CA1210391A

CA1210391A - Naphtalenic aminoalkyl derivatives, the acid addition salts thereof and the process for preparing same, as well as the application in therapeutics of these derivatives and salts

Info

Publication number: CA1210391A
Application number: CA000432243A
Authority: CA
Inventors: Alain-Rene Schoofs; Guy Bourgery; Bernard Bucher
Original assignee: Delalande SA
Current assignee: Synthelabo SA
Priority date: 1982-07-16
Filing date: 1983-07-12
Publication date: 1986-08-26
Also published as: ES524129A0; DE3375728D1; ZA835056B; AU1691583A; EP0100257B1; FR2530236A1; EP0100257A2; JPS5976032A; ES8403853A1; FR2530236B1; EP0100257A3

Abstract

Title : "New naphtalenic aminoalkyl derivatives, the acid addition salts thereof and the process for preparing same, as well as the application in therapeutics of these derivatives and salts"
(Invention of Alain-René SCHOOFS, Guy BOURGERY, Bernard BUCHER) Applicant : DELALANDE S.A.

ABSTRACT OF THE DISCLOSURE

New naphtalenic aminoalkyl derivatives corresponding to the for-mula :

(I) in which :

- R1 and R2 are identical or different and represent a hydrogen atom or an alkyl group comprising 1 to 4 carbon atoms or form, conjointly with the nitrogen atom to which they are linked, a heterocyclic radical chosen from the following : pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, 4-methyl piperazino ;

- n = 1, 2 or 3 ;

- R represent a hydrogen or halogen atom or a methyl group; and - R3 represents a hydrogen or halogen atom or a methyl or methoxy group, as well as the organic or mineral acid addition salts thereof.

These derivatives and salts are usable in therapeutics, more particularly as antidepressants and/or analgesics.

Description

~L2~LV 39~l The present invention relates to new naphtalenic aminoalkyl deriva-tives corresponding more particularly to the formula :

R ~ \ ~ (I) ~ R3 in which :
- R1 and R2 are identical or different and represent a hydrogen atom or an alkyl group comprising 1 to 4 carbon atoms or form, conjointly with the nitrogen atom to which they are linked, a heterocyclic radical chosen from the following : pyrrolidino, piperidino, hexamethylenei~ino, morpholino, ; piperazino, 4-methyl piperazino ;
- n = 1, 2 or 3 ;
- R represents a hydrogen or halo~en atom or a methyl group ; and - R3 represents a hydrogen or halogen atom or a methyl or methoxy group.
Among these derivatives, those may be more particularly mentioned in which group (n, NR1 R2, R, R3) takes any one of the following values :
(1, NHCH3, H, H), (1, N(CH3~2, H, H~, (1, ~ 3, (2 N(CH ) H, H), (2, N ~ N-CH3, H, H), (2, N(CH3)2, , 3 2 8-Cl, H), (2, N~CH3)2, H, para-F)~ (2,NH2, H, H), (2, NHCH3, H~ H), (2, N ~ , H, H), (2, N ~ , H, H), (2, N , H, H),.(2, N CH3~ H, meta-F) , (2, N CH3~ H, ortho-CH3), (2, N _ CH3~ H, meta-CH3), (2, N_ CH3~ H, para-CH3)9 : ------ 3 (2, N CH3, 6-Cl, H), (2, N CH3, 7-Cl, H), (2, N~_CH3, 6-F, H) J

(2, N CH3' 6-CH3~ H), (2, NHCH3, H, o.rtho-F), (3- ~ CH3' H, H)~

3~

`` ~ )3~3~

Particularly preferred compounds are those in which the group (n, N = R1, R, R3) takes the values (2, NHCH3, H, ortho-F) and (2, N CH3' H, ortho-F).
The present invention also relates to the mineral acid (such as hydrochloric acid) or organic acid (such as maleic acid) addition salts of the derivatives of formula (I).
The invention further extends to the process for preparing the derivatives of formula (I) and the salts thereof.
Thus the invention extends to the process which consists in conden-sing the amines of formuia :

H ~ (II) in which R1 and R2 have the same meanings as in formula (I), respectively with the compounds of formula :

(C~2~n~R4 ~ (III) ~ .

in which n, R and R3 have the same meaning as in formula (I) and R4 represents a good leaving nucleophilic group ; then possibly in salifying the derivatives obtained.
The good leaving nucleophilic group will be more particularly formed by a halogen atom or by the methylsulfonyloxy or p-tolylsulfonyloxy group and the condensation will be preferably carried out in an aprotic solvent.

The compounds of formula (III) for which R4 represents a halogen atom may be obtained by the action of a phosphorous oxyhalide or a phosphorous pentahalide, preferably in an aprotic solvent such as methylene chloride, respectively on the compounds of formula :
~ ~ (03Z)n~03 ~3 ~2~L~3~

in which R, R3 and n have the same meaning as in formula (III).
As for the compounds of formula (III) for which Rl~ represents a methylsulfonyloxy or para-tolylsulfonyloxy group, they may be obtained by the action of methyl or tosyl chloride, preferably in an aprotic medium (such as methylene chloride, for example) and in the presence of a base (such as triethylamine, for example), respectively on the compounds of formula (IV).
The compounds of formula (IV) are obtained by reduction with lithium and aluminium hydride (in a THF medium) of the compounds of formula :

~ ~ ~ ~C~2~m-CQOEt ~V) ~,~ , , - .
~ R3 .
in which R and R3 have the same meanings as in formula (IV) and m takes the value 0, 1 or 2.
The compounds of formula (V) for which m = 0 are obtained by esteri-fication, with hydrochloric ethanol in an ethanol medium, of the compounds of formula :
"^~ "-~ C00 R ~ I Q I
~VI) ~ 3 in which R and R3 have the same meanings as in formula (V).
The compounds of formula (VI) are obtained by aromatizing cyclisation in an aproti.c medium (such as benzene or methyl chloride, for example) and in the presence of a Lewi.s acid (such as aluminium chloride or boron trifluoride etherate, for example), of the compounds of formula :
O , R ~ (VII) ~ R3 12~
'~

in which R and R3 have the same meanings as in formula (VI).
The compounds of formula (VII) are obtained by condensation in acetic anhydride and in the presence of sodi.um acetate, of the compounds of ~ormula :

