AU650429B2 - Novel aryloxy alcoyl benzenes, processes for their preparation as well as the pharmaceutical compositions containing them - Google Patents

Novel aryloxy alcoyl benzenes, processes for their preparation as well as the pharmaceutical compositions containing them Download PDF

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AU650429B2
AU650429B2 AU64869/90A AU6486990A AU650429B2 AU 650429 B2 AU650429 B2 AU 650429B2 AU 64869/90 A AU64869/90 A AU 64869/90A AU 6486990 A AU6486990 A AU 6486990A AU 650429 B2 AU650429 B2 AU 650429B2
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produce
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Thierry Imbert
Dominique Marais
Didier Mesangeau
Gerard Moinet
Jean Louis Vidaluc
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Merck Sante SAS
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LIPHA SAS
LIPHA Liyonnaise Industrielle Pharmaceutique
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Description

Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION (OR IGINAL) Class I nt. Class Application Number: Lodged: 50 042 Complete Specification Lodged: Accepted: Publishcd: M rority Related Art Name of Applicant Address of Applicant Actual Inventor Address for Servilce LT-HA LYONNAISE INDUSTRIELLE PHARMACEUTIQUE 115 avenue Lacassagne, 69003 Lyon, France GERARD MOINET, THIERRY IMBERT, DOMINIQUE MARAIS, JEAN LOUIS VIDALUC and DIDIER MESANGEAU WATERMARK PATENT TRADEMARK ATTORNEYS, LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Complete Specification for the invention entitled: NOVEL ARYLOXY ALCOYL BENZENES, PROCESSES FOR THEIR PREPARATION AS WELL AS THE PHARMACEUTICAL CaVIPOSITIONS CONTAINING THEM The following statement is a full description of this invention, including the best method of performing it known to us This invention relates to novel aryloxy alkyl benzenes, their processes of production as well as the pharmaceutical compositions containing them.
It has more precisely as subject matter as novel compounds, aryloxyethyl benzene substituted on one or both rings and specifically the aryloxyethyl benzene of the formula i R R 1 I I Ar-C-CH-O-Ar' (I)
R'
wherein Ar is an aromatic mono- or bicyclic hydroxylated radical selected from the group consisting of phenyl derivatives having the formula (Z)p x where X is a free hydroxy, esterified by a carboxylic or sulphonic organic acid, by phosphoric acid, or by sulphuric acid, or etherified by a lower alkyl or alkenyl radical Z is a substituent selected from the group consisting of hydrogen, halogens, 15 hydroxy, a lower alkoxy, an acyloxy, a phenyl lower alkyl, a lower alkyl, a lower o alkyl substituted by a lower alkyl oxy carbonyl, a lower alkyl substituted by a hydroxy carbonyl, a moiety -CO(CH 2 )mCH3 wherein m is an integer of from 1 to 4, a moiety -CHOH-(CH2)m' -CH 3 wherein m' is an integer of from 1 to 4, a carboamido group optionally substituted by one or two lower alkyl radicals, a 20 phenyl a phenoxy
C
and the naphthalenic derivatives selected from the group consisting of the S: naphthyl derivatives of the formula .1 %ilA -2- (z)p wherein A is a free hydroxy or an esterified or etherified hydroxy group Z is defined as above-given and p is an integer of from 1 to 3 and those of formula (Z)p A wherein A, Z and p are defined as above-given Ar' is an aromatic mono- or bicyclic radical selected from the group consisting of e the benzenic derivatives of formula n wherein Y is a hydrogen, a halogen, a (lower alkylene) dioxy, a hydroxy, a lower alkoxy, an acyloxy derivated from an organic carboxylic acid, a lower alkyl, a lower alkyl substituted by a (lower alkoxy) carbonyl, an oxo alkyl chain of the formula CO(CH 2 )m CH 3 wherein m is an integer of from 1 to 4, or an hydroxy alkyl chain of o the formula CHOH-(CH) 2 m,-CH 3 wherein m' is an integer of from 1 to 4 *0 0 0 a- htb e- v0 the inaph~t-alen derivatives selected from the group consisting of -aphtyl derivatives of formula k wherein Y is defined as above-given and n is an integer of from 1 to 4 and the naphihalenic derivates of formula (Y)n where Y and n are defined as above-given R is a hydrogen, a hydroxy, or a lower alkyl radical, and R' is a hydrogen, or R and R' together form the oxygen of a keto group
R
1 is a hydrogen or a lower alkyl radical.
This invention also relates to the optically-active isomers of a compound of formula i when R 1 is different than a hydrogen and when R and R' are not a keto group.
Further when R, R' and R 1 are substituents, it is possible to create a pair of diastereo isomers erythro and ~l.eo and further to resolve it into the opticallyactive isomers by means of a chiral reagent.
15 This invention also includes the salts of the compounds of formula i with a mineral or organic base, when X is a hydroxy esterified by sulphuric acid or phosphoric acid.
Among the compounds of formula i according to this invention, the following groups may be more precisely cited: the hydroxyphenyl ethoxy benzenes of formula IA
O
R
(IA)
R
(Y)n \%qX 4 wherein X is hydroxy, a hydroxy etherified by a lower alkyl or a lower alkenyl or esterified by an organic carboxylic or sulphonic acid, by phosphoric acid or by phosphoric acid and R, R 1 Y, Z, n and p have the above-given definitions and as preferred compounds, 1-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane, the metallic or organic base addition salts of 1-(2-hydroxy phenyl) 2-phenoxy ethane such as the piperazine disalt or the sodium salt, or 1- (2-hydroxy 5-carboxamido phenyl) (4-fuorophenoxy) ethane.
the compounds having the general formula IB (Z)p (Y)n
D
o r r s wherein the definitions of the substituents X, Y, Z, R, R 1 n and p remain unaltered the compounds having the general formula Ic (Z)p, (Y)n wherein the definitions of the substituents Z, Y, X, R, R 1 n and p remain unaltered the compounds to having the formula ID
R
Z R' (Y)n
X
wherein Z, Y, X, R, R 1 n and p are defined as previously given the compounds according to this invention having the formula IE
R
S(IE)
(Z)P X R' R 'I(Y)n wherein R, R 1 X, Y, Z, n and p have the above-given definitions.
As far as this invention is concerned, a lower alkyl radical is a hydrocarbon chain which may be straight or branched, having up to 6 carbon :.atoms such as a methyl, ethyl, isopropyl, secbutyl, tert-butyl, neopentyl or nhexyl. A lower alkoxy radical includes an alkyl chain defined as above.
Among the various halogens, it may more particularly be cited fluorine or chlorine. However bromine and iodine are also of value.
:A lower alkenyl radical is a hydrocarbon chain including a double bond, having from 2 to 6 carbon atoms. As lower alkenyl radicals, it may be cited an allyl, a 15 methallyl, a but-2-enyl radical, an isopropenyl or a 3-methyl but-1-enyl radical.
A lower alkylene dioxy group has from 1 to 4 carbon atoms in the alkylene chain as for example methylenedioxy or ethylenedioxy.
When X and/or Y and /or Z are an acyl moiety, this moiety derives from -6a lower alkyl carboxylic acid such as acetyl, propionyl, diprop y l acetyl, or from an aromatic cyclic acid such as a benzoyl, ephf 1, 2,6-dich,orobe-.zoyl, 3,4,5-trimethoxybenzoyl, a veratroyl, a syringoyl, a 0-carbethoxy syringoyl, a nicotinoyl or a furoyl; or from an aryl lower alkyl carboxylic acid such as a phenoxy acetyl, a dichlorophenoxyacetyl or a p-chlorophenoxy isobutyryl.
An aryl lower alkyl radical is defined as a monocyclic aryl radical bearing a hydrocarbonated side-chain of 1 to 6 carbon atoms such as for example benzyl, phenylethyl, c-methylphenyl ethyl, 2,6-dichlorobenzyl, 2,3,5-trimethoxybenzyl.
When Z'is an alkyl carboxylic side chain, the alkyl moiety has from 1 to 4 carbon atom. The carboxylic function may be free or esterified such a (methoxy carbonyl) methyl, an (ethoxy carbonyl) methyl or an S, (ethoxy carbonyl) ethyl.
t* The substituent Y may further be an alkyl radical substituted with an *V oxo group or a hydroxy group. A preferred example of such group is acetyl or hydroxy ethyl.
When R and/or R 1 are a lower alkyl radical, they are preferably a methyl or an ethyl.
YerfTo n eX ,From all the compound of formula I, mentiennete hereabove, the presently preferred compounds are those for which X is a hydroxy, free, esterified, or etherified located in position ortho to the ethyloxy chain and those for which Y is a halogen and most preferably those for which Y is a fluorine.
The significance of Z may very broadly vary. The nature of this substituant is important but the number of the substituents Z plays a more reduced role.
This invention also extend to a process for producing a compound of genecal formula I j iu
V
R R, I I Ar-C-CH-O-Ar' (I)
I
R'
where Ar and Ar' are as hereinbefore defined and R, R' and R 1 are each a hydrogen, which comprises the steps consisting of condensing a phenolic derivative of the formula ii Ar-X
(IZ)
wherein Ar, X, Z are defined as above-given with an aryl aceto nitrile of the formula III (Y)n Ar' OCH 2 CN (III) wherein Ar', Y and n have the above-given definitions in the presence of an acidic catalyst to produce a diaryl ethanone of the formula
IV
(Z)p-Ar-CO-CH 2 (Iv)
I
t:11 wherein Z, Y, Ar, Ar', n and p have the above-given definitions and X is a free S 15 hydroxy reducing the latter by means of an alkali metal mixed hydride in the presence of a metalic catalyst or by reaction with a lower alkyl chloroformate and reducticn of the intermediary so-produced compound by means of an alka!i metal
I
borohydride to obtain a compound of formula I.
