NOVEL TRYPTOPHAN DERIVATIVES HAS REINFORCED CENTRAL NERVE ACTIVITY

The present invention provides novel

tryptophene

drift, having a

oEívité

cents has reinforced on the central nervous system, and their

utillsation

as

medikaments

.The compounds are represented by formula

lllnventiong4nêrala

:NHR-QY between _ oe2 CH-co0 w + i0 (EO) wherein R represents an acetyl group, m represents an alkali metal or Alchemy earth n-valent (n-mutant is equal I or 2) or the cation has=

monlumquaternaire

of an organic nitrogen base (n thus being equal to L) theS these

comp0sés

, coextruded=does tryptophan from which they are derived, can TREs Som 1 racemic dl or the form L).The cations represented within the formal above treal are preferably, those that EOM of £

ArentdérívésItlnvention

according to the neurotropic properties reinforced;

c'est

to say, among the alkali metals and

alcallno

earth " lithium and magnesium and, among organic nitrogen compounds SAL morpholine and

monoéthanolamiue

.The - CA by Tyl-tryptophan has, relative to the tryptophan, new properties and, in particular an improved penetration capability in the nervous system the DL-racemic form having activity substantially below that of the formal (+) biologically preferable for most amino

a¢Ides

essential.It is known, on the other hand, that administration

dë

Shereen Z lithium causes an increased

niethose

serotonin and

seide

5 hydroxy-

iadole

-acetic acid in the brain. Gold, tryptophan provides the substrate which, after 5-hydro-

ylation

and

décarboxylatlon

, gives rise the 5 a-of HY

zoxytryltanine

brain, n-CA by Tyl-tryptophan lithium, which is the UT of

eumposés

according to the

inventlon

, associates SAL shares lithium Aβ

Citylage

-to-

tryptophene

and presence of a neurotropic reinforced.I

L'acêtyl

-to-

tryptopha

,

oùe

tryptophan, circulates in the plasma combined with proteins, or "

çrotéo

-to-

llée

", bind - cautious' $

eoo

..the O $OE pp

ooo

GSL cents=

ivementalbumlnlque

on the moiety. 0r, magnesium plasma attaches to the DHW

síte

protein. N-

acêtyl~typtophanate

magnesium "one of the

inventloneomposés

" decreases the "protein-bound"

fzactlon

tryptophan increase and its Universitätsverein diffusion and penetration into the nervous tissue.The organic nitrogen compounds capable of forming derivative of formula (a Z) of £

nventlonsottselcr

the those with a

neurotropismeêeeabli

"=they that morpholine and m

oéthanolamlne

. The invention contributes in

particuliez

LEEs N-acetyl-

tryptophanatee

of

morpbolineérhanolamine

Monoï and 0.The SAL

eomposésinventlon

can TREs prepared from n-CA=yl the Tryp=

ophane

form dl or (+)=

recriatallisé

two of £IU in a mixture

hydroalcoollque

" by sheave cents

tior

with alkaline or alkaline based

erreuse

==or with the nitrogenous organic base.The ave rage thereof examples a-d illustrate the process of preparing the inventive

cmposés

cents.For example the preparation of n-AC-by Tyl-tryptophan.In n

tricol

500 of the EL with the D1, does stirring "

dlune

bulb to bromine and d a thermometer" is placed

içO

ml of soda and normal i0 g of DL-

rryprophane

(0: the O 9 meters). The agitation is started and is poured slowly, in 30 min "52" grams (30 ml) (0,318 meters) of acetic anhydride; the temperature Te of the m

dlelle

m-mth 40 °c " while indispensable

précipirent

white crystals. Thus agitated, between 35 and 40 °c=during 3 hours. The O °C is cooled and liquid is removed from the white precipitate this!

uß

is then washed twice with 50 ml of cold water=P-ls comstically cents

há

the ventilated oven. Is the ob=i0 g of crystals

lehr

melts at 20a °C that I ' is recrystallized UER in both aqueous-alcoholic mixture URs.Collected 8.5 e of colorless crystals (f o5 °C) of n-acetyl-tryptophan, the Ra emic cents. To obtain n-

acétyi

-to-rev

ptophane

L-(ranging) operation is carried out so as

mmís

mth m from L (+) - tryptophan. 6 obtained " 5 g of colorless crystals melt 187 °c.Example lbs preparation of n-AC-by Tyl Try-

tophanate

lithium ICs - iN

coee3

Q. 4 - ". "'" - .' " "" ": '":es

pozt

: th re:

