CA1151664A - Optical isomers of 2-(1-halonaphth-2-yloxy) propionic acids and salts and derivatives thereof - Google Patents
Optical isomers of 2-(1-halonaphth-2-yloxy) propionic acids and salts and derivatives thereofInfo
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- CA1151664A CA1151664A CA000341734A CA341734A CA1151664A CA 1151664 A CA1151664 A CA 1151664A CA 000341734 A CA000341734 A CA 000341734A CA 341734 A CA341734 A CA 341734A CA 1151664 A CA1151664 A CA 1151664A
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- propionic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
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Abstract
ABSTRACT OF THE DISCLOSURE
Optically active compounds of formula:
Optically active compounds of formula:
Description
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).
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).
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).
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)~
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).
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
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 ~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.
~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.
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 ~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.
~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.
Claims (8)
- 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 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.
- 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT09665/78A IT1109006B (en) | 1978-12-14 | 1978-12-14 | ACIDS 2 I HALOGEN NAFT 2 PROPIONOIC ILOSSI OPTICALLY ACTIVE FORMS AND RACEMIC FORMS THEIR DERIVATIVES AND RELATED MANUFACTURING PROCEDURES |
| IT9665A/78 | 1978-12-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1151664A true CA1151664A (en) | 1983-08-09 |
Family
ID=11132975
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000341734A Expired CA1151664A (en) | 1978-12-14 | 1979-02-12 | Optical isomers of 2-(1-halonaphth-2-yloxy) propionic acids and salts and derivatives thereof |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS55122735A (en) |
| BE (1) | BE880596A (en) |
| CA (1) | CA1151664A (en) |
| CH (1) | CH644577A5 (en) |
| DE (1) | DE2949106A1 (en) |
| ES (1) | ES486845A1 (en) |
| FR (1) | FR2444023A1 (en) |
| GB (1) | GB2047234A (en) |
| IT (1) | IT1109006B (en) |
| NL (1) | NL7909052A (en) |
| SE (1) | SE7910284L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3722778A1 (en) * | 1987-07-09 | 1989-03-09 | Raschig Ag | POLYALKYLENE GLYCOL NAPHTHYL-3-SULPHOPROPYL DIETHERS AND THEIR SALTS, PROCESS FOR PREPARING THESE COMPOUNDS AND THEIR USE AS A NETWORK IN GALVANO TECHNOLOGY |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE790363A (en) * | 1971-10-21 | 1973-02-15 | Menarini Sas | (1-HALOGENO-2-NAPHTYLOXY) -ACETIC ACIDS, RELATIVE ALPHA-SUBSTITUTE COMPOUNDS, THEIR DERIVATIVES AND THEIR PREPARATION METHODS |
-
1978
- 1978-12-14 IT IT09665/78A patent/IT1109006B/en active
-
1979
- 1979-02-12 CA CA000341734A patent/CA1151664A/en not_active Expired
- 1979-12-06 DE DE19792949106 patent/DE2949106A1/en not_active Withdrawn
- 1979-12-10 GB GB7942537A patent/GB2047234A/en not_active Withdrawn
- 1979-12-11 CH CH1097879A patent/CH644577A5/en not_active IP Right Cessation
- 1979-12-13 SE SE7910284A patent/SE7910284L/en not_active Application Discontinuation
- 1979-12-13 BE BE0/198548A patent/BE880596A/en not_active IP Right Cessation
- 1979-12-13 ES ES486845A patent/ES486845A1/en not_active Expired
- 1979-12-14 NL NL7909052A patent/NL7909052A/en not_active Application Discontinuation
- 1979-12-14 JP JP16167779A patent/JPS55122735A/en active Pending
- 1979-12-14 FR FR7930763A patent/FR2444023A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| CH644577A5 (en) | 1984-08-15 |
| FR2444023A1 (en) | 1980-07-11 |
| FR2444023B1 (en) | 1985-02-01 |
| ES486845A1 (en) | 1980-10-01 |
| NL7909052A (en) | 1980-06-17 |
| IT7809665A0 (en) | 1978-12-14 |
| GB2047234A (en) | 1980-11-26 |
| JPS55122735A (en) | 1980-09-20 |
| IT1109006B (en) | 1985-12-16 |
| BE880596A (en) | 1980-04-01 |
| SE7910284L (en) | 1980-06-15 |
| DE2949106A1 (en) | 1980-06-26 |
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