New derivatives of the amino-2 phénéthylamines and their preparation.

30-06-1982 дата публикации
Номер:
OA0000006756A
Принадлежит: Sarget Lab
Контакты:
Номер заявки: 57-00-1981340
Дата заявки: 21-02-1981

[1]

The present invention relates to novel derivatives1aninc-to-2 phenethylamines and their preparation method.

[2]

These products are characterized by the following general formula (formula I):

[3]

[4]

wherein R ^=phenyl unsubstituted or substituted by one or more substituents such as halogeno, GFy c1 c4 to lower alkyl, lower alkoxy-c1 to c45 R-COOH or ^=(O-} - HM=PGCs - or R ^=heterocyclic radical such as

[5]

[6]

THE R ^ t-I- R is the same or different ^=H or®3>

[7]

The RC , R, =lower alkyl identiaues or different κ / {

[8]

branched or unbranched of c1 to 06, the R ^ can be equal to hr where RG is a branched alkyl. Further regenerating complementary and R? the R had form with the nitrogen atom to which they are bound rV. heterocycle as

[9]

" o-o - o - - Q.

[10]

I j of the £

[11]

The rgF. ^ Q-P-P-R-GB R is the same or different ^=hr, hr&logéno, Clhydroxy, lower alkoxy of c1 to 04, two adjacent substituents may together form a chain

[12]

0 - - (CK202 )the n with n=1 - 0 - 2 - or - or c-ch-ch-- ^ - 05 -.

[13]

The rr.hén ethylamines emrloyées of formula I may be in the form of free base or salts thereof therapeutically compatible such as hydrochlorides, citrate, berzilates.

[14]

The orthoarylydèneajninophénéthylsmines which is contemplated by the present invention are novel chemical products.

[15]

The scientific literature mentions little dfort

[16]

- énéthyla -

[17]

lead e

[18]

in include for example Dir.4, thylaminoé

[19]

yl 2 aniline compounds synthesized by a Kr J of £PCHO & al, the MED J. Mal. 1966, 00 09 - 12, As a synthetic intermediate cinnamanilides to prorriétéshyrotensives and antisérotonines, the aminoéthyl-to-2 dinydroxy-to-4.5 e ^ iline described in French Patent no. 2644 drug properties or the tower anthypertensivesdihalogénoaminophénéthylsmines reported in the French Patent no. 6923 drug.

[20]

We have now discovered ore imines derived from ortho-amino-phenethylamines, although their structures are different structures products commonly used in this field, exert psychotropic actions be recovering from their emrlovées as medicines with anxiolytic activities antidénre and located.

[21]

The products forming the subject of the present invention are obtained generally by a reaction involving an amine of formula II and an aldehyde of formula III according to the scheme:

[22]

[23]

The substituents R to R ^ ^ having the meanings inai-to-uéesrlus high.

[24]

The amines of formula II are ootenues ARs therein various methods according to the substituents R ^ ^ to Β. The invention will be described so there read is detailed in the following examples illustrate without however the YES 1 ^ exrcsés thus reduce single points.

[25]

Æ3ÔE" IS 1

[26]

3 Synthesis of n - dimethylaminoethyl-6 (ryri convert it 1 I to do 3 ^ - ^ - phenylalkyl, 3 yl 5 amino (formula I :R1 =" RG represents the R=^ ^=hr=s4 ≈ R., the rg= " Rrj === ***®q~r~^ - 0 - Ch ç.

[27]

- 0 -) and its Quinuclidinyl (ORC 01,170).

[28]

1 -<dd Synthesis (hr, n DlM greatly accelerated the Thyl Amin to o - 2 ethyl)~6 benzodio --xol-a 1" 3 yl 5 amino

[29]

400 cm. ^ of thionyl chloride are added ε " 20 g acid benzcdioxole-to-1.3-acetic 5. The mixture is kept stirring overnight at room temperature. The excess of thionyl chloride is evaporated. Acid chloride phenylalkyl T, 3-acetic 5 is distilled (RBs 100°=0.2 mm Hg at the c). Yield 92 jfc * ^ a volume of 100 cm. of dimethylamine is carried to 0° C..

[30]

100 g of the acid chloride of the phenylalkyl-a 1, 3-acetic 5 are added very slowly with stirring.

[31]

The mixture is kept under stirring for one hour and then filtered. After evaporation and distillation of the filtrate, obtained acid dimethylamide phenylalkyl-to-1.3-acetic 5 *=0.3 mm Hg at RBs 145° c. yielding 90

[32]

9 g of LiAlH ^ are poured into a Grignard litree 2.

[33]

400 cm. ^ very dry ethyl ether are added and the mixture is refluxed. A solution of 24 g of dimethylamide in 300 hr 400 cm. ^ dry ethyl ether is poured dropwise. This is maintained at reflux with stirring for one hour. After cooling are poured 150 cms ^ ethyl acetate drop & drop and then 300 centimeters ^ saturated water with sodium sulfate.

[34]

After decanting the ether layer is evaporated and the dimethylamino derivative distilled. 0.1 Mm hg=95 °c to RB. Yield 89

[35]

Its maintaining the temperature between 25 and 30®C., 0.1 mole of amine (19 * 3 grams) is poured dropwise with stirring in 200 cm in nitric acid-d ^ " 1.2. The mixture is kept under stirring making two hours. The precipitation of the nitro compound is optionally amoreée by some water ice. The derivative of ortho nitro is washed to neutrality and dried yield 98 C.

[36]

40 g of the nitrated product are suspended in 1.8 liter of methanol and then reduced under a hydrogen atmosphere in the presence of Raney nickel at room temperature. After filtration and evaporation of the solvent n, n diméthylaffiinoéthyl-to-6 phenylalkyl-to-1.3 y1-to-5 amine is distilled. 0.06 Mm Hg at the c=125° RBs.

[37]

Yield 70

[38]

2 - Formation of the imine

[39]

A mixture comprising 0,025 mole of the amine previously prepared (5.25 grams), 0.05 mole of pyridinecarboxaldehyde 3 (5.35 gm) and 100 centimeters ^ of benzene is heated to 120° c in stirring. Water formed popcorn Peppers of reaction is removed using a Dean and Stark trap. When 0,025 mole of water has been collected (0.45 centimeters-to-'J benzene is evaporated, the excess aldehyde distilled then 1' imine compound. RB is 0.02 mm Hg at ≈ 165®C f=66" 0, * round? feels ≈ 6? cents.

[40]

3 Salinization

[41]

the K a solution of 0.01 mole of imine in 400 cm in anhydrous ethyl ether ^ cooled 0° c is slowly added a solution AEs 0.01 mole of benzilic acid in 300 cm in anhydrous ethyl ether ^. The precipitate is filtered and dried under vacuum.

[42]

This gives the Quinuclidinyl the dimethylamino ethyl-6 n-(pyridylidene and 3) phenylalkyl-to-1.3 yl 5 amine or COH from 01,170. P=13g °C. prepared similarly citrate 01,201 cOH group or the amine (hygroscopic).

[43]

quinuclidinyl,
5•HR, R.9 - R.
* 1=LQ
B., =CL
20B 1 *WHEREIN GX
B 1=LQ

[44]

2 EZjZTLE

[45]

More imine derived from the (n-, N-dimethylamino-2 ethyl) phenylalkyl-to-1.3 -6 yl 5 amine are prepared following the method described in the example I these are the products of formula I such that Rgrams The R=^ ^ ^===R-R-H-, GB " the R ^==the rg CNY

[46]

' 10=- 0 - - 0 - and Ch

[47]

quinuclidinyl,

[48]

free base,

[49]

R

[50]

.^ ^=■" HM=HM -, triethyl citrate,

[51]

THE Q -

[52]

I, =

[53]

R=brr - kg.

