Note: Descriptions are shown in the official language in which they were submitted.
7EI3243~,411~1 MIL~EN WIIIT~ ~ZEI ~NO F-134 T-3613 P-002~011 JUN 03 '92 17 4æ
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- N~ CO~ TI~N PR~P~aTIO~S Fo~ T~$~
OF P~RRI~SON'~ EASE
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The invention ~elates ~o the u~e of ~n~gonists of the
S N-me~hyl~D-~spar~a~e ~NMDA) re,cep~or ~omplex or their phy-
siologi~al~y compatible salts as ph~rmaceu~ical agents for
symptomatic tre~tment of. ParkinSon's disease ~s we~ as
- pharmaceutical agents which contain these co~pounds ~nd
their comhination with ~nti-parkinson agents with syner-
gisti~ ~tion.
~ lgh concentrations of excitato~ amino acids suoh as
glutamate and aspartate are pxesent in the cen~l 1 ner~us
system of mammals, including hum~ns, tFonnu~, F. ~ J.
~: Neu~ochem. 42~ 84). For the exci~ o~y ami~o
acid~, various xeceptors exist which ~re desic nated cor-
responding to their ~pe~ific agonis~s as ] I-~ethyl-D-
~spar~ate (NMDA~, kAinat~ (KA) and quisqual ~e (~UI$3
receptors. The ~uiæqualate receptors a~e also n~med ~PA
receptors after tha s~ecific a~onists tRS)~,'^.-a~ino-3-
~0 hydroxy-5-met~yl-4~i~oxazole pxopionate. The syn~p~ic
fu~ion of the exci~atory ~mino a~id L-glut~mAte is also
imparted ~y ~M~A receptors.
Fxom ~linic~l and anim~l-experime~tal ~indings, there
~re indications that in ParXinson~s disease (P~)~ i~cxeased
glutaratergia neurotran~ ion occurs in varic~- nuclei oi
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703~4~410 I~ILLEN WHITE &ZELRNO F-134 T-368 P-003/011 ~U~ 7:4
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the basal g~ngli~ a~ a result of ~he striatal ~e~ iiciency o~
dopamine. ~he neostri~tum (NEO~ represents the entry
struct~re of the ~asal ganglia; it ob~ains ~r~ the ~or~ex
a massive glutamatergia projection and from the su~stantia
nigra pars comp~cta (SNC) the dop~minergic ni~ rostxiatal
pathway, whi~h de~enerates in ~he case o~ PD~ From the
NEO, ~here ~re direct pa~hwa~s to the initial nullei ~f t~e
. b~s~1 ganglia, the in~er~al palli~um link (GPl) and the
substantia nig~ pars reticulata (SN~)/ as well ~s indirect
pathways, which run by the external pa~lidum link (GPe) and
nucleus subthal~iaus (STH). The STH receives a dire~t
- glutamatergic inner~ation of its own from the ~ortex; its
.~ neurons projecting to the i~itial nuclei ~ also use
L~ t~mate as a ~ransmitte~
~he synaptic funotions o~ dopa~ine in N~O ~re complex.
Its effect on the st~iatal neurons proje~ti~ iI ~to the GPe
is mainly inhibito~y, so that as a result o~ t~ .e stria~al
- dopamine deficiency, as it i~ present in PD~ the ex~itatory
;' glu~amate~gia influences on t~ese neurons p~ edo~i~ate
Since bo~h the striat~l pathw~y to the G~e a~d ~he pathway
pro~ecting to the STH st~r~ing from there ~re Inhi~i~ory,
in the case of P~ the phenomenon of disinhibition wi~h in-
c~ea~e of ~oni~ cellul~r activi~y in the ST~ results. By
its ~lu~amatergia proje~tion~, ~he ST~ finallylpro~uGes a
pathologically i~creased neurona~ a~ti~ity in the ini~ial
nuclei o~ the basal gangli~. Tests on animal mod~ls of PD
show that af~er administration o~ dopa~ine~gic su~tances,
~: a normalization of the increased e~citatory neuro~ransmig-
sion r~s~lts r which ~uns par~llel ~o the ,"alinical"
3 0 imprc~vement .
gurprisingly, it turhed out th~t NMDA reG~Iptor ~nta-
~ gonists, which also have a neuroprote~i~e eff ect on ~he
: MPP -ind~aed cell loss in ~he suh~t~nti~ ni~ra, ~ ~lone or i~
aom~ination wi~h ~-dop~ and ~ireçt dopa~inergi ~gonists,
have ~n effeat on the experi~ental Parkinson~s ~ e.
