OPTICAL ISOMERS OF 2-(1-HALONAPHTH-2-YLOXY) PROPIONIC ACIDS AND SALTS AND DERIVATIVES THEREOF

ISOMERES OPTIQUES DES ACIDES 2-(1-HALONAPHTH-2-YLOXY) PROPIONIQUES, LEURS SELS ET LEURS DERIVES

English Abstract

ABSTRACT OF THE DISCLOSURE
Optically active compounds of formula:
<IMG>
wherein R is selected from the group consisting of hydroxy, (C1-4) alkoxy,
aralkoxy, oxypropylsulfonic acid and salts thereof, primary amino, mono
(C1-4) alkyl amino, di (C1-4) alkylamino, and hydroxyamino groups and X is
selected from the group consisting of fluorine, chlorine, bromine and iodine
atoms. These compounds have interesting pharmaceutical properties including
analgesic, antipyretic, antiphlogistic, antipruritic, fibrinolitic and
normolipidemic activities. Methods for preparing the optically active com-
pounds are described.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
I. Process for the preparation of optical isomers of derivatives of
the formula
<IMG> I
wherein R is selected from the group consisting of (C1-4) alkoxy, oxipropyl-
sulfonic acid and salts thereof, amino and hydroxyamino group, which process
comprises separating an optically active isomer from a racemic mixture of 2-
(naphth-2-yloxy) propionic acid or 2(1-chloro-naphth-2-yloxy) propionic acid
and then transforming the acid into the appropriate compound of formula I.
2. A process for the preparation of an optically active compound of
formula I, as defined in claim 1, wherein R is (C1-4) alkoxy, comprising
separating an optically active isomer from the racemic form of 2(1-chloro-
naphth-2-yloxy) propionic acid and esterifying the d or 1 2(1-chloro-naphth-2-
yloxy) propionic acid or the acid chloride or anhydride thereof with a (C1-4)
alkanol.
3. A process for the preparation of an optically active compound of
formula I, as defined in claim 1, wherein R is (C1-4) alkoxy, comprising
separating an optically active isomer from the racemic form of 2(naphth-2-
yloxy) propionic acid, esterifying the d or 1 2(naphth-2-yloxy) propionic
acid, or an acid chloride or anhydride thereof, with a (C1-4) alkanol and
chlorinating the ester in position 1 of the naphthalenic ring.
4. A process for the preparation of an optically active compound of
formula I, as defined in claim 1, wherein R is O(CH2)3SO3H, comprising
separating an optically active isomer from the racemic form of 2(1-chloro-
naphth-2-yloxy) propionic acid, condensing the d or 1 2-(1-chloro-naphth-2-
yloxy) propionic acid with 3-hydroxy-1-propansulfonic acid .gamma.-sultone in a
basic medium.
12

5. A process for the preparation of an optically active compound of
formula I, as defined in claim 1, wherein R is O(CH2)3SO3H, comprising
separating an optically active isomer from the racemic form of 2(naphth-2-
yloxy) propionic acid, condensing the d or ? 2(naphth-2-yloxy) propionic
acid with 3-hydroxy-1-propansulfonic acid with 3-hydroxy-1-propansulfonic
acid .gamma.-sultone in a basic medium, and chlorinating the obtained ester in
position 1 of the naphthalenic ring.
6. A process for the preparation of an optically active compound of
formula I, as defined in claim 1, wherein R is NH , comprising separating an
optically active isomer from the racemic form of 2(1-chloronaphth-2-yloxy)
propionic acid, and condensing the d or ? 2(1-chloronaphth-2-yloxy)
propionic acid with ammonia.
7. A process for the preparation of an optically active compound of
formula I, as defined in claim 1, wherein R is NH2, comprising separating an
optically active isomer from the racemic form of 2(naphth-2-yloxy) propionic
acid, condensing the d or ? 2(naphth-2-yloxy) propionic acid with ammonia
and chlorinating the amide in position 1 of the naphthalenic ring.
8. A process for the preparation of an optically active compound of
formula I as defined in claim 1, wherein R is NHOH, comprising separating
an optically active isomer from the racemic form of 2(1-chloronaphth-2-
yloxy) propionic acid and condensing the d or ? 2(1-chloronaphth-2-yloxy)
propionic acid with hydroxylamine.
13