[54]

JQL

[55]

B 1=

[56]

B 1

[57]

eOPA - @ -

[58]

, citrates,

[59]

, citrates,

[60]

, citrates,

[61]

, citrates,

[62]

, citrates,

[63]

, citrates,

[64]

, citrates,

[65]

THE COR 01,151, P=139 °C

[66]

The COR 01,169 "w=151° C. CORs 01,171, w=117° C. CORs 01,176, w=144° C. CORs 01,179, w=171° C. CORs 01,181, w=c-ORC 171° 01,203" hygroscopic CORs 01,206, p=176®Q-ORC 01,207, hygroscopic CORs 01,208, hygroscopic CORs 01,209, P-≈ 178o C.

[67]

R

[68]

1

[69]

, citrates,

[70]

The COR 01,210, hygroscoricue

[71]

■aTCaTT 3 in.

[72]

Synthesis (the n-piperidino-2 ethyl) -6 n thienylidene and 2)

[73]

yl 5 berber.zodioxol-to-1.3 amine derivatives (formula I, the R ^ "

[74]

.h, =has, ≈

[75]

B4 =B.5 =H a, b.6 - B.7 =(OH-O )5 , b.8 D=,,=O, R.9 - b.10 - -=0) and its oenzilgte•(ORC 01,175)

[76]

0.25 moles (49.5 grams) acid chloride phenylalkyl~1, 3-acetic 5 are poured dropwise at room temperature in a mixture of 0.5 mole of piperidine derivatives, 0.5 mole of triéthylaraine, 40g ^ cm in benzene, the mixture is kept under stirring for one hour at room temperature. After filtration, the filtrate is washed with water, evaporated and distilled (BSI 175°=0.15 mm Hg at the c). A mixture of 0.26 moles of Li a1h. (10 grams) in susprension 40c in cmsJ ethyl ether bag is refluxed. 0.13 moles of d * amid previously prepared (33 grams) dissolved in 300 cm in ^ of tétraàydrofuranne is poured dropwise, the mixture is maintained at reflux for one hour. After cooling are added dropwise^200 cm in ethyl acetate then 3 cc per cm ^ has' a saturated aqueous solution of sodium sulfate. After addition of ether, the ether layer is washed to neutrality;

[77]

the solvent is evaporated; the amine is distilled (JSB 98.0 0.02 mm hg * 110 °c). 0.12 ' mole of pipéridinoéthyl-to-5 phenylalkyl-to-1.3 thus prepared is poured dropwise with stirring in 24c cms ^ nitric acid " 1.2 by maintaining the temperature between 25 and 30 °c. the mixture is kept under stirring for one hour. After cooling the nitro compound precipitates. It is filtered, washed with a little water and dried p=207 °c. Yield 76 tFs>.

[78]

25 g of the nitro compound are suspended in 2 liters of methanol and then reduced under a hydrogen atmosphere in the presence of Raney nickel. After filtration and solvent evaroration the amine is distilled. JSB 98.0 0.05 mm hg=160 °c, yield 64, 4 *

[79]

the mixture of 6.2 g of the amine (0,025 months), 5.6 g of thiophene compounds carboxaldehyde and 2 (0.05 moles) and 50 cm.* ^ of benzene is refluxed, the water formed during the reaction is removed using a Dean-Stark trap. the excess aldehyde is distilled and the imine is racristallized in petroleum ether. F =62 °C.

[80]

To a solution containing 0.1 mole of imine in dry ether éthylioue, cooled to 0° c is added dropwise to 0.1 mole of benzilic acid dissolved in dry ethyl ether.

[81]

The benzilgte is separated by filtration and dried. P=162 °C.

[82]

GBP 4&ZaTijrL

[83]

The method described in the example 3 allows the synthesis of derivatives of formula I with the rg=R-R-R-^ ^ ^===hr, the rg - ≈ 0-to-Ch a-c, I-the rg=' hr -H *'

[84]

0- Ch a-c, I-the rg=' hr -H *'
10" 1, RG represents R-P-- (cH22 )4 -
B 1- Çr"RG are" " ^®
15B 1Q" R.the R THE R ^- ŒgOHjOOH
B 1- Φ, Βς - Η γ ≈
B 1-, Β γ ≈ hr,B6 =- TBU such
20B 1- CH-CH-==^ -, Βς - Η ^=
B 1■Φ-, The rg-to-of Rj=

[85]

B., the rg-to-LF==" CHgCHgOCHgCHg -, citrates alamin 01,204

[86]

P=2100 C. 5 iSCs-to-aMPLii

[87]

Synthesis of R-cinnamylidene (D, N-dimethylamino-2 ethyl)

[88]

-2 aniline compounds (formula I, wherein R=- ch-ch-=^, ^ ^=≈ Β Β Β ^ ^==b-O,

[89]

The rg Β γ====RG are Y-ch-b-s * h ^ Q-GB) and its citrate salt (ORC 01,185).

[90]

50 grams of o-to-nitrophénéthylslcool are added dropwise to 425 cms ^ hydrobromic acid 48 to the mixture is heated under stirring for 3 hours at 100° C. cooling, it is extracted by ether. The ether layer is washed with water and dried on na2s0 ^ and then the solvent is

[91]

3 removed by evaporation. After cooling to 30 °c - (bromo-' 2 ethyl) the nitro 1~2 benzene crystallizes, it is purified by washing eth&nol, w / C. yielding 50° #82 . 56 g of said derivative are dissolved in 700 inthe IO ethanol. This solution is added

[92]

3•

[93]

govgov.tte to drop to 100 cm dimethylamine cooled 0° c the mixture is kept under stirring for one hour at room temperature and then heated to C. for 4 hours 70°.

[94]

The alcohol is evaporated, the residue is tough cooling dissolved in an aqueous solution of hydrochloric. The unreacted product is extracted with ether. The acid solution is alkalized and extracted with ether. The ether layer is washed to neutrality, dried, evaporated. N, n-dimethyl ethyl amine rr.hén nitro 2 is separated by distillation JSB 98.0 * 0.2 mm hg=95 °c yield=81 <F.0 . This amine is dissolved in methanol and reduced under a hydrogen atmosphere in the presence of Raney nickel. When the reaction is complete the mixture is filtered, evaporated and then distilled to give the (the n, n diméthylsmino and 2 ethyl) aniline--2. M is 0.1 to EB ≈ 85 - 90 mmHgW. 89 C. yielding a mixture containing 0.05 mole of aniline and - repaired (CT, 2 grams), 0.1 mole of cinnamaldehyde (13.2 grams), ^ 50 centimeters of " benzene is heated to 120° C. the water formed during the reaction is collected in a Dean-Stark trap. When 0.05 mole of water (0.9 εm ^} has been collected the " benzene is evaporated and the residue distilled. Jïb 0,025 mm Hg at 8.63 g=158° gms (0,031 moles) of the imine are dissolved in ether éthylicme anhydrous, tough cooling 0° grams, 5>95 g of citric acid dissolved in the minimum of anhydrous methanol are poured dropwise. An oil product separates, ârrès settling of ethyl ether is added to the oily residue. A cooling -40 °C can initiate crystallization; citrate is separated by filtration and dried;

[95]

hygroscopic product♦

[96]

[97]

hygroscopic product

[98]

7 BZBMPLB

[99]

The Syrthèse (D, N-dimethylamino-2 ethyl-methyl-methyl 1) -2:; the aniline - pyridylidene and 3; (formula 1 with R ^=

[100]

~S 5=

[101]

R 3=HM3 ,

[102]

R 8- R. 9THE R= 10 -=H

[103]

L 11

[104]

its citrate salt (ORC 01,123)"