îlux

, during 1 hr "

uù

kneading 24.6 grams (

Oìl

the m) of n-

seétyl

-a

cryptophane

(LID), 50 water

dlstillée

" 0 "5 g of black

carbons

and 4" Z-grams (0" I-m-) lignin.

chsuà

is filtered. The solution is concentrated under vacuum

slors

dry. The crystals OS T-

réempat

O several times in acetone " then the EH e e Way stove boil vacuum. Recovered 24 s of colourless crystals very soluble each SAU, melting point above 300 °c, n Ae-

tyltry

?

tophane

li, (LID).Elemental analysis:Cleat strip: C. 61.9í hr 5 "2; n-ll, 21 the Li 2" 8 th "found: 62 C.; 5 hr" the I; n-11.2; the Li 2.7 th.For

präparat

n-sc4tyl-tryptophan lithium "L-( +), operations are carried out in so-departing mth m n-ac4tyl-tryptophan/(+) 7; a product of melting point above 300 °c has" under colorless crystals soluble in 1" water and in

llalcooléthyllque

, sparingly soluble in chlorinated solvents in

aronmtlques

SAL.Elemental

Anslyse

:Found: 62 C.; from 1; 5, 3 hr; n-11.3; the Li 2.7 th.

préparaßion

n-

aeétyl

-to-rev

tophanste

magnesium.14 n - m2 - ch co0 I-d in 250 ml of a

triool

nsec, a

bounemûnça81tstlon

and refrigerant, mixed 24.6 grams (0" I-m-) of n-acetyl-tryptophan (LD) with i00 ml water dactual

11ée

! 00 and 3;22

oxyàehMà

g of magnesium (0,055 of m). involves heating the mixture at reflux for 1 hr followed by adding 1 g of animal black " and we again if re £1ux during 30 meters. Is filtered on paper and the solution is dirt, SOE dry vacuum. The residue is

rempiétécristsllßn

hanks

stio

PDA 200, 8 in acetone, and then spring and

suche

50qc

Aufpasser

without vacuum.The product-n-ac by Tyl-to the Tryp

ophsnste

magnesium (LID) is in the form of white crystals very hygroscopic cream " flux if above 300 °c.Elemental

Anslyse

:Calculates: 60.7 C.; 5.08 hr; the n 10 "8; mgs 4.7 7 ." T-orv: 60 C. "5; 5.38 hr; the n 10" 6; 4.9 mg of I.q is the product tends CR39 of £$

scslliaerfaciemeut

with two water molecules. The assays were

effectuês

on dry products.For

fseiliter

drying can be

entreißen

ESU by refluxing xylene " but then the product tends to color.

Porös

obtained: 2&grams.The synthesis of n-AC inverter by Tyl-tryptophan is L (+) magnesium is the identically K-that of the antirachitic. 23 obtained " 5 g of product.Elemental analysis:Found: 60 C." 6; hr 5.31; the n 10; mgs/4.8 degrees..Key point to 300 °c melting

supêrleur

Way " cream crystals very soluble

lleau

.n-SC-

prépsration

t71-to-

trTptophanste

of

morphollne

.- I - coch3 1t is a puree to reflux, with stirring, for 2 hr, a

mélsnge

of 12.3 grams (0 "054 the m) of n-AC-by Tyl-tryptophan (LID)" 5 th morpholine (0,o5 meters), 75 g of 1%

slcoo

absolute ethyl and

uoir

g of. carbon. The K is filtered hot " concentrate under vacuum and poured half 200 grams of d * stirring an AC

oEone

e ch-e. the crustacean

blaues

are dewatered and dried.

sinsi

obtained 16 mg N-CS by Tyl-tryptophan

eorpholine

(LID)" f 200 °c. The product may 8tre metered through the

seide

perchloric in medium set top tick; there is a dried 99 has i00=e - Enicostemmalittorale Blume analysis of £remarked:CAI from a UL cents .:61 C. "3;', 1, 6 9; LOQ 12" 6' 7 ., found: 61.4 C.; it-I-7; the n 12" 5 T-..It is U produit very soluble in each SAU, the Claus Glassware cleaner the sparingly soluble&STM

