CA1075708A

CA1075708A - Therapeutically active mixed esters of polyols

Info

Publication number: CA1075708A
Application number: CA267,026A
Authority: CA
Inventors: Adrian Schulthess; Jean-Paul Ricard; Pierre Baudet
Original assignee: Laboratories Om SA
Current assignee: OM Pharma SA
Priority date: 1976-01-08
Filing date: 1976-12-02
Publication date: 1980-04-15
Also published as: JPS5285139A; DD128400A5; EG12290A; NL7613457A; FR2337552A1; PL117246B1; PL194851A1; FI763529A; BG27537A3; YU286476A; PT65894B; GB1572035A; IL51039A0; GR61818B; DE2654951A1; RO70355A; SE7613426L; PT65894A; ES453795A1

Abstract

Abstract of the disclosure Therapeutically active compounds of the general formula:

Description

107570~
This inventlon is directed to therapeutically actlve mixed esters of polyols having the general formula:

IOACl IOAC2 H - f A - C - H
Rl R2 (F) wherein Acl is a first acyl group, Ac2 is a second acyl group different from the first one, A is a C-C bond or a divalent ; organic residue; Rl,R2 are a hydrogen atom or a lower alkyl group, ~-Rl and R2 being able to form a ring of up to 6 atoms of A, Rl and R2 can be substituted by -OH groups substituted or un-~ substituted by acyl groups.
1-~10 The latter can be Acl and~or Ac2 groups, or other t acyl groups, such as acetyl, nicotinyl, -SO3H or -PO3H2 groups.
t Compounds of formula F contain one or more Acl or ;, Ac2 groups.
The preferred Acl residue is the 2-p-chloro-phenoxy- -~i 2-methylpropionyl or clofibril residue having the formula:
,~ .

i C~3 ~ `

- and the preferred Ac2 residue is the acetylsalicyl residue of ~ ,t formula: --`'`''~' ~ - 1- -- -. . ': . , , : - , ~075708 ~C~o O - C - CH
~ 3 Compounds of formula F have pharmacological and clinical properties characterized by an hypolipemient, and hypo-cholesterolem~ent action, and which inhibits the aggregation of blood platelets. Said compounds can be compounded in pharma-ceutical compositions and administered in various ways in the various pharmaceutical forms, e.g. orally, in the form of tablets or capsules.
The methods of synthesis of compounds of formula F
are based on the introduction of acyl residues on polyalcohols - having free or partially protected functions. The protective functions can be removed by acid hydrolysis, hydrogenolysis or directly transformed into esters by the acylating function.
The choice of introduction of the acylating resldues depends on the ratio desired between the different klnds of acylating ..
functions.

~ The synthetic methods comprise:

-~ 1) The introduction of one or more acyl residues of one kind onto symmetrical polyols, protecting the integrity of one or more alcohol functions which will be esterified by one -~ or more acylating groups of another kind.

2) The use of an alcohol protecting function such - ,, -.:
~ 2 -s~:

;~
.:1 s., , .. . .. . .. . .
'~'' ''' - ''.' ' ' ' ~ ~ -' as a hydrolysable or hydrogenolysable acetal or cyclic acetal, protecting one or more alcoholic functions which will be acylated by one or more acylating groups of one kind. The : alcohol or the alcohol functions set free after eliminating the protective function will be acylated by the group(s) of a different kind.

3) The transformation of an alcohol protecting function, directly into an ester function by one or more acylating groups, for example:
3a) From an epoxy-1,2. By the action of an acid chloride or an acid anhydride according to the reaction scheme:

, >~__C -- 011 + Ac2Cl ~ __ O -- OAC2 + AC1C1 `~ Acl /
. , -- C -- C ~ C
Cl AC2 or ICl ICl . ~ ~ AC2 + (AC1)2 ~~~~ ~C - 8 I ~
., OAC2 ,:
~` - 3b) From a 1,2 epoxide or by the reaction with a ~ carboxylic function representing an acylating residue.
:, ' ~ -___C - OAc2 + ~ AclOH + Ac10 M

~, t ~
i~

'W,~ '.
: : ` :

OAcl OH
or ~ [(AC1 ~2 ~+~] ~ - C - C ~ C - OAc2 3c) From a dihalohydrin by reaction with one or more aIkal; metal or ~lelinc-earth metal carboxylates representing an acylating residue(s):

hal - CH2 - CH - CH2 - hal ~H
+ 2 . Ac10 M or IAc10 )2M
:

--- >'' ACl - -- CH2 - C~ -- CH2 - O - AC
OH

hal being a halogen atom, and M an alkali or alkaline-earth ;
metal; then the acylation of the free alcohol residue:

2Cl ~ Acl ~ ~ C~2 - CH - CH - O - Ac . 10 .' or on the contrary the acylation of the alcohol function of .
: - the acylated d~ohydrin with an aL~i metal or aL~line-~th metal carboxylate:

- hal - C~2 - CH - C~ - hal + Ac Cl ~-- OH

.-.hal - CH2 - f~ - CH2 - hal + or -, OAc2 (Ac10 )2M +

_ 4 _ . . :
. ~ .

.. ~,.~ .

. . ~ . . .