[105]

the mixture consisting of 50 g of o-nitrophenylacetic, 500 cm in methanol ^, ^ 4 cm in concentrated sulfuric acid is heated to reflux methanol overnight. After cooling and neutralization by sodium hydroxide dissolved in methanol, alcohol is evaporated and then the residue is dissolved in ethyl ether. the ether layer is washed with a dilute solution of sodium hydroxide and then with water and then finally dried and evaporated dry. With a suspension of 0.65 moles of NaH (16 grams) in 250 ml triamide this acid phosphoric hexsméthyl (HMTT) is added dropwise with stirring orthonitrophénylscétate 0.53 mole of methyl (103 grams) dissolved in 20 ml of hexamethylphosphoric triamide, then 0.53 mole of methyl iodide (76 grams). The mixture is kept under stirring at ambient temperature overnight then poured into ice water. Added ^ of ECU 250 cm. after extraction with dilute to benzene, the phases benzèniquas are washed to a neutral reaction, further dried and evaporated, and the distilled twice. The BB 0.03 mm ^ ® 92°<3 . 24 kilograms of 1' the ortho, nitro-phenyl-2 pronionate methyl are dissolved in 300 - 400 cmJ anhydrous ethanol. 15 g of EaBE ^ are added to the solution which is refluxed with stirring for 17 hours and. After cooling the excess NaBH ^ is. destroyed by acetic acid. The alcohol evaporated; water and ethyl ether are added to the evaporation residue. Chase ethereal is washed with water, dried on the Na " s0. and distilled. The BB °C. 27 g of 0.03 mm hg=105 - 110 (orthonitrorhényl) -2 rronanol are added to 220 cm in hydrobromic acid 48 ρ th ^.

[106]

The mixture is heated to C. for 6 hours 100°, extracted with ether. The ether layer is washed with water, dried on KajSO ^, évarorée and distilled. The BB=0.02 mm Hg at 90 ESA 112° c. yielding 35 g of the solution of bromo-1 (o-nitrophenyl) diluted in 100 ml propan -2 of absolute ethanol is added to 60 cms ^ dimethylamine cooled 0° C. the mixture is heated to 70 °c during 20 hours. The alcohol is evaporated. The residue is dissolved in a dilute hydrochloric acid solution and extracted twice with ethyl ether. The acidic aqueous phase is alkalized, chloroform extracts, dried on NagSO ^, evaporated and distilled The SB 0.2 mm hg=90I C 11.5 grams of n, n éiméthyl -2 (onitrorhényl) propylamine by solution in 500 cm in ^ methanol are reduced in the presence of Raney nickel under hydrogen atmosphere. When the reaction is complete the mixture is filtered, the filtrate evaporated and the residue distilled; Hg=0.1 kb in 82° C..

[107]

the mixture comprising 0.02 mole of (n-, N-dimethylamino-2 methyl-1 ethyl) aniline--2, 0.04 mole of nicotinaldéhyde, 120 cm in anhydrous benzene ^ 120° is heated to C. the water formed during the reaction is removed using a Dean-Stark trap. the benzene is evaporated and then the excess aldehyde nicotinic distilled. The imine is obtained by distillation. 0.03 Mm Hg at RBs 135° C=4" 16 g of the imine (0,015 mol) are dissolved in a liter of anhydrous ethyl ether. After cooling to approximately 32 -5 is added dropwise, 2.88 g acid citricue (0,015 moles) dissolved in the minimum of anhydrous methanol. the citrate is obtained after filtration and drying at vacuum tomre 4c to 0 degrees " hygroscorioue product. _

[108]

8 jgflrFIS

[109]

Synthesis of (n-, N-dimethylamino-2 methyl-2 ethyl} - 2 n ryriaylidene-to-3 aniline derivatives (formula I with R ^ -, R.grams THE R ^==

[110]

=hr, Rç=^ j-ch-ch-the rg Η γ==^ I-== Hr=^ K-) and its citrate salt (ORC 01,214)•

[111]

A solution of 78 grams (0.6 moles) of ethyl acetoacetate in 50 ml of hexaméthylphosphorotriamide ^ (HKPï) is added dropwise to 21.6 grams (0.9 moles) of NaH in 110 ml of hmrî.

[112]

WITH this mixture are then added dropwise 84.6 grams (C., 6 moles) of o-to-fluoronitrobenzene in 100 ml of hexamethylphosphoric triamide. The mixture is maintained at ambient temperature overnight. It is then poured into ice water with stirring. After adding 300 AE ^ HCl diluted at £is extracted to benzene, washed with water and then distilled, BSI 0.05 mm Hg at " 110 °c. 50 g of the (o-nitrophenyl) -2 oxo 3 ethyl butyrate prepared are heated to 120° scus C. stirring in a liter of diluted hydrochloric acid if *. After cooling, chloroform extraction, water washing, drying on NagSO ^, evaporation, methyl (O nitrobenzyll ketone is distilled. Yield 40 - 50 tM A mixture comprising 26 g of the ketone, 300 cm in ^ of absolute ethanol, 13 g of RaRH ^, is kept under stirring for one to two hours. the excess Dato NaBK ^ ^ CQOH OH is destroyed. The ethanol is removed by evaporation. After extraction with ether, washing of the ether layer with water, drying and evaporation 1' (o-nitrophenyl) -1 rropanol-a 2 is separated by distillation the BB=0.03 mm Hg at 105° C..

[113]

F.<^ 50° C. a mixture containing 15 g of ' this alcohol in 12ô cms ^ ^ 48 to hydrobromic acid is heated for 2 hours at 100 °c.

[114]

After cooling and extraction with ether, the ether layer is washed with water, dried and evaporated. The bromo 2 (o-nitrophenyl)

[115]

-1 propane is separated by distillation the BB 0.02 mm Hg at ® 120° C..

[116]

Yield ≈ 86 a mixture containing 11 g of this product, 40 cm. ^ dimethylamine, 20 cm from ^ of absolute ethanol is heated overnight to 70° c in an autoclave. The solvantB * are evaporated the residue is dissolved in a solution of HS foix extracted two and diluted with ethyl ether. The aqueous phase is alkalized, extracted, chloroform, dried on sodium sulfate, evaporated and distilled. The BB 0.2 mm Hg at 90° C=9.5 gm of n, n-dimethyl-O-nitrophenyl 1 propyl amine and 2 thus prepared are dissolved in 500 cm3 methanol and reduced under a hydrogen atmosphere in the presence of Raney îtickel. After filtration and evaporation of the filtrate (the n, n diméthylemino and 2 methyl-2 ethyl) -2 aniline is separated by distillation. The formed mixture of 5.9 g of the amine (0,033 moles), 0,066 mole of aldehyde nieotinic ^ heart 150 and is heated to anhydrous benzene 120° 0. The water formed during the reaction is removed by means of a trap DeanSiark.

[117]

The benzene is evaporated. Distillation eliminates the excess aldehyde nieotinic and retrieve the imine. 7.37 g of thereof (0,027 moles) are placed in solution in 1.5 liter of anhydrous ethyl ether. To this cooled solution and a driving -5 -10 °c are added dropwise 5.18 g citric acid (0,027 moles) dissolved in the minimum of anhydrous methanol. The citrate is obtained by filtration and drying under vacuum to 40° C..

[118]

hygroseopic product.

[119]

9 jgBIPLB

[120]

Synthesis of n - (where n, n dimé polyethylene resins 2 - amino-ethyl) benzo dioxol-to-1.3 -6 yl 5 formimidoyl-to-2 benzoic, inner salt ii (formula I,V. C00H

[121]

7.5 g (0.05 moles) phtalalaehydic acid are suspended in 800 centimeters ^ benzene. the mixture is heated at reflux of the benzene. Added 0,055 mole of (n-, N-dimethylamino-2 ethyl) -6 bensodioxol-to-1.3 yl 5 amino (11.4 grams) diluted in 200 cm in ^ benzene, water formed during the reaction is removed by means of a trap Eean-Stark apparatus, the precipitate is sénsré by hot filtration, washed with benzene and dried under vacuum. Yield 70 I THE C=204°.