Chlors

.Example 4 preparation of n-AC-by Tyl-to-

tryptophauste

of

mouodthanolamiue

(LID), 3 OH in a balloon

triool

250 of either ROL

munl

stirring and R fr1 manages, NC 50 g of ethyl alcohol mixture absolute and 24" 6 grams of n-DSC yl

tryptophaue

(LID), 0,i moles.AOO or obtain a paste quite

dpaissej

added then 6.5 g of

mon06thauolÆm

!do (0 "107 meters)" the mixture dissolves quite rapidly and then observed in the crystallization of the LEL. The K is heated 70 °c during 3om, le

zulange

is cooled to 20 °c. The crystals

íncolores

are springs has bottom,

lavas

K-ethyl ether then

sdchéfl

50 °c.28 g of salt is obtained based 200 °c quite soluble and insoluble in NAA 1es

drivasehlorés

and hydrocarbons. These 28 g are purified by the Claus

recriatalllsationthanolique

Con a mixture.AC

quí

gives 21" 5 s of pure salt.F." 202 °C.L-

ùneutaíre

analysis:Calculates: 61.93 C.; 7.17 hr; n-9.55% found: C. 61.71; 7.21 hr; the n 9, 38 7.The study

toxlcoloælque

n-acetyl-tryptophan

llthlum

customs has the following results:N-AC-by Tyl-tryptophan lithium CD minimally toxic, dl-50 by

intrapritonéale

in mouse

staut

of 3.40 grams/kg for the racemic and 3.25 grams/kg for the L-form (+). The toxicity of the peroral is low: LD 50: 8j70 grams

pouz

dl and 10.50 grams louse L (ranging).Latitudinal pharmacotherapeutic

ogique

n-acetyl-

tryptophauate

lithium has lose highlighting one hand-like properties sedative which

enifesteut

by:a) the action of £

hypotherm

health in the TDF. To the dose of lambdag/kg per intra-P-

ritonöale

,

l'a¢étyl

-tryptophan lithium causes a di

nution

gradual tee

érature

rectal up to 110 minutes post-injection.i-I-enjoying 7 1/b @

tgo

pp pp

ooo

b.) inhibition of

hyperactivlt

caused by associating

amphetamine

-to-

chlord±szdpoxyde

:Simultaneous administration "intra-P-

riton

Epitaxy" sulfate 4'

amphétamlne

(MSG/kilograms) and

chlordlazpoxyde

(25 or 50 kg weight/mth)

hez

mouse, has causes overactive Hyp-which has stored characteristics measured by a

actographle

" cents

unsistan

to record the movements of the mouse placed by

dcux

in three

sagettessuspendus

. The administration of a SC

tyltrïptophanatelithlum

of " the dose of 500 milligrams/kg per i000 and channel 0

intraIpdritonalej

one hour and three hours before yew simultaneous injection of amphetamine sulfate and cents

hlordlazpoxydej

has causes a very significant reduction of the

hyperactivitd

.c) decrease in activity in the pickup Ris DLR in "of the board holes" (

Bolsslet

and $1mon-to-Briefs-to-NTA. Pharma S.

odyn

Cents. 1964 "147" 3-): 1500 mg/dose-kg orally

vol

intra

pérlton

Epitaxy in mouse "

laientum

-tryptophan

hexerei

lithium has a significant lowering of the exploring. By against "at the dose of 1000 mg/kg body weight as Cintra intraperitoneal) this

kompost

causes an increase very sharp motility

Dtaunre

bet" properties and the

psychostlmulantesthymoanaleptlquesétylryptoçhanate

cents with lithium result in:d) an anti-ptotic

réserpinlque

: increasing doses of the product the

saal

compositions are administrated 2 m "by subcutaneous route" 30 minutes prior to intracoronary injection

pdrlton

Epitaxy of reserpine.2 the ptotic is appreciated all

deml

-hours for five hours according to the

kathode

of Rubin and neck (observation of occlusion of the eyelids of each eye). Calculating the percentage of