1075~08 AC10 - C~2 -- ~;EI - CH2 - OA
OAc2 3d) By the transformation of a cyclic or non-cyclic acetal by an acylathg function such as an acid chloride or acid anhydride.
.~ \C/
/ ~Cl ; 1 1 I f ~ f--f c OAC2 ~ AClcl ~ f f T
or C--O-Acl I Cl - f c c OAc2 + (Acl)20 ~ C l l C2 '` ~.
.
The present invention, in one aspect, then~resides in a ,:~ process for preparing therapeutically active mixed esters of ~,i formula .
,,i~ Ac-o-cH2-(fH)n-cH2-o-Ac :~ . O-Ac - :
wherein n is,an integer from O to 4, and if n is 4, the alkylene, . chain can form a six membered ring, and wherein at least one group Ac is the chlofibril residue of formula ~ '?~
. ~ ~ CH3 Cl O O _ l _ C~ ~~ -CH

` !: : ` -and at least one other group Ac is the 2-acetyl salicyl residue ~s of formula , . -- ~ -- -~c~

O

wherein at least one acyl residue of a first kind is introduced on the corresponding alkylene compound containing one or more first free OH groups and one or more second, protected OH groups, 2 the protective group on the second OH group(s) is removed, and 3 one or more acyl groups, of a second kind, are introduced --on the acylated compound obtained containing the second set of free OH group(s); or wherein 1 an acyl residue of a first kind is introduced on an OH-substituted side chain of a corresponding epoxy ethane or oxethane compound, and 2 two acyl residues of -: -a second kind are introduced on the corresponding acyl oxirane or oxethane, by means of an acid anhydride of formula (Ac)20;
or wherein 1 a corresponding dihalohydrin alkane is reacted with an alkali metal or alkaline earth metal carboxylate of formula AcO M or (AcO )2M , M representing an alkali metal or alkaline earth metal, to obtain an acylated derivative -containin~ one free OH group; and the derivative obtained is ~ :
reacted with an acid chloride of the other acid or 2 the acid -:
chloride is reacted with a dihalohydrin, to obtain a dihalo acyl derivative, which in turn is reacted with an alkali metal carboxylated AcO M or an alkaline earth metal carboxylate (AcO )2M of the other acid, M being an alkali or alkaline earth metal; or wherein 1 an acyl residue of a first kind on a corresponding oxirane or oxethane compound containing a hydroxy-substituted side-chain, 2 the corresponding a~.ylated ...
oxirane or oxethane derivative is reacted with an acylation ~5a-.~
' ~A~
p., .

; - . . '. :' reagent comprised of a mixture of a carboxylic acid and an alkali metal or alkaline earth metal salt of said acid to obtain the corresponding diacylated derivative containing a free OH group; and 3 an acyl residue of a second kind is introduced on the free OH group of the compound obtained; or wherein 1 an acyl residue of a first kind is introduced on a corresponding symmetrical polyol using 2 moles of acylating agent per mole of polyol to obtain an acylated derivative containing a free OH
group; and 2 an acyl residue of a second kind is introduced on the free OH group of the acyl derivative obtained; or wherein 1 one or more acyl residues of a first kind are introduced on a corresponding alkylene compound containing one or more free OH groups and a carbonyl group; 2 the carbonyl group is reduced to an -OH group; and 3 an acyl residue of a second kind is introduced on the compound obtained; or wherein 1 a corresponding alkylene compound containing several free OH groups is reacted with an alkali metal or alkaline earth metal lower alcoholate so as to obtain an alkali metal or alkaline earth metal monoalcoholate of said compound~ 2 the monoalcoholate obtained is reacted with an acid chloride of a first kind to obtain a monoacylated derivative~ and 3 one or more acyl -residues of a second kind are introduced on the monoacylated derivative obtained, said acid residues or derivatives of a first or second kind being either those of the above formulas II or III; and where desired, forming a pharmaceutically accept-able salt of said compound of formula I.
., In a more specific aspect, this invention provides a process for preparing the compound of formula ~- Clof-O-CH2-~H-CH2-O-clof -asp $ b ."

wherein clof is the clofibril residue of formula Cl ~ o 1 3 ~O

-and asp is the 2-acetyl salicyl residue of formula ~ ~ ~C~f ~
O - C- C~3 ..,'. . ' characterized in that the compound of formula ~CH2~CH~CH2~Cl -OH
is the first reacted with the acid asp-OH or with a halide :
asp-hal, to give the compound of formula :,- Cl_CH2_CH_CH2_Cl . O-asp ~ -' whereafter this compound is reacted with a metal salt of `- -`. formula clof-OM, where M is an alkali metal or alkaline earth metal, to give said compound of formula I~, or characterized 7 in that said compound of formula V is first reacted with salicyclic ~ acid to give the compound of formula ,~, .
ce- c~ ce :ff ; o'~
o~

~, ~ 5c-' ~ .

.. ... .
" ~ . .. .... . . , . :- . ...

whereafter this compound is reacted with a metal salt of formula clof-OM, wherein M is an alkali metal or alkaline earth metal, to give the compound of formula c70~-O-CHz-~ C~--O-c707P

~ C ~/~

'` 0~

and wherein finally the phenolic hydroxyl group of thi~ compound is acetylated.
In a further aspect, this invention resides in a compound of formula I as defined hereinbeore, and in a still further specific aspect the invention resides in the compound of formula ,,, Clof-o-cH2-cH-cH2-o-clof O-asp ~ wherein clof indicates the clofibril residue and asp the ."~! 2-acetylsalicyl residue.
,2, The above reactions take place in suitable organic solvents and can be catalysed by catalysts suitable for a - specific type of reaction.
The following non-limiting examples illustrate various methods for obtaining the compounds aecording to the invention.

' 3 ,3. .

~ .'~ . .

; t, .~ ~ ''.
W~ ~
-5d-. .
= .

~75708 EXAMPLE 1 ComPound (I) . .

_ . .. _ .
1,2-di-(acetylsalicyl)-3,4,5,6-tetra-(2-p-chlorophenoxy-2-methylpropionyl)-meso-inositol ._ __ 1 a) 1,2-isopropylidene 3,4,5,6-tetra-(2-p-chlorophenexy-2-methylpropionyl)-meso-inositol 176 g of 1,2-isopropylidene meso-inositol (0.8 mole) are suspended in anhydrous tetrahydrofuran (THF) containing 512 ml of triethylamine (TEA) (3.68 moles) and 200 ml of pyridine. To this solution is added, dropwise, with stirring during 5 hours 857.8 g (3.68 moles) of p-chlorophenoxy methyl-propionic acid chloride. After 24 hours, the tetra-ester is -- -separated from the TEA hydrochloride, and it is crystallized in absolute alcohol. -49H52C14O14 (1006,8) -F = 86-88 Rf = 0.83 (n-hexane/ethylacetate 2/1 vol.) I~ (characteristic frequencies) 1775, 1745, 1600, 1250, 1240, 1155, 878, 865, 852 cm~l .
1 b) 3,4,5,6-tetra-(p-chlorophenoxy-methylpropionyl)-- meso-inositol _ 40.27 g (0.04 mole) of 1 a) and 186 g of ethylene-glycol, as well as 80 mg of p-toluenesulfonic acid are heated -at 150 & for 8 hours under slightly reduced pressure and very , strong stirring. The excess of ethyleneglycol and the dioxolane ' formed are distilled. The residue ls extracted with water and ether. The ether phase is evaporated and the product is crystal-lized from ether.
.

