CA2030340A1 - Agroclavine and elymoclavine derivatives, process for their production and their use in pharmaceutical agents - Google Patents

Abstract

Abstract of the Disclosure Disclosed are ergoline derivatives of formula I and their acid addition salts I

in which R2 is halogen, C1-4-alkyl, C2-4-alkenyl, R6 is C2-6-alkyl, C3-6-alkenyl or C3-5-cycloalkyl-C1-2-alkyl and X is hydrogen, hydroxy or C1-6 acyloxy are described as well as their production and the pharmaceutical agents containing these compounds. The compounds exhibit a dopaminergic agonistic effect, and are useful in the treatment of Parkinson's disease.

Description

~3~
~, NEW AGROC~VINE AND ~ YMOCLZ~VINE DERIVATIYES, PROCE~;S FOR
THE~R pRoDuc~rIoN AN[) THEIR USE :~N PHARMACEU~rICAI. AGENT~

summarY o~ tha In~Qn~
The lnvention relate~ to new agro~lavin~ and elymoclavine derivatives, ~h~ir prod~ction and use in pharma~eu~ical agents as well a~ intermediate ~ompounds fox the production o~ the pharmaceutlcal agents, and thR process for the production of the in~ermediate compounds.
A~roclavine and qlymoalavine are hi~hly e~fective ~at~ral lo ergot alkaloids, which ar~ found on gr~es, whiah are infected by Claviceps purpurea. They show the en~ire ~pectrum of the effect~ known of ergot alkaloids.
~ y introduction of long~r-chain hydr~arbon~ in ~-position and by substltu~ion in ~-position, the influence of lS variou~ raceptor~ i~ c~hanged, and the ~etabolic stability is increased. The ergoline derivatives substituted accor~ng to the invention there~ore exhi~it an intensified dopaminergic effectivene~s and greater sele~tivity in comparison with the 6-me~hyl-sub~tituteda~rocl~vine and elymoclavine derivative~.
At the ~ame time, the metabolic catabolism is slow~d down.
The in~entlon relates to ~ompounds o~ formula 1 and their acid add~ t~ on salt~ R6 H~ ?2 ~3~3~

in which R2 i~ halogen, ~l.4-alkyl, C24-alkenyl, R6 is ~2.6-alkyl, ~3$~alkenyl or C35-cycloalkyl-C12-alkyl and X is hydrogen, hydroxy ~r Cl6 aayloxy.
The physiologically compatibl~ acld addit~on ~alts are derived from the known inorganic and organic aoids sush ~s, for example, hy~rochloriç acid, sul~uric acid, hydrobromic acid, citric acid, maleic acid, fumari~ a~id, tartaria acid, lo i.a.
By al~yl is meant in each case ~ ~traight-ahain or branched alkyl radical, such as, E~r example, methyl, ethyl, n-propyl, i~opropyl, n-butyl, i~obutyl, ~c ~utyl, ter~
~utyl, pentyl, hexyl, 2,2-dim~thylpropyl, ~-methylbutyl~
isopentyl, i.a.
If R2 or ~6 mean~ an alkenyl radi¢al, ~he l~tter preferably c~ntains only one double bond, and the double ~ond in ~6 cannot be adiacent to a nitrogen atom. For example, vinyl, 1-propenyl,2-propenyl, 1-methyl-2-prop~nyl, l-butenyl, metallyl are suita~le a~ alkenyl r~dia~ls~
If R~ means a oycloalkyl-alkyl group, for ex~mple, cyclop~opylmethyl t ay~lopropylethyl or cyclobutylmethyl is meant.
The acyl ~roups in substitu~n~ X are derived ~rom 2~ alipha~ic carboxyli~ acids such a~ formic a~id, a¢etic a~id, propionic acid, butyrio aoid, ~aproic ~ai~, trimethylaceti~
acid, and pre~erably acetic acid is ~sed. Pre~erred embodlment~ ~or R6 are alkyls and alkenyls with up to 4 car~on atoms and cycloalkyl-alkyls with up to 5 carbon atoms.
The compounds of ~ormula 1 can occur a~ E or Z isomers or, if a chiral c~nt~r i~ presen~ in radi~l RZl as diastereomers and as their mixture This invention also comprises the isomers and i~omer mixtur~s.

2~3~3~

The compound~ ~f for~nula I as well a~ thei~ ~aid ad~ition salts bec~use of their centrally dQpaminergi~ ctivene6~
are usable as pha~maceu~iaal agen~ inae th~y are distinguishsd espe~ially by dopaminergic agoni~t~ effects, without ~trong alpha-adrenergic e~E~t~ o~curring, the compounds accordin~ to the invention are eYpecially suitable ~or the treatment of Par~infion'~ di~ease.
The dopaminerg~ agonistic ac~ion was determined wi~h ~he method o~ the automatic re~ording o~ Ytereo~ype~ on rat6 lo described by ~orowski tArzneim. Forsch. 1~, 2281-a286, 197~):
immediately after intraperit~neal administration o~ the test ~ub~tance or vehicle, male WiRtar rats (90-120 g) are pl~ed in~ividually in ~triated cagss of a~rylia glas~. ~h~ num~er of con~acts on a steel bowl With a cen~ral me~al ~o~ as a re~ult of ~tereotypiaal ahewing, licklng ~nd gnawing movement~
during 60 minutes is recorded ~y an electrodynAmic recordin~
sy~tem applied in ~ront of the head o~ the anlmals. Mean value~ ~ 5~M of the number of con~a~t~ ~urin~ ~0 minute for the variou~ treat~ent groups, which consis~ of 1~ animal~
each, are aalculated, and the ~ignificanc~ of the differen~s between the mea~ ~alue~ of the various ~esk ~u~tan~e ~o~e~
ln ~omparison with the vqhi~le-treated control group is ~etermined wi~h the ~mple variance analysis in ~on~e~ion wi~h ~he Dunne~t te~t.
The xesulks are ~hown in the f~lowin~ table.