20 This invention more particularly relates to a process for producing a compound of formula IA which comprises the steps of condensing a phenol of f formula ITA ~A V 4.
-8-
OH
(Z)p X
(IIA)
wherein Z, X and p have the above-given defintions with a phenoxyaceto nitrile of the formula IIIA 0* 0 00 *00 a 0000 (Y)n wherein Y and n have the in the presence of an general formula IVA
(Z
p
OCH
2
CN
S(IIIA)
above-given definitions acidic catalyst to produce the ethanone of
O
II
C /o n IVA) 000 *0 a 0 00 0 *0 C S0 wherein Z, Y, n and p have the previous definitions and X is a free hydroxyl reducing the latter into a compound of general formula I A by means of an alkali metal mixed hydride in the presence of a metallic catalyst or by reaction with a lower alkyl chloroformate then reduction of the thus-formed intermediary compound with an alkali-metal borohydride which may be alkylated by means of an alkylating reagent in basic 9 medium or acylated hy-meeans of functional derivative of a carboxylic, sulphonic, sulphuric or phosphoric acid.
This process also includes another process for producing a compound of formula I which comprises the steps of blocking the phenolic function of a hydroxy acetophenone of formula V
OH
(Z)p Ar (V) CO
CH
3 wherein Ar, Z and p are defined as previously given and X is a free hydroxyl using a easily-split reagent submitting tha so-blocked phenol of formula VI Ar OB Ar (VI) c wherein B is a leaving group Z and p have the above-given definitions submitting the latter to the action of a brominating agent to produce an o-bromoketone of formula VII (Z)p Ar O (VII) SCO
CH
2 Br wherein Z, Ar, B and p have the above-given meanings condensing this derivative with a phenolic derivative of formula Ar' OH wherein Ar', Y and n are defined as previously indicated to produce a phenoxy ethanone of formula VIII
Z"
ft 10 (Z)p-Ar COCH 2 0 Ar' (Y) (Z)p Ar 2 n
(VII)
x wherein the definitions of the substituents Y, Z, Ar, n and p remain un '.tered and X is a hydroxy group blocked by an easily-split radical submitting the compound of formula VIII to a hydrogenolysis in the presence of a metallic-catalyst or to an acidolysis to make free the hydroxy group and produce a phenoxy ethanone of formula IX ^^_CO-CH2-O (Z)p Ar Ar' (IX)
SOH
wherein Z, Y, Ar, Ar', n and p have the above-given meanings *00 0 0. treating the latter with a reducing agent to produce the hydroxylated derivative thereof of formula X CHOH CH2 0 (Z)p -Ar 0 Ar' (X) OH n in which Z, Y, n, p, Ar and Ar' are defined as above-indicated and X is a free hydroxyl.
This process particularly applies for producing a compound of formula VIIIA which comprises the steps of S. blocking the free hydroxyl of a hydroxy icetophenone of forrula VA
COH
CO CH3(VA) 11 with an easily-split blocking reagent submitting this blocked phenolic derivative to the action of a brominating agent to produce the corresponding cm-bromoketone condensing this bromoketone with a phenol of formula (Y)n wherein Y and n are defined as previously to obtain a phenoxy ethanone of formula VIA OCOb 0 00 S S *0*S S0 S S sose *0
SS
0* S
Z)P
n (VI A wherein the meanings of the substituents Z, Y, p unchanged and X is blocked hydroxyl and n remain 0 0550
SSSS
OS
0* S *050 0 0*@SS
S
@5 0 0* 00
S
S S 0* submitting this compound to hydrogenation in t'ie presence of a metallic catalyst or to an acidolysis, to make free the hydroxyl function and obtain a phenoxy ethanone of formula VI A
Z)P
n wherein X is a hydroxy 12 and Z, Y, p and n are defined as previously indicated reducing the compound of formula VIIA by means of a reducing agent to produce the corresponding alkanol of formula VIII
A
/Z)p (Y)n (viii
A)
S
SS S
SS
a S *5 *O e a Sea .556 59 0 wherein Z, Y, n and p are defined as previously given and X is a free hydroxyl This invention also relates to another process for producing a compound of formula I wherein R is a lower alkyl radical, which comprises the steps of reacting a phenoxy ethanone of formula VIII (Z)p Ar CO CH 2 0 Ar' (Y)n
"X
(VIII)
*55 e a *SeS 5555 S SS S a 5* 0
S
S 55 0
S
a 55 wherein Z, Y, Ar, Ar', p and n have the above-given definitions and X is a blocked hydroxy group to the action of a triaryl alkyl phosphonium bromide under the conditions of the Wittig's reaction to produced an ethylenic d-tivative of formula XI
R
(Z)p Ar C CH 0 Ar' (Y) .Xn
(VI)
wherein Z, Y, Ar, Ar', n and p X is a blocked hydroxy group and R is a lower alkyl radical are defined as above-given 13 submitting this compound to hydrogenation in the presence of a metallic catalyst to produce the o-alkylated derivative of formula I R R 1 I I Ar-C-CH-O-Ar' (I)
I
R'
wherein r and Ar' are defined as previously, R is a lowar alkyl radical which may, when desired, be alkylated or acylated under the conditions previously defined, R' and R 1 are hydrogen.
This process more particularly applies for producing a compound of formula IA which comprises the steps of reacting a phenoxy ethanone of formula VIA
CO-CH
2 -O (Z)p (YMn
S(VIA)
wherein Y, Z, n and p have the above-given definitions and X is a blocked phenolic group with a triaryl (lower alkyl) phosphonium bromide under the conditions of the Wittig's reaction to produce an ethylenic derivative of formula IXA
R
15 I
C=CH
(Z)p (Y)n X (IXA)
X
wherein Z, Y, n and p have the above-given definitions R is a lower alkyl radical and X is a blocked phenolic group eO er
O
r oolo e *c 14 and submitting this latter to hydrogenolysis in the presence of a metallic catalyst to produce an o-alkyl ethoxy derivative of formula IA
R
(Z)p R (Y)n wherein Z, Y, n and p have the above-given definitions X is a hydroxy, R is a lower alkyl radical which may, when desired, be alkylated or acylated under the above-defined conditions, and R' and R 1 are hydrogen.
This invention also includes another process for producing a compound of formula I which comprises the step of reacting a substituted aryl aldehyde of formula x (Z)p-Ar-CHO (X) x where Z and p are defined as above and X is a blocked phenolic group 15 with a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Wittig's reaction to produce an ethylenic compound of the formula xii wherein Z, Ar, Ar', X, Y, n and p have the above-given definitions hydrogenating the latter by means of hydrogen in the presence of a metallic 20 catalyst into a compound of formula I R R 1 I I Ar-C-CH-O-Ar' (I)
I
R'
wherein the substituents Ar and Ar' have the above-given definitions and R, R' and R 1 are each a hydrogen.
This invention further includes another process for producing a compound of formula I wherein a substituted benzaldehyde of formula XA
.CHO
(z)t
(XA)
X
where Z and p have the above-given definitions and X is a blocked phenolic function is reacted with a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Wittig's reaction to produce an ethylenic derivative of formula
-IA
CH CH-O (Z)p )n
(XIA)
x wherein Z, Y, n and p have the above-given definitions and X is a blocked phenolic group which is further hydrogenated into a compound of formula IA by means of hydrogen in the presence of a metallic catalyst.
This invention also includes a process for producing a compound formula I which comprises the steps of blocking the reactive functions of a hydroxy aryl alkanol of formula xIII
R
20 (Z)p-Ar-CH-CHOH-R, (XII)
X
wherein Z, Ar, R, R 1 have the above-given definitions and X is a free hydroxyl by means of an easily-split reagent, then reacting the thus-blocked derivative with a phenolic derivative of formula xiv
OH
(Y)n
(XIV)
wherein Y, n and Ar' have the above-given definitions to produce an aryloxy ethyl arylidenic derivative of formula xv R R, (Z)p-Ar-C H- C H-O-Ar'- (Y)n (XV) wherein Z, Y, Ar, Ar', n and p have the above-given definitions, R and Ri are the same or different to each other and are a hydrogen or a lower alkyl radical, and X is a blocked phenolic group and to make free the hydroxy function by means of an alkaline agent to produce a compound of formula i.