-~' ' ' - '. -'' - - ' - - .
~ - , C46~46C14O14 (964.7) F = 126-128 Rf = 0.5 tn-hexane/ethylacetate 2/1 vol.) 1 c) 1,2-di-(acetylsalicyl)-3,4,5,6-tetra-(2-p-chloro-phenoxy-2-methylpropionyl)-meso-inositol .. ..
- To a solution of 58 g (0.060 mole) of 1 b) in dry ether containing 16.7 ml of TEA and 50 ml of pyridine, are added 23.8 g (0.120 mole) of the acetylsalicylic acid chloride. After 24 hours, the TEA hydrochloride is separated, and compound (I) is obtained.

~ 64 60 420 (1291.0) ; 224 nm-= S6 750 (ethanol 9s~) Analvsis: Calc. ~ Found %
C 59.54 59.63 H 4.68 4.83 Cl 10.98 11~15 Rf = 0.68 (n-hexane/ethylacetate 2/1 vol.) IR (characteristic frequencies) 1760, 1750-1730, 1610, 1595, 1585 cm .
EXAMPLE 2 Compound (II) 1,3-di-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-(acetyl-salicyloxy)-propane Method I
: ~ --------____ ~ 2.1.1. 1,3-benzylidene-2-(acetylsalicyloxy)-glycerol 1 - .
To a solution of 19.8 g ~0.11 mole) of 1,3-benzylidene glycerol (b.p. 110/0.1 Torr.) in dry ether containing 15.3 ml ~- -_ 7 _ '~ ~
. . .

, . . . . . ..
. .~ . , .

of TEA and 8.9 ml of pyrldine, are added dropwise, wlth stlr-ring, a solution of 21.8 g of acetylsalicylic acid chloride.
After 24 hours, the ester is separated from the TEA hydro-chloride and product 3 a) is crystallized at -18 in ethyl-acetate.
C19Hl~O6 ~342.3) F = 129-132 Rf = O.S9 (n-hexane/ethylacetate 2/1 vol.) IR tcharacteristic frequencies) 1760, 1710, 1610, 1195 cm 1.
2.1.2. 2-(acetylsalicyloxy)-glycerol ~-.
;~ 2.1.1. is hydrolysed in the presence of palladised charcoal at 10, after removing the air, and under hydrogen pressure at room temperature.

r C12H14O6 t254.2) Rf = without migration (n-hexane/ethylacetate 2/1 vol.) ' IR (characteristic frequencies) 3380, 1765, 1725 cm 1.
i- 2.1.3. 1,3-di-(2-p-chlorophenoxy-2-methyl propionyloxy)-2-(acetylsalicyloxy)-propane t, 20 - To a solution in dry ether of 14.9 g (0.0585 mole) - of 2.1.2., 16.3 ml of TEA and 9.4 ml of pyridine, is added, i dropwise with stirrLng, a solution in dry ether of 27.3 g (0.117 mole) of p-chlorophenoxy-2-methylpropionic acid chloride.
After 15 hours reaction, the product is separated from the TEA -- hydrochloride and the ether solution is washed with a solution -of C03~Na in water. After evaporating the solvent, a colour-~ less product (II) is obtained.

- ~ ~C32~32C12O10(647.5) - .-' .

. ~ ,-.
r~ ,~_, . .' .~ . . . ~ .
.. . . .
-Analysis: Calc. % Found %

C 59.36 59.38 ~ 4.98 5.02 Cl 10.95 11.11 ~226 nm = 29 730 ~ethanol 95%)Rf = 0.67 ~n-hexane/ethylacetate 2/1 vol.) IR: 5h 1765, 1750, 5h 1735, 1605, 1595, 1580, 1485, 1465, 1380, 1370, 1285, 1240, 1170, 1160, 1125, 1095, 1080, 1010, 965, 920, 830, 760, 700, 670 cm 1.

Compound (II) ~1,3-di-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-(acetyl-~ Lsalicyloxy)-propane Method II

2.2.1. 1-(2-p-chlorophenoxy-2-methylpropionyloxy)-2,3-epoxydo-propane To a solution of 7.4 g (0.1 mole) of 1,2-epoxydo-3-propanol contain~ng 13.93 ml of TEA, is added dropwise 23.3 g (0.1 mole) o~ 2-p-chlorophenoxy-2-methylpropionic acid chloride in dry ether. After 17 hours, the product is separated from 20 the TEA hydrochloride and the ether solut~on is washed with an aqueous 5% solution of CO3~Na. The epoxydic ether is distilled, then it is redistilled at 113-116/0.09 Torr.

13H15Cl 4 (270.7) Rf = 0.80 (n-hexane/ethylacetate 2/1 vol.) IR (characteristic frequencies) 1745, 1600, 1590, 1250, 840, 860 cm 1.

g _ ~,~J;