3 ~ 3 ~ ~
,~

~n ~L
o h 1~1 O ~ ~
x N

l ~ ~ ~ ~ I
o~_ :~: o ~W
O~ o ~ ~ ~ a~ __ n ~ ~ o h ~I X O . 1:~ ~t X C.~ ~ N ~_ .~ o . J~ Cb ~ I ~ I
h ~: o ~1 . ~ ~ o N M
. ~a a) i-~,1 3 ~ ~ ~ i ~ .~ __ ~ X
H U) ~J ~ IJ O ~ ~11 ~ a~
aJ ~; ~ h O ~) tO ,_ O ~ O
.
o ~ ~n . . ~ I ~ I
a) a~ ~ aJ q~ ~ _ O
E; ~ o r h O _~ x .- ~ J~ ~ X
~n , u~ ~ ~
. ~ 1 ~ I
h O ~ U ul o ~n ~
h o ~ 3 ~r ~ ~ __ .
h ~0 ~
~: +l ~ I
U ~ o~
ce~ .

~ ~ - e ~ ~
~:~ D i~
~:
~:P' ~3~3~0 ~ o u~e the compounds aocording to the invention a~
pharmac~utlaal ay~nts, th~y are ~ut in the fo~m of a pharmaceu~ical prepa~a~ion, Which~ in addition to the ~c~ive ingredlent ~ox ~e en~eral or parenteral admini~ration, contains ~litab~e pharmaceutical, organic or inorgani~ inert vehicles such as, ~or ~x~mpl~, water, gelatin, gum ~rabic, lacto~e, sta~ch, magne6ium steraate, tala, ~egetablQ oils, polyalkylene glycols, etc. The pha~ma~eutical pr~paration~
can ~ in ~olid form, ~or example a~ tahlets, coated ta~let6, suppo~ito~ies, ~apsule~, or in liquid forml for exampl~ a~
solution~, suspen~ion~ or emulclon~. Further, they optionally contain auxiliary agents ~U~h as preservatives, ~abilizers, wetting ayents or emulsifierst ~alt~ to ahang~ the osmotic pressure or buffe~s.
The compound~ a~¢o~ding to th~ invention are introduced in a dosage o~ 0.001 to 10 mg of a~tive sub~tance in a physiological~y compatible vehicle. The use of the compound~
~aaording to the invention takes place ln a do~age of 0.00001 to 0.1 mg~kgJday, preferably 0.001 to 0.1 mg~kg/day analogou~ly to the known agen~ bromocryptine.
The p~odu~tion of the compoun~ of formula I according to the invention can be performed a~cording ~ method~ ~nown in the art.
For example, compound~ of formula I are a~tained by Z5 a) ~ompounds of the gene~al formula II

2~3~

cu2 x ~N- 1 H~N R2 in which R2 and X h~ve the 2~}:)0V2 meaning, b~ing alkylated or alkenyla~ed ~o compounds with R~ with the above meanlng or b) ¢ompound~ of formul~ III
CH~-X

~N _ R t ll-N
in whiah ~ and ~ ha~ ~h~ abovR-named meaning, beln~
halogenated to compounds of formula ~ with ~2 meaning halogen or a) ~ompounds of formula IV

, .

2~)3~3~

'..1 l-Rf ~ ;~/" lV

~-N Ho in which R6 ~nd x hav~ ~he above-named m~anin~, alpha) being reaa~ed in a Wittig rea~tion to aompounds with RZ meanin~ a C24 alkenyl radical or beta) bein~ converted to a l-hydroxy C1.4-alkyl radi~al and ~he latter then optionally being dehy~rated to compounds wi~h R2 ~eanin~ a C2.~ alkenyl radical and then optionally the compounds obtained ac~ording to ~lpha) or bet~), optionall~ after esterifi¢~tion of the 2-CH2~H radical, being lo reduced to compounds with R2 mea~ing a Cl4 alkyl radical ~nd then op~ionally the ~yl group in ~-p~sition bein~ clea~ed, the isomers ~eing separate~, and the acid a~di~ion salt~ being formed.
The subs~i~ution in 6-pOBi~ion according to process ~) Gan, fo~ example, ~e performed accordin~ to A. ~ern~ et al.
~oll. C2ech, ~hem. Comm. 49, 2828 (1984) or ac~Qrding to the process de3cribed in EP-212Q6, by the ~H compound of formula II being reac~ed with the corresponding R6 halides (~romides, chlorides, ~odide~). Th~ rea~tion ~ui~ably take~ pla~e in an inert solvent such as dlmethyl sulfoxid~, dimethylformamider acetonitrile or nitromethane in the pre~en&e of ba~e~ ~ch a~
alkali hydroxides or alkali car~onates~
The h~logenation o~ the compoun~s of ~ormul~ III
according to pro~ess vari~n~ b) takes plac~ according ~o the ~5 processes ~es~ribed in EP-56358 or ~P-141387 by direct halogenation of the 2H compound with ~u~t~ble halogenatio~
agents or bromine in the presenae ~ hydrobromic a~id.