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7133~43~,41EI MILLEN WHITE 2.ZELf:lNtJ F-134 T-368 P-004~011 JUN 03 '92 17:51~
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Accor~ing to t~e invention, co~pounds a~e suitable
- which hav~ a high affini~y to NMDA re~eptors ~ndlaancel the
synaptic e~fects of NMD~. Such NMDA antagonists are, for
example.
1. ~ompetitive NNDA antagonists such a~ 3~ -2-
aarboxy-piperazin-4~yl)-propyl-~-phosphon~ a¢ic L (~PP) a~
analogs~ such ~s, for exampl~, CPPen~s; cis-4~phosphono-
methyl-2-piperidine ca~oxylic a~id (CGS 1~75~) or CGP
40116 and analogs; and 2-a~ino-7-phosphonoheptanoi~ acid
o (AP-7) and analogs.
- 2. Antagonis~s of the glycine bindin~ site, such ~s/
for e~ample, kynu~enic acîd and analogs; 1-hydroxy-3-amino-
pyrrolidin-2-one (HA-9~) and analogs~
3~ Polyamines, such as, ~br example, sp'~r~ine and
lS spermidine and polyamine ant~yonists, such as, f~r example,
; ifenprodil.
4. Inhil~itors of the excitatory amir~o ;~c~ syn~hesis
or o~ the release, such as, e.g., lambotri~en. ¦
In par~icular, competitive ~D~ receptor ~nt~gonis~s
~re suitable according to the invention ~or ~ymp~atic
treat~ent o PD~ ¦
The p~siologiGally compatible salts are d~ri~ed ~om
: a~kali o~ ~lkaline earth metals or the usual i~or~anic or
organic acids s~ch as hydro~hloric acid, hydrobro~i~ aaid,
sulfuri~ acid, phosphori~ ~id, citric a~id, ~alll ia acid or
~umaric acid.
~he effect according to the inven~ion is demonstrated
by the ex~ple of ~PP administra~ion following the ~rîgger-
ing of contral~e~al rotatio~ on unila~era~ly s~hst~ntia
nigr~-injure~ rats. I
Male Wistar rats were i~jured 8 month~ Ibefore the
e~perim~n~ ~y in~ection ~f 16 ~g Of ~-hydrlxyd~pamine
( 6-OHDA) in the left subst;~nt:ia nigra ~he mea$ure~ent of
th~ ro~ations ~ook pl~ce in auto~ted roto~e~e~. The
anim~ls were pla~d in pleX~glaSS hal~-~hells , (dia~eter
40 c~) ~nd mechanic~lly aonne~ted wi~h an : incremental
7E13~43~4113 MILLEN WHITE &ZELRNO F-134 T-368 P-005~E~11 JUN 03 '9~ 17:51
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an~le-position encoder The clo~kwise and counte ~ralo~kwise
movements were detected sep~rate.ly at 10 minute interval~.
for 2 ho~r~. ,
; The results of ~his test ~an be ~ummarized as follows:
The animals treated with sol~ents show ha~dly an~
spontaneous rotations. The tre~tment wi~h L+dop~ ~25 mg/k~
: i~p.) and benser~zide (100 mg/k~i p~) triggllrs sli~ht
movemen~s o~` ~otation. If the ~nim~ls are t~eated ~n ~ddi-
tion with ~PP (D 025, 0.8, 0.39, 1 5~ and 6.2S m~/k~/i p~)r
~he rotations ind~ced by L-dopa ~re enhanced dose-de~en-
dent. The n~m~er of rotation~ in ~ h~urs in ~he highest
do~ge of CPP diff~rs~signi~ican~ly from the L-dopa
treatmen~. (Fi~. 1). l
In the s~me way, ~he compoun~s ~ccordi~g to the
: 15 inven~ion were tested on t~ue marmosets, inl which an
exparimental Parki~50n's' syndrome was pro~uced ~y the
! neurotoxin MP~P.