This process more precisely applies for producing a compound of formula
IA
*6fe .4* *9 4 *4*4 4 4 4 4 4*4O 4 4 o o o o o 4 4 4o oo 0 **4 4.
a
(IA)
(Z)p (Y)n and R, R 1 X, Y, Z, n and p have the above-given definitions which comprises the steps of blocking the reacting functions of a 15 (hydroxyphenyl) ethanol of formula XIIA .1
C"/
of 17 1
CHOH
(z)p
(XIIA)
wherein Z and p are defined as above X is a hydroty R and R1 are a hydrogen or a lower alkyl by means of a gageae, which is easily split, contacting the thus-blocked-derivative with a phenol of formula XIIIA 0sD* i 0* 9 *9 be C -9S.S
HO
t nY)n
(XIII
A
wherein Y and n have the above-given definitions to produce a phenylethoxy phenyl of formula XIVA R R CH -CH-O
(XIVA)
(Y)n (z)p
C
a a wherein Z, Y, n and p have the above-given definitions R and R1 are hydrogen or a lower alkyl and X is a blocked phenolic group and making free the hydroxyl function by means of an alkaline agent to product a compound of formula I
A
Thi invention has as a further subject matter the intermediates of formula IX
*XA
C)
18
R
C CH
XA)
(Y)
X
wherein Y, Z, X, R, n and p have the above-given definitions and the compounds of formula XIA CH= CH O
Y)
x wherein Z, Y, X, n and p are defined a previously It is a further subject matter of this invention, the pharmaceutical compositions containing as active ingredient at least one compound of formula I in admixture or conjunction with an inert non-toxic pharmaceutically-acceptable carrier or vehicle.
*0* *0 The compounds of fcrmula I acccording to this invention show very interesting phamacological properties and namely diuretic, antihypertensive, platelets, anti-aggregating properties and anti-lipoxygenase properties.
4* so These vascular properties are very peculiar due to the fact that their site of action is not exclusively renal. The compounds according to this invention inhibit the contractions induced by Noradrenaline and by the potassium salts.
19 The results of this testing imply the existence of an extra-renal site of action likely vascular, in the mechanism of hypertensive action of the compounds of formula I. The pharmacological testing and the obtained results allow to think that the way of action of the compound of formula I goes through the intra-cellular movement of Calcium into the muscular wall of the vessels.
As a result of the pharmacological properties the compounds according to this invention find a use in human and veterinary therapy as a platelet anti-aggregating mdecine or as an anti-hypertensive medecine.
To these ends they are used in the form of pharmaceutical compositions which contain as active ingredient at least one compound of formula I in admixture or conjunction with an inert, non-toxic pharmaceuticallyacceptable vehicle or carrier.
For the therapeutic use, they are manufactured in those forms f convenient for administration through parenteral, oral, rectal, permucous or percutaneous ways. It may be cited in this respect the S- injectible solutes or suspensions packed in ampuls, in multi-dosis flasks, or in the form of auto-injectible syringes, in the form of coated or uncoated tablets, dragees, solft gelatine capsules, powders, rectal suppositories, solutions in a polar solvent, or the transdermal preparations.
The carriers which are appropriate for such manners of administration are cellulose derivatives, micro-crystalline cellulose, earth-alkaline carbonates, magnesium phosphate, starches, chemically-modified starches or lactose.
9 For parenteral use, water, aqueous solutions, saline, glucose solutions and the like are the most conveniently used ones. For rectal way of administration, cacao butter or polyethylene glycol stearates are the preferred carriers.
20 The dosology may vary within broad limits which are a function of the severity of the hypertensive disease, of the weight and the age of the patient and of the way of administration.
A a general rule, the unit dosage may range from 1 to 200 mg per :intake and the daily dosage may range from 2 to 500 mg per day in the man.
The manner of administration may also be modulated as a function of the duration of the action of the compounds of formula I.
The following examples are merely intended to illustrate the invention without limiting it in any manner.
0 *a EXAMPLE I 1. -(2-EYDROXY 5-METHOXY PHENYL) 2-PHENOXY ETHANE (Process A)
C*
StepA 1-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethanone To a solution of 32.2 g (0,27 mol) of boron trichloride in 200 ml chloroethane cooled to they are successively added a solution of 28,4 g (0,23 mol) 4-methoxy phenol in 100 ml dichloroethane, 36,6 g (0,24 mol) phenoxy acetonitrile then 15,2 g (0,11 mol) aluminium chloride while stirring. The mixture is kept under stirring for 20 hours at room temperature. After hydrolysis in acidic conditions for 30 mn, and extraction, it is obtained after crystallis ition from methanol, 26 g (ie a yield of 44%) phenoxy acetophenone. The pure compound melts at 1280C.
C
Step B l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane To 6,4 g (0,058 mol) of ethyl chloroformate at 0 C one adds a solution of 12.8 g l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethanone obtained at step A in 100 ml tetrahydrofuran in the presence of 6 g (0,058 mol) triethylamine. After one hour contact under stirring at room temperature, the thus formed 21 triethylamine hydrochloride which has precipitated is filtered and the filtrate is dropwise added to a solution of 5.6 g (0,15 mol) sodium borohydride in 50 ml water at 50C for mn. After stirring at room temperature for 1,5 hour the reaction mixture is poured on ice, one proceed' to an acidic hydrolysis with hydrochloric acid then extracts with ether.
The ethereous phases are separated, the solvent is evaporated off and 8.4 g of product recovered after purification by distillation under reduced pressure. The yield amounts to 69%. The melting point of the pure compound is 170 0
C.
Its piperazine disalt melts at 950C EXAMPLE II 1-(2-METHOXY PHENYL) 2-PHENOXY ETHANE 4 g 1-(2-hydroxy phenyl) 2-phenoxy ethane (ie 0,032 mol) and 16 g potassium carbonate (0,117 mol) in 100 ml acetonitrile are added with 4.9 g (0,039 mol) methyl sulphate. The whole mixture is heated to reflux for 5 hours. Thereafter the solvent is evaporated off and the residue extracted, 5,6 g (ie a yield of 80%) of the methoxy derivative are recovered as an only product.
0 EXAMPLE III 1-(2-ACETOXY 5-METHOXY PHENYL) 2-PHENXY ETHANE *0 To 4 g (0.016 mol) 1-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane they are added 1.5 g (0,019 mol) acetyl chloride and 2 g (0,019 mol) triethylamine for acetylation. After stirring of the mixture for 1 0 hour at room temperature, the mixture is extracted with a solvent to provide 4 g (ie a yield of 85%) of the 2-acetoxylated derivative.
EXAMPLE IV 1-(2-SULFITO OXY PHENYL) 2-(4-FLUOROPHENOXY) ETHANE AS THE POTASSIUM
SALT
S- 22 In a three-neck flask, under Argon atmospher, 6.53 g (0,47 mol) potassium carbonate and 10 g (0,43 mol) 1-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethanol are introduced with 100 ml acetonitrile.
The mixture is stirred for 30 mn at 40°C then 8.97 g (0,645 mol) of the complex (90 3 -triethylamine) are added. After stirring the mixture is cooled and the formed sulphate precipitates. After filtration 6.5 g of a white solid are recovered.
Melting point 163°C Yield 42 EXAMPLE V 1-(2-PHOSPHONYLOXY PENYL) 2-(4-FLUOROPHENOXY) ETHANE a Step A 2-(4-fluorophenoxy ethyl) phenyl phosphochloridate 10 g (0,043 mol) of l-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethane are dissolved into 36 g POC1 3 (0,235mol) and the mixture is heated to the reflux for 2,5 hours in the presence of 0.1 g Aluminium chloride. The mixture is concentrated then distilled. The formed phosphate distillates (Eb 0,25 210 2200C) 9,71 g of an oily residue are thus recovered (yield 64 "...Step B Hydrolysis of the phosphochloridate 4 g (0,11 mol) of the phosphochloridate are hydrolysed in ml water under stirring at 80°C. The reaction mixture is kept under stirring for three further hours. It is concentrated therafter under reduced pressure until dryness.
By scratching in petroleum ether, a white solid weighing 3.1 g is recovered.
Yield 86 MP 80-820 EXAMPLE VI 1-(2-HYDROXY PHENYL) 2-(4-FLUOROPHENOXY) ETHANOL (Process B) 23 Step A: -(2-benzyloxy phenyl) 2-bromo ethanone 250 g (1,1 mol) of 2-benzyloxy acetophenone are dissolved in 1000 ml of dry tetrahydrofuran, the solution is cooled to O°C and then added portionwise to 500 g (1,32 mol) of phenyl trimethyl anilinium tribromide for 4 hours. The so-formed precipitate is filtered. The mixture is distilled off to dryness and the residue is used as such for the next step of the synthesis.
Weight about 34 g Yield 70 Step -(2-benzyloxy phenyl) 2-phenoxy ethanone 125 g of the o-bromoketone obtained in the preceding step are added to 57 g phenol (0,'61 mol). 283 g (2 mol) of potassium carbonate in acetonitrile and the whole mixture is heated to o reflux for 2 hours. After filtration of the mineral salts and evaporation off of the solvent the residue is taken up dichoroethane, washed with a N solution of sodium hydroxide then with water until the washings are neutral. The solvant is further dried and evaporated until dry to produce 104 g of the phenoxy benzylated derive ive.
MP 141 0
C
Yield 80 S*o 0 Step C: 1-(2-hydroxy phenyl) 2-phenoxy ethane 52 g (0,164 mol) of phenoxy benzylated derivative of step B are let to be hydrogenated under an atmospher of hydrogen in ethanol (1000 ml), preferably in the presence of 3 g of palladized charcoal at 10%. After absorption of the required amount of hydrogen, the catalyst is separated by filtration, Ethanol is evaporated off and the dry residue is crystallized to provide 34,7 g of phenolic derivative melting at 1200C.