Description

664
Racemic forms of certain substituted 2-(l-halonaph-th-2-yloxy)
acetic acids are known (see ~nited States Patent Specifica-tion No. 3,968,145)
and have been found to have antipyretic, antiphlogistic and analgesic proper-
ties.
According to the present inven-tion there is provided a process for
the preparation of optical isomers of derivatives of the formula
~ O-CH-COR
wherein R is selected from the group consisting of (Cl 4) alkoxy, oxipropyl-
sulfonic acid and salts thereof, amino and hydroxyamino group, which process
comprises separating an optically active isomer from a racemic mixture of 2-
(naphth-2-yloxy) propionic acid or 2(1-chloronaphth-2-yloxy) propionic acid
and then transforming the acid into the appropriate compound of formula I.
These optically active forms have been found to have particularly
interesting pharmalogical properties as described hereinafter and can be
included in pharmaceutical compositions in combination with a pharmaceuti-
cally acceptable carrier or excipient.
Specific compounds of formula I and processes for their prepara-
tion will now be given by way o:E example. Examples of

i6~
optically active co~npounds of formula I include;
1) d 2(1-chloronaphth-2-yloxy) propionic acid (X = Cl, R = OH)
m.p. 162-3C. r~X72DO = ~ 17 (c = 2~ ethanol).
2~ e 2~ chloronaphth-2-yloxy) propionlc acid (X ~ Cl; R ~ OH)
m.p. 162-3C; ~DO = _ 17 (¢ 3 2~ ethanol3.
3) d methyl 2~ chloronaphth-2-yloxy) propionate (X- Cl, R =
OC~3) m,p. 43-4Cj~ ~ ~ + 18 (c = 2% ethanol).
4~ e methyl 2-(1-chloronaphth-2-yloxy~ propionate (X - Cl,
R = OCH3) m.p. 4~-4C ;~ ~ 20 = -18 (c _ 20& ethanol).
5) d ethyl 2-(1-chloronaphth-2-yloxy) propion~te (X - Cl, R .
OC2H5) m.p.48-9C;~;72 .. + 17 (c ~ 296 ethanol).
6) e ethyl 2-(1-chloronaphth-2-yloxy) proplonate (X ~ Cl,
R ~ OC2H5) m.p.48-9 ~ ~ 20 e -17(c=2pethanol).
7) d propyl 2~ chloronaphth-2-yloxy) propionate (X ~ Cl, R n
OC3H7) m.p,28 - 30 C;~ 20 ~ ~14 (c ~ 2~ ethanol),
8) e propyl 2~ chloronaphth-2~yloxy) proplonate (~ ~ Cl,
R ~ OC~H7) m,p.2C-3~,~J20 . ~ 14 ~o ~ 2~ ethanol).
9) ~ oodlum 3~ ohloronaphth-2-~loxy)-ethylcarbonylox~
propylculton~be ~X ~ Cl,R-OCH2CH2CH2S03Na) m,p, 180a (deo);
~ O ~ ~ ~3~ ~ 2% water)~
10) ~ oodlum 3~ 1-chloronaphth-2-yloxy)-~thyloarbonylox~
propyloulfonate (X ~ cl~R~ocH2cH2aH2so3Na) m,p. 180C (~ec);
O ~ _13 (O . ~/o w~er).
11) d 2~ chloronaphth-2-yloxy) propionam1de (X u Cl, R ~ NH2
m.p. 203-5C; ~DO ~ ~ 42 (c ~ 2~ ethanol).

l~S~;64
12) Q 2-(1-chloronaphth-2-yloxy) propionamide (x = Cl, R = NH2) m.p. 203-
5C; [~]20 _ -42 (c = 2% ethanol)
13) d 2-(1-chloronaphth-2-yloxy) propionylhydroxamic acid (X = Cl, R = NHOH)
m p 136-8Ci [~]20 = +8 (c = 2% ethanol).
14) Q 2-(1-chloronaphth-2-yloxy) propionylhydroxamic acid (x = Cl, R = NHOH)
m p 136-8C; [~] = -8 (c = 2% ethanol).
The optically active isomers of 2-(1-chloronaphth-2-yloxy) propionic
acids are obtained by the following methods:
1) by resolution into optical isomers of the racemic form of 2-(1-chloro-
naphth-2-yloxy) propionic acid.
2) by resolution into the optical isomers of dQ 2-(naphth-2-yloxy) propionic
acid, and subsequent chlorination of the optical isomers.
3) by chlorination by way of a diazo intermediate of d or Q 2-(1-amino-
naphth-2-yloxy) propionic acid. The d or Q 2-(1-aminonaphth-2-yloxy)
propionic acid is obtained either by resolution of dQ 2-(1-aminonaphth-2-
yloxy) propionic acid, or by reduction of d or Q 2-(1-nitronaphth-2-yloxy)
propionic acid which is obtained by resolution of dQ 2-(1-nitronaphth-2-
yioxy) propionic acid.
The optically active isomers of the 2-(1-chloronaphth-2-yloxy)
propionic esters are obtained by the following methods:
a) by chlorination of the appropriate ester of d or Q 2-(naphth-2-yloxy)
propionic acid in position 1 of the naphthalenic ring.
b) by chlorination of the appropriate ester of d or Q 2-(1-aminonaphth-2-
yloxy) propionic acid by way of a diazo intermediate.
c) by esterification d or Q 2-(1-chloronaphth-2-yloxy) propionic acid with
appropriate alcohol in acidic medium.
d) by condensation either of the acid chloride or the anhydride of d or Q
2-(1-chloronaphth-2-yloxy) propionic acid with the appropriate alcohol.
e) by reaction of a salt of d or Q 2-(1-chloronaphth-2-yloxy) propionic
acid with the appropriate alkyl or aralkyl halide.
f) by condensation of the d or Q 2-(1-chloronaphth-2-yloxy) propionic acid
with the internal ester of 3-hydroxy-1-propane sulfonic acid y-sultone in
-- 4 --