2.2.2. 1,3-di-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-propanol The mixture of 5.4 g of 2.2.1. (0.02 mole) with 4.3 g of p-chlorophenoxy-isobutyric acid (0.02 mole) and 0.47 g of Na p-chlorophenoxy-2-methylpropionate is heated for 2 hours at 120. After extracting the product with ether, the solution is treated with an aqueous 5~ solution of C03HNa. An oil is obtained which releases at 200/0.07 Torr. a small fraction of the initial product.
C23~26C127 (485.4) Rf = 0.62 (n-hexane/ethylacetate 2/1 vol.) IR (characteristic frequencies) 3480, 1740, 1600 and 15gO, 1150, 840 and 860 cm 2.2.3. 1,3-di-~2-p-chlorophenoxy-2-methylpropionyloxy)-2-acetylsalicyloxy)-propane To a solution of 10.4 g of 2.2.2. in dry ether containing 3 ml of TEA, and 1 ml of pyridine, is added dropwise, ~`! with stirring, 4.26 g of acetylsalicylic acid chloride. After - 24 hours reaction, ~e product is separated from the TEA hydro-chloride, and the ether solution is washed with an aqueous 5~ - -solution of C03HNa. A product (II) is cbtained, identical to that obtained under 2.1.3.
,.
~- - ` ComPound ~II) ., 1,3-di-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-(acetyl- -g~ salicyloxy)-propane , .~....
~ -- 10 -, .
' ~ , ~075708 Method III

2.3.1. 1,3-dichloro-2-(salicyloxy)-propane To a solution of 138 g of salicylic acid (1 mole) in 645 g of 1,3-chloropropanol, is added 40 ml of concentrated sulfuric acid. After 16 hours at 105C, the excess of alcohol - is distilled at 60/12 Torr. The residue is dissolved in ether ana washed with an aqueous solution of CO3NaH. The ether phase is dried and the solvent removed. The ester is distilled twice at 153-155/12 Torr. and at 125-126/0.5 Torr. It is crystal-lized in petroleum ether at -18.
F = 49-50 10 10 2 3 (249.1) Rf = 0.65 (n-hexane/ethylacetate 2/1 vol.) IR = 3240, 1685, 1610, 1580, 1480, 1460, 1400, 1395, 1370, 1305, 1295, 1250, 1180, 1150, 1130, 1085, 1035, 880, 780, 760, 710 cm 1, 2.3.2. 1,3-di-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-~sallcyloxy)-propane , - The mixture of 124.5 g of 2.3.1. ~0.5 mole) and ~ 236.5 g (1.0 mole) of p-chlorophenoxy-2-methylpropionate of ~--- 20 sodium is heated for 10 hours at 180. It is taken up in ether and flltered. The residue after evaporation of the -solvent gives the desired product. It cryst ~ izes in met~ F =58-59.
C30H30~129 (605.5) Rf = 0.68 (n-hexane/ethylacetate 2/1 vol.) IR = 3150, 1730, 1610, 1595-1580, 1485, 1385, 1360, 1310, . , , _ 1300, 1285, 1250-1220, 1200, 1170-1145, 1120, 1090, 1010, 970, 830, 770, 730, 700, 670 cm 1 i - -- 11 -- .
-, .

~B~
. ~ ,.. .
,; . . . .

2.3.3. 1,3-di-(2-p-chlorophenoxy-2-methylpropionyloxy) -2-(acetylsalicyloxy)-propane A solution of 280 g of 2.3.2. in 500 ml of acetic anhydride (d=1.08) is refluxed for 1~ hour, then the excess of anhydride is distilled and a product (II) is d~tained, identical to that obtained under 2.1.3.

Compound (II) 1,3-di-t2-p-chlorophenoxy-2-methylpropionyloxy)-2-(acetyl-salicyloxy)-propane Method IV

2.4.1. 1,3-dI- ~2-p-chlorophenoxy-2-methylpropionyloxy~- `
2-propanol A suspension of 118.3 g (0.5 mole) of sodium p- -chlorophenoxy-2-methylpropionate in a solution of 60 ml of anhydrous EtOH containing 7.5 g of INa and 64.5 g of 1,3-di-chloro-2-propanol ~0.5 mole) is refluxed for 90 hours. The solvent is evaporated under reduced pressure and the liquid residue ls distilled at 138-141/0.07 Torr.
~ . .
23 26Cl27 (485.4~
. ~ .
-~ 20 2.4.2. 1,3-dl- (2-p-chlorophenoxy-2-methylpropionyloxy)-2- (acetylsallcyloxy)-propane 24.2 g (0.05 mole) of 1,3-di-(2-p-chlorophenoxy-2-methyl propionyloxy)-2-propanol is taken up in 300 ml of dry ether cbntaining 0.055 mole of triethylamine, 10.9 g (0.055 mole) of acetylsalicylic acid chloride and 4 ml of pyridine.
After 16 hours reaction with stirring, the organic suspension , ~ .
~ ~r ~.~ ,.~i ` 1075708 is filtered and the filtrate washed with a solutlon of 5%
CO3~Na, then with 2 volumes of ~2~ and dried wlth SO4Na2. The solvent is evaporated under reduced pressure; a product (II) is obtained identical to that obtained under 2.1.3.
The 1,3-di-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-propanol used as a starting material in step 2.4.2. above can also be prepared as follows: a suspension of 23.7 g (0.1 mole) of p-chlorophenoxy-2-methylpropionate of Na in 14 g (0.11 mole) of 1,3-dichloro-2-propanol is heated in a closed steel cylinder at 155 for 14 hours. After cooling, it is taken up in ether and the soluble fraction is distilled at 138-141/
0.07 Torr.
'.
Co~pound lII) 2-(acetylsalicyloxy~-1,3-di-(p-chlorophenoxy-2-methyl-propionyloxy)-propane . _ .
- -~ Method V

~` 2.5.1. 2-acetylsalicyloxy-1,3-d~chloropropane .
; ~ To a solution in T~F of 12.9 g (0.1 mole) of 1,3-di-chloro-2-propanol, is added 10.1 g (0.1 mole) of TEA, then slowly with stirring, 19.9 g (0.1 mole) of acetylsalicylic acid chloride. After removing the TEA hydrochloride, acetylsalicyl-oxy-1,3-dichloropropane is obtained quantita~ively, and it ` crystallizes in petroleum ether.

C12~12C124 (291.1) m.p. = 67-69 . , .