The yield amounts to 92% 24 Step D: l-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethanol To a solution of 5 g (0,02 mol) of 1-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethanone in methanol cooled to 00, they are added dropwise 0.760 g (0.02 mol) of sodium borohydride.
After return to room temperature, at the end of one hour,the reaction mixture is concentrated and poured on ice then is acidified at pH 4. The whole mixture is extracted with ether to recover 4.5 g of the hydroxy ethylated derivative as an oily residue.
The yield amounts to EXAMPLE VII 2-(2-HYDROXY PHENYL) 3-PHENOXY PROPANE A solution of 53,5 g of triphenyl methyl phosphonium in 500 ml tetrahydrofuran under atmospher of argon, is added to 112,5 ml of a 1,6 M solution of butyl lithium in hexane at room temperature. After 4 hours of stirring, l-(benzyloxy phenyl) 2-phenoxy ethanone dissolved in tetrahydrofuran is added dropwise and the mixture is heated over a night at reflux temperature.
After concentration of the solvent, the mixture is poured into water and is extracted with ether. The residue recovered after evaporating off the solvent, is submitted to a flash-chromatography on silica, with a mixture of eluents (Petroleum ether/isopropyl ether 90:10) to so S recover 37 g of propenylated derivative which melts at 57 0
C.
*.oo 2/ g of propenylated derivative is hydrogenated under hydrogen atmospher in the presence of palladized charcoal at 10% Palladium, in 400 ml ethanole under vigorous stirring at atmospheric pressure and at 50 0 C, for 20 hours.
SS
S; After having separated the catalyst by filtration and evaporation of the filtrate, 16 g of 2-(2-hydroxy phenyl) 3-phenoxy propane are recovered (yield EXAMPLE VIII 1-(3-METHOXY 4-HYDROXY PHENYL) 2-(4-FLUOROPHENOXY) ETHANE 25 Preparation of (chloromethyl) 4-fluorophenoxy ether 59 g (0,47 mol), of 4-fluoroanisole are heated with 97 g (0,47 mol) phosphorous pentachloride at 120 0 C for 2 hours then the temperature is increased to 1400 then to 1600 as PC13 distillates. One maintains stil 2 further hours at this temperature after the distillation of PCl 3 is achieved, then one distillates under reduced pressure (15 mm Hg) at a temperature of 1000 to obtain 47 g of the chlorinated ether.
The yield amounts to Preparation of triphenyl 4-fluoroxy methyl) phosphonium chloride In 300 ml benzene, 42 g of chloromethylated ether (0,26 mol) and 81 g of triphenyl phosphine are introduced and the whole mixture is heated to reflux for a night. Afer evaporation of benzene, the salt of phosphonium is allowed to crystallyse from ether. 62 g of salt of phosphonium are recovered, melting at 248 0 C. The yield amounts to 57%.
Step A l-(3-methoxy 4-benzyloxy phenyl) 2-4-fluorophenoxy) ethene Je 0. 12,2 g (0,029 mol) (4-fluorophenoxy methyl) triphenyl phosphonium chloride are dissolved in 100 ml tetrahydrofuran and the solution is cooled to 78 0 C under atmospher of argon.
To this, 16 ml of a 1,6 M (i.e 0,026 mol) solution of butyl lithium in hexane are added dropwise. After 1 hour standing at this temperature, 5 g (0,02 mol) of 3-methoxy 4-benzyloxy benzaldehyde are added then the mixture is allowed to revert G* to room temperature in two hours. The mixture is then poured on ice, made acidic at pH 4 and extracted with ether. After evaporation of the solvent, the residue is filtered on silica and 6,2 g of the phenoxy ethene are recovered.
Step B 1-(3-methoxy 4-hydroxyphenyl) 2-(4-fluorophenoxy) ethane 8.2 g (0,0225 mol) of phenoxy ethenic derivative of step A is put in a vessel for hydrogenation under atmospher of hydrogen, in ethanol, in the presence of 2 g of palladized charcoal at 10%. The mixture is kept under vigourous stirring 26 for 12 hours. After filtration of the catalyst and having evaporated off the solvent, the residue is chromatographied on silica and after elution by a mixture of petroleum ether/ethyl acetate (90:10) to provide after evaporation of the solvent, 3.5 g of the saturated derivative in the form of an oily product Yield :60 EXAMPLE IX (Method B) 1-(3-HYDROXY PHENYL) 2-(4-FLUOROPHENOXY ETHANE) Step A 1-(2-methyl sulphonyloxy ethyl) 3-(methylsulphonyloxy) benzene 29 g (0,21 mol) of (3-hydroxy phenyl) ethanol in anhydrous pyridine are added dropwise to 41 ml (0,525 mol) methyl 0 sulphonyl chloride at 0°C, under stirring After return to room temperature and standing at this *temperature for 1,5 hour, the mixture is poured on ice. It is acidified then extracted with methylene chloride. The extract is washed with water until neutral, dried on sodium sulphate and evaporated to dryness. 53 g of di-methyl sulphonate are obtained. Yield 86% 0o 0 Step B 1-(3-methyl sulphonyloxy phenyl) 2-(4-fluorophenoxy) ethane A mixture made of 53 g (0,18 mol) of the dimethyl sulphonate of step A, 24,4 g (0,217 mol) of 4-fluorophenol and 28,8 g .(0,217 mol) potassium carbonate are introduced into 350 ml acetone and heated to reflux under stirring for 9 hours. The mineral salts are thereafter filtered and the filtrate is evaporated off. The residue is taken up in water and extracted with ether. The organic phases are separated, washed with sodium hydroxide then with water until neutral and dried on sodium sulphate. The ethereous solution is evaporated off to obtain 46 g of dry residue (i.e a yield of 83%) of (3-methyl sulphonyl phenyl) 2-(4-fluorophenoxy) ethane, pure enough for the progress of the synthesis.
27 StepC 1-(3-hydroxy phenyl) 2-(4-fluorophenoxy) ethane 46 g (0,148 mol) of the methyl sulphonate of step B are allowed to be saponified by reflux in 2000 ml of a 2N solution of sodium hydroxide for 16 hours. After cooling, one acidifies with 5N ClH, extracts with ether and dries on sodium sulphate. The solvent is evaporated off and 25 g of crude product substantially containing a 3-hydrcxy styrenic derivative are recovered. Using the Flash Chromatography and the elution with a mixture of petroleum ether/isopropyl ether (80:20) 11,68 g of pure (3-hydroxy phenyl) 2-(4-fluorophenyl) ethane are obtained as a crystaline form MP 640 0e 0 S* The following compounds of formula I have been prepared using one of the four syntheses methods B, C, The parameters have been numbered in Table 6, hereunder.
'EXAMPLE X TABLETS WITH 100 MG OF 1-(2-HYDROXY PHENYL) 2-(4-FLUOROPHENOXY)ETHANE active ingredient 100 g wheat starch 45 g o' MaYs starch 55 g microcristalline cellulose powder. 12 g ethyl cellulose 8 g magnesium stearate 5 g for 1000 tablets finished at an average weight of 0.225 g
S
Pharmacological study of the compounds according to this invention A DIURETIC ACTION 1. in the mice The compounds of formula I have been given to batches of 12 male mice
S
28 weighing between 25 and 30 g each. The mice, divided by pairs, are prior submitted to a load of liquid, constituted by the administration of the compound to be tested under a volume of 25 ml per kg, followed by administration of saline a 9 the total volume to be given, being of 1 ml per mouse.
The diuresis is studied for 4 hours. The urinary volume is measured every hour. Potassium and sodium are dosed by spectrophotometry on the pooled urines.
2. in the rat An overload of liquid is obtained in the rats of male sex weighing between 200 and 250 g and fastened for 18 hours before the testing.
The animals are located each in an individual cage for diuresis and receive by oral way an overload of 20 ml/kg of saline at 0,9% containing the compound of formula I to be tested. The diuresis is measured for 5 hours. The volumes of urine are determined every hour.
Dosages of sodium and potassium are performed by spectrophotometry.
0° Table I collects the main results obtained during this testing.
9 0* 09 00 Ge 9 0° ft«
*E
29 T A BLE
PROI~J~T
of example ex 25 Diuretic power en R RAT S =MICE minimal active doses in mg/lcg P0 R (12) S (25) 190 10 Ratio Na/1t en R =RAT S =MICE (x) minimal active doses in mg/kg P0 R (12) 46 S (25) 50 R (50) 40 S (100) 210 R (12) 40 S (25) 210 e 26R (50) 250 ex26S (100) 30 e 30R (12) 170 exOS (25) 40 888@ a.
9. 9 *j 9 0 *9OS *0 8 S
OS
8559
S
OS..
SB
9O a 0038 ex 36 ex 42 ex 169 ex 46 ex 48 ex 172 R (100) S (100) 140 40 R (100) S (100) 65 180 R (12) 190 R (12) 60 S (100) Inactive Inactive R (12) 70 R (12) 85 S (100) Inactive S (100) Inactive R :Inactive R :Inactive S :Inactive S :Inactive R (25) S (100) R (25) S (100) 80 20 80 68 R (25) S (100) 80 130 9..