~S~G~4
basic medi~
The optically active isomers of 2-(1-chloronaphth-2-yloxy) propion-
ic amides are obtained by the Eollowing methods:
a) by chlorination in position 1 on the naphthalenic ring of d or Q 2-
(naphth-2-yloxy) propionamide, obtained from the corresponding optica~ly
active form of the 2-(naphth-2-yloxy) propionic acid.
b) by chlorination by way of a diazo intermediate of d or Q 2-(1-amino-
naphth-2-yloxy) propionic acid and the transformation of the acid group of
the product into amide as described in method c).
c) by condenstion of the chloride or of the anhydride or ester of the d or
Q 2-(1-chloronaphth-2-yloxy) propionic acid with ammonia.
The optically active forms of the 2-(1-chloronaphth-2-yloxy)
propionyl hydroxamic acids are obtained by the following methods:
a) by chlorination of d or Q 2-(naphth-2-yloxy) propionylhydroxamic acid
in the position 1 of the naphthalenic ring. The 2-(naphth-2-yloxy)
propionic hydroxamic acid is obtained from the corresponding optically active
form of the 2-(naphth-2-yloxy) propionic acid.
b) by chlorination by way of a diazo intermediate of the d or Q 2-(1-amino-
naphth-2-yloxy) propionic acid followed by the transformation of the acid
group of the product into hydroxamic acid as described in the following me-th-
od c).
c) by condensation of the acid chloride or anhydride or ester of d or Q
2-(1-chloronaphth-2-yloxy) propionic acid with hydroxylamine.
The preparation of some of the optically active compounds of
formula I will now be described by way of example.

~s~
E~ample 1 ~-reparation of ~ 2~ chloronaphth-2-yloxy) propionlc
acid (Compound 2)
14.4 g of d~ 2-( naphth-2-yloxy) propionlc acid and 8,1 g of
~-methylbenæylamlne are di~solved ln 87 ml or hot etharlol 95~.
Upon coollng the ~slution 8 g of precipltate are obtaine~.
The preclpitate i9 repeatedly crystallized ~rom ethanol and
yield~ a product having a m.p. of 185-88C; ~J D = - 66
(c ~ 2~/' ethanol).
~ hiq product i9 treated with N HCl and extracted wlth ether;
the ethereal phas~ 1~ wa~hed wlth water and dried over anydrous
sodlum ~ulfate. Ethyl ether i8 then removed and the e 2-( naphth-
2-yloxy) propionlc acld 1~ obtalned: m.p. of 118 - 19C; ~20
- 88 ( c ~ 2~ ethanol).
Stoichlometrlc amounts of chlorlne are bubbled through a
solutlon of thls c ~ ound ln acetic ncld and ~ 2-(1-chloronaphth
-2-yloxy) proplonlc acld i8 obtalned s m.p. 162-3 (benzene):
O --17 ~o ~ 2~ ethanol),
~ 2~ chloronaph~h-2~yloxy) propioni¢ acld ca~ also be
obtalned by separatlng by fractional crystalllzation using en
approprlate 901v~nt i.~, acetone~ ethanol, water or chloroform,
Or the dla3terolsomerio ealts prepared by reactlon de 2
chloronaphth-2-yloyy) proplonlc acld wlth optically actlve bace~
like ~ ephedrlne (dlasteroisomeric salt mp. 137- 39C; ~DO
= - 14 (c ~ 2~ ethanol)), ~ O~-methylbenzyl-amine ~dl~terolsomerlc
salt m.p. 174-7C; ~720= -1 (c _ 2% ethanol)), e quinine
(diasteroi~omeric salt m.p. 168-70C; ~ 20_ _94 (c ~ 2~
ethanol)): the dlasterolsomerlc ealts obtained are then treated

