ,;. ~;
bu~fe~ sub~tAnoes, ~c~iv~ ~ubstance and sodiu~
2S pyroaulphlte, ~re dl~-olved ~ucc-~slvely in bolled water . :~
wh~ch h~a be~n ~ooled und~r CO2 g~. Th~ req~ir~d .~
~: ~olume 18 made up wlth boil~d water and filtQred to ~ ::
~;: remov~ pyroqen~.
Bottllng: ~n brown ampoules und~r a prote~tiv~ ga~ ;; -.
30 ~terli~tion: 20 mlnutes at 120-C. :;. .
The ~mpoulo solution ~ust be pr~par~d and bottl~d in a ~.
d~rk~ned room.
..
.'' "': '.~'' ~.-:.,::
:.

'",'; :'.~.,, ~367~ 21 ~273 204072 FBPEHN BRICHTON bll~)~4 ~ 2~2~3 : ~
.. . .. .

E~u~ e x ,:. :. '' Coa~e~ ~abl~ts ~ont~n~ha l ~g 0~ mino-6-~-~ r~ovl~mino-4 .5.~.7-~trahydro~@~Sh~azole s ~b~:

1 coatod tabl~d contalns:
Aotive ~ubot~nce 1.0 mg Laatose 35.5 mg 10 Corn ~t~rch 12.0 mg Gelatino 1.0 mg Magneslu~ ~tearate 0.5 mg 50.0 mg ~:

Mothod o~ ~r~pAr~tion An~lqo~ to Exa~ple I

Wei~ht of cores 50 mg ~ .
a o Punahs S mm, convex .
Welght o~ c04~d tablot loO mg as :

. . ~

.: . .

Claims (10)

1. The use of a dopamine-autoreceptor agonist for the treatment of drug dependency.

2. Use according to claim 1, characterised in that the treatment takes place during withdrawal and over a period extending beyond that and serves to break the psychic dependency of the patient on the drug.

3. Use according to claim 1 or 2, characterised in that the agonist has, in addition to its dopamine-autoreceptor-agonist activity, a postsynaptic dopamine D2-agonist activity under the conditions of dopamine depletion.

4. Use according to claim 3, characterised in that the agonist additionally has a central .alpha.2-agonist activity.

5. Use according to any one of claims 1 to 4, characterised in that the dopamine-autoreceptor agonist is 6-allyl-2-amino-5,6,7,8-thtrahydro-4H-thiazolo[4,5-d]-azepine or a pharmaceutically acceptable acid-addition salt thereof.

6. Use according to any one of claims 1 to 4, characterised in that the dopamine-autoreceptor agonist is (S)-2-amino-4,5,6,7-tetrahydro-6-n-propylamino-benzothiazole or a pharmaceutically acceptable acid-addition salt thereof.

7. A commercial package containing a 3 an active pharma-ceutical ingredient a dopamine-autoreceptor agonists together with instructions for use thereof to treat drug dependency.

8. A commercial package according to claim 7 wherein said pharmaceutical ingredient is in unit dose form.

9. A commercial package according to claim 8 wherein said unit dose comprises between 2.5 and 350 micrograms of said pharmaceutical ingredient.

10. A commercial package according to claim 8 wherein said unit dose comprises between 100 and 250 micrograms of said pharma-ceutical ingredient.