0 *53S 958055 9 5* 0 S S 89 50 *9 ex 56R Inactive ex~ 56: Inactive R (25) 160 5 (100) 208 R Inactive S :Inactive R (25) 60 5 (100) 220 ex 107 ex 134 ex 139 ex 163 R (25) S (100) R (6) S (25) 140 80 100 40 R (6) S (25) 50 140 R (25) 32 R (25) 80 S5(25) 40 S (25) 80 R (6) S (25) 260 34 R (6) S (25) R (12) S (25) 53 134 10 320
FUROSEMIDE
R (12) S (25) 30 120 S- 30 B ANTI-HYPERTENSIVE ACTION IN THE UNANESTHETIZED RAT This study has been carried out in batches of males rats SHR (strain OKAMOTO) 16 weeks old. The arterial systolic pressure has be measured by the sphygomanometric process using an electrospohygmograph NARCO (biosystems) type PE 300. The determinations of the blood pressure have been performed 24 hours after the administration of a compound of formula I to be tested. The arterial systolic pressure is calculated from the average of 6 to 8 measurements.
The obtained results are gathered in Table II It thus appears that the kinetic of the anti-hypertensive action is dissociated from that of the diuretic effect.
oo 0 *0 0 0 0 0 31 T A BLE 6e o o 400& 04 0 0* be ANTI-HYPERTENSIVE ACTIVITY STUDIED in the RAT A Acute Variation of the PRODUCT C chronic anti-hypertensive effect doses studied 24 hourS after in MG/kg PO administration of the product ex 25 not tested not tested ex 26 not tested not tested ex 30 A 11 mmHg A (30) 30 mmHg C (15) 16 mmHg ex 36 A (100) not active C (100) 20 mmHg ex 42 not tested not tested ex 169 not tested not tested ex 46 not tested not tested ex 48 A (60) 24 mmHg ex 172 A (60) 16 mmHg ex 56 not tested not tested ex 107 not tested not tested ex 134 A (15) 11 mrHg A (60) 37 mmHg C (30) 26 mmHg ex 139 A (60) 12 mmHg ex 163 A (10) 19 mmHg A (60) 33,5 nammH FURC3EMIDE FUROSEMIDE not active FUROSEMIDE HYDROCHLOROTHIAZIDE HYDROCHLOROTHIAZIDE not active
A-
S- 32 C BLOOD PLATELETS ANTI-AGGREGATING EFFECT These studies have been carried out on plasmas reach in platelets, coming from rat blood. The aggregation is induced by adding Adenosine diphosphoric acid (ADP). The nephelometric curves showing the aggregation are obtained using an aggregometer type BORN, plasma being incubated at 370 under continuous stirring at 100 RPM (cf. Born G.V.R, and CROSS J, J.Physiol. 168 (1962) 178).
Table III collects the obtained results with the many tested compounds of formula I a 4€ 0 a a a a t
S
0495 S 3 33 TA B LE III PLATELETS ANTI-AGGREGATIM~ ACTIVITY
M
IN VITRO"
M
(Aggrating agent is ADP) PROUJCT V at 50 M at TICLOPIDINE 0,75 mM 0,85 mM Ex 56 0,45 0,30 Ex 30 0,8 go:,Ex 174 0,55 0,40 00 o Ex 90 0,60 0,50 as Ex 82 0,65 0,55 0A06Ex 52 0,70 0,75 go0 loeEx 64 0,70 0,50 Ex 78 0,70 0,70 Ex 58 0,75 0,60 seeQ, ~Ex 129 0,8 0,6 Ex 84 0,8 0,75 $ag Ex 102 1,0 0,7 Ex 42 1,0 1,2 *:Ex 172 1,0 0,95 Ex 86 1,25 1,55 Ex 134 1,5 1,3 Ex 81 1,6 1 Ex 12 1,95 1,60 Ex 10011 Ex 169 2 inactive Ex 54 2 inactive Ex 36 2 inactive 34 These results are confirmed by the. results obtained "ex vivo" in the rats receiving for 3 days a compou-d cf £crm.la I by oral way.
It is stated an inhibiting efect on the platlets aggregation which is obDOnA os0.5q5 evidenced by a dbbleninHof the es- of ADP needed in respect of the
IN
-des-isgiven to the controls for obtaining an aggregation of AiosJ" Ticlopidine tested as reference substance at the same es-a/, give about the same results.
D ACTION ON THE SYSTEMS OF TRANSPORTATION OF SODIUM AND POTASSIUM IONS IN THE HUMAN ERYTHROCYTS This action has been studied according to the method described by G. GARAY and cowork in Naunyn-Schmideberg's Arch. Pharmakol. 334 (1986) 202 and in Bioch. Pharm. 33 (1984) 2013.
The following results have been obtained and are collected in Table IV. They appear to be better than those obtained with Furosemide and
XIPAMIDE.
o* 0 S 00 0 00 0 0 *o o *00.
o0 a .91 35 T AB LE PHARMACOLOGICA~L N'TTIE TRANSPORT SYSTEMS I of Na+ and K of the human erythrocyts S a *0 00 S- 36 E STUDY ON THE IMPACT OF THE COMPOUNDS OF FORMULA I ON THE POTASSIUM CHANNELS IN THE AORTA USING A MEASURE OF THE EFFLUX OF RUBIDIUM The action of the compounds of formula I on the potassium Channels has been determined using Rubidium (Rb which is the homolog of potassium. The entry of Rb+ in pieces of aorta has been studied in initial speed after 5 mn. and at 37°C. The content in Rb and K have measured using an apparatus of atomic absorption or by a -fr 10, 01 ehigh-perfornnance -%amemphotometer.
As an example, the compounds of example 1 and 4 have been studied using a dose-effect curve.
a 0 C 0
RESULTS
Figures 1 and 2 collect the obtained results.
-^-The compound of example 1 has a very clear positive effect on the opening of the potassium channels. Its activity is far higher than °ebb that of PINACIDIL but slightly weaker than that of CHROMAKALIM.
Compound of ex 1 is less active on the opening of potassium channels.
On the other part, in contrast of Cromakalim and Pinacidil, the opening effect on the potassium channels of the compound of ex.l is *not antagonized by GLIBENCLAMIDE. The same compound in contrast with those agents acting on the opening of the potassium channels -is glibenclamido-resistent- Its mechanism of action is not bound to the test ATP-dependent potassium channel.
ebb be
C
F MEASUREMENT OF THE VASOCONSTRICTION INDUCED BY POTASSIUM CHLORIDE
C
be* a) Method A vasoconstriction is caused in male rats of Wistar strain, weighing 200to 350 g by increasing doses of potassium chloride ranging from to 60 mM.
37 The rats are thereafter beheaded at the thoracic aorta and the diameter of the vessels is measured.
Curves 1 and 2 gather the obtained results compound of example 1 as the piperazine disalt shows an antagonist ee merely on the contraction induced by the weakest eessI of potassium chloride (ClK at 20 mM).
The mean inhibitory dosis (IC n) has been calculated at 22 pM. The 50 cxoz e contraction induced by the highest doesisof potassim chloride (60 mM) dosa
K
is antagonized only by a strong desi of the compound of example
(IC
5 0 1,12 mM) It thus appears that it exists a dissociation of the vaso-relaxing effect of the ccmpound of example 1 after vaso-constriction by potassium chloride depending on the utilized concentration as it has been previously shown only with the potassium agonists. In contrast thereof the calcium inhibitors induce a decontracting effect at both concentrations of the vaso-constricting agent to be administered.
G P1TI-LIPOXYGENASE EFFECT The anti-lipoxygenarp effect has been studied using soja lipoxygenase in accordance to the method discribed by W.L SMITH and W.E LANDS (J.
Biol. Chem. 247 (1972) 1038).
f The following results which have been obtained are gathered in Table V ee
R
ft 38 TA BL E &898 9 8 98 9 98 8 8 88@b ~9 6 8 OW
B
*99* 88 89 S 9*Oe
ANTI-LIPOXYGENASE
ACTIVITY
PRODUCT
IC 50 /pM ex 25 6 ex 26 6 ex 30 100 ex 36 Inactive ex 42 not tested ex 169 Inacti~eex 46 0,7 ex 48 ex 172 not tested ex 56 exl107 7 ex 134 166 ex 139 not tested ex 163 not tested NDGA 8988 9 9688 8889 S 98 8 8988 O 9 869* 88899 9. 9 8 6 S 8*
V
9 0 9 88
(Z~
n TABLEAU VI (Z)p n
MTHO
A
12 13 14 16 17 18 19 21 22
H
H
H
H
H
H
H
H
H
H
H
2-OCH 2-OCOCH 3 2-OCH 2 CH 3 2-OCO 2-0 2-OCH 3 2-OCO 2-OCO O-0CH 3 2-OCO -l 2-OCO 2-OCO
FORMUJLE
C
14
H
14 0 2
C
16
H
16 0 3
C
17
H
18 0 3
C
18
H
20 0 3
C
17
H
18 0 2
C
15
H
16 0 2 c 21 H 1 0 C 0 22 2.0 4
C
2 1
H
7 C10 3
C
2
;H
2 Q0 4
V
U *U'0 3RUTE J S 214,267 256,304 270,331 284,358 254,330 228,294 318,375 348,40 352,817 348,40Z 3812,844 45 Huile Hui le Huile Huile Huile 72 48 56 *70, 78,48 6,59 74,98 6,29 75,53 6,71 76,03 7,08 80,28 7,13 78,91 7,06 79,29 5,69 75,84 5,78 71,49 4,88 Z 5,78 69,02' 5,00 78,42 F 74,86 75,56 76,01 80,10 78,77 79,28 75,85 71,26 75,65 69,10
PFOC
-T
6,55 6,21 6,68 7,13 7,02 6,97 5,66 5,72 4,69 5,82 5,10 ANALYSE CENrESIMALE CALCULEE TROUVEE t IH N C H IN ANALYSE CENTESIMALE EX X R THODE FORMULE BRUTE PM PFOC C _H N C H N 23 24" 26 27 28' 29 31 32 33 34
H
5-OCH 3 5-OCH 3 5-OCH 3 3 5-OCH 3 5-0CH3
H
H
H
H
H
H
4-F 4-F 4-C1 4-Cl
H
H
4-F 4-F 4-Cl 4-Cl 4-Cl
H
H
H
H
2-0S02cH 3 2-OH 2-0COCH 3 2-OH 2-0COCH 3 2-OH 2-0COCH 3 240 2-0COCH 3 2-OH 2-0COCG 3 2-0C0 2-0C0 NO 2 2-0H
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
C15 H 16 0 4
S
C
15
H
15 F0 3 C7H17 F0 4
C
15 H15CI0 3 C17H17C104 C15H1603
C
17
H
18 0 4
C
14
H
13 FO 2
C
16
H
15
FO
3 C14H 13 C10 2 C16 H15C0 3 C19H2203
C
2 1
H
1 7 NO5 C15H1602 C17H1803 H H17N03 292,353 262,285 304,323 278,735 320,773 244,293 286,331 232,259 274,296 248,709 290,746 298,385 363,373 228,294 270,331 319,36.