~ ~ CD0~l . (YIII) in which R3 has the same meanings as in formula (VII), respectively with the aromatic aldehydes of formula :

~ CH0 (IX) in which R has the same meanings as in formula (VII).
The compounds of formula (V) for which m = 1 or 2 are obtained by : esterification with hydrochloric ethanol in an ethanol medium of the nitriles o~ formula :
(&H2)pCN
R ~ (X) ~ R3 in which R and R3 have the same meanings as in formula (V) and p = 1 or 2.
The compounds of formula (X) are obtained by action of an alkaline cyanide (such as sodium cyanide~ for example), respectively on the compounds of formula (III) ror which n takes the values 1 or 2, the reaction being ~arried out in solution in DMS0 or DMF.
In the case where, in formula tI), n takes the value 2 or 3 and -N ~RR1 represents the amino group (-NH2), the corresponding oompounds (I) may also be advantageously obtained by reduction, preferably catalytic, in the presence of Raney nickel of the corresponding compounds of formula (X).
Compounds (VIII) are either already known or are obtained according to conventional methods in the literature. Thus :

```` ~2~(~3~L

- in the case where, in formula (VIII), R3 represents the fluorine atom in the ortho or meta position or the methyl group in the meta position, the corresponding compounds (VIII) are obtained by acid hydrolysis, preferably with 6N hydrochloric acid of the compounds of formula :

~ COOE~ ~XI) in which R'3 represents a fluorine atom in position 2 or 3 or the meta-methyl group, these latter being obtained by condensation of ethyl acrylate, in the presence of a base (pref`erably sodium ethylate) in a THF-alcohol medium, respectively on the compounds of formula :
,CN
~ 3 (~

in which R'3 has the same meanings as in formula (XI), thems l.ves obtained by a so-called STRECKER reaction between 2-(or 3-) fluoro-benzaldehyde or 3-methylbenzaldehyde, morpholine and an alkaline cyanide (preferably potassium cyanide) in the presence of para-toluene sulfonic acid and in an aqueou,s medium ; and - in the case where, informula (VIII), R3 represents the methyl group in the ortho po ition, the corresponding compound (VIII) is obtainad by acid hydrolysis (preferably with HCl 6N) of the compound of formula :
COOEt CO ~ (XIII) ~ CH3 ~ CQOEt obtained by condensation of ethyl bromoacetat:e, in an ethyl ether medium, in the presence of sodium hydride on the compound of formula :

` ~Z~ )3~

CQ ~ CH2 - COOEt (XI~I) itself obtained by condcnsation of the ethyl monoester of malonic acid (HOOC ~ COOEt), in THF and in the presence of butyl lithium, on the compound of formula :

~ OCl (XV) The acid addition salts of the formula (I) derivatives may be obtained by simple reaction of an acid with the formula (I) derivatives in appropriate solvents.
The following preparations are given as examples for illustrating the invention.
Example 1 : 2-N,N-dimethylaminomethyl 4-phenyl naphtalene chlorhydrate (I) 50de number : Z
A mixture of 6.4 g of 2-mesyloxymethyl 4-phenyl naphtalene (III) and 36 ml of a solution, prepared from 100 g of N,N-dimethylamine in 800 ml of benzene, in 100 cm3 of benzene is heated, in a sealed tube, at 50 C for 12 hours.
Then the solvent is evaporated, the residue is taken up in methylene chloride, the solution obtained is washed with water, extracted with a 1N
hydrochloric acid solution, washed with methylene chloride, washed with water, dried on sodium sulfate, filtered and the filtrate evaporated. 6.6 g (yield 100 %) of an oil are obtained which corresponds to the desired compound in base form. This oil is dissolved in 100ml of isopropylic alcohol and 8.5 ml of a 3.9 N hydrochloric ethanol ~olution are added. The mixture obtained is diluted~ith 250 ml of ether and the precipitate obtained is filtered out. THus 2.9 g~
(yield : 37 %) of the expected product are obtained, of which a number of physico-chemical data are given in table I below.
By the same process, but from the corresponding reagents, the 3 compounds of formula (I) are obtained shown under code numbers 1 and 3 to 23 in table I below.

' .
. . .

)3~.

Example ? : 2-mesyloxymethyl 4-phenyl naphtalene (III) To a solution cooled to - 10 C of 16.9 g of 2-hydroxymethyl 4-phenyl naphtalene (IV) in 250 ml of methylene chloride are slowly added 25.2 ml of triethylamine, then 11.2 ml of mesyl chloride. The mixture is left at 0 C for 30 minutes, then diluked with water and ice, decanted, washed with water to a p~ ~ 7, dried on sodium sulfate, filtered and the filtrate evaporated~ 20.8 g (yield : 92 %) of a crude oil are obtained ( a single spot in T.L.C.) which is used in the synthesis of the corresponding compounds of formula (I) according to example 1.
. Empirical formula : C18H1603S
. Molecular weight : 312.37 By the same process, but from the corresponding reagents, the other formula (III) compounds are obtained which are required for the synthesis of thecompounds of formula (I).