[122]

the products of the present " invention have been determinations following physicochemical ii

[123]

1 - NMR spectra, internal standard msec

[124]

The COR 01,142, methyl ester prepared by diazotization, solvent CISC3

[125]

2.3 ppm 6 proton; the j ^ néch singlet),,

[126]

2.2 - 3.2 Ppm 4 proton} massive complex; - Ch-to-CKG's K-3.9 ppm 3 proton; singlet; CHyO

[127]

5.9 ppm 2 I-proton singulot; O CH.,-to-0

[128]

6.7 ppm 2 proton ii 2 singlets j-aromatic protons (benzodioxolyl)

[129]

7.2 - 8.4 ppm 4 proton; massive complex; (benzylidene) proton aromar ticks

[130]

9, 1 ppm 1 proton abstraction; singlet; -=Ν: 0 - Ε

[131]

The COR 01,151 solvent-DMSO d6

[132]

2.7 rpm 6 proton; singlet; ^ ^ (ch-^)

[133]

2, 9 - 3, 2 4 pNM are proton; massive complex - Ch-to-SDOH n 6.0 ppm 2 proton; singlet % 0 CH2 - 06, 7 - 7, 8 ppm 15 proton; massive complex; aromatic protons 7.5 - 9 ppm 2 proton ii peak spread the j ^ d-labile proton exchangeable with the O

[134]

8.8 ppm 1 j of the proton singlet; - the K=HM -

[135]

CRC 01,163 solvent DfêSO d-6

[136]

2.8 ppm 6 proton; singlet; NCCK ^) ^

[137]

3, 0 - 3, 4 ppm 4 proton; massive complex; - EMC Ch 6.0 ppm 2 - ^ n-proton; singlet; - O Ch O -

[138]

6, 8 - 8, 0 ppm proton; massive complex? aromatic protons 8.8 ppm 1 proton abstraction; singlet; d=- CH2 -

[139]

11 rpm 1 proton abstraction; singlet; labile proton exchangeable L.ave C. BMD

[140]

CCHs 01,169 CDC1 solvent,

[141]

2.5 ppm 3 proton; singlet; thienyl Ch ^

[142]

2.7 ppm 6. proton; singlet; NtOH ^) ^

[143]

2.8 - 3.2 ppm 4 proton; massive complex; - Ch-to-Ch-to-ii 5.9 ppm 2 proton; singlet; - the O-CH2 - O-- ^

[144]

6.4 - 7.8 ppm 14 proton; massive complex; aromatic protons

[145]

8.3 ppm 1 proton abstraction; singlet; d=- CH2 -

[146]

8.5 - 10 rpm 2 proton; peak spread; labile proton exchangeable with d ^ the O

[147]

0 - 1 170-solvent CCD ^ COI structure

[148]

2.6 ppm 6 j-proton singlet; d (HM3 )2

[149]

2.9 - 3.2 ppm 4 proton; massive complex; - Ch-to-EMC-n-5.9 ppm 2 proton; singlet; - O Ch O -

[150]

6.5 - 9.0 ppm 17 proton; massive complex which singlet to 8.3 ppm aromatic protons + n-CH2 -=

[151]

9 - 10, 5 ppm 2 proton; peak spread I-labile proton exchangeable with BMD

[152]

COH from 01,171 solvent

[153]

2.3 rpm 6 proton ii singlet; d (HM3 ) grams

[154]

. 2, 2 - 3, 2 ppm 4 proton the I massive complex; - Ch Ch ^ - n 5.9 ppm to 2 proton; singlet; - O Ch O -

[155]

6, 6 - 7, 5 ppm 5 j-proton massive complex; aromatic protons

[156]

8.4 ppm 1 proton from F. singlet; d=- CH2 -

[157]

CRC 01,173 solvent GDCl ^

[158]

1.6 - 2.1 ppm 4 proton 9.ï massive complex; c Ch-PMF-C. 2.7 - 3.4 ppm 8 proton; massive complex; Ch-to-to CKG n (to CKG)2 ~, 5.9 ppm 2 proton ii singlet; - O Ch O -

[159]

6, 5 - 9, 0 ppm 17 proton ii massive complex which singlet to 8.3 ppm aromatic protons + n-CH2 -=

[160]

5 - 11 2 ppm by proton; peak very spread; labile proton exchangeable with BMD

[161]

The COR 01,174 solvent CDC1 -,

[162]

3

[163]

1, 2 - 2, 0 ppm 6 proton; massive complex; 0 - {HM2 )3 2.4 - 3.3 Ppm 8 - C. proton; massive complex; HM2 - HC2 THE N - - (THIS2 )2 5.9 ppm 2 proton; singlet; - O SDOH O -

[164]

6.4 - 9.1 ppm 17 proton; massive complex which singlet to 8.3 ppm aromatic protons + - n-Ch -

[165]

6.5 - 10 ppm 2 proton, · peak very spread ; labile proton exchangeable with bgrams 0

[166]

EOC 01,175 solvent odcï ^

[167]

1.3 - 2.0 ppm 6 proton; massive complex;

[168]

2, 5 - 3, 4 Proton of FF®8; massive complex ;

[169]

5.9 PPs®2 proton ; j-singlet - O Ch O -

[170]

6.4 - 7.8 ppm 16 proton? massive complex having a singlet to c - (CH22 )3 - c. <M.O -<eO - has - (Œ10O )O

[171]

8.4 PPs®; aromatic protons +=n-human gh -

[172]

6 - 10 ppm to 2 proton; labile proton peak toroids spread ii

[173]

EOC 01

[174]

exchangeable with dgrams 0

[175]

176 solvent dms0 - d6

[176]

2.6 ppm 4 proton; singlet; - Ch O-Ch -

[177]

2.8 ppm 6 j-proton singlet; d - (human gh3 ) grams

[178]

2.9 - 3.3 PPs®4 proton; massive complex; Ch-to-to CKG n

[179]

6.0 ppm 2 j-proton singlet; - O SDOH O -

[180]

6.9 - 7.9 ppm 9 j-proton massive complex; aromatic protons + - 0 0 - Η Η ≈

[181]

6.4 ppm 1 proton abstraction} dipole; - the n=- HC

[182]

10.4 rpm 4 proton; broad peak; labile proton exchangeable with BMD

[183]

EOC 01,179 solvent ms0 - d6

[184]

2.6 ppm 4 proton; singlet; - Ch c-Ch -

[185]

2.8 ppm 6 proton; singlet ii the n (HM3 )grams

[186]

2.9 - 3.3 PPs®4 proton? massive complex} Ch-to-Ch n

[187]

6.0 ppm 2 j-proton singlet; - O Ch O -

[188]

6.9 - 7.9 PPs®5 proton; massive complex; aromatic protons

[189]

8.8 ppm 1 proton abstraction; singlet; d=human gh - -

[190]

10.6 ppm 4 j-proton RIE etching wide; labile proton exchangeable with BMD

[191]

C1 180 EOC bks0 - d6 solvent

[192]

2.4 - 3.2 ppm 12 proton; massive complex HM2 - hC2 - hence he (HM2 )2

[193]

2.4 - 4.0 ppm 4 proton? massive complex;

[194]

6.0 ppm 2 proton; singlet; - O Ch O -

[195]

6, 6 - 7, 9. 5 ppm based proton; massive complex;

[196]

; hM2 - c. Ch2 +

[197]

- this2 - o-OH2 -

[198]

aromatic protons

[199]

8.7 pPs®1 j is the proton singlet; d=- HC

[200]

10.5 ppm 4 proton, broad peak; labile proton exchangeable with dgrams 0

[201]

PCC. 0 '13' 1 solvent dks0 - d6

[202]

THE K (THE CK3 )2CHgCHgN + 2.4 - 3 - " 5 ppm 14 proton; massive comrlexe; Ch O-SDOH +

[203]

6.0 discount. 2 proton; singlet; - the O-CH2 - O-- ^

[204]

6.8 -7 , 4 6 rRMs letlet us rrotons; massive comrlexe; aromatic proton-proton 8.7 ppm 1; singlet; d=- Ciï

[205]

9.5 - ^ ΐ MPI 4 proton; peak spread; labile proton exchangeable with BMD

[206]

ORC 0 * 184 solvent dms0 - d6

[207]

2 4 6 rpia proton; singlet; - Ch c-Ch-

[208]

2.7 ppm 6 letlet us rrotons; singlet; NtCK ^ grams

[209]

2.9 - 3.3 Ppm 4 proton; massive complex; Ch Ch ^ - n-T-, 1 - 9, 2 ppm 9 proton; massive complex having a singlet to 8.7 RRMs; aromatic protons +=- HM - N.