203~3~

The in~r~duction o~ ~ubstituent R2 aan take place he~ore vr after ~ub~titution in 6-pv~ition, The conver6ion o~ the 2-formyl ~ompound of ~ormula IV t~
compounds of formul~ I, in whioh R2 means an alkenyl radia~l, takes pla~e according to method c alpha) in a Wi~tig reaction, by, for example, being reac~ed with alkyl ~riphenylphosphonium halide in polar ~olv~n~s such as cyclic and acycli~ e~he~, chlorinated hydrocarbons, dimethylformamide or dimethyl sulfoxide at temperature~ of -50C t~ +50~, and atrong base6 such as alkali alaoholates, lithium organyl, i.a. ~xe added ~o produc2 the ylene.
Compounds of formula I with R2 meaning an alkenyl radic~l can also ~e produced ~ccordin~ to proces~ cbeta), by ~h~
compound~ o~ ~ormula IV being converted by ¢~ignardization or lithium alkylation ~ the l-hydroxy alkylat~d ~eriVa~ves and then being dehydrated. The ~ri~naxd~z~ion can tak~ pl~e with the usual Griynaxd reagent~ such as ~l~yl~agnesium halidas $n an aprotic olvent suah as cyclic and acyali~
eth~rs at low temperature~ (-70C ~o 20C~. The reaatlon with alkyl li~hlum taXes pla~e under analog~us cond~tions. ~he subsequent introduotion of the dou~le ~ond can be per~ormed with the usual deh~dration methods ~uch a~, for example, wi~h sulfonate~ or aceta~e~ ~ch as mathane sul~oni~ acid chloride in polar ~olvents suah a~ ethers in the pr~sence of a base and 25 op~i~n~lly wi~h heating.
If su~stituent R2 cont~in3 an exocyclic double ~ond, the latt~r aan be rsduced to the aorre~pondlng al~yl derivati~e.
For example, the xeduction can b parformed With lithlum or sodium in liquid ammonia in an iner~ ~olvent Ru~h as ayalic and aayclia ethers in the pre~ence of a proton donor ~uch as aliphatia alcuhols.
Also, the 1-hydr~xy ~lkylated derivat~ves obtained acaording ~o process cbeta) can b~ redu~ed to ~he 203~3~

Gorre3pon~ing 2-alkyl d~r~v~tiv~ i~ th~ u~ual way, for example, by reaction with Na~ in acetic acid.
To introduce ~h~ H3 group, it i8 advantageous be~ore the reduction of the ~-~H2-OH radi~al to e~terl~y the l~tter with acid~ ~uch a~ pivalia ~old, acetia ~cid, benz~ic acid and then to reduce i~ ac~ording to the ~nown proces~s as de~cribed in Ge~man patent application P 39~3211.5.
The seleckive cle~vage o~ l-he acyl group in ~-po~ition take6 place according to the known proca~ses ~or e~ter clea~a~e such as, ~or examplR, with alkali alco~olates.
For the ~ormation of alts, a ~ampound o~ ~ormula I i~
dissolved, for example, in a little methanol or methylen~
chloride and mixed w~th a concentrated solution o~ the de~irQa acid.
The isomer mix~ures aan ~R ~epara~ed by the usual method~, such as, for example, crystallization, chromatography or calt foxmation in ~he diastereomers or E~z isomers.
The invention also ~omprises the compounds o~ ~ormula IV', whi~h repre~ent valuable intermediate products ~or the production o~ ph~rmacologically ef~cti~e compo~nd~. The conver~ion o~ the in~ermediat~ p~oducts ~o the ~ctive ~ubstance~ takes pla~e a~ording to the method~ de~cribed at the ~eginning to in~roduce ~he de~ired ~ub~tituents in 8-, 6-or ~-position.
If the p~oduction of the ini~ial compounds i~ not de~cri~ed, they are Xnown or ~an be produced analoqou ly to known compounds or prooe~e.~ des~ribed here.
F~r example, the produ~tio~ of the 2-formyl derivative of formula IV' accordlng to claim ~ can ~ak~ place by oxidation o~ ~h~ Mannich base or of the 2-hydroxymethyl compound analogously ~o the ~ethods ~escribed in EP-A-8~/730164. ~he in~rod~ctio~ o~ the ~-hydroxym~t~yl group i~ po~sible, for ~xample, with pa~a~ormal~ehydefdime~yl 2~3~34~

aluminum chloride aB deAaribed :Ln German patent ~pplication P 39~!3~!11. 5, ~ lthout further elaboratlon, it i~ beliaved that one skilled ~n the ar can, u~ing thR preceding de~cription, utill~e the pre~ent invention t~ ullest extent. The following preferrad specific e~odiments a~e, ~herefore, ~o be construad as merely illu~trative, and not limitative of the remainder o~ the di~lo~ure in any way what~oever.
In the foregoing and in l;he following ~amples, all o temperature~ are set for~h uncorreoted in degre~s ~elsius and unles~ otherwi~e indic~ed, all paxt6 a~d percentages ar~ by weight~
The anti~e di closure~ o~ all application~, pa~ent~ an~
publications, if any, cited above and below, and of cor-responding application Federal Republia o~ GermanyP 39 38 701.1, filed No~ember ~0, 19~9, are hereby incorporat~d by r~erence.

203~3~

Initial ~o~pound-~
1. 8,~-Didehydro-8~ hyl-ergol;ne-6-car~onitrile 56 g (0.23 mol) of agr~cl~vine was d~olved in 1.4 1 of diox~ne o~ reagent purity and 3~.8 g (0.23 mol) o~ potas~ium carbonate waB added. 50 g (0.47 mol) o~ cyanogen bromid~ ~a bottle, ~erck) was dis~olved in 300 ml o~ dioxane and added all a~ once. It was reflushed with 100 ~1 of dioxane ~nd allowed ~ s~ir ~or 2 houxs at room ~empe-~ture. Then, most of the ~olvent was d.i~tilled off in a v~cuum ~80C bat~
'cemp~rat~re), and th~ re~eiver for destroying the excess cyanogen bromid~ was fed wi~h KOH. The remainder of th~
d$oxane was removed on the rotary evaporator; the residue wa~
extra~-ted with diohloromethane and concentrated by evaporation. A total o~ 47.7 g t~%) of pur~ product was obtAined in three ~raction~ by cry~tallization ~rom methahol~
The remaining ~.0 g of mother liquor was ohromatographed (1 kg of ~ilica gel, diisopropyl etherJhexan~ 2:1, 3~ 1, and diisopropyl ether). An additional 3.~ g (6%) was ob~ained, zo yield: 87~ crystalline, C~]D = +53.5 (C = 1.0 in chloro~or~), melting point 180-190~ ~d~ompo.-ition).
2. 8,~Didehydro-~-hydroxymethyl-~-ergOlinQ car~onitrile The preparation ~ook pla~e as in th~ example a~ove, yield g%~ ~C~D - ~30 (0-5% ln pyridiile), 3. 8,9~Didehydr~-8-methyl-ergoline 37.9 g (0.15 mol) o~ ~,9-didehydro 8-msthyl-erg~line-~-carbonitrlle dissolved in ~0~ ml of ~etrah~dro~uran wa~ added to 1.2 1 of an~ydro~s ammonia ~before the conden~ation, dried on KOH). It wa~ ~llowed ~o stir ~ox 10 minute~ to l~t the temperatur~ drop again to -7~C and then a ~otal o~ 18 ~ (Z.2 mol~ o~ pota~sium wa5 added in ~mall pieces. ~han, the solution was ~olored ~ed~ The addition o~ ~ ~ew ml o~