e' I 68 60 Huile 86 Huile 59 Huile Huile Huile Huile Huile Huile 97 Huile Huile S6-: 61,62 68,69 67,09 64,64 63,65 73,75 71,31 72,40 70,06 67,61 66,09 76,48 69,41 78,92 75,53 '75,21 5,51 5,76 5,63 5,42 5,34 6,60 6,33 5,64 5,51 5,28 5,20 7,43 4,71 7,06 6,71 5,36 61,85 68,56 67,03 64,49 63,41 73,63 71,40 72,26 69,89 67,39 65,88 76,32 69,29 78,80 75,37 5,68 5,70 5,59 5,50 5,18 6,69 6,35 5,82 5,40 5,40 5,39 7,58 4,72 7,01 6,63 317 38 3 5rCH 3
H
2-OCON 2-0C0 1-4 0 'at 4,38 75,19 5,46 4,44
EX
39 41 42 43 441, 46 47 48 49 51 52 53 54 ANALYSE CENTESIMALE x R ATE-UC) FORvLE BRUTE PM PFOC CALCULEE I TROUVEE Z I c HI N C H N
H
5-F 5-OH 5-OAc 4,5
(CH
2 3 4,5(CH 2 3 3,4benzo 3,4benzo 5,6benzo 5,6benzo
H
H
5-t.bu 5-t.bu S-Me 5-CH 3 H 2-0C9 -F 2-OH OAc -F 2-OAc H 2-OH
H
H
4-F 4-F 4-F 4-F 4-OCH3 4-OCH3 4-F 4-F 4-F 4-F I 2-Ac 2-OH 2-OAc 2-OH 2-OA 2-OH
-OAC
2-OH 2-OCOCH 3 2-OC 2-OCOCH 3 -2-OH 2-OCXH 3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H,
c23 20 5
C
14
H
12
F
2 0 2
C
16
H
14
F
2 0 3 c14 1403 18H188 5
C
1 7
H
1 8 0 2
C
19
H
2 0 03 C 1 H 15FO2 c18 15F 2 "20H7o C18 15 F0 2 20 17 FO3 c15 16 3 C 17H 18 c18 21F 2 IC H F c20 H23 FO3 C5 H 1 5 F0 2 CI- F13 376,42 250,251 298,288 230,266 314,34 254,332 296,369 282,32 324,356 282,32 324,356 244,293 286,331 288,367 330,404 246,286 *6 *3i
A
A
A
B
8
B
72 68 86 Huile 92 Huile 80 72 113 91 70 Huile 86 Huile Huile
NOW...
73,39 67,19 73,02 68,78 76,58 74,06 76,58 74,06 73,75 71,31 74,97 '72,70 73,15 :70,82 ,b 5,35 4,83 6,13 5,77 5,35 5,28 5,35 5,28 6,60 6,33 7,34 7,01 6,14 5,94 73,39 67,04 '72,87 68,61 16,44 74,12 76,47 74,12 73,69 71,40 75,07 72,54 72,97 7Q,61 5,24 5,32 5,35 5,33 6,54 6,55 7,29 7,16 6,19 6,69 5,35 4,78 6,27 5,81 ANALYSE CENTESIMALE x R 3TKXE FORMILE BRUTE PM PF 0
C
CALCULEE TROUVEE C IH N C H N 56 57 58 59 61 62 63 64 66 67 68 69 71 -72 73 zo 2-OH zo 2-OCOCH 3 70 2-OH ZO 2-OCOCH 3 ,0 2-O1 0 2-ocOcH 3 2-OH 2-oCH 3 2-OH 2-o oc2j 2-OCO 4- CO 2
H
2-OC 3 2-CC-d 3 2-OH 2-OCOCH 3
H
5-OCH 3
H
5-OCX 3
H
H
H
H
4-F 4-F 4-F 4-F 2-CCH 3 2-OCH 3 ,6(OCH 3 ,6(OCH 3
H
H
H
H
H
H
H
H
H
H
B
B
B
B
B
B
A B
A
A
A
A
A A
B
18 H162
C
20
H
18 0 3
C
18
H
16 0 2
C
20 H 1803
C
15
H
14 04 c 17 H 16 05 C1 5
H
16 0 2 C 17 H 18 0 3
C
17
H
18 0 3
C
19
H
20 0 4 18,7FO5 C1 9 H 1 9
FO
6 CisH 15 F0 2
C
16
H
17 F0 3
C
15
H
16 0 c 17 H18 0 4
C
16
H
18 0 -o 0 N-fS20 5 C .~i 264,328 306,364 264,328 306,364 258,277 300,315 228,294 270,331 270,331 312,369 332,33 362,359 246,28 276,311 244,293 286,331 274,319 ::316,3s3 80 73 82 50 87 57 Huile Huile 58 Huile 82 69 Huile Huile 96 70 81,79 78,41 81,79 78,41 69,75 67,99 78,92 75,55 75,53 173,05 65,05 62,979 73,155 69,55 73,75 71,31 70,05 34
S,
6,10 5,92 6,10 5,92 5,46 5,37 7,06 6,71 6,71 6,45 5,15 5,285 6,14 6,20 6,60 6,33 6,61 6,37 81,66 78,33 81,75 78,33 69,52 68,03 78,77 75,38 75,42 72,91 65,15 63,03 73,09 69,49 73,68, 71,26 69,86 68,19 6,07 5,81 6,02 5,77 5,28 5,24 7,04 6,90 6,61 6,29 5,09 5,20 6,24 6,10 6,56 6,42 6,52 6,37
L
2-OH 2-OCXoIl 3 84 :Huile.
C
0
EX
74 76 77 78 ANALYSE CENTESIMALE n x R. THO)DE FORMULE BRUTE PM PF 0
C
CALCULEE TROUVEE t c H NI C H N 79 81 82 83 84 86 87' 88
H
H
H
H
,4(CH)2 3,4(CH 3 2 -i Pr -iPr -iPr iPr
H
H
3-nPr 3rnPr 3-OC 2
H
5 2.3-Cl 2 2,3-Cl 2 3,4,5-
(OCH
3 3 3,4,5-
(OCR
3 3 4-F 4-F 4-F 4-F 4-F 4-F 4-OH 4-OCOCH 3 4-F 4-F 4-F 2-OH 2-0cOcH 3 2-OH 2-OCOCH 3 2-OH 2-OCOCH 3 2-OH 2-OCOCH 3 2-OH 2-OCOCH 3 2-OH 2-OCOCH 3 2-OH 2-OCOCH 3 2--OH H A H A H A H A H A H B H B H A H A H. A S, S p Sei 5i~ 5
C
14
H
12 C1 202
C
16 H1 4 C1 2 0 3 c17H20 5 c19 22 6 c16 17F 2 2 H 0
C
18
H
19
FO
C
17
H
19
FO
2 C1 H 19EQ 19 21F 3
C
17
H
19 F0
C
19
H
21
FO
C
14
H
1 4 0 3
C
1 8
H
1 8 0 5
C
17
H
19 F0 2
C
19
H
21 F0 3
C
1 6 H 17 F0 3 *5~ 283,161 325,198 304,346 346,383 296,343 302,35 274,34 316,377 274,34 316.377 230,266 314,341 274,34 316,377 276,311 C Si 81 75 110 S50 65 61 Huile 53 61 Huile 90 Huile Huile Huile Huile 59,38 59,09 67,09 65,88 64,83 71,50 74,43 72,13 74,43 72,13 73,02 68,78 74,42 72,13 69,55 4,27 4,34 6,62 6,40 7,14 6,33 6,98 6,69 6,98 6,69 6,12 5,77 6,98 6,69 6,20 59,43 59,14 66,95 66,01 65,12 71,33 74,28 7-2,03 74,30 71,96 72,84 68,60 74,34 72,06 69,38 4,34 4,50 6,60 6,45 6,25 6,91 6,72 6,99 6,54 6,28 5,62 6,88 6,74 5,96 ANALYSE CENTESIMALE Y)n x R TKX)E FORIJLE BRUTE PM PF 0 C CALCULEE TROUVEE C H N C]H N 89 91 92 93 94 5-C 2
H
5
H
H
H
H
H
4-F 4-CO 2 Et 4-CO 2 Et 4-CH 2 C0 2
E
4-CH C02E 4-C CO2 H 2-OH 2-OCOCH 3 2-OH t 2-OCOCH 3 2-OH
C
18
H
19 F0 4 c 17
H
18 0 4 c19 20 5 c18 20 4 c20 22 5 c16 16 4 318,35 286,331 328,368 300,358 342,395 272,304 Huile 72 60 60 Huile 108 67,91, 71,31 69,5nl 71.98 70.15 70,57 6,01 6,3 6,14 6,71 6,47 5,92 67,96 71,13 69,57 71,97 70,20 70,45 5,99 6,28 6,24 6,68 6.39 5,84 97 98 99 100 101 102 103 '104' 105 106 H 4CH 2
CO
2
CH
5-Ph 4-F 5-Ph 4-F 5-OPh 4-F 5-OPh 4-F 5-OH 4-F 5-OCOCH 3 4-F 5-OCO 2 Et H 5-OCO Et H H 4-F 13 2ocH 3 2-OH 2-OCoCH 3 2-OH 2-OCOCH 3 2-cIO 2-OCOCIH 3 2-OH 2-OCOCH 3 2-OSo 3 Na
C
18
H
2 0 04
C
2 0
H
1 7 F0 2
C
22
H
19 F0 3
C
20
H
17 F0 3
C
2 2 H 1 9
FO
4
C
14
H
13 F0 3
C
18
H
1 7 F0 5
C
1 7
H
1 8 0 5 C- H 0 .1 20 6 'HI FO SNa 300,358 Huile 308,35 Huile 350,39 Huile 324,35 Huile 366,39 Huile 248,259 88 332,333 76 302,23 55 44,367 A, le.