11~16~;4
with acld
Example 2: preparation o~ d 2~ chloronapht-2-yloxy~
propionlc acid, (Compound 1)
14.4 g of d~ 2-( naphth-2-yloxy) proplonic acld and ~
g f e ~-methylbenzylamlne are dl~olved ln ~7 ml of hot ethanol.
Upon coolin~ the ~olution, a precipitate 19 obtained, The
solution i8 then reduced to 1/3 of ita orlginal ~olume; the
precipitate obtalned by cooling i~ cryQtallized from chloroform:
m p. 161-3C;~ ~ 20~ + 43 (c c 2~ ethanol).
The product is treated wlth N HCl and extracted with ether,
the ethereal phase ls wa~hed with water and the ~olvent removed
by evaporation under reduced pressure, ~he d 2-( naphth-2-
yloxy) proplonic acld.obtalned has a m.p, 118-119C; ~ ~ 20
88 (c ~ 2~ ethanol).
Stolchlometri¢ ~mount~ of chlorlne are bubbled through a
solutlon of thls compound ln acetio acid and d 2-tl-chloronaphth
-2-yloxy) propioni¢ Rcld 1~ obtalned: m,p, 16Z-~ (benzene):
0~ ~ 17 (o ~ 2~ cthanol),
d 2~ ohloro~aphth-2-yloxy) proplonlo acld can alao be
obtained by oopar~tln~ by fractlonal crystalllzatlon ucing app-
roprlate ~olvent~ l,e, acotone, ethanol, water or chloroiorm,
th~ dlasterolsomerlc ualts prepared by reactlng de 2~
chloronaphth-2-yloxy) proplonic acld with optlcally actl~e
base~ like ~ ephedrine (diasteroisomerlc salts m p. 121-3~C;
0 ~ _ 36 ~c = 2~ ethanol)), e qulnine (diasterolsomerlc
salt m.p. 154-6C; ~20 = _ 104(c 2~ ethanol)),

~S~
Q~-methylbenzylamine (diasteroisomeric salt m.p. 148-51 C [~]D = ~ 21.0
(c = 2~ ethanol)~.
The d 2-(1-chloronaphth-2-yloxy) propionic acid is then obtained by
treating the diasteroisomeric salts with acid.
Exam~le 3: Preparation of d or Q ethyl 2-(1-chloronaphth-2-yloxy) propionate.
(Compounds 5-6)
A solution containing 3 g of d or Q 2-(1-chloronaphth-2-yloxy) pro-
pionic aeid in 30 ml of absolute ethanol and 1 ml of coneentrated sulfonie
acid is refluxed for 8 hrs and o~oled. The solution is then neutralized with
5~ NaOH, and the solvent is removed under redueed pressure. The residue ob-
tained is treated with water and extraeted with ethyl ether. The ecmbined
ether extracts, are dried over anhydrous sodium sulfate.
The solvent is removed to yield the produet, d or Q form, which has
a m p. 48-9&; [~]20 = + 17 (e = 2%) ethanol).
Example 4: Preparation of d or Q sodium 3-[1-(1-ehloronaphth-2-yloxy) ethyl-
earbonyloxy] propyl sulfonate. (Compounds 9-10)
2.5 g of d or Q 2-(1-ehloronaphth-2-yloxy) propionie aeid are added
to a solution of 0.230 g of metallic sodium in 30 ml of absolute ethanol:
the solution is stirred at room temperature for 15 minutes. 1.45 g of 3
hydroxy-l-propane sulfonie acid y-sultone are added and the mixture is heated
under reflux for 3 hours. After eooling the preeipitate, d or Q form, is
eolleeted and reerystallized from ethanol; m.p. 180& (dee) [~]D0 = _ 13
(e = 2% ethanol).
Example 5: Preparation of d or Q 2-(1-ehloronaphth-2-yloxy) propionamide.
(Compounds 11-12)
1 g of d or Q 2-(1-ehloronaphth-2-yloxy) propionylchloride was
slowly added dropwise, with stirring to 150 ml of concentrated aqueous
ammonia solution at a temperature of -5 -o&. The preeipitate, d or Q form,
is eollected and crystallized from isopropyl aleohol; m.p. 203-5 &
[ ]20 = + 42 (c = 2~ ethanol)-

