Note: Descriptions are shown in the official language in which they were submitted.
~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 :
/ R1
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)
~ .
R3
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)
H3
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~
1 1
- ~ -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
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37
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~
38
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
~ . . _ . _
1 140 1205 10
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
1 1 75 1 0
12 82 7~4
13 260 24 18
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~
39
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.