352,31- ssi 6,71 5,55 5,46 5.28 5,22 5,27 5,15 6,00 5,85 4,00 71,81 77,69 75,44 72,77 72,18 67,56 65,20 67,52 66,17 47,76 6,67 5,42 5,42 5,21 5,20 5,42 5,31 5,95 5,76 3,85
EX
107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 ANALYSE CENTESIMALE (Y)n R -THODE FORMULE BRUTE PM PF 0 C CALCULEE TROUVEE Z HN H N 4,5-0- 4-F 2-OH H A C16H15FO4 290,296 89 66,2 5,21 66,08 5,37
(CH
2 2 0 4,5-0- 4- F 2-OCOCH 3 H A C 18
H
17 FO 332,333 59 65,05 5,15 65,00 5,06
(CH
2 2 0 4,5-0- 4-F 2-OCR 3 H A C 1 7
H
1 7
FO
4 304,323 61 67,10 5,63 66,98 5,70
(CH
2 2 5-OCH3 4-iPr 2-OH H A c18H2203 286,374 Hiile 75,49 7,74 75,33 7,65 5-OCH 3 4-iPr 2-OCOCH 3 H I A C 20H 2 4 04 328,41 Huile 73,14 7,36 73,24 7,29 5-OCH 4-iPr 2-OcR 3 H A C 1 9
H
24 0 3 300,40 Huile 75,97 8,05 75,88 7,91 5-CH 3 H 2-0-0 3 Na H A C 1 5
H
1 5 0 5 SNa 330,33 pte5u, 4,57 3a i 3 155 15 542 4500 4-CH 3 4-F 2-OH H A C 15
H
15 F0 2 246,28 66 73,15 6,14 73.02 6,12 4-CH 3 4-F 2-OCOCH 3 H A C 17
H
1 7 F0 3 288,32 Huile 70,82 5,94 70,78 5,84 4-CH 3 4-F 2-OCH 3 H A C 16
H
17 F0 2 260,31 Huile 73,82 6,58 73,81 6,51 4-OCX 3 4-F 2-OH H A C 15
H
15
FO
3 262,285 62 68,69 5,76 68,63 5,82 4-OCH 3 4-F 2-OCO(: 3 H A C 17
H
17 F0 4 304,323 54 67,09 5,63 66,91 5,57 4-OCH 3 4-F 2-OCH 3 H A C 16
H
17 F0 3 276,311 70 69,55 6,20 69,41 6,14 3-OH 4-F 2-OC 3 H C H FO 262,285 Huile 68,69 5176 68,63 5,75 3-OH -F 2-CH3 1 15 F0 3 3-OCOCH 3 1 4-F 2-OaZH 3 F0 4 3O4,3Z3 f- 633: %:7,09 5,63 67,16 5,70 3 -OCOCH3 4 -F 2-01H q 17 U I
EX
P (Y) P n UI 9 t~THOOE FORMULE BRUTE PM PFOC ANALYSE CENTESIMALE CALCULEE 3 TROUVEE Z C I H N C I H N 122 123 124 125 126 127 128 129 130 131 4-CH 3 4-CH 3 4-CH 3
H
H
H
H
H
H
H
H 2-OH H 2-OCOCH 3 H 2-OCH 3
OCH
3 4-F 2-OCO O OCH 3
OCH
3 &3 4-F 2-0 4-F 2-OCO C 4-F 2-OSO2NH2 4-F 2-OCO o 4-F 2-OCO 4-Ft 0 2-o=o 0- 0 0
C
15 H1602 C17H 1803
C
16
H
18 0 2 c24H 23F06 C1 9
H
2 1FO2 C23 H19 F5 C14H14FN04S C 20H17C1FNO3
C
21
H
17
FO
3
C
27
H
19 C1 2 F0 5
S
2 C 228,294 270,33 242,32 426,44 300,378 394,40 311,33 373,82 336,367 545,419 6 50 Huile 78,92 75,53 Huile 179,30 96 Huile 91 Huile 155 Huile 67,60 75,97 70,04 54,01 64,26 74,98 59,46 64 9 7,06 6,71 7,48 5,44 7,04 4,85 4,53 4,58 5,09 3,51 78,86 75,31 79,28 67,42 75,78 69,89 53,82 64,47 7,06 6,55 7,40 5,41 6,96 4,97 4,69 4,75 4,93 3,62 4,50 3,74 3,70 128 6*0 p ,4180 59.41
I
R THOOXE ANALYSE CENTESIMALE FORMU1LE BRUTE PF 0
C
I CALCULEE %TROUVEE t, j. J. J 2 0 H P CIFNO 3 A C 24
H
22 CIF0 4 A c 14
H
14 F0 5 p A C 15
H
17 0 5 p A c 20
H
17 CIFNO 3 A C 22
H
19 FO 4 A C 22
H
18 ClF0 4 A c 22
H
26
FNO
4 373,82 428,89 312,23 308,269 373,82 366,39 400,~84 387,45 274,31 125 I-iiile 82 104 152 52 70 64,26 67,21 53.86 58,44 64,26 72.12 65,92 68,20 4,58 5 ,17 4,52 3,74 64,29 67,12 53,71 58,32 64,12 71,98 4,53 5,26 4,62 5,67 3,72 5,55 4,58 5,22 4,52 6.76 6,61 3,74 3,61 165,83 68,04 7G, 12 4,64 5,33 4,64 6,79 6,64 3,66 3,62 H A
C
bee, he
S.
S be be S Huile 545
S
S
A
70,05 4G
C
S
C
(ANALYSE
CENTESIMALE
(Zp I(Y)I p X r~D FORIWLE RTEI PM PO CALCULEE TROUVEE t cI H N cI HL N 241 142 143 144 145 146 147 148 149 150 151 152 153 3,6(OCH 3
H
H
CH
O
5-CR CO H
C
3 2 2 3,4-Cl 3,4-Cl 3.,6(OCR 3 5-CH3 5-CH 3 5-F 5-Cl 5-Cl H OCH3 4-F 2-0 Co 2 Et 4-F 2-0 A Co 2
H
4-F 2-OH, 4-F 2-OH 4-F 2-OH 4-F 2-0 -CO 2
H
4-F 2-OH 4 OH 4-F 2-OP .O
OH
0 4-OH 2-OH H 2-OH 4-F 2-OH H 2-CsH
C
17
H
20 0 4 C H FO S18 19 4
C
6
H
15 F0 4
C
17
H
17 F0 4
C
16
H
5 F0 4
C
16
H
13 1 2
FO
4
C
1 6
H
17 1F0 4 c 16 H17
FO
C 15
H
18
FPO
288,34 318,35 290,29 304,323 290,296 301,15 359,19 292,31 344,26 244,29 232,259 266,701 i* 248 70 or I. SE 44 4 4 4 4 a s Huile Huile 112 70 127 68 105 68 63 86 50 luile Oule 70,81 67,91 66,20 67,10 66,20 55,83 53,50 65,74 52,28 73,75 72,40 63,05 67,6.1 6,99 6,01 5,20 5,63 5,21 3,68 3,64 5,86 5,22 6,60 5,64 4,53 5,27 70,74 68.02 66,3 66,32 66,03 55,77 3,41 65,53 52,03 6,12 5,31 5,57 5,19 3,69 3,68 5 4,95 6,66 5,76 4,66 5,40 H B S I c 15 16 3 H B C H FO 14 13 03 H B C H C1FO 14 12 2 H. EV. C S1 73,58 72,29 62,88 67,45 *.c 6 4 51 tALCULEE 71.
