(2-thio) ureas, 1,3-disubstituted.

The oresente - invention relates to novel ureas and thioureas, substituted on each of the two nitrogen atoms through a chain or branched alkyl radical, itself attached to the nitrogen atom of an optional lactam ' ard substituted, methods of preparing these compounds as well as their applications in the therapeutic field.

These novel compounds are of the following general formula I:

The R ^, the rg, RG represents the R ^ * are independently of one another a hydrogen atom, an alkyl radical containing from 1 to hr carbon atoms, an alkenyl radical containing 2 to U carbon atoms, an alkylene radical forming with the carbon atom to which it is attached a ring having 5 or 6 atoms cycloalkanique carbon, a TiN aryl group or a substituted aryl group,

The R ^ and b, . represent indlpendaanent of one another a hydrogen atom, an alkyl radical containing 1 or 2 carbon atoms or a group phfinyle,

n and Q are indépendaamient each other an integer from 3 to T,

m and P are independently 1' of each other 0, 1 or 2,

X is oxygen or sulfur.

When n and Q are equal to 3.1 ", 5.6 or 7 *, lactams groups of compounds of formula I are respectively the radicals 2 oxo-pyrrolidino groups, 2 oxo-piperidino, hexahydro 2 a-oxD lh-azepin l-yl, hexahydro 2 oxo-L-azocinyl (2:00) and octahydro 2 oxo-lH azonin l-yl. Preferentially, n and Q are equal to 3.

The substituents R ^, the rg, the R ^, the rg, and RG can occupy all the positions on the groups lactams, as an example of the aryl group, examples of the cores in particular phenyl and naphthyl. These cores may be optionally substituted, for example by halogen atoms.

The compounds of formula I have particularly interesting pharmaceutical properties. Inter alia, exhibit both beneficial activity processes mnesic and protects against electrical type hypoxic insults. They thus have first application in géropsyohiatrie, domain in which generated essentially srfaoire disorders linked both to cell damage due to GE in the LL&mth decrease 1' aapoit ά²⁵orygsae at brain following stroke unique had repeated (see to be subject, for example, yen. C.. EACIHSH, cancer types, IX. " (197 * 0, 20?). The compounds of formula I also find KAU be used advantageously in many other fields, bends by exeaple the prevention and treatment of stroke or eardio-to-vaseulaîree, coma post traumatic or toxic, memory disorders, difficulties in mental® concentration and so on .,, finally, th @ e compounds exhibit interesting activity in the field of platelet aggregation. They are in effect of platelet aggregation inhibitors and they can therefore find application in the treatment of myocardial xyoeard® resulting from platelet hyperadhêsivitêhyperagrégabilîté or, in extracorporeal circulations in the using or vascular prostheses, or still in the treatment of thromboembolic disorders and 1' hyperagrégabilîté of coronary®.

There are already known compounds having properties of the same type, and in particular the piraeêtam/2 a-© Xo to L-pyrrlîdiaeacétamide © (British Patent has®1.039"113j7"^C. compound® has the drawback will be effective that high-dose. An object of the invention is therefore to provide eesæasés having the same advantageous properties as the piracetam, but active amounts weaker.

The general method for the preparation of (2 thio) ureas of formula 1.3-disubstituted (9.ï) consists in reacting an n - β (eminoalkyl) of formula (ll) lactaine and n - (asino&lfcyl) lactam of formula (III-) with a compound of formula (alkylthio) carbonyl (VI) in an inert medium in the presence of a basic condensation agent in accordance with the following reaction scheme:

in which formulae the n, has, a P, Q-, confectioneries kg and X has the abovementioned meaning, Y and Z are each a halogen atom or an imidazolyl group, or Y is a halogen atom and Z an alkoxy radical having from 1 to

hr carbon atoms.

When systole I and Z are halogen, the compound of formula (VI) is preferably phosgene (the X "0, the Y" Z-"c1) or thiophosgene (the X" O, Y-Z plane-LC).

When the Leu ayaaolee Y and Z are each an imidazolyl group, the compound of the formula 5 ^ (VI) represents the 1.1 'a-diimidazole (Χ· 0, 9.ï * Z-"iaidazolyle) or 1.1' a-thioearhonyldiimîdazole (X-" e, ** 9.ï Z-imidazolyl).

When 9.ï is halogen and Z is a radical alkozy having

1 to the K carbon atoms, the compound of formula (VI) is an alkyl haloformate, preferably ethyl chloroformate.

In addition to the general method for preparing compounds of formula (I-) just described above, then there are also particular methods for the preparation of compounds, of formula (I) symmetrical, it is to say in which R ^ "* the rg, DMMs ^ * ^ R., the n *" Q and ω ·ρ.

In a first operative variant " proceeds as in the general method but using two moles of an n - (amino alkyl) lactam of formula (III) with one mole of a compound of formula (alkylthio) carbonyl (Tg), the operating conditions being the same as in the general method described above.

In another embodiment, dedicated to the preparation of ureas 1.3-disubstituted symmetrical (* X-oxygen), by reacting an acid chloride lactas " - H alkano£que of formula (V-) with an azide organosilicon, as 1' trîméthyisilyle azide, the laetame-n-alkane-isoeyanate of formula (IV) obtained is hydrolyzed and décarbexylé (selectively), according to the equation:

in these formulae R to R ^ ^, the n, and m have the meaning given above.

According to yet another embodiment, dedicated to the preparation of (2 thio) ureas 1.3-to-disubstituéee symmetrical, reacting two moles of a lactam of formula (binding of) with one mole of a 1.3 bis - (2 thio hydroxyalkylK) -

O the RT -

in FBA forÆïileo R., T- 1,_O , has₅ and I the ajrcat. in Douai iifîeation CDs® * above.

f. "•*" X i Tt of!'¹ •theS - *" '

Finally çuivant each alternatively reserved, the|. grêparafcioji. d. L-drées *, 3 "disubstituted th ^ aêtrifues in the ^ quelleç. mPax s © gên® ^, ^ 8"! ^ *®, * tirOj SPPs, reacted eassabl ^. . a I © the urea, I-® XU SLM®8 IF * formaldehyde

aTs two dirty a lestacs of fossil (yen Xl), according to the I^O equations.

>, the T ", . THE J ' ., - V-. "", "

I-·, ... ^ Û VBE1. ""~, - catalyst

ν / C. the O ^ * hr² The K ** ^ ^>·τ ··.

H₃ , . _ *. symmetrical..., ......

^H .^J (X * 0)

, ·ΐ ;.... ; '•

(meters)

.■? ii Y The K * Λ. ;. :■.. tg > . *.

in these foratules. The rg, 8^and m.ayant EOPA sigaiçiçatipndgnaé® C.?,, - top.

Certain N " lactase cautious (gmiaealkjrl)_grams ,₅ - ^ - R-substituted of formula

(it) or R a-j, the R ^, it,, the rg-substituted formula, (llï), ■eonposéi are YES

VBE1 '_F. . p-φ... (', ■. ^0 - Λ;♦the I * VBE1 , -|û. "." the II_; THE K ". "^••-" - - *

the synthesis of starting donations. csiigosSs. aw. fpripule_{The JT} (i)" .have. already₀ been described in the literature. Ainei." by * exœpple..., the, 1 - τ (s .aaiapâîhyl), degrees 2 a-pyrrplidinone

is described by yen. REPPS et, Da are " O L-GBP, ébigs ANNs.596(1955). 2Q3. - and the

J., the j '., •the I'■*' * ii "¹ '.•.^UvBE1 e ' 1 - (3 a-uninoprôgÿi) "2" pyrr-to-alîdiiioneeçt described in Chem.Abatr. 53. (l959).

48l6. Those not yet die crita.daps AEs hundred - literature: can all be prepared according to any known methods following:

- channel was; asaonolys® halogen compound, ... , •. -.*•. '•*

- route B: reacting or aur Hofœaan SU caide,

" HTV.. ¹

- c pathway: reduction of SU-nitrile,

the I "' i: ■ > " J.¹^ ' V * - - Js is ii j-P-E...