Example 3 : 2-hydroxymethyl 4-phenyl naphtalene (IV) Code number : 1A
To 250 ml of THF cooled to 0 C are added 3.7 g of lithium alu-minium hydride, then slowly 27.1 g of 2-ethoxycarbonyl 4-phenyl naphtalene (V).
The mixture is left for two hours at 0 C under agitation, then hydrolyzed with damp sodium sulfate, diluted with 100 ml of ether, filtered, the filtrate is evaporated and the residue chromatographed on a silica column (medium pressure liquid chromatography, eluent : 60 % heptane - 40 % ethyl acetate mixture). Thus, 16.8 g (yield : 73 %) of the expected product are obtained af~er crystallisationin petroleum ether and recrystallization inisopropylic ether.
By the same process, but from the corresponding reagents, the formula (IV) compounds are obtained~required for the synthesis of the formula (III) compoundsJand particularly the compounds shown in table II below under the code numbers 1B, 6A, 6B, 7A, 7B, 8A, 8B, 14A, 14B, 15A, 15B, 16A, 16B, 17A, 17B, 18A,18B, 19A, 19B, 20A3 20B, 21A, 21B and 1G.
Example 4 : 2-ethoxycarbonyl 4-phenyl naphtalene (V) Code number : 1D
To a solution of 24.4 g of (4-phenyl 2-naphtalenyl) carboxylic acid (VI) in 350 ml of ethanol are added 30 ml of Ll 3 N hydrochloric ethanol. Then, the mixture is heated at reflux for 7 hours, the solvent is evaporated, the residue taken up in methylene chloride, the solution obtained is washed with a 1 N hydrochloric acid solution, then wikh water, then with a 1N NaOH solution,then with water. It is dried on sodium sulfate, filtered and the filtrate eva-~L2:~03~33l .

porated. 27 g (Yield ~ 100 %) of a crude oil are obtained which corresponds to the expected compound (one spot in TLC) and which is used immediately in the synthesis of the corresponding compound of formula (IV) according to example 3.
By the same process but from the corresponding reagents, the compounds of formula ( V) are obtained for which m - 0, under code numbers 6D, 7D, 8D, 14D, 16D, 18D, 19D, 20D and 21D required for the synthesis of the compounds of for-mula (IV), as well as the compounds of formula (V) for which m- 1 or 2, but from the compounds of formula (X), and particularly the compounds of code numbers lE, 6E, 7E, 8E, 14E, 15E, 16E, 17E, 18E, 19E, 23E and 21E, sh~ in table II below.
Example 5 :(4-phenyl 2-naphtalenyl) carboxylic acid (VI) Code number:1C
To a mixture of 24.7 g of aluminium chloride in 250 ml of benzene cooled to 10 C are added, after an hour, 15.3 g of o~-benzylidene-~ - phe*yl-~ ~-butenolide (VII), while maintaining to temperature between 10 and 20 C
during the addition. Then the mixture is left at room temperature for 3 hours, 1N hydrochloric acid is added, it is extracted with ether, washed with water, dried on sodium sulfate, filtered, the filtrate is evaporated and the residue crystallized in isopropylic ether. 8.5 g (yield : 55 %) of the expected product are isolated.
By the same process, but from the corresponding reagents, the compounds of formula (VI) are obtained ~equired in the synthesis of the corres-ponding compounds of formula (V ~and particularly those of code number. 6C, 7C, 8C, 14C, 15C, 16C, 17C, 18C, 19C, 20C and 21C shown in table II below.
Example 6 : c~-benzylidene- ~-phenyl, ~ ~ ~butenolide (VII) _ A mixture of 10.2 ml of benzaldehyde (IX), 17.8 g of /~-benzoyl propionic acid (VIII) and 8.2 g of sodium acetate in 32 ml of acetic anhydride is heated until a solution is obtained, then heated at 100 C for four hours.
Then the solution is left to cool 3 water is added, the precipitate obtained is filtered out, washed with water on the filter and recrystallized 30 in alcohol. Thus 15.3 g of the expected product are obtained (yield : 62 %~.
. Melting point : 145 C
. Empirical formula : C17H112 . Molecular weight : 247.26 By the same process, but frcm the corre~ponding reagents, the compounds of formula (VII) are obtained which are required for the synthesis of the compounds of formula (VI).

.

3l~ )3~i~

Example 7 : 2-cyanomethyl 4-phenyl naphtalene (X) Code number : 1F
A mixture of 28.5 g of 2-mesyloxymethyl ~-phenyl naphtalene (III) and 17.8 g of sodium cyanide in 300 ml of DMS0 is stirred for 12 hours at room 5 temperature. Then water and ice are added, the mixture obtained is extracted with methylene chloride, the extract is washed with water (to a pH fJ7), dried on magnesium sulfate, filtered and the filtrate evaporated. Thus 22 g (yield 98 %) of the expected product are obtained which is in the form of an oil.
By the same process, but from the corresponding reagents, the compounds of formula (X) are obtained Ehich are requ:ired in the synthesis of the compounds of formula (V) for which m = 1 or 2]and more particularly those of code numbers : 6F, 7F, 8F, 14F, 15F, 16F, 17F, 18F, 19F and 20F shown in table II.