Here, ~oo, it is shown ~hat the ef~ec~~of ~-dopa
(20 mg/kg/i~p.) and ~enserazide (20 mg/kg/i.p.) is
enhanced dose~dependen~ by CPP (0.1, 0.3~, 1.56 m~/kg/i~p.
(fi~- Z). . I
I In the sam~ model, ~PP (0.1, 0.39, l.S~ /k~ i.p~)
was ~e~ted wi~h the direct ~op~minergi~ agonist apomorphine
(0.05 mg/kg i~p ) or ~isuride tO~ kg i.p.) f ~ nd
1 25 4). Here, too, ~he ,c~mbined treatment leads ~o a
: signi~icant syner~is~ (vari~nce ~na~ysis and Tu~y ~ast, *
. ' p ~ 0Ø1)
; These test~ show tha~ antagonists o~ the N~A recep-
tors in ~osages, which alone are without effJ~ts, zfter
systemic a~ministration,, enhance the e~fe~ ofi L-~OPA in
~he ~-DHDA rotation model and on MP~P-~reated true
marmosets. ' '
~he blocking ~f the central NMDA recep~ors in
s~ruatures whi~h wi~h P~rkinson's d~se~se exhibit an
incre~sed neur~nal aa~iY~ky, is s~lta~le ~or sy~pto~atia
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707.~-'43641l~ MILLEN WHITE ~ZEL~NO F-134 T-368 P-0~6~011 JUN 03 '9~ 17:52
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treatment o~ Parkinson's ~isease by co~pounds wi~h selec-
~ tive and no~selecti~e eff~c~ on NMDA reaeptor~ IE~pecially
: adv~ntageo~s is ~he com~in~tion wi~h usu~l an~ p~rkins~n
agents such as L~DOPA, ~-~OPA in com~ination with ~en~era-
zide and dopamine~gi~ ~onists, such a~, fo~ example,
lisu~ide, bromo~ryptine, per~olide, terguride, ~opinirol,
N-0437 (~N,n-propyl-N~ hienyl)ethylamino~- 5-hydrbxy-
tetrali~e, cab~rgoline as well as an~i~holin~rg: L~ age~ts~
: ~y aombin~tion of ~he pharmaceu~ical ~gen~ ac~ordin~
to the invention with usual anti-parkinson ~gen~tr the dose
of ~e usual pharmaceutical a~ent to be ~minis~lred i~ re~
: duced and its e~f eGt is inGre~sqd. The synergistic effeat
of ~he combination prep~r~tions there~ore m~kes ~ossible an
earlier occurrence of ~he desired effect and ~ reduc~ion of
. 15 ~he side effects~ The effect ~hen observed is mor~ pro-
nounced and sustained lonyer than a~t~r sin~le adminis~ra-
tion of the indi~idual co~ponents
The invention also comprises pharmaceutibal agents
which contain the above-mentioned co~pounds, ¦~heir pro-
duc~ion and combination pr~para~ioh~ wit~ syner~istia
e~fect. ~he pharma~euti~al agents are pxoducec L ac~ording
to pro~esses known in the ~rt, by the ~tive ingredient
being brought into the for~ o~ a phax~aceu~i~al~ )reparation
wi~h sui~ble vahicles, a~xiliary ~gent~ a~d/or Additives,
~ Z5 a prep~ation which is suit~ble for ~nteral or p~rente~l
.~ ~d~inistration~ ~he a~mînis~ra~ion can t~e p ~e orally
or sublinguall~ as a s~lid in ~he form of capsules or ta~-
~: le~s or as ~ liquid in the for~ of solutions, slspensions,
:~ elixirs or emul~ions or ~ectally in the ~o~m ~f supposi-
.: 30 tories or in the form of injection ~olutions optionaliy
. also usable subcutaneausly~ As auxili~ry agents ~or the
:~ de~ired ph~rma~e~ti~]~age~t ~ormula~ion, ~he inle~t organic
~nd ino~ganic ~ehi~les known ~o ~ne skil~d in ~ e art ~re
suit~le, su~h as, for ex~mple, water, ~elatin,l~u~ ~r~bi~,
3S la~tose, s~rch, magnesium ste~ra~e, talc, ~e~e~ble oils,
polyalkylen~ ~ly~ols, etc~ Moreover, p~ ~erv~ti~es,
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7~)3~'13~411~3 MILLEN WHITE ~ZELf~l`10 F-134 T-368 P-007~ 011 JLlN 03 ) g~ 53
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sta~iliz~rs, ~etting a~ents, emulsi~iers or salts to change
the osm~ic pressure or ~u~fers option~lly can al~o be
; com~ised.