2~3~340 me~hanol produ~ed the u~ual blue color, whloh wa~ de~troyed ~ft~r lo mi~ute~ by the addition o~ a to-tal of 150 ml o~
methanol. A~ter evaporating ~hle ammonia, th~ ~olvent wa~
removed in a vacuum and the re6idue wa~ thoroughly e~tract~d with dichloromethane. The extra~t was wash~d with water and saturated NaCl solution andl a~t~er drying on ~odium sul~at~, was concentra~ed by evaporation. Th~ residue wa~ crystallized from mathanol, and 22.2 g ~65%) o~ pure product was obtained in three fractions. ~he chrumatoqraphy of the mother liquor yielded another 3.8 g, yield: 76% cry~talli2e~, ~]D e 11~ ~ ~ (~- 1. 0 chloro~o~n ), melting point 125~133~C

4) 8,3-~idehydro-8-hydroxym2thyl-~rgoline 37 g of lithium am~de (1.6 mol~ u~pend~d i~ about a liter~ of dried liguid ammonia at -7~C and then 54 g o~ 8,9-didehydro-8-hydroxymethyl-6-ergoline c~rbonitrile ~0.2 mol) in solid ~orm is ad~ed. After 30 min~tes, it is mlx~d with 7.5 g of c~t lithium, and aft~r 30 minute~ ~n in~ensive blue aoloring ocaurred. 5 minute~ later, ~he mlxtur~ is bleached by addition of ammonium chloride. 50 ml o~ wa er i~ added, the ammonia is evap~rated off and 1~ is ~ar~fully mixed with a total o~ 1.5 1 of water. The mixture i~ ~tirred for 30 minutes wi~h ice ~ooling the crystals are suatione~ off, washed and dried~ Yield 40.~ ~8~ o~ th~ory), ~]D -99 ~0.5% in pyridi~e).

5) 8,9-~idehydro-8-hydroxmethyl-~-methyl-e~goline A) ~-A~tQxYmethYl-8.~-did~hydro-2-hydro~yme~hyl-6-ergoline carbonitrile 44.4 g o~ 8-acetoxymethyl-8,9-di~ehydro-~-ergoline carbonl~rile ~144 mmol) i~ diss~lved in 7.5 liter~ of di~hloromethan~, 65 g of paraformaldehyde (2~1 m~l) is add~d and thq mixtur~ i~ cool~d to -50~C. 800 ml o~ a one~mola~

2~ 3~

~olution of dimethyl ~luminum chloridc in hexan~ ~800 mmol) i3 quickly instilled in it. Aft~r 10 minu~e~ rrlng the ~olutlon ls aare~ully poured i~to 6 llter~ of water, ~h~
mixture i~ ~tirred ~or 30 minuteC~ and then the ~olutio~ o~ 240 g o~ tartaria acid in l.~ liter~ of water i~ added~ After 30 minutes it i~ made alkaline with 450 ml o~ ~onc. ammonia solu~ion, the organio phase i~ separated, ~he agueo~ phase is ex~ractRd three ~im~ with Idiahloromethane, ~ll organia pha~es are dried with ~odium sulfate and th~ solv~n~ is e~aporated o~f. The residue is chromatographed on ~ilica ~el with hexAne/a~etone and o~y~tallized from ethyl acetate~iisopropyl ether. Yield 17.2 g ~35~ o~ theory) -, [ ~ ] D = +~ ~ (O.5~ in ohloroform)~
B~ 8-Acetoxymethyl-8,9-didehydro-2-trimethylacetoxymethyl-~ olIn~on- I:r~
10.1 g o~ 8-acetoxy-8,9-didehydro-2-hydroxymethy~-6-ergoline carbonitrile (3 mmol) 1~ di~olved i~ 150 ml o~
pyridine and 30 ml of piv~lic aaid chloride and stirred for 30 minute3 at room temperature. Then, ice iB added, lt i~
stirred again for 30 minutee, diluted with water, ma~Q
alkalina with ammonia and extracted with dichloromethans. The organic phases are dried, ~oncentrated by ~vap~ra~on and chromatographe~ on aluminum oxide with dichloromethan~. 8.9 g (70~ of theory) i~ obtained by ~ry~ ion from ~5 diisopropyl ether, [~]D = ~16 ~0.5~ in chloroform).

c) 8,9-Di~Qhydro-~-hydroxymethyl-2-t~imethylacetoxymethyl-6-ergo~ oar~oni~ B
4 . ~ g o~ 8-acetoxymethyl-8, 9-didehydro-2-trimethylaoe~oxyme~hyl-6-ergoline caxhonitrile (10 mmol~ is 3 0 ~u~pended in 100 ml of methano}, 100 mg oi~ ~otlium me~hyla~e is added, ~nd it i~ ~tirred ~or one hour at room temperatur~.

'~0'~4~

It i~ diluted wit~ ice cooling wi~h water ~n~ the pr~oipi~ate is ~iuc~tione~l o~, yi~ld 3 . 65 g (96% o~ kh~c~ry), [~]~ 8 +31 ( O . 5% in chloroform) .