Exa_ple 8 : ~ -orthofluorobenzoyl propionic acid (VIII) 1st step : b~-morpholino 2 fluoro benzonitrile (XII) 200 g of orthofluorobenzaldehyde are slowly added, at 0 C, to 306 g of paratoluene sulfonic acid. Then, within 1 hour, 280 g of morpholine are added, then within 15 minutes 105 g of potassium cyanide in solution in 170 ml of water.
Then the mixture is heated at reflux for 1 hour, the solutionis thrown into 3 liters of a 10 % solution of sodium bicarbonate, extracted with methylene chloride, the extract is washed with a 10 % solution of sodium bicarbonate, thenwith water, dried on magnesium sulfate, filtered and the filtrate evaporated.
Ihus, 350 g (yield : 98 %) of the expected product are obtained.
~ Melting point : 76 C
. Empirical formula : C12H13FN20 . Molecular weight : 220.24 By the same process, but from the corresponding reagents, are obtained :
- C<-morpholino 3-fluoro benzonitrile :
3 . Melting point : 78 C
. Empirical formula : C12H13FN20 . Molecular weight : 220.24 - ~ -morpholino 3-methyl benzonitrile (liquid) :
. Empirical formula : C13H16N20 . Molecular weieht : 216.27 . NMR spectrum ( ~ ppm/CDCl3) = 7.2, m (4 aromatic proton~) ~ ~Z1~3~
CN
4.7, 9 (H ~ N O ) 3.7 and 2.5, m (morpholine protons) 3.95, s (CH3) Znd step : 4-cyano 4-morpholino 4-orthofluorophenyl butyrate of ethyl (XI) To 450 ml of ethanol cooled to 0 C are added 9.3 g of sodium in small pieces, the mixture is heated to 40 C, then, when the sodium is dissolved, it is cooled to no C and in 2 hours 15 minutes is added a solution of 200 g of compound (XII) obtained in the preceding step, in 800 ~l of THF. Then a solutionof 135 ml of ethyl acrylate in 100 ml of THF is added in 1 hour. The mixture is left for 72 hours at ambient temperature and the solvents are evaporated, thus a reddish oil is isolated (yield ~100 %) which is used immediately in the next step.
3rd step : ~ -orthofluorobenzoyl propionic acid (VIII) 289 g of compound (XI) obtained in the preceding step in 500 ml of 6N hydrochloric acid are heated to reflux for 12 hours. Then the mixture is basified with concentrated NaOH, washed with ether, acidi~ied with concentrated hydrochloric acid, extracted with methylene chloride, the extract is dried on 20 magnesium sulfate, filtered J the filtrate is evaporated and the paste obtained is crystallized in a mixture of heptane (70 %) and ethyl acetate (30 %). Thus, 82 g (yield ~ 44 %) of the expected product are obtained.
. Melting point : 980 C
. Empirical formula : C10H19F03 . Molecular weight : 196.17 . NMR spectrum (~MSO) ~ ppm = 7.1 to7.9,~(4 aromatic protons~; 14.3, m (COOH) ; 3.2, m (CHz-COOH) ; 2.6, t (J = 7 Hz) (-CO-CH2) . IR spectrum (KBr) : 1680 cm ; -CO-band 1720 cm ; -COOH band By the same process, but from the corresponding reagents, are obtained :
- ~ -metafluorobenzoyl propionic acid :
. Melting point : 99 C
. Empirical formula : C10H9F03 . Molecular weight : 196.17 3~

- ~ -metamethylbenzoyl propionic acid :
. Melting point : 113 C
. Emp~rical formula : C11H1203 . Molecular weight : 192.31 Example 9 : chlorhydrate of(2-amino)2-ethyl 4-phenyl naphtalene (I) Code number : 9 To 10 g of compound lF, described in example 7, in 50 ml of methanol are added 600 mg of ~aney nickel. The mixture is heated to 60 C then llO ml of hydrazine hydrate are added drop by drop within 6 hours. Then it is filtered, the filtrate is evaporated, the residue is taken up in water, extracted with ethyl ether, then the organic phase is extracted with a lN hydrochloric acid solution, basified with concentrated NaOH, extracted with methylene chloride, the extract is dried on sodium (or magnesium) sulfate, filtered and the filtrateis evaporated. The residue is dissolved in ethyl ether and ~ 6N hydrochloric ethanol is added, the precipitate obtained is filtered and recrystallized in a mixture of ethanol and ethyl ether. Thus, the expected product is obtained.
Example 10 : ~ ~orthomethylbenzoyl propionic acid (VIII) 1st step : ethylic ester of orthomethylbenzoyl acetic acid (XIV) To a solution of 77 g of ethylic monoester of malonic acid in 950 ml of THF, cooled to ~ 70 C and in a nitrogen atmosphere, are slowly added in

2 hours 30 minutes 750 ml of a 1.55 M solution of butyl lithium in hexane.
Then it is left to come back to - 5 C, it is left at this temperature for 1 hour 30 minutes, then again cooled to - 650 C and a solution of 90 g of the chloride of orthomethylbenzoic acid (XV) in 250 ml oP THF is slowly added in 35 minutes. The mixture is left for 1 hour at - 65 C, then the reaction medium is poured into 2 liters of iced water and 500 ml of 2 N HCl, the mixture obtained is extracted with ether, the etherated solution is washed with water, dried on magnesium (or sodium) sulfate, filtered and the filtrate is evaporated.3 The oil obtained is distilled (Boiling point [0.05 mm/Hg] = 100 C). Thus 7~ g (yield : 65 %) of the expected product are obtained.