In each of the lanes;: has₂ b and Q_{- e} . the E © © e|Ag by halogen, ljeaaide and

the nitrile derivative. are obtained from the L ^&etaasa R., the rg, e ^ - substituted or compliance from lg * ^ I-R.₉ The rg-to-subatitués corresponding.

' **_% "* '* - *' 9.

Part. espériceatatle.

!S■preparation " (Gi-asikvl ^) lactaae 3 of formula II.

1.1. A. Aamdnolyae of SU>aogëbalogésé (lane)

I-■"'

1.1.1. Preparation ofa H hydroasyiaitbyl-to-laetMies.

WCT is preceded the Li liCtéTsturedéjl described 3ms 4voir■AI ^ ' eaieuple, chea.àbstr. ^, (i960)_O 12S6e) 'and' it has Itïasdifié horn follows:

ttoe ' solution is of Û forEaldêegtieuee of ^ 3? * T-CD is added a solution, made by bssioae. the tydroas ^ of sodium, of lactems in ethanol, & tèll® speed T-tii! "lîi t6ffipl" atare AEs to°e not exceed... The isélangeenkuité is' carried 'I'¹¹ ' th&ullition to refiLus, boom I © © does atrê under reduced pressure. The¹ residue is resumed by ethanol and concentrated again, so ii 1®rid¹ the IsVailree traces of neat formaldehyde "

Thus, by the Exe of £theS>the, is & prepared L "© symitiiylhydr-a 2" pyrrolidinone derivatives of d * as follows. In a balloon to 3 necks of 20 liters, is placed a solution of 1355 grams (15.94 moles) of 2-pyrrolidinone and 30 grams (0.75 moles) of sodium hydroxide in 2.8 liters of absolute ethanol. Slowly added 5250 grams (56.35 mol) of an aqueous formaldehyde solution to 35!?. The temperature of the reaction medium increases gradually during the addition and settles to 40 °c. When the addition is complete, the solution is brought to boiling at reflux for 5 1/2 hours. Ethanol and excess formaldehyde are removed under reduced pressure. The residue is taken up by 1.2 liter of absolute ethanol and the hot solution is brightened by filtration through hyflo aparatus. The solvent is evaporated under reduced pressure and the residue is recrystallized in the minimum of isopropanol. Obtained 1575 grams (yield 86!?) L-hydroxymêthyl-to-2 pyrrolidinone. PP DESIGNATION: 83 AND 84°.

I.R. spectrum (on KBr) in cm "¹ : 3280, 2990, 2950, 2900, 1665, 1395, 1045.

Was prepared in the same manner the following compounds:

a) hexahydro-L-hydroxymethyl-2h-azepine and 2" - one derivatives (yield: 47 ^). I.R. spectrum.

(On KBr) in cm "¹ : 3260, 2940, 2840, 1630, 1030.

This compound is already described in the literature: S.O. Benson and T. L. Cairns Group, J.Am.Chem.Soc.J0, (1948), 2115 - 8.

b) L hyàroxyméthyl-to-2-piperidinone (yield: 90!?). I.R. spectrum (foil) in cm "¹ : 3320, 2940, 2870, 1630, 1045.

c) an L-hydroxymethyl-5-methyl 2 pyrrolidinone (yield: 78)?). I.R. spectrum.

(foil) in cm "¹ : 3360, 2970, 2900, 168O, 1630.

d) oetahydro L-hydroxymethyl-2h-to-azonine-to-2 One (yield: 95!?). I.R. spectrum.

(foil) in cm "¹ : 3340, 2930, 2870, 1630, θ θ 1 4.

e) hexahydro-L-hydroxymethyl-2 - (1:00) (yield: 99) azocinone?). I.R. spectrum.

(foil) in cm "¹ : 3340, 2930, 2880, 1630, 1040.

f) 4 P-chlorophenyl L-hydroxymethyl-3-methyl 2 pyrrolidinone (yield: 59%).

I.R. spectrum (foil) in cm "¹ : 3360, 3020, 2970, 2930, 2880, 1680, θ θ 1 4, 910, 890.

g) of L-hydroxymethyl-3.5-dimethyl 2 a-pyrrolidînone (yield: 45)?). I.R. spectrum (foil) in cm "¹ : 3360, 2970, 2930, 2870, 1670, θ θ 1 4.

h) of L-hydroxymethyl-4.5-dimethyl 2 pyrrolidinone (yield: 78!?). I.R. spectrum (foil) in cm "¹ : 3350, 2970, 2950, 2880, 1750, 1420, 1045.

i) 3-allyl-L-hydroxymethyl-3 phenyl 2 pyrrolidinone (yield: 85!?).

I.R. spectrum (foil) in cm "¹ : 3400, 3080, 2980, 2950, 2900, l68o, 1435, 1275, θ θ 1 4, 700.

j) an L-hydroxymethyl-4 phenyl 2 pyrrolidinone (yield: 71!?). I.R. spectrum.

(On KBr) in cm "¹ : 3270, 2955, 2880, 1685, 1440, 1025, 710, 660.

hr) 3 "hly L ^" ^ ^ ^ E6 of HY étî ^ ^ 3 L-fcényi " 2 * gÿT? oliclinone (yield: 92%).

I.R. spectrum, (foil) in SFS¹ : 3380, θ θ 3 6, 2970, 2880, 1675, ^ 1 60, 765, 700. l) 5~p * e&lsfGpàênyl L-îiydrœ5Fmêthyl-a 2 - pîp rids of £Moreover! * (yield: 83 $) *•I.R. spectrum (on KBr) in cm "¹ : 3300. 2990, 29^0, θ 288, 30 ΐ δ, lUtO, 1050, θ 84, 830.

ta) L hydro3qrmétayl and 3_B 5.5 "sorts ^ tliyl '" 2" pyrrolîdinone (yield: 55 ^)•

^V. Spectrum! (IWF) I.R. in cm "¹ : 3370, 2970, 2230, 2870, 1670, ^ 5 - 10

the n)₍ 2 a-h5fero2çraStnyl-to-3 'Tïiêtliyl>-2' ^ ^ of £azasp ER, 5./ ' dêcane ^ L one derivatives (yield: 91 ^) ·. I.R. spectrum. (GBP I-U-VBE1) in ES cm."¹ : 3380, 2§70, 2930, 2860, 1675, 1450, 1010.

o) 3~fcufyl " l~faydr035âEetliyl ' and 2 a-pyrrolî<linone (yield: 99%). I.R. spectrum.

(foil) in cm "¹ : 3370, 2960, 2880, θ ΐ β 8, 1u65.

1.1.2. Preparation of ii-to-ehloromsthÿi-to-KLaetsHea,

a) L chloroaêtliyl ^ ' - pipérîdînone C.

To a solution of (7 moles) 903 grams of L'a-îxyüro: ^~~2 aetrijrl piperidinone

' dgins 600p AL of anhydrous benzene, is added dropwise under vigorous stirring and 6l8 AI (8.6 mol) chloride tiiîoayle - in ensuring that the temperature does' not exceed 10 °c. After the addition, the reaction is' ottoman followed by-during. , 2 hours, at room temperature. The mixture is filtered on a HY-the FLS ^ 'LEC':, évtipbré under reduced pressure and then dissolved three times in the naphtha anhydrous, " the solution benzenic being each 'times evaporated under reduced pressure' Peppers to expel the last traces of thionyl chloride 'of' and hydrochloric acid (which has formed during the reaction). The oily residue is first degassed under a pressure of 15 mA to Hg and then purified by distillation (lk3-to-1 ^ 5 °C under 15 SAA mmHg). 64 G at θ obtained (4.34 mol) of L-chlorométiiyl-to-2-piperidinone (yield:

62%). (IWF) I.R. spectrum in SFS¹ : 2950, 2870, ΐ β β 0.