prooEectlcnvls

- -

vlsDosis

of the least relative have priority. L-aw

tylrypoçhanale

lithium causes a decrease in the ptotic produced by the reserpine gradual up to 800 mg per kg (5 4th decrease).e) the

potentiallsatlon

of 1' power and an AC

ivlthyperthe

- crumb triggered by an inhibitor of the mono ameba oxidase (MAOI) the

nranylcypramlne

: section is rats are

raltéa

after guilt or rectal temperature by the

sulfertranylcyprsmlne

the dose of 20 mg of/kg per channel of £ter P-

rlton

Epitaxy twenty minutes after " streets receive the

produlnblessais

ol either by intra w

rltoneale

either orally. We score "encapsulated in all cases" the

apparitlon

a

hyperaetlvlt

of HY and NC -

hermle

very big in the tops and

traltds

. The mimics

elfns

have T-

deels

in the alpine.the EO

æoçoog

- F.) the

potentiallsation

the

hyperactlvitéamphétamlnique

:With the dose of 5 mg/kg orally intra-

périton

Epitaxy, sulfate -

dexamph

dearth does not cause " in mouse, excitation very marked. 500 mg/associated ae4tyl kg of a-

tryptophanaoEe

of

líthlum

, noting a

excltatlon

mice, measured perse

actographie

" significantly greater than that obtained with dexamphetamine sulfate alone.

Anfing

were found, for the test of the heating plate, an absence of action of the ac4tyl-tryptophan lithium on the FNR!

gésle

by morphine,

diffdrenclan

=Te-product has the

6tyl

cents=

ryptophane

and - 5 hydroxy-

cryptoohane

.with fo n-

acéryl

-tryptophan magnesium AE=also minimally toxic in mouse, dl-50 by intravenous

périton

Epitaxy is 2 "80 grams/kg for the RAC

mlque

and 2, 30 grams/kg for the L-form (+) the HDD-50 orally is 16" 50 grams/kg for the dl in of 18.25 grams/kg for L (+). In the TDF dl-50 by intra-peritoneal is 1.35 grams/kilograms, and buccal greater than 8 g/kg.The pharmacologic study of n-acetyl-

trypto

?

hanate

magnesium has my=re it has similarly

l'acétyle

-tryptophan lithium, on the one hand like properties are sedative (it causes an increase of the tempo means sleep, proportional to the dose, =the HER AOO mouse having received 35 mg/kg of pentobarbital sodium five minutes after receiving the product Pal subcutaneously) and properties of £

thymoanalypsychostimulantes

and er: if it has only a very small effect year I ptotic

réserplnlque

, it

poteatialise

by against i=

hyperactivlté

and hyperthermia caused by a

IMKO

(the

tranylcypramine

); its action, measured by SAL mimics test " AST testing more slot but more prolonged than

Nachtasyl

-tryptophan lithium.The

acdtyltryptophanate

magnesium has, moreover, an action leak-

ulcdreuse

gastric that ground than that of MUs

komparseomposé

reference: bromide

prlfln

MU.Two techniques were used to study this property

ulcéríg

born mouse: a technology on the ROS is Da are $1 in neck.said stress ulcers "which

consistë

horizontally suspended the

annal

donation SAL

immobìlisées

tabs are" so that SAL feet off the ground, and

surre

technology on the the Skat is a complete in-pylorus ligation.i-I-an í 7 9.ï

L'acétyl

-tryptophan Hg, placed in solution in the gaming 5idis f wha, administered 48 hr which braces "24 hr prior to, and at the time of stressing" or 24 H and I hr integrated process water outlet ligation of the pylorus.PSTs orally, de-50 (dosage

ntí

ulcerative 50) L AEG "

étyltryptophanate

Mg" D.