2nd step : ethylic diester of CX-orthomethylbenzoyl succinic acid (XbI) To 12.5 g of 80 % sodium hydride are added 400 ml of ethyl ether, it is cooled to 0 C and a solution of 7~ g of the preceding compound (XIV) in 150 ml of ethyl ether are added in 1 hour 15 minutes. The mixture is left for 30 minutes at 0 C then 52.5 ml of ethyl bromoacetate are added in 45 minutes.
The mixture obtained is left for 27 hours at room temperature, then poured into

3~

700 ml o~ iced water, decanted, the organic phase i9 washed with water, dried on magnesium (or sodium) sulfate, filtered and the filtrate evaporated. 110 g (yield ^~100 %) of raw product are obtained, one spot in TLC, which i~ used as it is in the next step.
3rd step : ~ -orthomethylbenzoyl propionic acid A mixture of 110 g of the preceding compound (XIII) in 650 ml of 6N
hydrochloric acid is heated at reflux for 16 hours. Then 2 liters of iced waterare added, then 350 ml of concentrated potash. The mixture is washed with ethyl ether, then acidified with concentrated hydrochloric acid, extracted with methy-lene chloride, the extract is washed with water, dried on sodium or magnesium sulfate, filtered and the filtrate evaporated. Thus, 40.5 g (yield : 56 %) of the expected product are obtained.
. Melting point : 99 C
. Empirical formula : C11H1203 . Molecular weight : 192.21 ~21 1)~
_. . . _ ~ __ _ . , :~!; ~0 ~ ~9 u~ 1~1 ~ oJ0 ~o r/~ __ __ ___ __ _ r~--. 5 H :~: Oo N ~ 0~ p t_O

Z _ ~ N N r ~ N 0 0 z 3~ O O C~ _ 3 o :' '31 ~ O
.' ' . , ' ~0~ , ,", ~U ~ . ~ . , ~O~J .

___ ~ . __ ~ ~

- 0 3 . 0 ~ G

H 3 ~ ~
~ ~ ~ . ., ~
~/ ,~ z~ z ~ 'o~ ' , v~ .

~- Z5 ~ r ~~1 ~~ ~ _~ e 0~
~- ~ ~ . ~.0~ ~_ o~ F . _ _ _ . e .

R I_ _ ~ --_ _ ~ ~1 3~
_ _ ~ .
. Z 0~ 1~ N N 3 oo r V7 __ __ _ _ _ _ H :~: ~ O --61 ~o It~ N CO

¢ ~ _ _ _ . _ _ Z ~ 30 CO N N O O~ ~0 ~'U
:~ _ _ _ _ _ _ _ _ _ r~l ¢ ~ o ,, O O _i o .

¦ ~ V N ~ -- - N . tU
.. . . __ _ __ ~D .

1 5 ~ ~ ~ ~ . f~: o .
~ ~ ~3 ~ ~_____.

2n e z~ æ ~ z,~, .

e . ~N o ~ o : a _ _ _ . . __ . .

. _ u' ~ ~ ~_ ft~ ... ~' . ~

. R___ _____ ___ ~
_ _ ~ ___ __ ~ ~ `, . ' 35 o ~ r~ u _~ = . ~

¦ " e ~

~ 3 2:~39~

__ __ ~,-- U~ _ ~' _ Z a~ ~ ~ J3 J9~ 5 a~ _ ~Q _ r __ ____ __ ~ _ __ .
~ O~ CO ~ 0~ ~D _ U~ ~O
~r r~ O ~ 00 ~ ~ ~ U~
_ _~ _ ___ . _ _ _ . o~ o ~ ~r o o o.
E~ c~ ~0 ~ ~ ~o c~ oo o~ oO
~: _ __ _ _ __ t~l ~ ~1 D ~1 D ,1 D ~i D
C~ O C~ O C~ O C~ o --O _ _ .. __ '~ ~ ~ 1n ''f' ~ 7 ~:: ~ ~ .
__________ , . O
bO ~ 1~ ~) O
O 3 ~ ~i ~) ~1 ~ _ _ . ~ ~

~ æ z æ z d 1~ ~O C~J ~1 S~ :~- ~:~' ~ ~ 5 0 o~
_ _ ., ~) = _ - _ . . _~
3~ = _ _ _ ~
~; ~: = _ . _ . , ~ '`.,~
._ ~ - . , .

H _ ~ __ 3 ~ Q

l '~f' - ' - ------- -)3~L

__ , ___ __ _ ~O O ~r) J O ~ C- ~1 V~Z o~ ~1 ~ ~ ~ 1~ ~
H _ _ _ __ _ . . _ ~1 ~r ~ u~ ~ ~ ~o Lr ~; ~ o~ ~ J~ ~ Jo V =~O
c~ ~o ~o ~o u:) t-- r- t-- t--_ _ _ _ _ _ .~O t\.l J J O Il~ ~0 t~J
E I 6~ q~ O ~ ~ ~t O
ZiC.) ::~ J ~J ~I C- ~D ~O
~ C- C- ~ t- ~_ ~ t- 1 ~ _ ___ _ _ __ ~ ~æ D ~ D ~ oD 'i _. ___ _ _ _. _ _ bO J~
~ C,) 0 CC) _ _ , O~ I~ J ~I
~3 ~r) ~ . 0 O
æ ~ o~
æ ~ æ z ~I N ~ ~r _ __ O~ ~, O~
~ ~ + ~ ~ ~-. _ _ ~ U~
_ _ : ' '_ _ _ - T

~2/ `' ~0~ \~ _ ~, O O
i~l _ a: _ ~ , ' _ _ _. _ ~L2:~lV39~l t--o =, o o~ ~ ~ m~ ~.
N 'O ~ ~ 2 ~ co ~o - ~ . ~o~ ~o~ ~ ~ ~ ., ~1 . O ~1 ~O L- ~ J ~ O
~ C~ ~ t~- ~D~ O~ O~ ~D~ \D~

~ a~ ,~ J~ r-i ~ r~ J~ r~ ~
_ ~d o ~d o .~ O 0 ~ `O O O O
~ ~ ! ' ~-3 f~ ~ O 0~
~ _ ._ .~

E O
r~ r-l r l r l Z
,C) C~ ~) C~ ~ ~
r N N O N
~ ~ - .~-- : - -~
~ - ~- ~ ~
=

Cl& ~I:N ~ _ _ _ -- = . . . _ . N
E-~ .

- ~2:~L039~

_ Z 3 D 3 3 3 N _ . -H -- D 3~ D N N _ g c~ ~o Lr. ~ a~ ~

_l --- V ~ / D __ V _ _ l ~ ' O
~ ,C ~ o C ~ O N
. : . , a~ ~ ~I o N
l ~) (~ Y) C J t , N I ~
'0~'- .. _~
.. ~ -~ . _ ~n ~ ~ :C
.. . _ _ . _ _ . .

~;/ \zl Z~ = . .
H¦ . . I . _ _ _ ~

~¦ ~ N . __ ~ _ .

.2~ )39~

~ i 1 5 . . ~; . ~ oq 0 _ aP ~ 11 , ~> ~1 ~
o~~r ~ ~ ~ ~-- .
. t~_ O~ ~ ~
~ ~ _ ~-. c~ Q V "

2 0 . _ _ _ _ _ . . . 1--.~c ~ ~o , 8 ~
oO a o - , ' ','0 . ¢ ~ ~ ~ . .. _ ~. o - .' ~ i ~/~ 0 3 C~J C~l CtD . ~R .
~(_\J ~ .. . ~ _ ,_ _ _ ~

~ ~ E U O~, . . ~rl. - O . .

__ __ ___ .. ~1'' ~ -.¢ . N: ~N . . . a~ ~ U . -:
. ~ .', _ . _ ~ ~ __ . . ~ :: = : .~, . ~ :
_ ~ ~ ., .
,., ~ . ~'., . ~ ., - ._ __ -~ . . . ~ ~ ¢' a~ , " `~D ~' '' ~ '.'~ ,';
~ . X ~ ~ ~ ~'''~`'`' v~

_ ~ _ ,__ E ::C ~ __ 5 ~ 9~

O I

æ ~ ~ ~ _ ~ ~ . .
. .. co _ ~n cD ~~ ~ .

. a r . . C I . ~ .
. ._ _ _, __ _ ~ ~
a ~ u~ .~ = Y~ .
'' S. ' ~ ' ----~ .................... , ~_ ~ ~ N ~ ~ ~
~ ~ ~ . c~l . ~ CD
. ~ ~ . . . . ~ ~ __ L ~ ¦ O ¦ O ¦ O O
~ _ _ _ _ ~ ~
' ¢ 0~ , O ,, , ~ J.' ' '~ :', . - -' . . ~ - ~ ::
35 . . O ~ . ~L~ . -~ , z , .. ~ . .....

1_1 _. _ ~ ~
H _ ~ _ _ ~ - ........ ..
m : _~ . _ r- C~ ~ ' ~i - ~ ---:
., a v 8 o e e ~ ~ e ~ ~ ~I c .,. . . ~ _ ~ _. ~,_ ~3 ~ _ ~ ~ ` 6 'J .
~ e 8 e O j91 "~ I ,0, . ~ o ~ ~ .: ~ ~ o . t-3 r- r ~ i~

. C~ ~ ~ . .
20 ~ __ . . ~ ~ ~

5 ~ ~ N N . N 7 ~ _ . _ _ ~ ~ N

~ e oN oN _ ~

. ~ __ ~ fi a :

_ _ ~ __ _ _ _ _ _ N
~ ~
,' `- ~ =.'.~' _~ ~