The H "=Chlor0aéthyllaetesies have lté prepared following the same procedure:

b)=L-ehloroEéthyl "=2 (yield: 87 $) pyrrolidiïione. (Movie) I.R. spectrum of KF in¹ : 3038, 2970, 2885, 1700, 1260.

e) the L=- chlorophyll^thereinofssétM3rl "hsxahyârô" 2:00 "azêpine" gm " one derivatives (yield: 99%). Pp.eb. Il8 and 120'³ C/3, 3" ^ mm. '1 ¾. - cP CE/mpoeè is already described in the literature, see'? 1l. SIDSL ' EOVSIffitâeolT.w and,->Clîem.-to-DISS-Rn, (l960). , 1286." *'

d) the L "ChloroEéthyl" he2iah3rdrO "2 (Is)" asoeinone (yield: 32%). I.R. spectrum.

(iWF) in CSAs "¹ : 2930, 28 β θ, ΐ β β θ.

e) L-oetahydr "ehloramlthyl" © "21=agoa GBP does" 2=0 ne (yield: $8l). I.R. spectrum.

(iWF) es "¹ : 3020, 2930, 2882, θ ΐ 66, 1255.

f)=L-chloroaéthyl " 5^, =aéthyl - "=2 - pyrî^,olidinone (yield: 5 ½). I.R. spectrum.

*' Cfils) EDD "¹ : 2970, 2880, 17 ^ 0,

g) of L-cblorométhyl and 4 P-chlorophenyl 'and 3'^- methyl 2 pyrrolidinone (yield: 68%).

I.R. spectrum (foil) in cm '¹ : 3030, 2970, 2930, γ θ 28, 1710, 900, 830.

h) an L-chloromethyl-3.5-dimethyl 2 pyrrolidinone (yield: #77). I.R. spectrum (foil) in cm "¹ ; 2970, 2930, 2880, 1700.

i) an L-chloromethyl-4.5-dimethyl 2 pyrrolidinone (yield: #28). I.R. spectrum (foil) in cm "¹ : 2970, 2930, 288 θ, 1715.

j) 3-allyl-L-chloromethyl-3 phenyl 2 pyrrolidinone (yield: #91). I.R. spectrum (foil) in cm "¹ : 3 6 θ θ, 30k0, 2980, 2950, 2890, 1710, 1270, 700.

k) of L-chloromethyl - ^ - phenyl-2" pyrolidinone (yield: #96). I.R. spectrum.

(foil) in cm^-1 : 3060, 3030, 2980, 2950, 2880, 1715, 1255, 765, 700.

l) an L-chloromethyl-3 ethyl 3 phenyl 2 pyrrolidinone (yield: #78). I.R. spectrum (foil) in cm "¹ ; θ θ 3 6, 3 4 θ θ, 2970, 2880, 1770, 1265, 765, 700.

m) L chlorométhyl~5 P-chlorophenyl-2 a-pîpérîdinone (yield: #46). I.R. spectrum (foil) in cm "¹ : 3 4 θ θ, 2940, 2900, 1670, 1480, 830, 800.

n) L chlororaéthyl and 3, 5, 5 trimethyl 2 a-pyrrolîdinone (yield: # + 3 *). I.R. spectrum (foil) in cm "¹ : 2970, 2940, 2880, 1715.

o) 2-chloromethyl-3 a-mêthyl and 2 a-azospiro/9.ï ". 5/decane L-one derivatives (yield: 93#).

I.R. spectrum (foil) in cm "¹ ; 2970, 2930, 2860, 1710, 1450.

p) 3 ~n-butyl-L-chloromethyl-2 pyrrolidinone (yield: #62). I.R. spectrum.

(foil) in cm "¹ : 2960, 2880, 1720.

1.3 l. Preparation of n-£minomethyl) - lactams.

The ammonolysis of an n-chloromethyl-lactam is achieved by introducing slowly, in commotion, a solution of this compound in toluene in a large excess of liquid ammonia to -30 °c. The reaction is accompanied by the formation of ammonium chloride which precipitates. Ammonia is then evaporated, the solution is filtered and distilled under reduced pressure to remove toluene. N-feminométhyl) lactam thus obtained can be used as such for the synthesis of compounds of formula I according to the invention.

&) L eminométhyl-to-hexahydro 2 - azocinone (LHRH).

A solution of (3 mole) 526.8 grams of L-chloromethyl-hexahydro 2 (LHRH) in 1.5 liter of azocinone anhydrous toluene is added dropwise to and under commotion to 2 liters of liquid ammonia. After the addition, ammonia is evaporated, the ammonium chloride separated by filtration and the solution remaining is evaporated under reduced pressure. The oily residue is taken up twice per 1 liter of anhydrous toluene and each time the solution is evaporated under reduced pressure. This provides 463.3 grams (2.97 mole) of a clear yellow oil (yield: #99). I.R. spectrum.

(foil) in cm "¹ : 3400, 3320, 2930, 2860, 1635, 1470.

Prepared therefrom mimics aaaière ^ oslscoé the following:

lF the I ". siain6iltiyl==PPs has!: - rQlidinoneoRendeseat: 98 $. (Movie) ï.r. spectrum in this¹ ! 3380 'o ^ 331: ^ 0 29' 2880 F.* ikîO LCI, 1260.

c)' L-" aainoaétàjl-to-~pipêridinone 2. Yield: 98 $. (Movie) spectrum ï.r. CM-1 3380, ^0 29, 28tog 1635o

to) I MIS "^ k3itl-LAN bexaâydro" 2nd "a2épiîïe-a 2" oae. Yield: 89 $. Ï.R spectrum. T- "*

(iWF) enen.est¹ : 3390, 3320, 294Ô, 286ü, lo and Û ^, ^ 1 90, ikhO,

cautious) I-"eiiin0mltfiylr&etah7dro" - 2e "- 00 grams © sinc=" 2" gold of £th. Yield: $u6. I.R. spectrum.

. The EH cms (Aîà) - "¹ : -3395 has 3320, 2930_O 2880, l6s0, lWiO.

f) the I " ^ a5dnoslt LAN^: ^===- P-ehlor © piiea3rl=3'⁼metliji=2'=gyrrolidinoneo yield: 95 $.

(Movie) spectrum tarue its cm."¹ : 3380, 3030. 2980, 2f30_O 2070, l68o_O 830, 870 ■■th) I- the I ^ ^ aainôâtlÿ'l' J-metbjl s-pyrroliûiaoBe. Yield: 52 $. I.R. spectrum.

(iWF) -<eaW¹ : 3380, 3520, 2976 - ν ≥ 88 θ, is8o.

h) yield: 98 $. (IWF) in I.R. spectrum " T-¹ : 3^603310₉ The MB ^ ^ ^ O-TOj-to-'I', 2870The HS&RF-léêO, 700, 650. i) L emâoâ§ttiylêthyl "3" " ^ ^ 2~3 hinylyrrôli<ïînonè;, Hëridiaent: 70 $1 spectrum systems

the I; the R. (Îîiia) ëâ pDE "¹ * ^ 5380 3320, -2960, 29 ώ, θ έ 88, 1680, 1i9ô, 770, 700.

j) L amnoaëtSÿiT ^₉ ' 5=âimii; "2" fayïpÿi-to-r©lîaino£ie. Yield: 65 $. I.R. spectrum.

(îiïü)êa is¹ : 33Û0, 3320, 2970, 2930, 288 θ, 168o, 126o.

the K) 3 "aAlyl"~I=3 eMaGmétbyl 'phésyl~2=' " w; frroiidinene. Yield: 90 $. Spectrum.. L is its I.R.Ifil&<AAs⁼¹ : 3350, 3220, 3 θ β θ, 2980, ^0 29, 288 θ, θ ΐ 68, 1250, 700. l)=L-of £kia0aëtfcÿl~5 "TSs" eblôiQpaëàylpipêri~=2 (linoae. Yield: 87 $. Spectrum

9.Ï>sec. (GBP F. ùa) EDD.⁼¹ - 3380, 3300, ^0 29, 2900, 28T0, 1670, 1490, 830, 8l0.

m) the L - 3 ê3tayl © saltatrix==="confectioneries" bntylpyrrolidinoae=2. Yield: 89 $. I.R. spectrum.