~5~664
Example 6: Preparation of d or Q 2~ chloronaphth-2-yloxy) propionyl-
hydroxamic acid. (Compounds 13-14)
A solution of 1.28 g metallic sodium dissolved in 35 ml of methanol,
is added to 60 ml methanol containing 3.7 g of hydroxylamine hydrochloride.
The precipitate is discarded and 10 g of d or Q ethyl 2-(1-chloronaphth-2~
yloxy) propionate are added dropwise to the supernatant liquid with stirring
at room temperature over a period of 12 hours. The resulting solution is
poured into cold water and acidified with conc. HCl and the precipitate, d or
Q form, is crystallized from isopropyl alcohol; m.p. 136-8C; [~]D = + 8
(c = 2~ ethanol).
Optically active compounds of formula I show interesting pharmaco-
logical properties and they can be used in therapy, in particular as analges-
ics, antipyretics, antiphlogistics, antipruritics, fibrinolitics, normo-
lipidemics.
In table I examples of the biological activities of scme optically
active compounds of formula I are compared with the corresponding racemate.
Antiphologistic activity was tested on carrageenin induced paw
oedema in the rat according to A.C. Winter, E.A. Risley, G.W. Nuss, (see Proc.
Soc. Exp. Biol. Med. 1 , 544 (1962): analgesic activity was determined
according Hendershot L.C. and Forsaith J. (see J. Pharmacol. Ex. Therap. 125,
237, (1959). The platelet-aggregation inhibition was tested indirectly by
measuring the arachidonic acid-induced bronchoconstriction in the guinea-pig
(Silver, M.J. Hoch, W., Kocsis, J.J. Engeman, C.M. Science 183 1085 (1974).
It can be seen that the biological activity of at least one optical
isomer is greater than the activity of the corresponding racemate.
The gastro-intestinal tolerability, tested according to Brodie, D.A.,
Cook, P.G., Bauer, B.J. and Dagle, G.E., Toxicol. Appl. Pharmacol., 17, 615,
(1970), was about 10 times higher as ccmpared with the standards (i.e.
indomethacin 8-10 mg/Kg/os) for all conQounds of FormNla I.

Cbmpound Antiflogistic Analgesic Anti-aggregatory
Activity Activity Activity Potency
Potency ratio Potency ratio
(a) ratio
(bl) (b2) (Cl) (C2)
1) d 2(1-chloronaphth
-2-yloxy) propionic
acid 30 - 2.30 - 1.0
2) Q 2(1-chloronaphth
-2-yloxy) propionic
acid 4.2 - 1.94 - 0
3) dQ 2(1-chloro-
naphth-2-yloxy) propionic
acid 16 - 1.80 - 0.5
4) d methyl 2(1-
chloronaphth-2-ylaxy)
propionate 20 - 1.88 1.3
5) Q methyl 2(1-
chloronaphth-2-yloxy)
propionate 5.1 - 0.50 0.2
6) dQ methyl 2(1-
chloronaphth-2-yloxy)
propionate 16 - 1.60 1.0
7) d sodium 3[1-(1-
c~lloronaphth-2-yloxy)
ethylcarbonyloxy]
propyl sulfonate - 3.22 - - 0.8
8) Q sodium 3[1-(1-
chloronaphth-2-yloxy)
ethylcarbonyloxy]
propyl sulfonate - 1.07 - - 0.7
9) dQ sodium 3[1-(1-
chloronaphth-2-yloxy)
ethylcarbonyloxy]
propyl sulfonate - 1.59 - - 0.6
10) acetylsalicylic
acid 1 1 1 - 1
Notes for Table
(a) Compounds 1,2,3,4,5,6 were administered per os at a dose of 7.5 mg/Kg.
Acetylsalicylic acid was administered per os at a dose 200 mg/Kg.
(b) 1) Compounds were administered at a dose 25 mg/Kg, subcutaneously V2
hour before administration i.p. of phenylquinone.
-- 10 --

~s~
2) Cbmpounds were administered at a dose 50 mg/Kg per os 1 hour before
administration i.p. of phenylquinone.
~c) 1) Compounds 4,5,6 and aminophenazone were administered m tradu~denally
at a dose 200 ~/Kg.
2) Cbmpounds 1,2,3,7,8,9 and acetylsalicylic acid were administered i.v.
at a dose 200 ~/Kg.
The pharmaoeutical compositions containing the above described
optical isomers can be formulated such that they are suitable, for example,
for oral, parer.teral or rectal administration. Examples of suitable forms of
administration include tablets, coated tablets, capsules, losanges, dispers-
ible pow~ers, syrups, elixirs, suppositories and ampuls with a dosage from
5 mg to 500 mg of active substance. Preferably the compositions are pre-
sented in dosage unit form.