- ``` g~Z~ )39~

____ _ . _ .
._~ ~_ 03 . u~ 8 ~ e E ¦ ~_ J j ~ ~ ~
~ ~ o~ ~ _ E~ r- ~ e-- -1~1 ~ _ N a) N t~ 1~3 C) .
~ ~ ~ o~-~ .' "~ ' ~
~ ~ " ~U ~ ~û ~ .
, ~_. ' ...... .~ '.' _ . _~ _ t~ C.) o oO

~- . .~ _ _ ~
'~ ~ o~ o = , _ , X
~ _ . , _ ~ . ___ ~ N O ~ ~
,, __ _ . . .
. . . '' ~U-, .~1 . 3: sO o Sr_ ~
- __ ~ ~ ~ , .~ _ . . _ _ . . ~ ' ':

_ _ _ ___ _ ___ _ L_ i~--H tl: . . = 2 ~ . . i .
H _ _ . __: ~ _~_............... : .

. ' ~ . '_ ' ~ _ ~ ~

~Z~03~

_ ! ~., ---- e ~ r- ' .~ ~ _ .
~ ' ~ _ ~ ,_ E~ =r ~ ~n . ~ .

0 ~ _ D~ o . ~ ~ ~ ~ ~2,; ' 0 ~
15. z~ " :~ " . ~ . ~, ") .
a~ ~o7r7 ~ ~- a~-"

. _ ~ Q O
~ u ~ ~ z.~_ ._ ~ ~o , 0 _ a~
~}: ~ ~
~5 ~ N O . a> :

__ _ . , _ ~ ' 0~
r~ ~ O O . N C

o . _ _ _ __ "

D ~ D D 1- -.. . = ' ~
35: u . . _ _ o H , _ _ . _ _ _ ~_ _ , ~ '. ' _~ ~ -- __ ~ ' - ~0 ~ _ ~ ~ . . .

- ' . ' -' ~ ~ .

~ ~ a ^âT a ~ ~v 10 _, . 5~ _~ _ . o :c ~ ~ .
O~ N ~ ~a -- O ~ .

~1 O ~ _ ~ N ~ O~ N-Q
~:; .. G) o 1- 110 o 0~ a~ . .
~:: ~ ~ n _ ~ . cr. t~
. ~ ~, ~ ~ ~ . .

I ~ I I
~, __ _ _ __ _ .
a ~ _ O = = . _ . ~ ~ ---- ~

~~5 ~ ~ ~ ~ - c~ - ~o ~ _. _ . ___ _ ' ' ~ ., 'L~ O~`. oO~ S~D; S~-~ I ~ ' j a~
~. ~ _. ' :- ~ .
O _ I -- _ ~ S

~1 1 ~ 1 `" ~L2~)3~L

_ ~ . _ _ ~: ~o ~ ~ .
a ~1 C- " " -~
., ~ ~ ~, CO Y ~ ~ _, ~ .
.~ ~ ~ oq I a~ cs~ 3 3 a~ ~o l ~ l ~O' S ~D tr) bl)~ _ ,_ ~ ) O O

1 :~ ~' , ~ _ __7 _ , _ _ :' . . . . ~ ' E I t~

~ ~) 3::~ i _~
o~ ~ _ = _ _, _ __ _ . . __ _ __ H¦ ~ U __ A =, 3~3L
_ ~ ~. , O ~ O ~ _ I O

N O X _ ~O
_1,rlll~ ~ oi ~3 ~ _ _ ~ ~
- ~ O ~ , . . l ~ ~ ~ ~ =

~ ~ -~
_ N . _ S~ e O O N
.5, . N . 00 ~:~

. _ ___ _ _ l~ -~ -~--~ u~- ~ -E~ , ' ~:

L2~ 3~

. . . , _ _ ~ ~ a ~ ~1 ~ I

~ ~ 0~ l ~0 O a~ ( 0 ~

6 ~ ~ ~ N li3 N _ o N -- .
Z ~ ~C) (;I ~ N n~ ~D N
O ~ 1 O 11 1 ~ O 11 t`~ O ~
e I ' --~ ;~ _ ~ ~ cI ~ ~ '' ~loI

- 6 U~ _ ~ _ _ ~ _ ~
~ _ ~ In _ _ _ ~ 0 ~ ~ t-~_ C~
'~ ~ = =

_ t~J _ _ _ _ ~ _ ~ _ , C~I, _ .

= ~ Z N O

~ . ~ l l ,._ _ . . .' - tr~ .. _~ .
~ ~;~ ~ = : . ~
H ¦ _ , _ . _ _.
I ~ _ ~ __~ ~ . ~. _ _ , ~ ' .
' ~ .