(wires). " ^ âà of KF¹ -; 3380, 3320, β θ 29, 28 ΘΟ, θ ΐ β 8, 1u95, θ ΐ 46.

fl) ii ^% VaaQEêt FWD) of O ^ a5 tfimithylVVpyrrol-to-iôinoae. Yield: 37 $. Î.rô spectrum (Ùlu)' its FSD¹ : 3390', 3320 ^ 2970, 2930, 2870, θ ΐ β 8.

o) 2 a-Bmaoaitbyl " '3'=mitîîy^, 9.ï "2 '" à2a8pira/ii'₀ 5, /(iêbaae L-speed bumps. Yield: 95 $.

âgeèirè 'I.R.' (wires) in ℮Λ 3390, 3320, 2970, 2930, θ 286.

I. A-2 *•"MariSIsa ' e^8,lsfcsa on - a-aside (route B).

&) feiparatïsa de the, 1 ≈ ο ¾ lassl¹ 5 - 1iiyl *¹ °î " hlnyi°2°pygrolidinone.■' VBE1 . ji in; :.. - Has enjoying " mixture of a solution of 21.8 grams (0.1 moles) of 2 - - 5 - οχ σ

phls5yl L=pffrelidineaegt&and using a solution of 15.28 grams (0,382 moles) of welded eàustig, üe KBES 250 AI water, added, in commotion,: 'P-*' the I: j.; ", 19.98 grams (0, 25 a male ΐ) bromine, EA for ensuring that the temperature does not àépassG 10 a-c. Aprls the I ' the addition, the reaction mixture is stirred pëaâàst - confectioneries, hour room temperature and for 2 hours under reflux.

It is then freeze-dried and the residue, treated with 500 ai of absolute ethanol, is filtered to remove the inorganic salts. The ethanolic solution is evaporated under reduced pressure. Oil remaining is dissolved in methylene chloride, filtered through hyflo aparatus and on the solvent is evaporated to dry under reduced pressure. Obtained 13.7 grams (0,072 moles) of L-aainométhyl-to-5 phenyl 2 pyrrolidinone. Yield: 72%.

I.R. spectrum (foil) in cm "¹ : 3350, 3060, 2950, 1670, l60, 735, 700.

According to the mimic method, the following compounds were prepared:

b) an L-amino methyl 2 pyrrolidinone (it is the same compound that at paragraph 1.1.3. b above). Yield: #68,

c) 1 - (L-aminopropyl)~2 a-pyrrolidxnone.

The compound was used as such, without being isolated.

d) the L - (L-aminoethyl-) - 2 pyrrolidinone.

The compound was used as such, without being isolated.

e) 1 - (alpha aminobensyl) - 2 pyrrolidinone.

The compound was used as such, without being isolated.

I R. 3.nurturingexcept of unnitrile (C pathway).

a) preparation of L - (2 amino-L - " éthyléthyl) - 2 pyrrolidinone.

To a solution of 13 grams (0.09 ^ mol) alpha-methyl 2 oxo-L-pyrrolidine acetonitrile in 250 ml of methanol, is added 0.1 g of sodium hydroxide and 1 g of Raney nickel. The hydrogenation at ordinary temperature and pressure is continued until th that there is more hydrogen absorption and the catalyst is separated by filtration through hyflo aparatus. The filtrate is evaporated under reduced pressure. 9.2 Grams obtained (0,065 moles) of L - (2 amino-l-methylethyl) - 2 pyrrolidinone, used as such for following the synthesis (yield: 69%)•I.R. spectrum (foil) in cm ^ 3380, 2970, 2930, 2870, 1670, 1290.

Was prepared in the same manner the following compounds:

b) the L - (2 a-a " inoéthyl) - 2 pyrrolidinone. Yield: 51% -I.R. spectrum (CHCl ^) in cm '¹ : 3380, 2990, ^0 29, 2870, θ ΐ 66, 1290.

c) the L - ^ T éaminométhyl) propyl7-to-2~pyrrolxdinone. Yield: 75%. I.R. spectrum.

(foil) in NFTs¹ : 3370, 2960, 2930, 2870, 1670.

11, 1, Action of the phosgene or D.u-thioureaphosgene on the n - (a.m.innocentthe alkyl) lactams of formula ITHE I.

11.1.1. Action of the phosgene.

a) the L, 3 a-EBG/t2 oxo-pyrrolidino groups) méthyl7"ur6e. (N°l compound).

H

WITH spent solution 8ô2 grams (7.03 ε ο ℮ 1 3) L=^ ^ 2s2îaos polyethylene resins 2 * pg? rrelîdinone

β. therein.

. 52152 - and-graphite iron (5, 16 hearths) of trîëthylcaiae in 5 liters of chloride

The I /■9.ï⁹

dabydre■methylene -,, I-saintesue *" 10®C.₉ oA is added leateaeat₉ sounds commotion and by ensuring the confectioneries AE unterstanding tespirature does not exceed 5^hasC₉ a " solution 232.2 gm (2_S 3 ^ T-mole) 1 liter of phosgene ODBC ehlorure of æSthyl&°g AEs cooled also a - 10. Tackles the I^O addition allowed the mileage reaction at the temperature slowly return to ambient and then, again cool 1s confectioneries °C - lo, and gaseous ammonia is introduced # e^: '^{the K} ie " fcaiiî-US - - aëin release the triêthylcmime of ε οη hydrochloride. 11

i~♦₄ .

sê chloride 'drilled .' to ' cmmsaiima. which is filtered (is in retrieves 123 grams, or 980 of the theoretical weight) and the solution is evaporated to surviving ΣeE under reduced pressure. The residue is reeristallise in 2 liters of alcohol isopropyligue. This provides 3 θ ¾ the g (yield: 64₉ U0) ^ of 19, 3 - 4 Μ ^ (-êso-to-pyrroliainojEétïiyl / ^ urêe neat. Pp.f " e l8fe₉ 5 °C.

aAMs géuk - C.₁₁H_lambdag the n_{the U} 0₃ (1 ¾ Ρ. Α ≈ 25} (OA is 0}

^; ' o-calculated 51₅ 9 T-HR₅ 1 li 22_has 0

^: found _ 51" OCT 21 9_has 9

Spfeetre ii, andb. (Ethidium) in w 3350₉ 2900₉l68û_has 1&5, 15 ^ 5.

Variant 2;.

20 HAS, 6 f0 grams₉ ^ rgTîsslej ci '. hypoventilation âsingmétîïrl-to-a-2 -===- oÿirolidiïXQnesaethyleae chloride in 100 ml₉ 50 pa_ajoute " ideal of a saturated aqueous solution of sodium earboaeto FISs, toostte slurry is added_has in commotion, taae solution to q-& 5₉ 95 grams (0_has 0S hearth) of phosgene in 50 ml of H§thylâne chloride_P in to ensure that the temperature of the reaction remains below 10®ailieu after 1 gr.⁵ adding_has stirring continued for K hours dahioate temperature aqueous phase is decanted.₂

the LS? apèalio&GMOs extracted several times with methylene chloride.

S

© rgamiques Leo extracts are combined and evaporated under reduced pressure.

The residue is in the reeristollieé minimus in isopropyl alcohol and n-© reeceille thus 7₀ 2 gm (O.₀ O283 role) of pure n°l compound, having the Esmssearaetaristiques than previously. Seadesent? lit * 20.

the I.

- -. vBE1, . F. , ·ν - ·.

Alternatively 3s .