U) ~3.9-DidehYdro-~ v~lrQ ~ ethyl-2-methyl-~rq~
Z5 ml of dry ammonia is condensed in a ~lask under an argon atmosph~r~, 0.7 ml vf anlline (7.5 mmol) and 920 ~g of lithium amide (40 m~ol) are add~d and s~lrred f~r 15 minutes at -45~. Then, 1.~9 g o~ 8,9-didehydro-~-hydroxy-methyl-~-trim~thylac~toxymethyl-~-ergolina car~onitrile (5 mmol) i~
lo added and ~tirr~d ~or 30 minute~ ~t -45~C. Then, it i~ cooled to -70C, mixed with ~90 mg of li~hium and ~tirred until th~
formation o~ an intensive blue aoloring. Then, 5 minu~es later, ~o much ammonium chloride i~ ~dded th~t the coloring disappears, some water i~ instilled and the ammonia is evapora~ed. With ~urther dilu~ion With wat~r with iae cooling, a pr~cipitate re~ult~, which is suctioned o~ and dried, yield 782 mg (56~ of theory), [a]p ~ 0.5~ in pyridine)~

S. 8,9-~idehydro-2,~-di~e~hyl-erg~line ~ Didehydro-6,8-~imethyl-2-hydroxyme~hyl-ergoline is produced ~rom 8,9-didehydro-~,8-dimethyl-ergoline, ~s d~crib~d in ~he preceding example, by Prin~ re~ction ~st~p A). Yield, a~ter ary~tal~ization ~rom dichloromethane, ~7~, ~]D = -1~3 (0.5% in pyridine). B,9-Didehydro-~,8-di~ethyl-2-trimethylacetoxymethyl-ergoline is obtained by ~qyla~ion (~tep B) with ~rimethyla~etyl ahloride in an 80% yiel~, [~]D
= -147~ ~0.5% in chloro~orm~.
8,~-~idehyd~-2,~,a-trimethyl-~rgoline is obtain~d ~rom the abov~ by reduc~ion with lithium in ammonia ~tep D~ in a ~o 95% yield, ~]~ = _179D (U.5% in chloro~o~m). Then, ~he 8,~
didehydro-2,8-dimethyl-6-~rgolinylca~b~ni~r1le is pxoduaed - 15 - 203~

with cy~nogen bromidq (as de~ri.b~d under 1) ln ~ 74~ yi~ld, ~]~ - l36~ (0.1~ in chloro~rm~,.
5~4 y o:~ 8,!~-didehydro-2,8-d~mqthyl~ rgollne carbonitrile t20 mmol) i~ di~solvQd in 1 liter o~ glacial aeetic acid with 20 ml o~ water and mixed with 5 g o~ zinc du~ an~ he~ted for 2 h~ur~ to llO~C. A~ter adding an additional 3 g of zin~ dust and 10 ml of water, the rea~tlon was ended a~ter ~0 minute~ at 11~C. Then, it i~ ~iltered o~f from the precipitato, the filtrate i~ to a great extent lo conc~ntrated by evaporation, ma~e alkalin~ wi~h ammon~
~olution and shaken ~ut with ethyl aoetate. ~he organic pha~e~ are dried wi~h sodium ~ul~ate and con~entr~ted by evaporation, ~he reæidue is crys~allized from ethyl ac~tate, yield 2.~ g (~3~ of ~heory), r~D = ~ 0,5% in ~hloroform).

7. General proced~re for alkylation in 6-~osi~ion 1.0 mmol o~ ergoline, 7.D mmol of p~ta~ium aarbonate, 0.5 mmol of tetrabutylammon~um hy~rogen ~ulfate and 50 ml of nitromethane are added together in ~he indic~ed ~equen~e and mix~d with ~ mmol o~ alkylating agent. ~In the case o~
chlorome~hyl ~y~lopropane, 10 equiv~len~ i used and in addi~ion, 2 equival~n~s of anhydrous lithium iodide i5 added.) It is tirred at 20 ~o 50C (~etween 2 and 47 h~urs, TLC) and then filt~red on ~and/Calite. The filter residue i~ w~hed thoroughly with ~i~hloromethane and the solvent i~ remoYed i~
a vacuum. The re idue is filtered (glacial acetic aaid~ on aluminum oxide ~act. 3) and the crud~ product obtained a~er th~ removal of the olven~ i~ crys~llized, In som~ case , it then also h~ to ~e chromatographed.
Analogously, there are produce~:
~,9-Didehydxo-8-methyl-~-n-propyl-ergollne :, .

~3~
-- 16 ~

Yield: G4~ ryE;talllne ~rom ethyl ac~te), [~]D =
-121.6 (C - 0.5 in chloroiEorm), melting point 127-130C! (~rom ethyl acetate.) ~~Allyl~8,9-dldehy~ro-8-methyl-ergoline Yield: 15~ (crystalline from et~yl acetate/hexane), e~D
-161.5 ~c - ~.4 in chloroform), melting point 156-1~8C
(from ethyl acetate~h~xane) 6-Cyclopropylmethyl-8,9-didehydro-8~methyl-ergoline Yield: G8% ~41~ crystalline from e~hyl acetate/hexane), 0 [~]D = -126.6~ ~c - 0.5 in chloroform)~ mel~ing point 1~2-195C ( from ethyl ace~ate~hexane~

8,9-Did~hydro-6-ethyl~8-methyl-ergoline Yield: 30% ~25% ~ry~tallins from ethyl aceta~e), melting point 225-22~C, ~u~limated starting from 1~0C (~rom ethyl acetate~