33'3~
I - -=

I

a ~: ~: ~ ~
_ ^~ O ~,0 O ~"
0 .~1 ~ ." C_)l O ,t) E~ a ~ a o ~ o o ~ o-- _ o ~ e ~ _ a N O N td ~3 ~
O t~ O ^ al o O :~ X 1 E~ e~O:l ~ 1 _ I "~
___ ~ u~-- I e--~ ~ _ ~ _ ,. ~ ~ ~ ~ _ ~ ~ ;0~ ~
a~ J ~I _ _ t O, .~, .=t ~ 3 O
., _ t~ J 1~ 3 N N t--~ ~ ~ ~ ~ N
J~ ~
~1 0 _ O _ = = N
. " _ _ _ ~ _ - ~

O N N . O ~0 ~_ ~ _ __ _~, ... .
~ 00 o- o~O o~ =r ~ _ ~ _ . . . - . ~ . ~ . ~
el ~ :2 :C E~3' :C
I ~ ~ ~ ~
~r~ ' - ~- _ :' ~ . Y l _ _ _ _~ ~ _ __ _ ,, H ~: X = = :
~3 __ _ _ _ __ _ ~ ~ ~:
. ~ ~ _ ~ ~ , ~ `O : ~
.~

3~3~1L

__ . __ _ _ o N ~ o N O N . o (~ O ^ .
_ ~ c~ 1~1 _ ~ o ~ 1~ ~ 3~3~a~ 1 _~ ~ ~ ~ ~- ~ ~ OD
- Ir. - - ~ - - - - ~ ~ ~
~ (~1 ~u ~ ` t~ ) ~ . ~ t~ N ~ 3 N ~i ,~ ~ .

- t-- N _ _ ~i o1~ t~9 ~5 - . ' _ ___ _. .

~ ~ o~ ,~ æ ~o s~ ~ ~ 3: ~ C~

_ ~ ~ a~ 3~
. _ _ -- -~ - ~ ____ .~ .
~, , . ~ .
H PC ~T~ = = _ _ =
~ ,. _ _ ~ ~ ~ _ ~

-~ ,.`, :

`` ~L2:~1)39~L

__ _ . _ ~:; o _ ~ ~

~ ~ ~ t ~ ~ ~ ~ l .
~, o~ ~ ~ o 2 ~ .
~ . __ ~............. .

~ ~ mco mm mO mm ~ ~) _ ~ E~ ~ c~

~ . ~ o ~_ ~ m C~) ~;~ ~ ~ = _ H ¦ O; m ~ ._ ~1 ' ~ ~ ~ o~ OD _ O,D .
.E~

9~L

~ .

e O r ~7 ~3 .
i~l _ ~ ~ X i ~ 1 P~ E N ~0 ~0 ~3 ~ ~ ~ e ) ~ ~ ^ ~ .
C~ ~ ,.. ~ I _ r~ ~ _~ o o 'o ~ ~ '~' ~.

. . . . . . .

C~ ~1 O ~1 N O
. :~ ~)~ C~ V ~
~ S~ , ~ V~ ~ ico - _ _ C __ _ q~l ~_ . ' ~ _ ~) i~
~~;~ ~ : _ H.. -- _ . _ _ ~) - ~-~ -.
¢ i r c~ ~ ~ N 0 2 _ ~ O I N
D ~ Y e ,e a:l ~-~3 o ~, _ _ ~ ~ ._~_ ~ ~~ ~ .,,~ ~ O ~ ~
. ~ ~ t-- ~ ~ =t 3 ~3 ~1~ t-~ (`J ~3 ~0~ _ _ .
J~ O _ ~ O
. ~ ~ .
~ '~ ~ ~ o~ O
3 ~ ~ , t~.l t'~l " - O 0~ .
S~ ~ , O 'C-~/ C~
E3~ ~Co ~ c~ ~) ¢ _ ''-Z O ~y ~ _ ~ ~ 3:: ~ ~3 ~: CC~ X = = =

H . . ~1 . _ _ t_ ~ _ _ ~: : _~ _ _ _ __ . . . _ __. _ 14D39~

~ V ~ ¢o~ ~oOI~O ~ ;

~a e ' ' e " " :~:
2 ~ 'D ~O ~ `O ~
e ~, ~, 0l t, I ~ e ~1 I
l ~.
~ U~ ~ _ ~ _ _ . ._ ....... _ .
V~ ~, ~ ~ ~ .

. ~ . N O N N

~ ~ ~ ~ /i~

H ~ ~

c~ ¦ m N N .
~ ' ` ' 3Sal~

_ _ _ _ ._... ... .

~ ~ 1~ Lr~ ~ ~
. , . ,`_ I _ _ 0~ . ~ J l ~ , ~ D
I ~ 3 .- l 1~
, _ _ ~S ~ X O O ~
O __ _ _ _ _ _ '~1 -~/~ ~ f' ~ - ..

.~i ~
`` .~21~

__ _ _, o~ ~ ,o , ~ 1 o X r~ O ~ ~0 0 ~ . ~ ) ~ a o C~ ~ .

1:~; (d N N ~ O N N O
~ . ~ O ^~ --O ^ ~D ~ ~
_ ~1 3~ cl ~i -~
~ C~ I ~c~ I I I ~ ~ ~a r- I
__ _ _ ~ ~_ _ _ "_ _ _ ._ ~____ ~___ ~ ~_ ~3 o ~ N co ~ 00 0~ J J J ~) t--::t 1~ N ~ t~ i ~ ~
. _ ~ 1-.. S . , .

~ o 0~ o ~e~
_l _ . _ . - r .

. ~ . N 0~ N .~
, C_) __ , C') C.)~, q . ~ 0~ æ
_ _ . . ~ ~ .,, .
a~;~ ~ = =
0: .~ _ ~" . . . _ H . __ . _ . _ _ _ m .. ~ ;~ CC ~ ~ ~
i~ ~: ~ . . _ __ ~ : ~ ' ';~

~ \
)391;

_ .