" üw ' solution of KAU © 27 grams (0_has 1^5 ringer)₉ l-ssànoaéîhyl-to-2 pyrrolidinone and 57 gm (erffective powerU₀ ?2 moles) in 300 ml anhydrous pyridine-Si - chloride mSthylèae₀ is ajsstegôutte to drop₉ by ensuring that the temperature δ s ^ Làcarémstimmmal AIS not exceed 0®C.₉ 3 îas solution₉ 6 grams (0₉ 036

THE T, i-erffective powerU

molebe qJ group Located phsfgSme ml of methylene chloride. The reaction mixture is heated to reflux for 2 hours then evaporated to dryness under reduced pressure. The residue is purified by chromatography on silica using as eluent a mixture chloroform-methanol (10:1). In the minimum recristallisê is isopropyl alcohol.

The invention collects 3.5 grams (0.0138 moles) of the compound n°l, which has of course the same characteristics as previously. Yield: 38 ^.

b) an L - / t2 oxo-pyrrolidino groups)/3 - méthyl7 and 3 - (2 oxo-pyrrolidino groups} - propyl methacrylamide/urea (compound no. 2)

In a solution of 5.55 g of phosgene (0,056 mol) cooled to -70 °c, 12 successively introduced,k2 gm (0,123 moles) of triethylamine and 6.39 grams (0,056 moles) of L-amino methyl 2 pyrrolidinone dissolved in 20 ml of methylene chloride. The mixture is stirred for 30 minutes in ensuring that the temperature does not exceed - 6o °C. Then added a solution of 7.97 grams (0,056 moles) of L - (3 aminopropyl) - 2 pyrrolidinone in 20 ml of methylene chloride. After the addition, the suspension is stirred for 1 hour at room temperature and then cooled to -60 °c, temperature at which the triethylamine hydrochloride crystallizes. The precipitate is filtered and the solution evaporated to dry under reduced pressure.

The residue is ehromatographié on a silica column (eluent: acêtoneméthanol, 96a amount). Collected 3.1 g of L - / t2 oxo-pyrrolidino groups) -

. , ... - T- . under. form of unêjiuilemétbyl 3 - / - / 3" (2 oxo-pyrrole 1 BMD) /-propyl - urea/yield: 19,6/5.

3 ^ ^ 22 Analysis for ^ 3 (^{the P} *^M *"² ®² ) (ⁱⁿÆ)

55.3 7.9 h-n-c-calculated 19.8

found 55.3 7.9 19.1

I.R. spectrum (foil) in cm "¹ : 3380, 2970, 2930, 1680, 1550, 1500.

- 0n prepared similarly the following compounds of formula I:

c) the L, 3 "the bis/" (2 oxo-piperidino) méthyl7-urea. (Compound no. 3)

Yield: 3k %. F.w.: l6l-a 2 °c.

Analysis for (ⁱⁿ

calculated C. 55.3 hr 7.8 19.8 N.

found 55.0 7.9 19.9

d) 1.3 to-'bis/Thexahydro~2 oxo-lH azepin l-yl) méthyl7^- urea (compound n°u) yield: 3k %. F.w.: l69 above 70 degrees Celsius.

Analysis for ^ⁱⁿ ^

calculated C. 58.1 8.5 hr 18.1 N.

found 58.9 8.5 l8,l

e) 1.3 bis/Thexahydro and 2 oxo-L-(2:00) - azocinyl) methyl / - urea (compound no. 5) yield: uljï. F.W.: 224 AND 5 DEGREES CELSIUS.

sSS-? (0>AAs

i salS&℮ 60" 3 hr 8_O 9 I-l6₉ 5

i/teeir 60j4 8₂ 8 ΐ β, 5 the L, O "2~^ tastaî2yâp3 m3 of £X-;~~grams of L=lïïaseain" 7l)/ffiêtàyl "the m=ee ' 3" (Goaposl has®6) ftaadSEaafe; fe00. PP DESIGNATION: 20?~8 °C.

VAAS Aaaljo® * (P-its)

eDI ' Ælê ℮ 62₅ 3 HR 9.4 15.3 THE I

trm.vû 2 β, the L 0, 9.4 15.3₉ 3~Mo/s (v=2^m © s9gà&7l "^ ^ ^ 3 ^ IH-T-P-=^ © Hâiae) Eîk&h3rl /"u5?êe. (These ^ it has⁰ ?). SsaScssæS: 360=P.F.t 202 above 3 degrees Celsius.

Aaclyospsïüs⁵ the GC ^ ^ ggSlgïïj.Qg (its 0)

cdeulfS ℮ 59.6 e 5, β 1, 11.1 l4 LC_O l-teeracâ 59.2 5.5 11.0 14.7 1.3"mojj5 *=e3ta§'=the 2'=os9" pgnre^, ^ / oli0lsoJaStfcsrl aces' le<>(Cosçoaê has®8), BoaâeasîKs 70. PP DESIGNATION? 120=1®C..

AaalyoGgsîs³ C.:. J. (EDD 0}

55.3 g of I-e 7.9 eclealê? 19.9

55.3 7.8 19.7 1.3 ·=Μΰ tswvxl δ ≈ ℮Ε α ≈ 5=^ ^ ^ ^ 1 · β ΰ δ Ε ρ ΐ=ΘΗΰΐ άΐΕ 3 0 5 1 / τ ΐΒ ηΐ Θο=4 (n-CoEgosë®9) of £3afcBsis&<2ï: 330" 1§9 and 2 degrees Celsius.

00 M.: Oycoiîsîs³ (in 0}

3 ℮ο, 6 C. ℮κΐ 67.9 hence he 6.4 ii 13.8

tmmû 67.3 6.4 13.7 l.₅ 3"mq £l^iC (S=e: 2ài " - P2Y^; GBP⁾ © aias GBP-L) P-!, '^! © p7l_ /" urie. (Coaposi no. 10) KcaâGnGafcs 580, w, F., 130=l e^has C..

09 ^ £223 (its 0)

1 ℮ο ℮ΐ, 6 58.0 grams ΐΐ 18.1 lii 8.4 sec.

feosvS 57.9 8.5 17.9 1₉3 ≈ Μο ^ ≈ (2=02 Θ ≈ 20 ^ ^ άΗάέ Σ 43) (≈ ΰΐ ^ ^ 1 · ≥ 1 / ℮. (Coapocê n-® lu) GSP €AIG: rÆs. 150, 158~9®C. F.F.s.

Mcâ, ycopsai? (®^has 0)

55.3 ℮οΐ℮ Ω ΐ β C. ii 19.8 7.9 hr

ïwmiï 55.2 7.9 19.7!_GBP ) 2^=,, î5 £c £{2'=sï: © j'=pïi5ayl^p5rap © l £âieî'd) sltlî3rl_{the I} =/ - IU^{the I} 6th (n-Cesposi®12)&aêc23fcj 680, pp.f, :188 - 9®C..

VAAS AaolyoG?^C §3% ©^1] 4⁰ 3 (eDD 0)

68.0 edgraXS C. lii 6.4 l-13.8

the ts' owâ 68.0 6.3 13.8

(7, ^

V-RH

calculates C 55a3 hr 7.8 19.8 hr

found 55_S 1, 8.0 19.2

u) 1_has 3a/2 - (2 oxo " of pyrrolidino) propyl methacrylamide / - urea. (N ° 2l compound)

Yield: 43 /?. Spectrum I,, the R. (foil) in cm 3360, 2980, 2930, 2870, 1660.1550.

v) the L, 3a/2 - (2 oxo-pyrrolidino groups)/- butyl-urea. (Compound no. 22)

Yield: 55 $.

This compound is in the form^! an oil non-distillable additive.

Mass spectrum: a/e 338, 253, 183, 170, 4 ΐ θ, 139, 126, 112, 98.

MR spectrum (CDC1₃ in IMS ψ):

v) L._O 3 "of bis of £3 - (2" 03îo~of pyrrolidino) propyl methacrylamide / - urea. (Compound no. 23)

Yield: fourth KL %. F.W.: 87 AND 8 DEGREES CELSIUS.

Analysis for (ⁱⁿ $)

h-I-c is calculated 58.0 8.4 18.1

found 58.0 8.5 18.2

II. 1.2. Action of the thiophosgene.

a) the L_O 3 "the bis /. (5" w "cKLGropiiényl" 2 a-oro~pipéridino)/2methyl - 2-thiourea. (Compound no. 24).