~' ~;

. wt~,n.~ -' ` . , Rf - 0.58 ~ethylacetate/n-hexane 2/1 vol.) IR 3 1750, 1725, 1610, 1580, 1485, 1335, 1295, 1270, 1250, 1200, 1135, 1075, 1010, 915, 820, 760, 700 cm 1, . .
2.5.2. 2-(acetylsalicyloxy)-1,3-di-(p-chlorophenoxy-2-methylproplonyloxy)-propane To 29.1 g ~0.1 mole) of 2.5.1. and 47.3 g of sodium p-chlorophenoxy-2-methylproplonate are almixed. The paste-like mixture ls heated at 160 for 5 hours. The product ls taken up in ether and the solution ls extracted with a solution of 5% -' -CO3HNa in water, it ls washed twice with water and dried with anhydrous S04Na2- The sclvent is remDvedf~nd a product (II) if~*ical to that obtalned under 2.1.3. is obtained quantitatively.
, -i EXAMPLE 3 Compound ~
.; I :-"-' 3-(acetylsallcyloxy)-1,2-di-12-p-chlorophenoxy-2-methyl-`~' proplonyloxy)-propane , :i ~lethod I
'~ 3.1.1. 1-~acetylsalicyloxy)-2,3-epoxydo-propane ' f To a solution of 44.4 g (0.6 mole) of 1-hydroxy-2,3-, ~ ' epoxydopropane in dry ether, 84 ml of TEA are added, dropwise wlt~
i, ~ . . ~, ~ stirrlng, 119.1 g (0.6 mole) 2-acetylsallcyllc acld chloride . ~ j , ' are also added. After 24 hours, the product is separated from the TEA hydrochlorlde, and the ether solution is washed,with 1:
. ~ .
aqueous solutlon of 5% CO3HNa. An oily product ls lsolated.
, B.p. 114-115/0.02 ~orr.

: ' ~

. .

.~:

f~

, . . . . . .

12 125 (263.2) E227 nm = 14'120 (methanol) Rf = 0.52 (n-hexane/ethylacetate 2/1 vol.) IR (characteristic frequencies) 1760, 1735, 1610, 1265 cm 1.

3.1.2. 3-(acetylsalicyloxy)-1,2-di(2-p-chlorophenoxy-2-methylpropionyloxy)-propane .
23.0 g (0.1 mole) of 3.1.1. are mixed with 41.1 g lO.l mole) of p-chlorophenoxy-2-methylpropionic acid anhydride, at a temperature of 100. The mixture becomes homogeneous, the temperature of the mixture is then brought to 120 for 1~ hour.
The product is extracted with ether, washed with an aqueous solution of 5% CO3HNa, then decolored with active charcoal.
colourless oil (III~ is obtained.

C32~32C1210 (647.~) Analysis: Calc. % Found %
C 59.35 59.32 H 4.94 5.22 Cl 10.97 11.11 E226 nm = 30'900 (ethanol 95%) Rf = 0.67 (n-hexane/ethylacetate 2/1 vol.) Cc - homogeneous peak ("Carbowax"* 4%, temperature 152, N2 30 ml/mn IR ~characteristic frequencies) 1760-1730, 1610, - 1600 and 1595, 840 and 860 cm 1.
Note:

- For the 3.1.2. reaction, the temperature can be between 60 and 220; in the presence of a Lewis acid such as BF

.. . . . .. . . . _ _ *Trademark of Union Carbide Corporation for a series of polyethylene glycols.

~? ~

: .

1075708 t ` (introduced in the form of BF30(C2H5) or BF3(C5H6N), the reaction can be carried out at ordinary temperature. The reaction can also be effected in a solvent inert to the anhydride and the epoxide function.

Compound (III) 1,2-di-t2-p-chlorophenoxy-2-methylpropionyloxy)-3-acetyl-salicyloxy)-propane . _ Method II

3.2.1. 3-chloro-1,2-di(p-chlorophenoxy-2-methylpropionyl-oxy)-propane --41.1 g (0.1 mole) of the p-chlorophenoxy-2-methyl-propionic acid anhydride are added to 9.25 g tO.l mole) of epichlorhydrin. It ls heated to 130, then the excess of un-reacted anhyd~ide is removed by hydrolysis with C03~Na. An oil $s obtained.

^i C23~25 3 6 (503.8) IR = 1745, 1592, 1490, 1480, 1390, 1370, 1280, 1240, 1150, i 1130, 1100, 1015, 970, 855, 845, 770, 725, 710, j 680 cm 1.
. . .
3.2.2. 1,2-di-(2-p-chlorophenoxy-2-methylpropionyloxy)-. 3-(salicyloxy)-propane 25 g (0.05 mole) of 3.2.1. are mixed with 12 g (0.075 mole) of sodium salicylate and heated to 180 for 16 h.
:- ~he sodium ch}oride is removed by desalting the product in ether. An oil is obtained.
:~
: ,~
~ - 16 .
., ,~ . .
.,~".,~,.

~ . . . .. ...

30 30C12Og (605.5) IR - 1740, 1680, 1590, 1575, 1485, 1380, 1360, 1300, 1240, 1180, 1160, 1120, 1090, 1010, 965, 850, 825, 760, 695, 680 cm 1.

3.2,3. 1,2-dl-t2-p-chlorophenoxy-2-methylpropionyloxy)-3-acetylsalicyloxy)-propane 28 g (0.04 mole) of 3.2.2. are dissolved in S0 ml of acetlc anhydrlde, and heated to 105. The excess of reagent is removed by washing the ether solution with an aqueous solution of 5% CO3HNa. The organic phase is dried with SO4Na2. An oil (I}I) ls obtained identical to that obtained under 3.1.2.

EXAMPLE 4 Compound (IV) . .
l-(acetylsalicyloxy)-3-(2-p-chlorophenoxy-2-methylpropio-nyloxy)-2-acetoxy-propane .

4.1. 1-(acetylsalicyloxy)-3-(2-p-chlorophenoxy-2-methyl-; propionyloxy)-2-propanol .
A solution of 21.4 g (0.1 mole) of p-chlorophenoxy-2-methylpropionic acid and 23.6 g (0.1 mole) of l-(acetyl-salicyloxy)-2,3-epoxydo-propane in 100 ml of dimethylformamide is heated to 80 for 18 hours. After distilling the solvent,~-the residue is washed wlth CO3HNa from an ether solution. 26 g of ~- an oil are obtained.
22H23C1 8 (450-9) Rf = 0.12 (ethylacetate/hexane 1/2 vol.) IR = 3500, 1770, 1735-1740, 1610, 1595, 1580, 1490, 1370, 1290, 1260-1~40, 1200, 1140, 1080, 1010, 830, 750, 705, 570 cm~ .