[210]

11 ppm 4 proton; broad peak; labile proton exchangeable with BMD

[211]

CRC 01,185 solvent dks0 - d6

[212]

2.6 ppm 4 proton; singlet, •HM - ^ c CHj)

[213]

2.7the RR the m 6 proton; singlet; NCGH ^) ^

[214]

2.9 - 3.3 ppm 4 proton; massive complex; Ch Ch ^ n-proton - 6.9 - 7.9 PPs®11; massive complex; aromatic protons +=- ch-ch--

[215]

8.3 rpm 1 proton abstraction; dipole;=n-CH2 -

[216]

10.2 ppm 4 letlet us rrotons; a dome; ^ 2° exchangeable with labile proton

[217]

COPS. 0<186 solvent bks0 - d6

[218]

1, 7 - 2, 2 ppm 4 proton; massive complex; O OHj-to-OKg O 2.6 ypm 4 proton; singlet - Ch O-EMC -

[219]

2.9 - 3.5 ppm 8 proton ii massive comrlexe; HM2 - HC2 THE N - (HC2 >2 6.0 letlet us rrotons' R-m 2; singlet; - O CEîg O -

[220]

6.9 - 9.2 rRMs 7 proton; massive complex having a Sign-Land to 8.7the R rm.; ii=HC + aromatic protons.

[221]

9, 5 - 10, 5 ppm 4 proton; dome; labile proton exchangeable with BMD

[222]

The COR 01,195 solvent 33eso - d6

[223]

1.3the R r-proton®9; T-singule; C. (HM3 )3

[224]

2.6 ppm 4 proton; singlet; Ch c-Ch -

[225]

2.9 - 3" 3 ppm 4 proton; massive comrlexe ii - 2 - CHgCHgS and 6.0 ppm based proton; singlet; O Ch O

[226]

6.9 - 9" 2 ppm 7 proton; massive complex whose starting motor. singlet 8.7 PPs®ii proton aromatiaues Ν ≈ + (2 - Η

[227]

5 - 11 ppm to 5 proton; peak spread; labile proton exchangeable with BMD

[228]

The COB 01,200 solvent'd?.' a SC-d6

[229]

1 7 - 2, 3 ppm 4 proton; massive complex

[230]

2.6 ppm 4 proton; singlet; Ch c-HC

[231]

2.9 - 3.6 rpm 8 proton; massive complex

[232]

6.0 ppm 2 proton; singlet; O Ch O

[233]

6.9 - 7.9 PPs m-proton; massive complex;

[234]

; C. CH2 - HC2 - i

[235]

2

[236]

; HM2 - HC2 THE N (HM2 )2

[237]

aromatic proton " + - g K=HM '

[238]

6.4 ppm 1 Croton Tiglium; dipole;=n-CH2 -

[239]

9.5 - 11 ppm 4 proton; dome; labile proton exchangeable with d2 0

[240]

The COB 01,201 solvent dks0 - d6

[241]

2.6 ppm 4 proton ; singlet

[242]

2.7 ppm 6 proton; singlet

[243]

2.9 - 3.2 ppm 4 proton; massive comrlexe

[244]

6.0 ppm 2 proton; singlet; toilet 1800 to U-shapes

[245]

6.9 - 9.2 ppm 7 proton; massive comrlexe which a singlet to 8.7 ppm} proton Ν ≈ 0 - + aromatinues Κ

[246]

HM2 - C. CH2

[247]

the n (j of 0:00O

[248]

CEgCHjJ: -

[249]

9, 5 - 10, 5 ppm 4 proton; peak spread; labile proton exchangeable with BMD

[250]

The COB 01,202 solvent diis0 - d6

[251]

1, 3 - 2, 1 ppm 6 letlet us rrotons; massive comrlexe; C. - (HC "), - C.

[252]

5 d.

[253]

2.6 ppm 4 proton; singlet; - Ch c-Ch -

[254]

2 ,t above 3.5 ppm to 8 j-proton massive comrlexe; ch-ch-^0 W ' (Cïï *)2 6.0 ppm 2 proton; singlet % - O Ch O -

[255]

6, 9 - 9, 2 ppm 7 proton; massive comrlexe which a singlet to 8.7 ppm; aromatic protons + -=- OH-Ν

[256]

4 Lo Prom proton; broad peak; labile proton exchangeable with BMD

[257]

The COR 01,203 solvent bes0 - d6

[258]

2.6 ppm 4 proton; singlet; LEC c-HM, .

[259]

6 4a

[260]

2.7 ppm 6 proton ii singlet, ii * - {HM,)0

[261]

_ the j - T.

[262]

2.8 - 3.3 PPs®4 proton; massive comrlexe; ch"c7,jf

[263]

6.0 rRMs 2 proton; singlet; - C. Ch ^ - C.

[264]

6.8 - 8.8 7 rTMs proton•massive comrlexe which a singlet to 8.6 ppm; aromatic protons + - 0 - Η Ν ≈

[265]

10.1 ppm 4 proton; broad peak; proton Irbiles exchangeable with BMD

[266]

01 2C4 bms0 - d6 COH from solvent

[267]

2, 5 - 3, 3 12 PFMs proton; massive comrlexe; Ch g-ch-■Ch + ^2 - hC2 hr (HM2 )2

[268]

3.4 - 4.0 ppm 4 proton; massive complex; Ch O-Ch 6.0 ppm 2 proton; singlet; - the O-CH2 - O-- ^

[269]

6 "9 - 9" 2 ppm 7 proton ii massive complex having a singlet to 8.7 ppm; aromatic protons + -=- OH-Ν

[270]

Lo, 2 ppm 4 letlet us nrotons; broad peak; labile proton exchangeable with BMD

[271]

C1 205 CORs dms0 - d6 solvent

[272]

2.3 - 3" 2 ppm 19 proton} massive complex; Ch O-Ch + n-Ch3 EMC-to-Ch n + (CHgCHg) grams

[273]

6.9 - 9.2 ppm 9 proton; massive complex having a singlet to 8.6 ppm ii aromatic protons + NeCH - -

[274]

10.3 ppm 4 proton; broad peak; labile proton exchangeable with BMD

[275]

The COR 01,206 solvent dms0 - d6

[276]

2.4 rpm 3 proton ii singlet j. CNY-C.