To a solution of 6.9 grams (0,029 moles) of L-aminomêthyl and 5 P-chlorophênyl-a 2=piperidinone and 2.34 grams (0,023 moles) of triethylamine in 50 ml of methylene chloride, maintained at low temperature (-20 °c), is added slowly, in commotion, a solution of 1,334 grams (0, 01 ΐ 6 moles) of thiophosgene in 10 ml of methylene chloride. After the addition, the reaction is allowed to return to ambient temperature Kêlange confectioneries which is then cooled to - 50 °c - to precipitate of triethylamine hydrochloride.

Is filtered, and the filtrate is evaporated to dry. The solid obtained is recrystallized in methanol. The invention collects 4.1 grams (0.0079 moles) of 1.3 to-(a)/t5-to-p~chlorophényl and 2 oxo-pîpéridino)/methyl^- 2-thiourea.

Yield: 68 $. F.W.: 212 AND 3 DEGREES CELSIUS.

Analysis for^C 25^H 28^C1 2^NR 4 °2^S (in $)

calculated C. 57.8 hr 5.4 n-10.8 LC 13.7 found 57.8 5.5 10.7 l4, 0 6.0 6.2 sec.

Was prepared in the same manner the following compounds:

b) 1.3 bis/t2 oxo-pyrrolîdino) méthyl7~2-thiourea. (Compound no. 25) yield: 68 $. F.w.: l83 and 4 degrees Celsius.

Analysis for ^ ^ ^ ^ ΐ 8 4 2 ^ ^ⁱⁿ ^

6.7 48.9 h-n-c-calculated 20.8 11.9 sec.

found 48.8 6.8 20.8 11.7

c) the L, 3a/('3 n-butyl 2' oxo-pyrrolidîno) methyl - /^, 2-thiourea. (Compound no. 26) yield: 7 $. 657:119 AND 20 DEGREES CELSIUS. I.R. spectrum (CHCl ^ in cm^-1 : 2940, 2860, 1670, 1555, 1340, 1200, 1050.

NMR spectrum (cd01₃ THE TMS +):

The compounds 26 and 27 are two diastérêoisomères which were separated by chromatography on silica column.

I.R. spectrum (on KBr) in cm "¹ : 2940, 2860, 1670, 1555, 1340, 1215, 1040.

NMR spectrum (CDC1₃ THE TMS +) *.

℮)

1 - Ahejtahydro s-WSW-lH aaêpi:

2 - thîouree. n-fCosiBose®28)

I~■-yl} methyl - 3~//(2 a-oropharyngeal of pyrrolidino) methyl-n - /

(0

To a solution of 3.8 ai (V-, 5 moles) of thiophosgene and 1g,1 grams

, 1 mol.' of triéthylssine in 50 AL of methylene chloride, maintained confectioneries -70 °g, is added slowly and under stirring a solution of sharp fa, 2? gm (0,055 moles) of L-substituted aminomethyl 2 pyrrolidinone ODBC 50 ml of methylene chloride. After the I^O the addition, the reaction mixture is allowed to return to room temperature and slowly adding a T, 8 grams (0,055 moles) of L-aaaineffiéthyl-to-hexahyàro SH-to-asépine - ^ ' - one derivatives. The stirring is continued for 15 min._O then the mixture is cooled to -50 °c to precipitate the hydrochloride triéthylssaine " is filtered, and the filtrate is evaporated to dry. The residue obtained is purified by column chromatography on silica (eluent: chloroform). 5.9 G of 1 is obtained - / Chesa-hydro 2 and Prognoz-lH a2epin L "GJs)~methy3V 3p regulated/t2" Q-: OS~PYR degradation: rGlidin 0) methyl /■thiourle~~2. Yield: 39) 5. F.w.: the L ^ t~8^has C..

Analysis for (en/5):

calculates C 52.3 hr ΤΛ 18.8 and 10 sec., T.

52.2 18.7 10.1 is

II. 2. The action of the L ^the L'a-fthiojearbisyldiasolwthe starting motore iHhninbone

of formula II.

11.2=1. L-^ ' - earbonyldiimidazole.

a) the L "/ 03sToctahydro-a 2=-: O lH azonîn '=- L 'yl) methyl /' 3 - / -) (2 a-ozo-to-of pyrrolidino) methyl/urea. (Compound no. 29)

To a solution of 5.7 grams (0.05 moles) of L-a.iüinomethyl-to-2 pyrrolidinone in 20 AL of methylene chloride cooled i - 70 °c, is added under stirring a solution of sharp 8.1 (0.05 moles) of g to 1.1 ' a-carbonyldiîaidaaole in 20 AL of methylene chloride, then 8.5 grams (0 "05 moles) of L-sainoE.éthyl~oetahydrQ-to-2h" a2enine-to-2 One in 20 ml of methylene chloride. After the addition, the reaction medium is heated under reflux for 2 hours. After evaporation of the solvent under reduced pressure, the residue is purified by column chromatography on silica (eluent:

chloroform). This gives 5.7 grams (θ, 0l8I moles)/L - (octahydro 2 a-oro~lïï "asonî2i"l=yl)/2methyl "_ - 3/(2 O ': gm~pyrroliAino)/- methyl-urea.

Yield: 36, 7 /?. F.W.: 1 ^ 9 ABOVE 50 DEGREES CELSIUS.

Analysis for c - ^ ^ ^ O-hgglï (in /)

calculated C. 58.0 hr 8, U-hr 18.1

found 57.6 8.1 18.3

Ga-prepared of 1

so the following compounds:

b) the incorpora! x Cit! n°l already previously. Yield: Vf of?.

c) the compound N^I the LL already mentioned. Yield: lHRH %.

d) 1.3 to-'bis/r3-to-7t) utyl' and 2 oxo ' a-of pyrrolidino) methyl urea / -. (Compound no. 30) yield: 65?. Pp designation: l86 and 7 degrees Celsius.

Analysis for 3 (in %)

62.3 hr 9 c is calculated,¹ THE N * 15.3

found 6l,7 9.2 15.6

i) an L - / t3-methyl-L-oxo-'and 2' to-azospiro ^ R., Yi/dec ^ --yl) methyl - 3/^, / - j2 ' a-oxo~pyrrolidino) mêthyl ^ / urea, (compound N^I 3l)

Yield: 18?. I.R. spectrum (CHC1) in cm "¹ : 3380, 3000, 2970, 2930, 2860, 1670, 1555.

f) the L - / Thexahydro-a 2 'oxo-lH azêpin'<' l^rl) méthyl7"3"/t2 oxo-pyrrolîdino) mêthyl7-urea. (Compound N®32), yield: ** 3?. Pp designation: ll4 and 5 degrees Celsius.

Analysis for^C₁ 3^H₂ 2^NR 1 * ^ °3ⁱⁿ ^

55.3 7.9 h-n-c-calculated 19.8

found 55.3 7.9 19.5

g) an L - / Thexahydro and 2 oxo-L-(2:00) - azocinyl) méthyl7^{the R} '3 - / T2' oxo-pyrrolîdîno) méthyl7-urea. (Compound n * 33). Yield: 18?. W, F: 118~9®C..

Analysis for (in?)

calculated 56.7 C. n-18.9 8.2 hr

found 56.5 8.1 3 ^, 3

h) the compound N®22 already mentioned. Yield: 75?.

II. 2.2. Action of the 1.1 ' a-thiocarbonyldiimidazole.

To a solution of 1 ^, 25 grams (0,125 moles) of L-aminométhyl~2-to-pyrrolîdi'none in 100 ml of anhydrous methylene chloride, low temperature (- U0. °C), is added with stirring a solution of 8.9 grams (0.05 moles) of ljl' a-thioearbonyldiimidazole θ in 6 ml of methylene chloride.