' .

4,2. 1-(acetylsallcyloxy)-3-(2-p-chlorophenoxy-2-methylproplonyloxy)-2-acetoxy-propane 9 g of 1-(2-acetylsalicyloxy)-3-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-propanol (0.02 mole) are dissolved in

5 ml of acetic acid containing 5 ml of acetic anhydride. After 4 hours at ordlnary temperature, the excess of reagent and the solvent are removed. It is taken up in ether and the solution ls washed with a solution of 5% CO3HNa in water. An oil (IV) is obtained.
C24H25C1 g (492.9) Analvsis: Calc. ~ Pound C 58.48 58.39 H 5.11 5.19 Cl 7.19 7.16 ~227 nm = 18 700 (ethanol 95~) Rf 2 0.38 ~ethylacetate/hexane 1/2 vol.) IR = 1770, 1740, 1600, 1595, 1580, 1490, 1270, 1230, 1195, 1130, 1080, 1010, 960, 910, 815, 750, 700, 680 cm 1.
~, .
~ EXAMPLE 5 ComPound ~V) --~ 20 1-(acetylsallcyloxy)-3-(2-p-chlorophenoxy-2-methylpropionyl-¦ -~ oxy)-2-sulfopropanol Sodlum salt . ~ , 9 g (0.02 mole) of 1-(acetylsalicyloxy)-3-(2-p-chloro-phenoxy-2-methylproplonyloxy)-2-propanol 4.1. are dissolved ln 100 ml of acetonltrlle to whlch ls added 6.04 g (0.038 mole) of pyrldine-sulfurlc anhydride (C5H5NSO3). After 12 hours stlrring ~ .

at ordinary temperature, the excess of ether is flltered. It is neutrallsed with CO3HNa, and 5.4 g of a solid (V) are obtained.
C22H22C1 11 SNa (552.9) Analysis: Calc. % Found %
C 47.79 47.57 ~ 4.01 4.21 S 5.80 5.85 ~226 nm = 19 175 (ethanol 95~) Rf = 0.7 (n-butanol~acetic acid/H2O 10/2/3, vol.) IR = 1770, 1750-1725, 1605, 1595, 1580, 1485, 1280, 1240, 1200, 1130, 1090, 1040, 1010, 940, 830, 750, 700 cm 1.

EXAMPLE 6 Compound (VI) ~:. _ ; l-(acetylsalicyloxy)-2-(2-p-chlorophenoxy-2-methylpropionyl-~ oxy)-ethane ,.,~ ' Method I

6.1.1. 1-(2-p-chlorophenoxy-2-me-thylproplonyloxy~-2- -chloro-ethane 107.3 g ~0.5 mole) of p-chlorophenoxy-2-methylpropio--, nic acid are dissolved in 241.5 g t3 moles) of 2-chloroethanol.
i- 20 me solution is saturated with HCl gas. The excess of solvent ~ is d~stilled under 11 Torr. The ester is distilled under 0.02 Torr, -~, at a temperature of 97-98.
, C12H14C1203 (277.1) --Rf = 0.88 (ethylacetate/n-hexane lt2 vol.) ~, IR = 1740, 1590, 1580, 1485, 1385, 1280, 1240, 1180, 1140, --, - 1090, 1010, 970, 825, 6?0 cm 1.

~. -- 19 --t :: . . . .

6.1.2. 1-(2-p-chlorophenoxy-2-methylproplonyloxy)-2-(sal$cyloxy)-ethane 50 g (0.18 mole) of 1-(2-p-chlorophenoxy-2-methyl-propionyloxy)-2-chloro-ethane are mlxed with 43.3 g (0.27 mole) of sodium sallcylate. The mixture is heated to 195 for 8 hours.
The products are taken up in ether, and NaCl is removed by filtration. The die~ter crystallizes quantitatively from the ` ether solution.
m.p. = 43-45 - 10 Cl9Hl9C1 6 (378.8) -~ Rf = 0.7 (ethylacetate/n-hexane 1/2 vol.) IR = 3220, 1720, 1675, 1605, 1590, 1575, 1480, 1330, 1290, 1240, ~180, 1150, 1090, 1040, 980, 820, 760, 720, 660 cm 1.
, - 6.1.3. 1-~2-p-chlorophenoxy-2-methylpropionyloxy)-2-- ~ ~acetylsallcyloxy)-ethane .. ~ .
To a solution of 68 g of 1-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-(salicyloxy)-ethane in 30 ml of pyridine, ~;~ 34 ml of acetic anhydride are added. After 2~ hours, the excess of reagent is removed, then the product is heated to 150, under ~ a vacuum of 0.05 Torr. An oll ls obtained which crystallizes ; spontaneously at ordinary temperature (VI).

~ ~ C21H21Cl O7 ~420.9) ., .
- Analysis: Calc. % Found %

C 59.93 60.03 H ~5.03 5.12 226 nm = 19 950 ~ethanol 95%) ~. ~
i ' .
-!. ~ .
:

m.p. = 48-50 Rf = 0.55 (ethylacetate/n-hexane 1/2 vol.) IR = 1760, 1710-1720, 1600, 1590, 1570, 1485, 1265, 1195, 1150, 1080, 1050-1040, 1000, 910, 820, 750, 700, 665 cm Compound (VI) ._ .
l-(acetylsalicyloxy)-2-(2-p-chlorophenoxy-2-methylpropionyl-oxy)-ethane _ -Method II

6.2.1. 1-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-ethanol 23.6 g (0.1 mole) of 2-p-chlorophenoxy-2-methyl propionate of Na are lntroduced into 18 g (0.22 mole) of chloro-ethane. It is refluxed for 2 hours at 160, then the excess of solvent is removed. The residue is taken up with ether and the - alcohol is distilled. B.p. = 110-117/0.02 Torr.
Rf = 0.35 ~ethylacetate/n-hexane 1~2 vol.) IR = 3440, 1730, lS90, 1580, 1485, 1385, 1360, 1280, 1240, ~- --1180, 1140, 1090, 1010, 970, 890, 850-830, 670 cm 1.