8. ~ iaehydrO-8-hydroxymethyl-6-n propyl-~r~oli~e 19 ~ o~ s,g-didehydro ~-hydroxymethyl-ergoline (8~ mmol) is di~solved in 1.5 liter o~ D~F, 4~ ml o~
diazabicy~l~undecene and 73 ml o~ l-bromopropane ~0.~ mol) ~re added and it i~ st~rred for 5 hour~ at room tempe~atu~,~e and for ~ hour a~ 50~ It is allowed to cool, m~xed with a semisaturated ~mmon alt ~olution and extxaate~ with dichlorometh~ne. The or~anla phas~ are drled and, finally after the addition of toluene, evaporated ~o drynes~. ~he re~idue i~ ~hromato~raphed ~n silica gel and crystalliz~d ~r~m ethyl acetate, yield 13 g ~58% of theory), ~]D = -41 ~0-5% in pyridin~.
In an an~logou~ way, ~here were prepared:
6-Ethyl-h,~-didehydro-~-hy~roxymethyl-ergoline Yield 43%
6-Al~yl-8,~-didehydro-8-hydroxymethyl-ergoline Yield ~7%

2~3~

Ex~mple 1 Analogously to pro~dur~ ~7) ~or alkyla-tion in 6 p~si~ion da~crib~d in ~he produation of 1:h~ initial ~ompound~, there are obtained:
8,9-Didehydro-6-ethyl-2,8-dimethyl-ergoline Yield 15~ [~] D - -184~ ~0.1% ln ahloroform) S,~-~idehydro-~,8-~imethyl-6-n-propyl-ergolin~
Yield 60~, [~]D ~ -152~ (0~ 5~ in chloro~orm) 6-Allyl~B,9~didehydro-2,8-dimethyl-ergoline Yleld 18~, [~]D = -1~2 (005~ ih ohloroform) 6-Cyclopropylmethyl-8,9-~idehydro-2,~-d~m~thyl-ergoline Yield ~. [~]D = -153 (0.1% in chloro~orm) ~x~mple a AnalogoU~ly to methods (8) described in ~he production of the ini~ial ~ompounds, ~here are obtained:
8,~Didehydro-~-ethyl-8-hydroxym~thyl-2-methyl-ergoline Yiold 2~%, [a]~ = -141 (0.5~ in pyridine~
8,9-~id~hydro-8-hydroxymethyl-~-methyl-6-n-propyl-ergoline Yield 13$, ~ -78 ~0.5~ in pyridine) 6-Allyl-8,9-didehydro-8-hydroxyme~hyl-~-methyl-ergoline Yiel~ lg~, t~]D - -150 (o.~% ~n pyri~ine) 6-Cy~lopropylmethyl-8,9-~idehy~ro-8-hydroxyme~hyl-~-methyl-ergoline ~5 Yield ~7%

8-Acetoxymethyl-8,~-dldehydro-2-m~thyl-6-n-propyl-ergoline 231 ml o~ 8,~didehydro-8-hy~roxym~thyl-2-mR~hyl-~-n-pro~yl-ergo~in~ tO.79 mmol) i~ dissolved i~ 4 ml of pyri~ine, 0.8 ml of ~CRtiC anhydride i~ a~ded and s~irred ~or 30 minu~e 2~3~3~a - 18 ~

at room tem~eratur2. ~hen, ice i~ ~dded, it i9 A~lowe~ to ~tand ~or 1 hour, made alkaline with ammon~a and extraate~
with dichloromethane. The organic phaRe~ ar~ driad wi~h sodium sulfate and ~onc,en~rated by ev~por~ion, yield, a~ter crystallization of diisopropyl ether~hexane, 160 mg (6~ of theory~ ]D = ~113~ (~.5% in ~hloroform) xampl~ 4 2-chloro-8,~-didehydro-8-hydroxym~thyl-~-n-propy~
ergoline 0.97 g of 8-a~etoxymethyl-8,9-dldeh~dro-6~n-propyl-ergoline ~3 mmol) i~ oolYe~ in 900 ml o~ ~ioxane, 1 g o~
N-chloro3uccinimide i~ added and ~tirr~d for 16 hours at gO~C.
Then, it is ~llowed to cool, mixed with saturated common ~alt 6~1ution and ~haken three t~mes with ethyl a~etate. The organic phases are dried with sodium sul~ate, concentrate~ by evaporation and chromatographed on aluminum oxide with diahloromethane and ethyl a~atate. The aruda produ~t is di~olved i~ 20 ml o~ tetrahydro~ur~n and 20 ml o~ IN
potassium hydroxide aolution and stirred ~or 4 hours at room tempera~ure. It is worked up as des~ribed ~hove, the residue is chromatographed on silica gel with ~thyl aaetate~methanol and finally cry~tallized from dic:hloromethane. Yiel~l ~;3 mg ~6% of th~ory), [~D = -126~ ~0.1~ in pyridine)~
The follow1 ng ~ompounds are analogou~l~ prepare~d:
~5 2-Chloro-8,9-didehydro-a-methyl-6~n-propyl-arg~line Yi~ld 27~
~-~hloro-8,9-didehydro-6-ethyl-8-methyl-ergoline Yie~d 1~
2-Chloro-8,9-didehydro-6-ethyl-8-hydroxymethyl-ergoline Yield 2~

2 0 '~

The initial compound 8-aaetoxymethyl-8,~-didehydro~
propyl-ergoline i~ o~tain~d an~logously to ~xample 3, yield 52~ ]D ' -~ ~0-5~ in chloro~orm).