After the addition allowed the reaction medium at room temperature and the solvent is distilled under reduced pressure. The residue is recrietalliaé in methanol in the presence of activated carbon. The invention collects 7.1 grams (0.0263 moles) of 1.3^T the bis - / t2 oxo 'a-pyrrolidîno) méthyl7-a 2'-thiourea, which is compound no. 25 already mentioned. Yield: 52.6?.

II. 3. Action of a haloformate alkylth.

To a solution of 3, ^2 grams (0.03 moles) of L'a-araînoraéthyl and 2 a-pyrrolidînone and 1 *, 6 ml of triethylamine (0,032 mol) in 50 ml of anhydrous toluene, is added slowly, by ensuring that the temperature does not exceed 10 °c, a solution of 1.63 grams (0,015 moles) of ethyl chloroformate in 30 ml of anhydrous toluene. After the addition, the reaction medium is stirred for

2 hours '50®thereof to complete the rêaetîo' to the AV is subsequently cooled. ordinary■temperature and filtering the precipitate formed which contains product wants "this' precipitate is suspended in methylene chloride and treated with 1' assroniac gaseous" chloride if aæoaiua YES is formed is filtered and the filtrate is evaporated to ΣeE under reduced pressure.

The residue is in isopropyl alcohol reeristallized " bone obtains 0_S 5 grams (0_O 002' months) L₅ 3~Ms £f2=3xo^p;p^,raIifiiaQ)/mêîhyl " urea_O which is the compound prieedessest n°l already cited. Yield? 13₀ 3 $

it " hr " Action of the azo AUT-eRUs "

". Has a solution (0.1 hearth) 16.15 g of chloride of 2 ^ asîdeοχο-a 1 a-pyrrolidineaeltique AI b9nsêae 300 based on a Dess_O added₉ in commotion at room temperature_C. " l4s (θ, 12 ¾ mol) of trimethylsilyl aaoture (prepared according to the method described by SSA MSaBOMS ^ and. eoll. The j. Gfgaaosetall. ChemSecurity 33 ., (1971), ρ. 153). Then₀ the reaction medium is heated

5 reflux up to FIA with the release of nitrogen. The solution is EIS^C. © APs RIE dry and isocyanate (2 oxo-pyrrolidiao) methyl obtained is used as such (checked GJS& the presence of a group I-a QAC by a band has 2260 cm ^{the X} in I.B.). The isocyanate is dissolved in gasoline, to which is added a few ml.d ' water " the mixture is stirred 1 hour at temperature asabiaate.

0 After evaporation under reduced pressure the residue is reeriotallisl in 1' isepropyiique alcohol. This gives 1.0 gm (0.0039 mol) of L, 3~the bis/r2 Q2æ>pyrrQlidino==)/E3thyl " which is the compound Urêe n°l already cited.

BesaâQESQt: 8 $. "._T- '

Il.5. Acting thatit is L, 3~ms (hydrogyallyflH2~tmo) ureae.

' 5 II. 5.1. Use of the ' L-₅ 3~Ms (hydrqpiéthyl © 5)=- urea.

To a solution of 2550 grams (30 male) of 2 pyrrolidinone and 22.5 grams (0.12 a male) of p<toluèaesulfenique heated confectioneries=120 °c_S oA is added 900 grams (7₀ 5 e © 1q] ^ of the L.₅ 3=his (^ hydro2lthyl)~urêe. After dissolving the same, OA is ëteulfféeaeore mins to 120 °c during 5. Then the mixture is cooled 5 © réaetiesael (ee>80®C.) and © N the lodging under stirring in 5 liters of a mixture of ethyl acetate and isopropanol (77 ; 23).

The solid obtained is filtered, washed with 2 liters of the ethylacetate/isopropaaol cites above and dried under reduced pressure. 763 G of product is collected which is recrystallized in 3.5 liters î5'd 'iséjaropîanol;' of OA, isolates, as well. 650 grams (2₉ 56 mole) of 1₉ 3a/(2 Mo-pyrrolifii n ©)/polyethylene resins - 5th§nrSe₉ which is the eossposfa⁰ !' already cited. Yield: 3 ½.

0a has prepared the DHW manner:

The compound N®=U-gréeldessaent already cited. Yield: 16%

? cFCs

- l, 3a/t3^W. methyl 2 oxo-pyrrolidino groups) methyl - / urea. (Compound no. 3 ^} efficiency: k9, 6%. F.w.: the Li<- 5 - 6⁰ C..

Analysis for c₁ (Ρ. Μ.=282) (in %)

calculates C 55.3 hr 7.8 19.8 N.

found 55.2 7.8 19.8

- the 1.3 bis/t5, 5 a-dimethyl-a 2 oxo-pyrrolidîno) méthyl7-urea. (Compound no. 35) yield: 32, li. F.w.: l80-to-l°c.

Analysis for c ^ ^ HggN atrial (Ρ. Μ. 31=θ) (in %)

calculated C. 58.1 8 hr, 1 + NR 18.0

found 57.7 8.2 19.0

11.5.2. Use L, 3a (L hydroxyethyl) - urea.

To a solution of 3 ^ grams (0, hr moles) of 2 a-pyrrolîdinone and 0.3 grams<0.0016 moles) of p-toluenesulfonic acid heated to 60 °c, added read, 8 grams (0.1 moles) of L, 3a (L hydroxyethyl) - urea (prepared according to the method of E. NINAGAWA et, Japanese KagakuZasshi, 87, (1966), ^ 3 13; 67 Chem.Abstr., (1967), ^ ^ 07 p 3). The mixture is heated for half an hour. The residue is recrystallized from a mixture of ethyl ethyl ether acetate. This provides U-grams (0,011 + 2 moles) of 1.3 bis/I - (2 oxo-of pyrrolidino) ethyl / - urea, which is the compound n°ll already cited. Yield: the LK %.

11.5.3. Use of 1.3 to-(a) (bales) - 2-thiourea.

To a solution of 3 ^ · grams (0, U-moles) of 2 pyrrolidinone and 0.3 grams (0, 00 ΐ 6 moles) of p-toluenesulfonic acid heated to 120 °c, added 13.6 grams (0.1 moles) of L, 3a (hydroxymethyl) - 2-thiourea (prepared according to the method of TAKEICHINISHIKAWA, J.Soc.OrgChem. (Japan) Library ., 11, (1953), 78;

Chem.Abstr. ^, (1953), 7252). The mixture is heated for one hour at this temperature, cooled to 60 °c and poured into 80 ml of methanol.

The suspension obtained is filtered hot and which are separated from the medium by crystallization L, 3a/t2 oxo-pyrrolidino groups) methyl - 2-thiourea /, which is compound no. 25 already cited. Obtained therefrom 5.3 grams (0.0196 moles), either efficiency 19,6/5.

Was prepared in the same manner L, 3 a-(a)/(hexahydro 2 oxo-lH azepin l-yl) methyl - 2-thiourea /. (Compound no. 36). Yield: 18.5 $. F.W.: 213 A-1U °C.

Analysis for c - ^ ^ ^ n-hence he MCOs (Ρ. Μ.=326) (in %)

calculated 55.2 C. 8.0 H-n-17.2 9.8 seconds

found 55.5 8.1 17.1 9.5

II. 6. The ACtiO2n with formaldéhydth euRs L.has 2 a-PYR degradationroliD.inone and the UsOE.

Gradually heated up to 70 °c a mixture of 17 grams (0.2 moles) of 2 pyrrolidinone, 6 grams (0.1 moles) of urea and 21 grams (0.2 moles) D.^C. ^ foraddêkâô 350 to its prlseae © of 0.5 g of Large p toluëaesulf©aique in ISO - if *'d '-water.¹ The solution * e © disorder and observed AU gassing.

Then the reaction mixture of OA èbauffe 1 '^ eflujL'peMGnt-to-'U'iieures₉ then cooling and the filter. The filtrate is evaporated dry confectioneries and subjected

- cbroaatograpîiique purification on silica column using e © e33 lluoat a mixture of chloroform with 50 of mltbanol. The invention collects. 3, Α grams (O.₀ ^ O13 dirty) of 1₉ 3 a-bîe/c2 ' ^ ^ O-yrrolidine)/- aéth3rlurêe which

Is the compound■n°ï dêjl cites. 13 SeadeEsats ΐΛ 0.

iSsultats ' pharmacological.