! 6.2.2. 1-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-:- 20 (acetylsalicyloxy)-ethane .
-,~ To a solution of 5.17 g (0.02 mole) of 6.2.1. in dry sj ~ ether, 2.8 ml ~0.02 mole) of triethylamine are added and, drop-wise with stirring, 4.05 g (0.02 mole) of acetylsalicylic acid chloride are introduced. The hydrocAloride of triethylamine formed is filtered, and the ether solution is-extracted with an - 21 ~

, .

. _ . . .

aqueous solution of 5~ C03~1Na. The solution ln whlch the product crystallizes spontaneously ls dried. It ls recrystallized ln petroleum ether, and a product (VI) ldentlcal to that prepared under 6.1.3. ls obtalned.

Compound (VI) . ~
l-(acetylsallcyloxy)-2-(2-p-chlorophenoxy-2-methylpropionyl-oxy)-ethane Method III

6.3.1. 1-sallcyloxy-2-chloro-ethane ; 10 A solution of 13.8 g (0.1 mole) of salicylic acid in 48.3 g (0.6 mole) of 2-chloro-ethanol ln the presence of 4 ml of sulfurlc aald is heated to 110 for 2 hours. After removing the excess of 2-chloro-ethanol, the ether solutlon of the product is extracted wlth an aqueous solutlon of 5% C03HNa. The ether ls removed and the product is dlstllled. B.p. : 128-129/
11 Torr.
:, 3 (200.6) Rf = 0.80 (ethylacetate/n-hexane 1/2 vol.) A, 6.3.2. 1-salicyloxy-2-(2-p-chlorophenoxy-2-methyl-; proplonyloxy)-ethane . ,~ . ._ .
`~ A mixture of 2 g (0.91 mole) of 6.3.1. and 3.55 g - ~ (0.015 mole) of Na p-chlorophenoxy-2-methylpropionate is heated ~ for 4 hours at 180. It is taken up in ether, filtered, and the --~ product is crystallized; it is identical to 6.1.2.

. , .
~ - 22 -. .

6.3.3. 1-~acetylsallcyloxy)-2-(2-p-chlorophenoxy-2-methyl-proplonyloxy)-ethane From the l-sallcyloxy-2-(2-p-chlorophenoxy-2-methyl-proplonyloxy)-ethane obtalned under 6.3.2., product (VI) ls prepared, as under 6.1.3.

ComPound ~VI) acetylsallcyloxy)-2-(2-p-chlorophenoxy-2-methylpropionyl-¦
oxy)-eehane Method IV

6.4.1. 1-~2-p-chlorophenoxy-2-methylproplonyloxy)-2-ethane To a solutlon of 6.2 g ~0.1 mole) of ethyleneglycol in T~F, 13.93 ml ~0.1 mole) of trlethylamlne, and dropwlse 23.3 g ~0.1 mole) of p-chlorophenoxy-2-methylpropionlc acld chloride ln THF are added. The trlethylamlne hydrochloride preclpltated ls flltered, the ether solutlon 18 washed with an aqueous solutlon of 5~ C03~Na. The solvent ls removed, and the product is dlstllled at 0.02 Torr. The product ls identlcal to `i that obtalned under 6.2.1.; from the thus o~talned 1-(2-p-chloro-' phenoxy-2-methylproplonyloxy)-2-ethanol, product (VI) is prepared ~` 20 as under 6.2.2.
Compound (VI) l-(acetylsallcyloxy)-2-(2-p-chlorophenoxy-2-methylpropionyl-oxy)-ethane ' i~ .
.~ ~
. .
~ - 23 -.~ ~

, Method V

6.5.1. 1-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-chloro-ethane . _ _ To a solution of 80.5 g of chloro-ethanol ~1 mole) in THF containing 101 g (1 mole) of triethylamine are added, drop-wise with stlrring, 233 g (1 mole) of p-chlorophenoxy-2-methyl-proplonic acld chlorlde. The triethylamine hydrochloride is flltered, and the ester formed is distilled; it is ~entical to that obtained under 6.1.1.; the synthesis of (VI) is continued as under 6.1.2., and then 6.1.3.

PHARMACOLOGICAL PROPERTIES

A) Acute t.oxicity The acute toxicity of compounds I to VI was determined on the male rat (Table I).

Product ation means LD50 g/kg ` _ _ I p.o. > 5 g/kg II p.o. ~ 7.5 g/ky III - p.o. > 6.2 g/kg IV p.o. > 5 g/kg ; V P.o. ~ S g/kg VI p.o. ~ 6 g/kg .
. ~
All these derivatives are therefore much less toxic than the clofibrate (LD50:1.2 g/kg) and acetylsallcylic acid (LD50:1.75 g/kg).

- i - - 24 -~075708 B) Pharmacoclnetics All the compounds this patent is dlrected to release clofibrlc acid and acetylsalicylic acid in the blood. The metabolites were determined by gas chromatography after trans-formatlon to silane derivatives. Two peaks are observed, one representing the sum of salicylated derivatives and the other clofibric acld. In Table II, the maximum plasma levels attained in the rat after a single administration are glven.

TABLE II

~ ~,p~, I els ~g/ml ¦

Product Dose p.o. sallcyl cIoflbrlc After mg/kg derlvatlves acid hours ; + acetylsal. ac. 300 + 100 180 280 1 Compound I 400 30 45 16 " II 400 40 60 16 - " III400 45 58 16 " IV 400 150 115 8 n VI 400 150 200 , . . ..
It is seen that the release of two actlve metabolites can be influenced by modifying the steric hlndrance of the `~ 20 compounds in question, indeed, when the sterlc hlndrance is in-... "
.~, i~ creased, the metabolisation thereof ls slowed down.
~ 1 ~
'1 ' ' s~
; - 25 -, ~ , '~

,~

, - .- . . . . . . . .
: . . :- . . - , .