~xamPl~ _~
2-Bromo-8,9-didehydro-8-m~thyl-~-n-propy].-ergoline 533 mg of 8,~-did~hydro 8--methyl-6-n-p~opyl-ergoline (2 mmol~ is ai~601v~d in 40 ~l o~ dioxane and mix~d with 1.092 g of pyr~olidone-hydrotribromide (2.~ mmol) in ~ portions, which ~r~ added in intervAl~ o~ 15 ~inutes~ 0.5 ml of a~e~one i5 added ~o it, re~t$rred f~r 15 minut~ and ~hen m~d~
alkaline wit~ ammonia. The mixture is dilu~ed wi~h water ~nd s~aken out with dichloro~ethane. The organi~ p~3e9 ar~ dried ~nd ~on~entr~ted by evap~ration. ~h~ re6idu~ is chromatographed on ~ a gel wi~h hexane/a~etone and then ~rystallized from ethyl acetate, yield 3~4 mg (47% of th~ory~, [~]D ~ 3 ~0.5~ in pyrldine).
Analogou~ly, ther~ are prep~red:
6-Allyl-2-bromo-B,~-didehydro-8-methyl-~oline Yield 47~
2-B~mo-8,9-didehydro-~-e~hyl-8-hydroxymethy~-ergoline ~leld 73%
2-~romo-8,~-didehydro-8-hydroxyme~hyl 5-n-propyl-~rgoline Yield 43~, t~]~ ~ 125~ (0.5~ in p~rldine~
6-Allyl-2-bromo-B,g-didehydro~ hydroxymethyl-~rgoline yield 38 ~x ~ la ~
~,~-Did~hydro-~-methyl-6-n-p~opyl-2-~inyl-~gol~e 1. 8,9-Didehydro-B-mRthyl-2-morpholin~m~hyl~
propyl-ergoline ?,47 g of 8,~-didehydro-8-meth~1-6-n~propyl-~rgoline, 24.0 g (0.19 m41) of morpholinehydrochlorid~, 4.5 g (O.lS mol?

203~3~

Of paraformaldehyde a~d 22Q ml of ~ry dimethylfor~amlde ar~
adde~ togeth~ in the lndlo~ted seguence and the mixtU~e is stirred in an oil hath heated to 100C for 30 minUtR~. For w~rking up, the reaation solution i8 pour~d on ice, made alkalin~ with a 25% NH3 ~olution and extracted with toluene.
The crude p~oduct obtained a~tex drying on Na2S~ and remo~al of the to~uene in a vacuum is di~olved in loO ml o~
~rifluoroacetic a~id and ~tirred for 30 minute~ ~t 60~. ~heh, the re~ction mixture is poured on ice and made ~lkalinQ wi~h o a 25~ NH3 solution. A~tRr extraction with dichloromethane, drying on Nazs04 and removal ~f the ~olvent in a vaauum, ~ dark oil i~ obta~n~d, which is puri~ied by chroma~ograph~.
Yleld: ~0~, t~ 108.~ (c = 0.5 in chloro~orm) ~, ~, 9-Didehy~l~o-2-fo~Dyl-8-mel~hyl-ç-n-propyl-ergol~nR
3.65 g o~ thi~ ~anni~h ~ase (lo mmol) is dissol~d in 160 ml of ~etrahyd~ofuran o~ re~nt p~rity, Goole~ to -40c and 1.6-3.2 ml ~11.5-23.0 mmol) of triethylamine is added. Then, a solution of 1.5 ml (12.3 mmol) o~ tert-but~lhypochloride in 25 ml of tetrahydrofura~ is r~pidly instill~d. After 5 minutes, ~he mixture i5 cheaked by thin-layer chromatog~aphy.
If an edu~t ean still b~ detected, more h~po~hlo~ide iB added.
30 minutes a~er th~ la~t addi~ion (TLC), the bat~h i8 po~red on i~e, alkalized with 25~ NH3 solution and extracted with eth~l acetate. The crude produ~t obtaLned after the r~mo~l of the Rolvent has to ~e ~hromatographe~, Yield: 38~ D = -223 - 8 (~ = 0- 1 in ~loro~orm) 3~ 8,~-Dideh~dro~ hydroxy-ethyl)-8-~e~hyl-6-n-propyl-Rrgo~ine 1.4~ g of ~ld~hy~e (5.0 mmol) i~ dissol~ed in 150 ml of dry te~rahydro~uran and oool~d to -~5~. 10-15 mmol of methyl-lit~ium ~1.6 M ~olution in ekher) iB ~dded in 5-7 portio~s. A~ter th~ last ~ddition, it is allowed to thaw and 2~33~3~a i~ ~t~rr~d ~or another 30 minutes at ~oom t~mperature. The co~r~e o~ the reactio~ ollowed wi~h thin-layer chromatography. For the worki.n~ up, ~t is poured on iC4, alkalized with 25~ NH3 ~olution and extracted with athyl a~etata. The crude produc~ o~tained a~r removal o~ the solvent i6 chromatograp~ed.
Yield: 63%~

4. ~,g-~d~hydro-8-me~lyl-6-n-propyl-2-vinyl-ergolin~
300 mg ~f the crude product above i~ dis olved in 40 ml of tetrahydro~uran o~ reagent purity and mixed wi~h 1.4 ml (lO
mmol3 of triethyl~mine. After a~din~ 0.8 (10 ~mol) o~
me~hanesulfonic acid chloride, it is stirred ~or another 30 minute~ at room temper~ture (TLC after 5 minut~). Then, the mixtUre is poured on i~e, alkalized wi~h 25~ NH3 solution and extraated with ethyl aoe~ate. The ~rude produ~t obtainad after evaporation of the solven~ in a vaauum i~
chromatograph~d.
Yield after chromatography ~thyl aaetate/dichlorome~hane l:l)s 41~ (12% ar~alline from e~hyl a~eta~e/hexane~, melting point 172 174.5~ tde~ompc~ltion), [~Jp - -~01~3 (c = 0.2 ln chloroform).

~xam~le 7 8,9-~idehydro-~ hy~roxyme~hyl-~-n-prop~1-2-vinyl-e~goline 1. 8-AcetoxymR~hyl-8,g-didehy~ro-~-hydroxymethyl~
propyl-er~olin~
As ~eso~i~ed as step l in the example above, 3~85 g of the 2-hydroxymethyl ~ompound ta~out 5~% of theory) i~ obtained as an o~l from 5.99 g of ~-a~e~oxymethyl-8,9-didehydro 6-n-propyl-ergoline (l 5 mmol) aPter worki~g up ~nd ~hromatoyraphy.