termlnéepar

!has technique

iIul

=Re of stress, is 1700 mg/kg in the. By

voße

has -: peritoneal, de-50 of the

aeêtyltryptophana

e of 230 mg/kg to mg is P-R the technique's ulcer

eonuralnte

(been involved

lfiOe

IS39 DL 50) Sao - s it is of 16 mg/kg for the

prLflnlum

bromide (evening 33/i00e of dl-SO2); by the technique I

Shay

,

lç

de-50 mgs ESCs EEO 3ao 14/i00e KE is dl-50) fear

l'scêtyl

-to-

tryptophaùate

of} lg; in the mimics the conditions de-50 bromide is 25 mg/kg body of

prifinlum

(either 52/i00e dl-50).N-AC-by Tyl-to-

tryptophabate

of come have an action ulcerative slightly lower than bromide

prLfinium

" but with better comstically=URIs therapeutic.N-

aeétyl

-tryptophan

m0rpholine

has a DL 50 orally of 16 grams/kg and n-

aeétyl

-tryptophan monoethanolamine a DL 50 peroral greater than 18 grams/kilograms, in the ls=m being the gaming.N-AC-

tyltryptophanatemorpholíne

of mono

thanolamine

have pharmacological

propriétês

closely approaching Keller's of the acetyl-as TR - 1: oph&>Q-n-Te of magnesium.For the

emplol

in human therapeutics, 1es composed according to the invention?

cuvent

be present in forms which include:- orally, such as tablets, dragee capping capsules, solutions containing the active product to the unit dose of 0 "25 has 1 g and for solutions of e 2, 5 g/10 either ROL, - parenterally, such as injectable solutions conditioned

empor

, SAL, containing 0.25 to 0, 50 g of active product per vial, - by=

toplquelouions

such as" creams and in-a-a-

ùdes

.aE following examples of formulation are given as non-

1ímltatif

.Formula I

einstehen

=the product of the example I-" coated pellet:N-acetyl-tryptophan lithium 0.50 grams

q.s.p

carrier, a dragee formula 2 containing the product of the example 2 in 10 ml of drinking ampoules:N-acetyl-tryptophan magnesium 1 gm

ExclpÆent

sacral

axiomatisé

Q e, e. i0 i0 1, 9 ml of the O * ou formula 3% it containing the product of the example 3" in 5 ml of injectable

smpoules

:The n-SC-

tylryptophauatemorphollne

0, 50 grams of 5 ml the vehicle q.s.

expérimentstion

clinical confirms the interest of compounds according to the I ' disclosure.N-acetyl-tryptophan lithium stored characteristics " in the treatment of psychoses

utllisémaníaco

-depressive. It has been found that it is better tolerated by patients that the lithium carbonate. 11

paraat

originate in the SAL

reehutescyclothymie

.N-AC-by Tyl-tryptophan magnesium m mth that n-

aeétyl

-tryptophan morpholine and n-

aeétyl

-tryptophan

monoéthanolaníne

have

revsctifs

strips in the treatment of vacuum.They appear to have the particularity of normalizing sleep while exerting

turne

asthenic and controlling SAL intractable migraine.A few observations made with the novel medicinal products according In

entlon

are given below by way of examples.Observing Hal-Madam ester L

Rgée

of 3a years is treated since 6 years for each psychosis

manlaco

d-pressor. Relapses is usually

reproduceer

if spring: they do are prevented nor by SAL procyclical nor 1es MAO. A=ERUs by lithium carbonate

enttarneollgospanloménorrhée

in each said female usually much rule. During the

traltemeut

"

eile

showed" while the lithium levels of Na exceeded either i

neq

" nausea and vomiting. A orally 2 months performed during 3 of 1/2 to

ausesdralles

of formula 1 is

affairement

tolerated and causes regression of disorders as risk marshal "n-

Observatlou

" grated cheese 2 henries I-g of 57 years "engineer

électronlcleu

" is a chronic anxiety and asthenic on bottom depression. !l transitions being planar

dlgestlfsuype

to functional disorders of biliary eis

dyskindiEestlf

cinema of bloat. The "

fortlflants

" antispasmodic multiple it has set the smoothness does not alleviated permanently.The

presoErlptiondaune

bulb drinkable each of three meals of formula I during 6

semalnes

,

íée

=associations to a Sardinian of i0 IR-ECD - ion of I bulb daily intravenously of formula 3

amens

regression of the set of symptomatology " without

rehuis

- W-a - to OEO OII

OEnitialelpe

months after this treatment.L-study cents

llnique

dose proved the therapeutic value of eompos4s novel according to the invention, as well as their good clinical tolerance and biological, EBG that sometimes noted, during processing, the occurrence of constipation 4

IQw

e vv AQI

ueiüq

* U-of gG

OUSUUeQtoeeq

b. Guernsey. $* u-P-egg