~ ~_. __ __ ~
'o --, :
,o ~ . o~ : ~ :
__ ~ _ ~ . . __ ~ ~

~ ~ ~ . ~ : ~
. _ ~ ~ `~:, o ~ . _ . . . . ~ ~ ~
~ _oe :q _ ___ _.___ ~ ~
' ' ,CI ~ ~ _ _ ~ _ ~ ; '~
~ _ _ ~ ' ~ ~ "-~ ~ ~

39~L

The compounds of the invention have been tested on laboratory animals and have shown pharmacological properties, particularly activities in the field of the central nervous system and especially analgesic and/or antidepressive properties.
The analgesic activity was demonstrated in mice (by intraperitoneal administration of the compounds of the invention) using the phenylbenzoquinone test according to the method described by E. SIEGMUND in Proced. Soc. Exp. Biol.and Med. 95, 729 (1957).
The antidepressive activity wa~ demonstrated in mice by the antagonism test with respect to ptosis observed one hour after an intravenous injection (2 mg/kg) of reserpine in mice according to the method described by C. GOURET and J. THOMAS in J. Pharmacol. (Paris), ~, 401 (1973).
To illustrate the invention, the re~ult~ obtained in these two ~ests with ~ome compounds of the invention are shown in table III belo~. Thi~ table further gives the acute toxicity (LD 50) of the tested compounds.

. !

~ )3~3~

TABLE III
. . .~ _ ._ ~
Code LD 50 mice Anal~sic properties Antidepressive properties Number(m~/kg/i.p.) ED 50 (mgtlcg/i.p.) ED 50 (mg/kgtl.p.3 ~ . . _ . _ 2 70 4.~ 5~3 3 47 6"2 3~2 1~ 83 3"2 ~6 165 6 ~ ~ - - -6- ~ ~0 _ ~ - V~6 7 90 2~,8 8 11 5 3 2~5 -9 58 2~,2 3 2~4 006 12 82 7~4 14 93 2D8 0~8 16 . 90 5 17 17 130 3.5 3~5 18 120 4~8 9 19 110 5 8~7 22 65 6l 22 10~7 23 71 25,4 .
._ . ,, ___ 3~

The difference between the toxic do~es and the active doses allows the compounds of the invention to be used in therapeutics.
The present invention thu3 relates also to the application, as drugs, of the derivatives of formula (I) and the pharmaceutically acceptable acid addition salts thereof, these drugs being used in the treatment of disorders of the central nervous system, particularly as antidepressant3 or analgesics.
The invention finally relates to the pharmaceutical compositions which contain at least one of the above defined drugs in association with an appropriate pharmaceutically acceptable carrier.
These compositions will be administered :
~ orally in the form of tablets, pills, capsules etc..., in amount~
up to 400 mg of active ingredient per day, taken in 3 or 4 doses ;
- intravenously, in the form of injectable ampoules in amounts up to 100 mg of active ingredient per day taken in 3 or 4 doses ;
- intramu~cularly, in the form of injectable ampoules in amounts up to 100 mg of active ingredient per day taken in 3 or 4 doses ; and - in the forM of suppositories in amounts up to 200 mg of active ingredient per day taken in 3 or 4 doses.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the general formula (I):
(I) in which:
- R1 and R2, which may be the same or different, is each a hydrogen atom, an alkyl group of 1 to 4 carbon atoms or may jointly form, together with the nitrogen atom to which they are both linked, a heterocyclic radical selected from pyrrolidino, piperidino, hexamethyle-neimino, morpholino, piperazino and 4-methyl-piperazino;
- n is 1, 2 or 3;
- R is hydrogen, halogen or methyl; and - R3 is hydrogen, halogen, methyl or methoxy, and its pharmaceutically acceptable salts the process comprising:

(a) condensing an amine of the formula (II):
(II) in which R and R1 are as defined above:
with a compound of the formula (III):
(III) in which n, R and R3 are as defined above and R4 is an easily removed nucleophilic group; and (b) when n is (1) or (2) and R1 and R2 are both hydrogen reducing the compound of the general formula (X):
(X) and, if required, converting the product in each case into a pharmaceutically acceptable salt.

2. A process as claimed in claim 1 in which the nucleophilic group is halogen, methylsulfonyloxy or parato-lylsulfonyloxy.

3. A process as claimed in claim 1 in which the condensation in (a) is carried out in an aprotic salt.

4. A process as claimed in claim 1 in which the reduction in (b) is catalytic reduction.

5. A process as claimed in claim 4 in which the catalyst is Raney nickel.

6. A process as claimed in claim 1 in which the set (n, NR1R2, R, R3) is selected from:

7. A process for preparing 2-N,N-dimethylamino-ethyl-4-phenylnaphthalene and its pharmaceutically accep-table salts that comprises condensing 2-mesyloxyethyl-4-phenylnaphthalene with N,N-dimethylamine and, if required, converting the product into a pharmaceutically acceptable salt.

8. A process for preparing 2-N,N-dimethylamino-ethyl-(2-fluoro)-4-phenyl-naphthalene that comprises condensing 2-mesyloxyethyl-(2-fluoro)-4-phenylnaphthalene with N,N-dimethylamine and, if required, converting the product into a pharmaceutically acceptable salt.

9. A process for preparing (2-N-methylamino) -2-ethyl-(2-fluoro)-4-phenylnaphthalene that comprises reac ting 2-mesyloxyethyl-(2-fluoro)-4-phenylnaphthalene with methylamine and, if required, converting the product into a pharmaceutically acceptable salt.

10. A compound having the general formula (I) defined in claim 1 when produced by the process as claimed in claim 1 or by its obvious chemical equivalent.

11. (2-N,N-dimethylamino)-2-ethyl-4-phenyl-naphthalene when produced by the process as claimed in claim 7 or by its obvious chemical equivalent.

12. (2-N,N-dimethylamino-2-ethyl-(2-fluoro)-4-phenylnaphthalene when produced by the process as claimed in claim 8 or by its obvious chemical equivalent.

13. (2-N-methylamino)-2-ethyl-4-(2-fluoro) phenylnaphthalene when produced by the process as claimed in claim 9 or by its obvious chemical equivalent.