~3~

2. 8-Ace~oxyme~hyl-~,9-didehydro ~-for~yl-6~n-propyl-ergoline ~ hl~ p~oduct is dis~olvPd in 2~5 ml o~ dichloromethan~, mixed with 12.~ g o~ manyanese dioxi~e and stirred for 5 hour~
at room tempera~ur~. Then, it i~ ~hromatographed on aluminum oxide with dichlorome~hane and concentrated by evaporat~on.
~ield 1.~8 g 3. 8-A~etoxymethyl-~,9~didçhydro-6-n-prOpy~-2-vinyl-ergoline 9.~4 g of methyl-triphenylphos~honium br~mid~ i&
s~spend~d in 1~0 ml of anhydrou~ tetrahydro$uran and mixed with 2.42 g of pot~s~ium-tert-butyla~e with ice cooling. ~t ~ r~d for 30 minutes With ic~ ~oolin~, then the temperature i~ lowered to -50~ a~d the solution o~ th~
aldehyd~ is instille~ in ~0 ml o~ tetrahydrofuran. Within ~
hours, it is allowed ~o heat to -10C, then mixed with sa~urated common salt ~olu~ion and ~haken with ethyl aceta~e.
The product i~ chromatographed on Rilic~ gel wi~h hexane/acetone.
Yield 1.48 g.

4. ~ didehydro 8-hyd~xyme~hyl-6-n-propyl-2-~inyl-erqoline The s~ponification o~ the acetyl group is ~ch~eved by di~solving the ~u~stance in 40 ml o~ di~hloromethane and 40 ~5 ml of me~hanol in the pre~en~e o~ 80 mg o~ sod~um m~thylate within ~ hour~ at room te~per~ur~ The mixtur~ i~ poured into a saturated oommon salt solution, extracted with dichloromethane and the or~anic phase~ are dried with so~iu~
sulfate a~d conc~ntrat~d. ~y ev~poration. The x~sidue i9 chromatographed on aluminum oxide with et~yl ac~tate~ y~eld 3 ~ ~

s27 mg, from whiah 133 mg i~ crystalli~ed ~rom ethyl acetak~
(~o~l yield 2.3~), [~]p - -141 (o.1~ in pyridine).

Examsle ~
8,9-Didehydro-Z-ethyl-~-hyd;roxymethyl-6~n-propyl-ergoline 370 mg of 8,~-didehydro-8-hydroxym~thyl-6-n-propyl-2-vinyl-~rgoline (1.2 mmol~ 1~ rRduced with lithium in ammonla as desaribed in the pr~duction of the initial ~mpound~ and in 5~ (aniline i~ no~ neces~ary), worked up, chroma~ographed on ~ilica gel with ethyl aG~tate/methanol and ~rystallized lo from dichlorome~hane/diisopropyl eth~r/hexane, yiel~ 108 m~
(29~ o~ theory), [~]D = -117 ~0.1% in pyridine~.

Ex~
8 ~ ~-Di~ y~lLu~~~~L~Iyl-E~~metnyl~e~~n~prl:)pyl-er9roline 2.o ~mol of didehydro-2~ hydroxyethyl)-8-methyl-6-n-lS propyl~ergoline is di~solved in 25 ml of glacial ace~ic acid and 1.0 g ~26.4 mmol) of ~dium ~orohydride ~half-~abl~ts) i~
added under argon. After the end o~ the rea¢tion (~L~), it is poured on ice, alkali~ed with cooling with a ~5~ NH~
solution ~nd extra~d with di~hlorometh2ne. The crude produat ob~ained after removal of ~he solven~ in a va~uum is chromatographed on aluminum oxide with dichloro~ethane.
Yleld: S5~ (5~% cry~talline from ethyl ace~ate/diisopropyl ether), mel~ing poin~ 152-154~, [~D =
-149.7 (c = 0.5 in c~loroform~.

Claims (10)

1. An ergoline derivative of formula I

wherein R2 is halogen, C1-4-alkyl or C2-4-alkenyl, R6 is C2.6-alkyl, C3-6-alkenyl or C3-5-cyoloalkyl-C1-2-alkyl and X is hydrogen, hydroxy or C1-6 acyloxy, or an acid addition salt thereof.

2. 8,9-Didehydro-2,8-dimethyl-6-n-propyl-ergoline,, 8,9-didehydro-8-hydroxymethyl-2-methyl-6-n-propyl-ergoline, 2-bromo-8,9-didehydro-8-methyl-6-n-propyl-ergoline, 8,9-didehydro-8-methyl-6-n-propyl-2-vinyl-exgoline, or 8,9-dictehydro-2-ethyl-8-methyl-6-n-propyl-ergoline,each a compound of claim 1.

3. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.

5. A process for the production of compounds according to claim 1, comprising alkylating or alkenylating a) a compounds of formula II
to produce compounds substituted by R6 as in formula I, or b) halogenating a compound of formula III
III
to produce a compound of formula I wherein R2 is halogen, or c) reacting a compound of formula IV

IV

(1) in a Witting reaction to produce a compound wherein R2 is a C2-4 alkenyl radical or (2) converting a compound of formula IV to a 1-hydroxy-C1-4 alkyl radical and optionally dehydrating to produce a compound wherein R2 is a C2-4-alkenyl radical and then optionally esterifying the 2-CH2OH radical of the compounds obtained according to (1) or (2), optionally reducing to form compounds wherein R2 is a C1-4-alkyl radical and then optionally cleaving -the acyl group in the 8-position, separating the isomers, and forming the acid addition salts.

6. A compound of formula IV' IV

wherein R7 is a carbonitrile or R6 is C2-6-alkyl, C3-6-alkenyl or C3-5 cycloalkyl-C-1-2-alkyl and X is hydrogen hydroxy or C1-6-acyloxy, or an acid addition salt thereof.

7. A process for the production of an intermediate compound of formula IV', according to claim 6, comprising oxidizing a compound of formula V

V

wherein Y is CH2-OH or CH2 .

8. A method for achieving a dopaminergic effect in a host, comprising administering to said host a compound of claim 1.

9. A method for treating Parkinson's disease, comprising administering an effective amount of a compound of claim 1.

10. A method for treating Parkinson's disease, comprising administering an effective amount of a compound of claim 2.