[277]

2.6 ppm 4 proton; singlet $Ch c-Ch

[278]

2.7 ppm 6 j-proton singlet; nçch ^) ^

[279]

2.9 - 3.2 ppm 4 proton; massive complex; Ch-to-CHgN

[280]

6.0 ppm 2 proton VBE1 singlet; - the O-CH2 - O-- ^

[281]

6.9 - 8.0 ppm 6 proton *, ** AA which system the BB + 2 singlets;

[282]

aromatic protons

[283]

8.5 mPI 1 proton abstraction; singlet; Η Ν ≈ 0 -

[284]

8.5 - 10 ppm 4 proton; peak spread; labile proton exchangeable with BMD

[285]

The COR 01,207 solvent dks0 - d6

[286]

2.6 ppm 4 proton; singlet; HM - ^ c EMC

[287]

2.8 ppm 6 proton; singlet; NCCH ^) ^

[288]

3, 0 - 3, 3 I-PM 4 proton; massive complex; CHgCHgN

[289]

6.0 ppm 2 proton; singlet; O Ch O

[290]

6.9 - 8.2 Ppm 5 proton; massive complex; aromatic protons

[291]

8.6 ppm 1 proton abstraction; singlet; d=- HC

[292]

10.5 ppm 4 proton; IEP wide; labile proton exchangeable with BMD

[293]

The COR 01,208 solvent dks0 - d6

[294]

2.6 ppm 4 proton; singlet; Ch O-Ch

[295]

2.7 ppm 6 proton singlet therein|HCCH ^

[296]

2.9 - 3" 2 ppm 4 willwill prprons; massive complex; GKgCEgK

[297]

6.0 ppm 2 proton; singlet; O to CKG O

[298]

6.9 - 8.1 ppm 6 proton ii system AAs + 2 singlets' the BB ' j-aromatic protons

[299]

8.6 ppm 1 nroton; singlet; d=human gh -

[300]

8 - 10 ppm of proton 4; peak spread; labile proton exchangeable with BMD

[301]

The COB 01,209 solvent DKSC-to-d6

[302]

2.6 ppm 4 proton; singlet; Ch O-SDOH

[303]

2.7 ppm 6 proton; singlet; d (HM3 ) grams

[304]

2.9 - 3.2 ppm 4 proton; massive complex} OOTW-to-CHgN

[305]

6.0 ppm 2 proton ii singlet; O Ch O

[306]

6.9 - 8.1 ppm 7 proton; massive complex; aromatic protons

[307]

8.6 ppm 1 proton abstraction; singlet; d=- HC

[308]

9.8 4 proton; broad peak; labile proton exchangeable with BMD

[309]

The COB 01,210 solvent dms0 - d6

[310]

2.6 ppm 4 proton; singlet; Ch O-EMC

[311]

2.7 rpm 6 proton; singlet; d (ch-^) grams

[312]

2.9 - 3.3 ppm 4 proton; massive complex; CE cu ir ^

[313]

3.8 ppm 3 proton; singlet; ^ Osh

[314]

6.0 ppm 2 proton; singlet; O Ch O

[315]

6, 7 - 8, 0 ppm 6 NRs ο tones; massive complex; aromatic proton-proton 8.5 ppm 1; singlet; d=- HC

[316]

9.9 ppm 4 proton; broad peak; rrotcns labile exchangeable with BMD.

[317]

The COB 01,213 solvent dms0 - d6

[318]

1.3 Celaton 3 proton; dipole ii HM ^ - C.

[319]

2.4 - 4.2 rpm 13 proton; massive complex

[320]

To CKG and 0 to-Œïg Ν + (HC3 ) CHCHg n + grams

[321]

7, 1 - 9, 2 ppm 9 proton; massive complex having a singlet to 8.7 ppm, aromatic protons +=- HM - K.

[322]

10.6 ppm 4 proton; broad peak; labile proton exchangeable with BMD.

[323]

The COB 01,214 solvent dms0 - d6

[324]

1.1 ppm 3 proton; dipole; HM - ^ - C.

[325]

2.4 - 3.8 ppm 13 proton; massive complex

[326]

Ch c-Ch + n-(HM3 )2 + Ch Ch n -

[327]

7.0 - 9.2 ppm 9 j-proton massive complex which a singlet to 8.7 ppm; aromatic protons +=- OH-Ν

[328]

Lo, 5 ppm; 4 proton; broad peak; labile proton

[329]

exchangeable with BMD

[330]

5 -ProductCARBONHYDROGENNITROGENOXYGEN: "
theoryfoundtheoryfoundtheoryfoundtheoryfound
1001,15167.9067.105.705.885.284.8915.0814.54 * T-
01,16968.3669.175.926.275.144.9514.69* 14.01 9.ï•9.ï
01,17070.8470.945.955.967.998.1815.22the I 15.68 ii:
15, 2001,17371.8571.086.036.497.627.4614.50** 13.95 O
01,17472.1972.076.24; 6.167.437.4214.14e 13.75 T-
01,17569.4569.266.006.00 the I4.914.7714.0213.68 9.ï•"
01,17660.6959.905.885.845.445.3527.9927.88 e
01,17955.4553.155.305.845.664.9229.12••
2501,18146.0846.254.394.654.894.3125.1125.59 i-I
01,18563,&264.08<6.436.705.955.8523.8023.18•* e
3001,19558.0258.886.046.738.127.8727.8228.17 ii
01,20062.2162.935.976.465.184.7426.6426.59 seconds
3501,201.56.4456.675.565.958.508.5429.4230.25 ii **
01,20354.6554.905.385.598.318.1731.65T-
01,20456.4956.605.505.677.917.3630.10•29.85 ii

[331]

2 - Elemental microanalysis

[332]

01,20559.9959.596.446.5011.1910.56' 22.37
01,20659.7559.776.026.175.575.3326.6629.62! ii
G1 20751.7251.884.705.175.034.6725.83♦25.02! :
01,20855.1255.255.205.545.364.9027.54** 27.33:
01,20959.0058.985.786.0 85.735.1729.4829.66 ii 1

[333]

GEA nroduits which is contemplated by the present invention have undergone various pharmacological tests which we give the following results.

[334]

The percentages of induced by the products of the present invention orally available oral Swiss mouse are shown in table 1. Animals free of specific pathogenic organisms are stalled in 24 to 48 hours climatic room before the start of the experiment. They are sorted into batches of 5 male and 5 female. In animals fasted from 24 hours, the substances are administered intrags e sorting that in a julep of gum arabic 6 % in a volume equivalent to 0.1 ml per 10 g animal weight. Mortality is observable at^40 day.

[335]

The analgesic activity was determined in mouse a male Swiss in using as the nociceptive phénylbenzoquinone (iBQ) (variant of the method of Siegmund & transporter. Process. Share.

[336]

Med.iîxr.., 1975, 95,729 - 31)•twenty five minutes followed by administrationT- the R - - oral products testing suspended in a julep gummy to 6 is injected into the solution and then observing the L<FBQ - e mouse after 5 min making the 5 minutes thereafter " the results are gathered in table 2.

[337]

The psychotropic profile of the present invention has been characterized in animals by several tests with a few results are shown below. The products of 1' invention are always administered orally in a julep gummy to 6 £>. The table no. 3 indicates the effect induced in the test of the evasion in mouse and expressed by the percentage of change of the number of outputs of the animal in 5 min.

[338]

table 1

[339]

Toxicity in the mouse

[340]

Froduits
e n° e expressed as mg/kg body weight administered: ***••••••••••••: I-150, 5 250! 500 750, 8 1000 9.ï: 1500 2000•I-e "§••!" **
1 EOC 01,142! ""••••9.ï ii ii ii 0:! 50! ••••••••••0••"
THE COR 01,151•0 * 10 * 40 * 60 O *• ii
: 01,163 EOC25 * 70:100: ii ii e ii••••••th
: ALAMIN 01,169::: ii %% ii ii: 50 ii > 20 * 80 ii
the COB 9.ï 01,170::: i-0 the I100 ::
: 01,171 EOC20! 80 * 90 *: * ii 9.ï: ii:::::
: ORC 01,173ii: 0 sec. 30 sec.:::: ii:::::
:: EOC 01,174:: ii 0:: 10 sec. 9.ï 50: "•••••••
ii alamin 01,175: 0 ii 10 ii 10 ii e ii:
: ORC 01,176**•••••0:: O:: ii:
ii EOC 01,179: the I ii: i-9.ï :! , 10 ii 90! ii I-9.ï ii
: ORC ' 01,180::: 8 e:: ii ii 0 ii: 70 ii e ii••■•••••
: ORC 01,181:: ii :::: 0 e? 30 Ii ii: O :•••§* ""
i '•••••"•"•#•♦*••••9.ï alamin 01,184 9.ï: ii: e: 0 9.ï 30 ii
: ii 9.ï: O:: I-: ii EOC 01,185 ii ii the I 3 o O 0 100, 8 sec.