C) Hypocholesterolemiating and hypolipemiating activity Groups of 10 normolipemiating rats were treated for 10 days, by gastric probe, with the equivalent of 75 mg/kg of clofibrate, administered every 12 hours. After 10 days, 12 hours after the last administration, they were sacrificed and the cholesterol and triglycerides analysed (Table III).

;

TABLE III

Product Triglycerides Decrease Cholesterol Decrease mm mole/l. mg/100 ml Test: without treatment1.13 90.79 Test: clofibrate 0.83 27 65.24 28 Compound I 0.96 15 78.25 14 : ~. n II 0.92 19 73.90 -19 . n III O . 91 19 75.63 17 . . n IV O ~ 9 7 14 72.12 21 n V 0.89 21 68.38 25 n VI 0.83 27 67.34 26 L

, D) Anti-aggregating and anti-adhesive actlvity , The anti-aggregating and anti-adhesive activity of ~ compounds I to VI was tested ex vivo on the rabbit after an - , 20 adminlstration equivalent to 50 mg/kg of acetylsalicylic acld.
All the compounds possess both anti-aggregating and anti-adheslve activity (ADP, collagen) identical to that of the blanks (50 mg/kg of acetylsalicyllc acid). The blood was taken, ,. ~
. 3 ~ under narcosis, 24 hours after administration of the dose 3 (intubation).

: .
~.

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-THERAPEUTICAL APPLICATIONS

Compounds I-VI are intended for the treatment of mixed hypercholesterolemiae and hyperlipidemiae, hyperaggrega-bility of the platelets, as well as atherosclerous effects connected with such disorders. The compounds are administered orally in one or several doses daily at a dosage of 0.30 g to 4 g per day according to the gravity of the illness and the results of laboratory examinations. The compounds are given alone or with pharmaceutically acceptable vehicles, e.g. in the form of hard or soft capsules, plain or coated tablets, granulate~
or syrups.

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Claims

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

1. A process for preparing therapeutically active mixed esters of formula I

wherein n is an integer from 0 to 4, and if n is 4, the alkylene chain can form a six membered ring, and wherein at least one group Ac is the clofibril residue of formula II

and at least one other group Ac is the 2-acetyl salicyl residue of formula III

wherein at least one acyl residue of a first kind is introduced on the corresponding alkylene compound containg one or more first free OH groups and one or more second, protected OH groups, 2° the protective group of the second OH group(s) is removed, and 3° one or more acyl groups, of a second kind, are introduced on the acylated compound obtained containing the second set of free OH group(s); or wherein 1° an acyl residue of a first kind is introduced on an OH-substituted side chain of a corresponding epoxy ethane or oxethane compound, and 2° two acyl residues of a second kind are introduced on the corres-ponding acyl oxirane or oxethane, by means of an acid anhydride of formula (Ac)2O; or wherein 1° a corresponding dihalohydrin alkane is reacted with an alkali metal or alkaline earth metal carboxylate of formula AcO-M+ or (AcO-)2M, M representing an alkali metal or alkaline earth metal, to obtain an acylated derivative containing one free OH group; and the derivative obtained is reacted with an acid chloride of the other acid or 2° the acid chloride is reacted with a dihalohydrin, to obtain a dihalo acyl derivative, which in turn is reacted with an alkali metal carboxylate AcO-M+ or an alkaline earth metal carboxylate (AcO-)2M++ of the other kind, M being an alkali metal or alkaline earth metal; or wherein 1° an acyl residue of a first kind is introduced on a corresponding oxirane or oxethane compound containing a hydroxy-substituted side-chain, 2° the corresponding acylated oxirane or oxethane derivative is reacted with an acylation reagent comprised of a mixture of a carboxylic acid and an alkali metal or alkaline earth metal salt of said acid to obtain the corresponding diacylated derivative containing a free OH group; and 3° an acyl residue of a second kind is introduced on the free OH group of the compound obtained; or wherein 1° an acyl residue of a first kind is introduced on a corresponding symmetrical polyol using 2 moles of acylating agent per mole of polyol to obtain an acylated derivative containing a free OH group, and 2° an acyl residue of a second kind is introduced on the free OH group of the acyl derivative obtained; or wherein 1° one or more acyl residues of a first kind are introduced on a corresponding alkylene compound containing one or more free OH groups and a carbonyl group; 2° the carbonyl group is reduced to an -OH

group; and 3° an acyl residue of a second kind is introduced on the compound obtained; or wherein 1° a corresponding alkylene compound containing several free OH groups is reacted with an alkali metal or alkaline earth metal lower alcoholate so as to obtain an alkali metal or alkaline earth metal monoalcoholate of said compound; 2° the monoalcoholate obtained is reacted with an acid chloride of a first kind to obtain a monoacylated derivative; and 3° one or more acyl residues of a second kind are introduced on the monoacylated derivative obtained, said acid residues or derivatives of a first or second kind being either those of the above formulas II or III; and where desired, forming a pharmaceutically acceptable salt of said compound of formula I.

2. A process for preparing the compound of formula wherein clof is the clofibril residue of formula and asp is the 2-acetyl salicyl residue of formula characterized in that the compound of formula V

is first reacted with the acid asp-OH or with a halide asp-hal, to give the formula whereafter this compound is reacted with a metal salt of formula clof-OM, where M is an alkali or alkaline earth metal, to give said compound of formula IV, or characterized in that said compound of formula V is first reacted with salicylic acid to give the compound of formula , whereafter this compound is reacted with a metal salt of formula clof-OM, wherein M is an alkali metal or alkaline earth metal, to give the compound of formula , and wherein finally the phenolic hydroxyl group of this compound is acetylated.

3. A compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.

4. The compound of formula wherein clof indicates the clofibril residue and asp the 2-acetylsalicyl residue, whenever prepared by the process of claim 2, or by an obvious chemical equivalent thereof.