The products prepared■i.e.(internal excitation) - ^ dsssus have been subjected to pharmacological tests,, the results of which oont reproduced i.e.(internal excitation) aprls ^ "

1. Action on the tgnêsierass process "

a ' inaction on the process is demonstrated in ES first Eaêsiaues_T- place by

•. ;. e._# '*⁴ > VBE1 ' VBE1 •' *:^! " the R * -. ;."^{the R} the ability of the products to improve retention in miffioriellé. rats. Test principle active avoidance developed in the laboratory of the applicant and uses therefor may be described

•© dared follows; ' © has observed the reaction of tab removal rat subjected

_T- - -.I•0^I

at an increasing pressure and quantified (see m ghsïhblpreaï and S._S

© Areh. ïntcPharEaeôynïhérap. 223.₀ (Ï976) (I)₀ l68 - LIT *). The pressure for

_T- . the I *;, " ;■* Λ w '

which the reaction occurs is called reaction threshold. The latter eêt fencing by the elîiffre read on the graduated scale in cms of

t-T-|*

the apparatus used (Malgesy-a method of determining OGOBABILS=DAN) and corresponds dose to the pressure siaîeia who_O applied to the tab animals,,

■•causes " 1g•removal.

■festés; shush plué. the tardg * "anisau2rtimsins exhibit no apparent retention of proof outer; 4' avoidance occurs for a. intensity, of - stimulating" comparable to that of the standby. Conversely, are treated with KAU substance having a positive effect on the

. prssssçuasaïesiques (cosas e.g. piracêtea) show a degree significatif.de_T- retention, ? the stimulus to which rats react by a reflex 4' avoidance is statistically inferior I of test patches.

. 0 ¾ uses AU siniîsua of 20 rats by testing (10 treated rats and 10 rat controls) etet.on defied comae active dose the dose minimum lowering the stimulus EDD-to-âeocous gradations of 11.

The an oral route sua-to-eutsaie of certain compounds of formula I. (3, given a TES SEA ^. the ISS condition effects listed in Table I eidGCDOuCiLFerovaa of this table. " against unterstanding Eanifeatenteeux-IXC. all in one of the test a - higher activity than the I-piræltcsi₉ the process whose action on the PKC agonist is well known.

TABLE I

reference)

b.. The action on the mnestic processes is also demonstrated by the decreased spinal fixation, testing that has been described in the literature (- the need for immediate TJ and al, J.Neuro-to-Physiol. 26, (l963, n°4), 662 - 673); i. e. MQUFAVIEFF-to-LESUISSEGIURGEA NDA, archarch.int. Pharmacodyn.

191, (97 ΐ ΐ, n°2), 279) as an elementary model memory and that is capable of pharmacological reactivity in good correlation with the clinical physiopathology. In rats, after unilateral lesion of the cerebellum, there is asymmetry postural hind legs. This asymmetry can persist spinal section if the animal has spent a significant time in this situation.

This time, said spinal fixation, is in the experimental conditions applied herein, of 45 min.

In contrast, if the spinal section is made before the expiration of this interval, e.g. 35 timed after installation of the asymmetry, this, last disappears.

Animals treated with placêbos holds asymmetry under these conditions.

ïaverefeeat₉ for any product osaz burps âe 'gcrfier the ccÿffiétrie (thus electing 1. fastening nanocrystalline ε) when the seetîea spinal is performed after 35 àisu&ES is "" ssàüîâlpâ' étesa. active "

L^O intraperitoneal administration of some of eoEpssée of formula X gave the results listed in the table " hence he El aprèa ^. The products are all tested has d @ is of Θ, 32 oiï!" the metered sîaiEales the active heap have been reeberebées, except the gs®? the G © PIT>comstically a°l® TM 1®piraeetca. For LOC injectors compounds_I this derived ssaiain® made U-GBP is' Infiiftiiefiesa. the table " its results esatreat *® @ e d of the compound N® Confederal<hand-L Qotgjaepiraeéto® the most active and the EP®, already at the dose of 0_S 32 sSs/communication lines, other eeapeoâspréoeateatteas wears activity of the greasâas order&SARs fairy the giraeStCEiosageriesreo see® .m mm

'■*. THE O~ ■■ ℮ has

The protection EVA 'ERC's SMI cgresafe®© of tjfge ". content claims © R.% UEs TCEs âéssntrie by a dfcâsmtiea-induced lethality" has eurariooatd'aetie-to short duration, the © Merere of JE dlpeateaiaa ^ " {megahertzdeseoutîlîoles_O this eararissatdlpreesieu respiratory mistletoe prsvsfae used will® turn_V. sU. ^ ^ ii sjairscapeâçmerecpaiaQo ^

U.S. product capable of protecting the brain within this short period IF Peppers ^ pasîe ensures survival " products ESAW administered & IQ groups of £URs © C. O-KAU hour avast L.^V. the injection® euroriGontjparallèlesent AU group 10 if téadbâ FISs ssarie reaffiliates oérophpiielogigueeurarisaat prior. 6th test has also been the OIS point made of lafearateires LEEs. the fieparfGrecûs (see w " WiïW and eollos, teehoïntoacs '. EaeofiÿnThérap. S3₅ . (2J53_P a°l), ^.!) ". '

The adniriotratioa by intraperitoneal of certain th e® I® © MPs © SLE-of

23

formula I gave the results described in Table III.

TABLE III

The test compounds thus having equal dose, or lower, a much higher activity than the piracetam.

Toxicity.

The test compounds are remarkably low in toxicity. For example, intraperitoneal administration toxicity for some compounds of the invention is given in table VI.

TABLE VI

1>6 > 1530, 2>3>81 + 6 3>3>81 + 6^3, 1099.5>3,930 5, 3 1001 + 6 T->3 > 1509

which AE ^ aw the nsrt in a animated e®? based on the eight care during the testing of it ' îlïî (e, bïïï7ï0, Gordon's Besearelî conferencing is cfeejaiet ^ R." Eldad a junior Pathologists, aerating? Loadea, 1959).

On the other hand the j eheg rats, when administered intravenously or orally, tested are also unlikely tonics, by eseaple:

TABLE V

The compounds of the present invention thus have potentialities on the plane of the activity on the central nervous system and particularly in neuro-psychiatric. They are also useful as inhibitors of platelet aggregation.

The compositions of the invention suitable for oral administration may be solid or liquid, for example in the form of tablets, pills, dragees, gelatin capsules, solution, syrups, andc... similarly, the compositions for parenteral administration are the known pharmaceutical forms for such administration, for example solutions, suspensions or emulsions aqueous or oily.

For rectal administration, the compositions of the invention are generally in the form of suppositories.

The•" pharmaceutical dosage forms such as injectable solutions, injectable suspensions, tablets, drops, suppositories, are prepared according to the methods commonly used by pharmacists. Mixing the compounds of the invention with a solid or liquid carrier, non-toxic, pharmaceutically acceptable carrier and optionally with a dispersing agent, a disintegrating agent, a lubricant, a stabilizer, or the like may be added ., if desired, preservatives, sweetening agents, agents colorantsi andc..

Similarly, the conveyed solid or liquid pharmaceutical used therein are well known to the skilled person. Solid pharmaceutical carriers for the preparation of tablets or capsules are for example starch, talc, calcium carbonate, lactose, sucrose, magnesium stearate, andc.

The percentage of active ingredient in the pharmaceutical compositions can vary within very wide limits according to the conditions of use, in particular according to the frequency of administration.

Human dosage has an order of magnitude of 3 x 50 mg/day but

optionally variable of 10 mg to 4 g per day.

OA is âmm ~i.e.(internal excitation) θg? confectioneries ο AAs the IQ qzigk ^ has @ has Moltatif ' I-a-œieforaale th @ bg3gê®1 sec. to Eg üq the