[341]

e # mortality in a dose dependent manner

[342]

C0H 01,186

[343]

50 %

[344]

:

[345]

following table η0 1

[346]

- - - - -

[347]

Products: $mortality ergeant n° dosage: mgs administréeen&kg.

[348]

150250500750100015002000
: COH FROM 01,19502030
: ORC 01,199050
! 01,200 COH FROM01070
: ORC 01,2011030
: ORC 01,20210' 3060
the COR 9.ï 01,20301040
: ORC 01,204010
: ORC 01,20501010
: ORC 01,206050
: ORC 01,2070202040
: ORC 01,208030202080
the COR 9.ï 01,209"04060
! THE COR 01,210O01020
i-ORC 01,2130
j-ORC 01,214:I03070

[349]

2 ÏÜBLBAU
Product n°$> D.1 analgesic activity in: fonction.de the dose expri - : mêe in mgs /' kg. * 9.ï
50100200 ii
THE COR 01,142222010:
THE COR 01,1514179•"••
THE COR 01,16317.5*••
THE COR 01,169743.""•
THE COR 01,1703039 9.ï
THE COR 01,17151
THE COR 01,1744818 the I
THE COR 01,1751371 the I
THE COR 01,1762339 j.
THE COR 01,180182634: *"
THE COR 01,1812542"•" 1 e
THE COR 01,184344455 sec.
THE COR 01,1952431!
THE COR 01,199824.556.5:
THE COR 01,2022033 j.
THE COR 01,20303647 sec.

[350]

following table 2
; Product η0$analgetic activity in; a dose dependent expri -: mée in mg/kg body weight:
50:100: 200 ii
; 00 Β 01,204•"s * 0 ii 45 ii 42 ii•*"
: ORC 01,205: 10 ii 36 T-- - -••••■%
: ALAMIN 01,209The I -•■-••' *: -: 17. :..: - ii ' - - 9.ï■
the COR ΐ 01,210: o•T-O 27. 33 t.
! THE COR 01,214- ^ ;;· · · *...: ' 21. t-VBE1 - 30 ii
acetylsalicylic îicide: 55 61 ii: ; - - 9.ï■•■•'; -■•••■■*••-•••

[351]

' 1 ïroâuits! ^ activity in a dose dependent expressed NC
i-J.; the O, 51!1of i3j is the jI-I-510!;25J. 5°75100 {150r; 200;
!;CRCC1151 !1, 1the j;the j;i-J.t-T-THE HSnsec;NSEC-41;i-j of the j?
of iCCHS01the I ^ Oj is; j.t-T-ii iii-J.t-J.nsec;NSEC- 32jof i - 59 ΐ ;
i-J.COH FROM01173;i-J.; i-i-J.*" 33j!;-13-29;-26-50; -55; - 9oi
5j is the jTHE COB01176•-29i 40t-F.-39of i'33 the I!;-32" 37;-33;I-43 !
t-T-GÛB01-•80;i-J.;!the R iinsec;NSECj is the jNSEC- 2l|-37;; - 75;
j is the jORC01184;1!; j.the I;-34|-26" t--23" 34;-47;;|- 46
i-I-ORC01195; THE RS!;NSEC1 + 54the I;+ 53;NSEC; i-NSEC+ 19;+ 28;i-I-; nsec;
i-J.ORC01200;i-J.t-J.i-I-nsec;+ 25; j.NSEC+ 38;NSECNSEC;; i-I-J.
10i-I-ORC01202;t-J.THE HS; i-the T!NSEC;NSECof iNSECnsec;NSEC; j.! the I; J.
; L.ORC01203;; r.t-J.T-J.NSEC;j is the jNSECnsec;NSEC;; j.; the I
; iiORC01204;; i-the j ii1!-28;NSEC" j.-31-24;-20-15;; - 24;
j is the jCRC01205;i-J.T-the T!NSEC;-ii!•NSECnsec;NSEC; t-a j-34j
! j_ORCLC206;the j ii1 i-1!; i-NSECt-T--18-28;-63;1! 1!
15Y LORC01209;1!i-J.J.|-20;J IS 1-38-32|-37 ;1 ^! ; - ^ the V;
t-I-CRC01210;[t-; i-1 t.NSEC;1, 1NSECNSEC;-20; - 26! * "!
! LCRC01213|THE I 1THE HSi-iiT-J.; t-NSEC1 j.the j;NSEC-20; NSEC1 W! F.
t-J.CRC01214;t-J.THE HSr. J.1 J.j is the jNSECI-J.of ii-nsec;1! 1 I-

[352]

table

[353]

The Te ST 1' evasion

[354]

the mention nsec signifies unterstanding the difference between the recorded results for the product and the results recorded for the excipient alone is not significant at 0.05 is garlic as judged-distribution *

[355]

the products of the rrésente only have generally not activity cateleptic high potency. Only the ORC 01,176 has caused a slight catalepsy to 400 mgs/kg of 60c and. Few derivatives exhibit antagonism as it relates to the R to apomorphine stereotypies effect in the COR 01,176, 202, 206, 209, 210.

[356]

The test results are shown in the table no. 4 *

[357]

U-TéBLüf ^ 4
ïroduit n°,Q " pick the j {dosageas such the ictivity s by the pomorphine in administered expressedstereotypic infonction mgs/kg of said SN
!25; 50i-I-; 75;100! Y150;200
ORC01176; i-i-J.j-j-j-j is! !;;-64
ORC01202! ~35! "32! ~29 !NSEC; j.t-T--20
ORC01206; nsecj - 53T-I-j-;-71I-J.the j;-22
ORC01209i-J.|-54j is the j; T--51j is the jT--42
ORC01210; i-I-i-I-I-;; 1, 1 i - 33!T-I-I--33 of ithe R

[358]

Inhibition assay is the toxicity of the amphetamine-induced group was rejecting the hypothesis of activity for these derivatives neurolertic.

[359]

A number of products have anxiolytic activity highlighted in the test of the LAN^4 - uies Dr Chee the mouse (table no. 5)

[360]

5 TÜBLBTÜBLB.AÜ

[361]

confectioneries * increase in the number of displacements:

[362]

the animal with respect to the dose expressed as mg/kg.

[363]

1.53 ii 510202540506075
icOR 01,170+ 18+ 57+ 36+ 69+ 72
THE COR•01,173NSEC+ 30+ 47+ 60+ 82
tCOR 01,176NSEC+ 101117 ++ 72+ 72+ 66NSEC
: CRC 01,180NSECNSEC+ 6, 9+ 88+ 35
: ORC 01,184+ 89+ 73+ 56+ 61NSEC
: C0E 01,200+ 112+ 180+ 292+ 142+ 84
THE COR 01,202•+ 48+ 96

[364]

Some tests were to demonstrate antidepressant activities. It e1 acts tests of antagonizing the effects of reserpine, an L * of the oxotrémtfrine @ Bverett after G.K. & al, forensic science, 1956, 124, 79 and Levÿ J & transporter. Therapy 1965, 20, 265) and despair (based Forsolt r.33. & transporter. The Bur. THE J.

[365]

Hyg ., 1978, 47, 379 - 91)•autostart results are shown in tables 6, 7, 8.