The ph~rmaceutical prepar~ions ~an ~e ~ ~r~ent in
solid for~, for example as ~able~s, ~oated ~ ~ le~s, ~up-
positories, cap~ules or in liguid f~rm~ for exa~ple ~s
solutions, ~uspensions or emulsions.
!
The dosage of ~he ac~ive ingredients can ~c l~y depend-
ing on the metho~ o aaministration, age and weight of the
patient, nature and severity of th~ disease to¦b~ treated
and simil~ factors~ The daily dose for th~ ~A receptor
an~gonists i~ 0 01-5000 m~, and the dos~ ~n ~e given as
a single dose to ~e administered one time or~6ubdi~ided
into 2 or ~ore daily doses. For the above-mentioned ~ypes
o~ sub~tances, the f~llowin~ single dose ranges ~r~ ~o ~e
considered as suitable:
. 1. ~or competiti~e NMDA ant~onists, such ~s AP-7:
10-500 mg, preferably 150 mg, such as CPP ald analogs:
1-250 mg, preferably 25 mg, such as CGS 19755: 0~1-100 mYr
~o preferably 10 ~g. . .
2. For ~ntagonists o~ ~e gly~ine ~inding si~e, such
as kynurenic ~cid and an~lo~s: 100-S000 m~, prefer~b~y
500 mg, such as HA - ~66: 0.01-100 mg, pre~e~bl r 5 mg.
: 3. For polyamihe antagonists, such as 5 ermine and
spermidine: 100-5000 mgr preferably 500 mg.
In the combination prepara~ions ac~ord ng to the
invention, the active i:ngredients can be pre ent i~ one
formula~ion or el~e in rPspective~y sep~r~te fo ~ulati~n-,
~ and the entire dose i~ ad~inisterea once or is d~vided into
.~ 30 se~eral doses.
The daily dose o~ th~ to~al a~tive ingredient~ in the
combination p~eparations wit~ typical anti-p~rklnson a~ents
is a~out half the t~pi~l dos~e ~ known ant~-parkinson
a~ents, depe~din~ ~n the nat~e and seve~ity ~f ~ e di~e~se
as well ~s the a~e And weight o~ th~ p~tien~. The ~hera-
peutic dos~ges of NMDA ~t~goni~ts ih ~he ~o~ ~in~tion o~
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` 703~4~6410 MILLEN WHITE &ZELRNO F-134 T-368 P-00B¦011 JUN 03 '92 17:54
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~nta~onist and anti-p~rkinson agent is ~lso zlho It h~lf ~he
dos~e of the NMDA antagc~nis~ ~dminis~ered ~lone, no~ed
abo~re~ ¦
Without further ela~oration t it: i5 believe d ~ha~ one
5 skilled in the ar~ can, using ~he preceding d~ scription,
utilize the presellt invehtion to its fullest e~ :en~.
~he e,htire disalosuxes of all ~pplicatio~ s~ p~te~ts
and publications, cited a~ove and ~elow, an~ of corre-
sponding ~pplication Ger~nan P 41 18 740. 7, Pil ed June 5,
1991, are ~erel3y inoorporated ~ referen~e.
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