[366]

TABLE 6
ptotic PGRs induced inhibition of the reserpine as a function of the orally administered dose expressed as mg/kg.
2.5510255075100200
THE COR 01,173-12-21-23
The COR 8 01 ΐ θ-18-34-26-20NSEC
THE COR 01,184-13-39-34
THE COR 01,195NSEC-22-22
01,200 ORCNSEC-28NSEC-24
THE COR 01,203NSEC-33-27
C1 205 ORCNSEC-31-25-31
THE COR 01,209NSEC-45
THE COR 01,210NSEC-21-38

[367]

TABLE 7

[368]

Products { the I * the d * inhibiting the induced tremor n° oxotrémcrine depending on 1? adminisj dosage expressed as mg/kg in inlets
t-ii255075the T;1001 j.! .150 !2001, 1
ORC01170 j.-40i-I--50the T;the R;-781 T.
ORC01173;-20-20-401;-60;-70;t-9.ï
ORC01176 the j-401|-50t-T-THE T!-20t-T-
ORCLC180 j.-22the j!-44; t-T-J.-44t-T-
ORC01184 the j-200; j.-221 r.1;-17T-T-
ORCiC202;0-67-44; I-t-T-the T!T-ii
ORC01203 j.-701 j.-50;;! !-201!
ORC011,204!;-30! ;!-20; t-11; 1-30t-j-|
ORC01205;-301;-301;1, 1-401;
ORC01209|-60-601!-55; 1-60;-30T-T-
o-O DCFs01210 VBE1-50-40j is the j-501 t.-30;-50ii ii
11;TT-

[369]

8 TA3LÜAU

[370]

Iroduits n°Testing the despair of antagonism $j is a function of the dose administered orally department NAR MgAg and expressed
50100200
01,170 COH FROM" 39-39-33
THE COR 01,173-18" 41" 53
THE COR 01,184" 20-18
THE COR 01,202-49-67

[371]

None of the tested products does activity in the test at 5 Hepreceptor; derivatives which is contemplated by the present invention have heretofore not inhibitory activity of monoamine oxidase.

[372]

Some products have anticholinergic activity detected in the inhibition test of the pilocarpine-induced salivation (table's French).

[373]

:•productthe n the O$inhibiting soiled -: lower power requirements induced OLIN -: carpine depending on the: dose administered expressed: in mg/kg body weight:
5075100200:
: ORC 01,170NSEC-18-57;
: ORC 01,173NSEC-39-48-76:
: ORC 01,184" 23 sec.
: ORC 01,203 - L.-32NSEC-30:

[374]

In view of their pharmacological properties characterized by an analgesic activity, activity antidérressive not IN O, anxiolytic activity and - for some anticholinergic activity, these activities manifested to IERs dose very lower than the toxic doses, the products forming the subject of the present invention may be employed for example in the treatment of depressive conditions of various etiologies to component of anxiety, in the treatment of anxiety states observed during certain psychiatric or organic, in the treatment of the depressive component and entertainment akinetic Parkinson's disease; in children, they will treat insomnia, tics, the stammerings, enuresis, nocturnal scare; the elderly, they will be useful for the treatment of insomnia, relational difficulties with the surrounding, psychiatric disorders involution; they can also be employed for the preparation to the small procedures and treatment for certain pain.

[375]

Dosages and treatment regimens will be dependent on the subject, generally fine, instituting a dosage should be gradual and-matter ' from the progressively tert. The products forming the subject of the present invention may be admitted. nistrés EOR orally (e.g. in the form of capsules, comtrimes, drinkable drops) or by injection (solute injectsbls intramuscularly or intravenously; intravenous perfusion). Following the indications the daily dose will vary from 3 to 300 mg in one to three doses. The vaccine following non-limiting examples of formulation.

Oral drops

[376]

The COR 01,176 0.6 g of base per vial of 30 ml or 0.5 mg per drop

[377]

Comrrimés

[378]

' 01,184 Tablets containing 25 mg CORs base

[379]

The COR 01,173 tablets containing 100 mg base

[380]

The COR 01,202 comrrimés dosed to 5 mg base

Injectable solutions

[381]

The COR 1,202 injectable ampoules apportioned 25 mg base

[382]

ϋ

[383]

EOC 1,184 injectable ampoules apportioned 25 mg base



[384]

Compounds, exhibiting central nervous system activity, of the formula <IMAGE> (I) wherein R1 is phenyl which is unsubstituted or substituted by at least one member selected from the group consisting of halogen, CF3, C1-C4 alkyl, C1-C4 alkoxy and COOH, or R1 is <IMAGE> or R1 is a heterocycle selected from the group consisting of <IMAGE> +TR <IMAGE> R2+L, R3+L, R4 and R5, which may be identical or different, are H or CH3; R6 and R7, which may be identical or different, are C1-C6 alkyl, which may be straight-chained or branched, or R7 can be H when R6 is a branched-chain alkyl, or R6 and R7 can form, with the nitrogen to which they are bonded, a heterocycle selected from the group consisting of <IMAGE> +TR <IMAGE> R8+L, R9+L, R10 and R11, which may be identical or different, are H, halogen, CF3, hydroxy or C1-C4 alkoxy, or two contiguous members of R8+L, R9, R10 and R11 may together form a chain -O-(CH2)n-O-, where n=1 or 2, or a chain -O-CH2-O-CH2-; and pharmaceutically acceptable addition salts thereof are disclosed, along with a method of producing the same, and pharmaceutical compositions comprising the same.



1. - Novel products of general formula

THE R,

The RR

with R a-j=phenyl substitute ' or not by one or more substituents as hslogéno, FS ^ I-lower alkyl of c1 to c4, lower alkoxy of 01 to 04, the COOH, or R ^ ^ 0===CK from HM - or heterocyclic radical such as

(LQ fifeJgJL " *O-9 (§R."

with " GTA Η ^, the R ^, ^ R is the same or different H or CH ≈ ^, with the rg, Rrj ==same or different lower alkyl branched or not c1 to 06, R-γ can ster equal to H in the c? s wherein regenerating complementary rerrésente a branched alkyl; moreover the rg and R? can close with the nitrogen atom to which they are attached - - such a hétérccycle™ - g - - 0 '- - the O' - the O - *'

with the rg "RG represents" hr10 , R is the same or different ^ ≈ hr, halo, MC ^>hydroScy, ai 01 to 04 coxy lower, two substitiu-: z's contiguous can together form a CRH-bly - - C. (CK202 ) n=1 or n Cavec - 2 or the O-CH2 - O-Ch ^ ^ - ore and the addition salts with acids - pharmacologically compatible.

2. - Novel products made up acid salts such as hydrochloric acid, benzilic acid, citric acid products according to the paragrrrhe 1; ^

3. - New products according to paragraphs 1 and 2 of the R====^ Q-O.

4. - New products - according to paragraphs 1 and 2 such as the rg s - h, Rç R ^ Q-forming together a CH sinc - O HM - ^ - erffective powerU.

5. - Method of preparation of the products according to paragraphs 1 to 4 characterized in that comprises reacting an amine of formula

with the rg, the R ^=same or different lower alkyl branched or not c1 to c6, R-T-. ^ ouvant be equal to H in the case where Rg rerrésente a branched alkyl; moreover the rg and R ^ may form

with the rg, R.oCR10 , The R ^=K to the same or different, halogen, CP-a-j, hydroxyl, lower alkoxy Cl to c4, two substitute; - e contiguous rouvant together constitute a CH groin - 0 - (Ch)the R n=1 - 0 and suitable method or 2 or - O Ch O-Ch -, and an aldehyde of formula R CHO-^=phenyl unsubstituted or substituted with the R? R or olusieurs substituents as-HR logéno, MC ^, lower alkyl c1 to c

c1 c4 to lower alkoxy, COOH group, or R1 =

=© -

HM=HM - or R=heterocyclic radical such as

- Qt CPLI. (§>R.