MOUVEE V CALCULEE TaOuVEE
I
N
I
I 1 I I I 161 162 -163 164 165 166 167 168 169 170 171 250,251 250,251 250 ,2S1 275,284 23D..Z6.6..2 244,293 230,266 .304,323 228,294 246,294 228,294 270,33 1 50 72 50 168 :102.
HuilIe 86 638 Huile Huile Hui I e H-uile 6T,19 67,19 67 t,19 65,44 73'9026 73,75 73,02 67,09 78,92 73,,15 78,92 75,53 4,83 4,83 4,83 5,126 6,12 6.6 6,12 5,63 7,06 6,14 7,06 6,71 5,08 67,18 66,99 67,22 8 65,32 72,8 73,87 72,83 67,0 1 78,69 72,98 78,76 75,37 5,01 5,02 4,99 5,26 6,25 6,74 6,32 5,68 6,85 6,01 5,01 S. a 4 0 C 00190 00 00 4 0 o~'a 0 S. 0 4 04 e h a a 4 40 4 00 ae a a -00 09 0 09 9 40 a a 0 0 000 9 C 4 a 0 i cae 4 a
EX
172 1 73 1 74 175 176 177 17P 180 181 182 183 a a ag a a a. *e a 0 a 0 00 0. agg a ag co oes aee 9~a a 0 o a a ,6 0 0

Claims (2)

130- A process for producing a compound of formula I according to any of claims 1 to 11 which comprises the steps of condensing a phenol of formula IIA S.. S. 6 45 OH (z)p x wherein Z, X and p have the above-given definitions with a phenoxy acetonitrile of the formula IIIA OCH 2 CN (III wherein Y and n have the above-given definitions in the presence of an acidic catalyst to produce the ethanone of general formula IVA 0 0 (IVA) wherein Z, Y, n and p have the previous definitions and X is a free hydroxyl reducing the latter into a compound of general formula A by Smeans of an alkali metal mixed hydride in the presence of a metallic catalyst or by reaction with a lower alkyl chloroformate then reduction of the thus-formed intermediate compound with an alkali metal borohydride which may be alkylated by means of an alkylating reagent in basic Smedium or acylated by means of functional derivative of a carboxylic, sulphonic, sulphuric or phosphoric acid. oe* 46 14°- A process for producing a compound of formula I acording to any of claims 1 to 110 which comprises the steps of blocking the phenolic function of a hydroxy acetophenone of formula V OH (Z)p Ar (V) CO CH 3 wherein Ar, Z and p are defined as previously given and X is a free hydroxyl using a easily-split reagent submitting the so-blocked phenol of formula VI OB (Z)p Ar (VI) CO CH, wherein B is a leaving group Z and p have the above-given definitions submitting the latter of the action of a brominating agent to produce an c-bromoketone of formula VII OB (Z)p Ar 0 (VII) COCH 2 Br wherein Z, Ar, B and p have the above-given meanings condensing this derivative with a phenolic derivative of formula OH 0* Ar' Z(Y)n wherein Ar', Y and n are defined as previously indicated to produce a phenoxy ethanone of formula VIII ee -47 Z ACOCH2 O Ar' (Y) (Z)p Ar n(VIII) SX wherein the definitions of the substituents Y, Z, At, n and p remain unaltered and X is a hydroxy group blocked by an easily-split radical submitting the compound of formula VIII to hydrogenolysis in the presence of a metallic-catalyst or to an acidolysis, to make free the hydroxy group and produce a phenoxy ethanone of formula IX SCO-CH-O (z)p Ar Ar' (IX) OH wherein Z, Y, Ar, Ar', n and p have the above-given meanings treating the latter with a reducing agent to produce the hydroxylated derivative thereof of formula X CHOH CHO 0 (Z)p Ar Ar' (X) OH S*2' in which Z, Y, n, p, Ar and Ar' are defined as above-indicated and X is a free hydroxyl
150- A process for producing a compound of general formula r according to claims 1 to 30 which comprises the steps of blocking the free hydroxyl of a hydroxy acetophenone of formula VA OH Sr. x CO CH 3 3 48 with an easily-split blocking reagent submitting this blocked phenolic derivative to the action of a brominating agent to produce the corresponding c-bromo Ketone condensing this bromoketone with a phenol of formula OH S(Y)n wherein Y and n are defined as previously to obtain a phenoxy ethanone of formula VIA VI Sm *x wherein the meanings of the substituents Z, Y, p and n remain unchanged and X is blocked hydroxyl a submitting this compound to hydrogenation in the presence of a metalic catalyst or to an acidolysis, to make free the hydroxyl uo 0 i S i >i S Se K VA (Z)p n myq\ 49 wherein X is a hydroxy and Z, Y, p and n are defined as previously reducing the compound of formula VIIA by means of a reducing agent to produce the corresponding alkanol of formula VIII A OH (Zp n (Y)n (VIIIA) wherein Z, Y, n and p defined as previously given and X is a free iydroxyl S 160- A process for producing a compound of formula I according to any *5 of claims 1 to 3 wherein R is a lower alkyl radical which comprises the steps of submittting a phenoxy ethanone of formula VIII (Z)p Ar CO CH. 0 Ar' (VIII) \x wherein Z, Y, Ar, Ar', p and n have the above-given definitions and X is a blocked hydroxy group to the action of a triaryl alkyl phosphonium bromide under the conditions of the Wittig's reaction to produced an ethylenic derivative of formula VI S R I (Z)p Ar C CH 0 Ar' (VI) N n wherein z, Y, Ar, Ar', n and p are defined as above-given X is a blocked hydroxy group and R is a lower alkyl radical submitting this compound to hydrogenolysis in the presence of a metallic catalyst to produce the a-alkylated derivative of formula I R R, I I Ar-C-CH-O-Ar' (I) I R' wherein Ar and Ar' are defined as previously, R is a lower alkyl radical which may, when desired, be alkylated or acylated under the conditions previously defined, R' is a hydrogen, and R 1 is a hydrogen. 170 A process for producing a compound of formula IA wherein R is a lower alkyl radical according to any of claims 1 to 30 which comprises the steps of reacting a phenoxy ethanone of formula VIA CO-CH2-O (n -X V (VIA) wherein Y, Z, n and p have the above-given definitions and X is a blocked phenolic group with a triaryl (lower alkyl) phosphonium bromide under the conditons of the Wittig's reaction to produce an ethylenic derivative of formula IXA R C=CH (Z)pI (Y) S(ZX)p (IXA) x m j 7t r LS^ wherein Z, Y, n and p have the above-given definitions R is a lower alkyl radical and X is a blocked-phenolic group and submitting this latter to hydogenolysis in the presence of a metallic catalyst to produce an a-alkyl ethoxy derivative of formula IA R (Z)p R (Y)n wherein Z, Y, n and p have the above-given definitions, X is a hydroxy and R is a lower alkyl radical, which may when desired, be alkylated or acylated under the above-defined conditions, R' is a hydrogen and R 1 is a hydrogen. 180 A process for producing a compound of formula I according to any of the claims 1 to 30 which comprises the steps of reacting a substituted aryl aldehyde of formula X (Z),p-Ar-CHO (X) X wherein Z and p are defined as above and X is a blocked phenolic group with a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Wittig's reaction to produce an ethylenic compound of the formula XII (Y)n-Ar'-O-CH CH-Ar-z (XII) wherein Z, Ar, Ar', X, Y, n and p have the above-given definitions hydrogenating the latter by means of hydrogen in the presence of a S metallic catalyst into a compound of formula I R R, I I Ar-C-CH--Ar' (I) R' wherein the substituents Ar and Ar' have the above-given definitions and R, R' and R 1 are each a hydrogen. 190 A process for producing a compound of formula I according to claims 1 to wherein a substituted benzaldehyde of formula XA (Z)P x (XA) A wherein Z and p have the above-given definitions and X is a blocked phenol is reacted with a triaryl (phenoxy-methyl) phosphonium salt under the conditions of the Wittig's reaction to produce an ehtylenic derivative of formula XIA CH CH- n- (XIA) 53 wherein Z, Y, n and p have the above-given definitions and X is a blocked phenolic group which is further hydrogenated into a compound of formula I A by means of hydrogen in the presence of a metallic catalyst. A process for producing a compound of formula I according to claims 1 to 30 which comprises the steps of blocking the reactive functions of a hydroxy aryl alkanol -S formula XIII R I (Z)p Ar CH CHOH R, (XIII) \x wherein Z, Ar, R, R 1 have the above-given definitions and X is a free hydroxyl by means of an easily-split reagent, then reacting the thus-blocked derivative with a phenolic derivative of formula XIV OH SAr' (XIV) (Y)n .n wherein Y, n and Ar' have the above-given definitions to produce an aryloxy ethyl arylidenic derivative of formula XV :0V R R (Z)p Ar CH CH 0 Ar' (Y)n (XV) x wherein Z, Y, Ar, Ar', n and p have the above-given definitions R and R 1 the same or different eachother, are a hydrogen or a 1 lower alkyl raidcal and X is a blocked phenolic group -54- and make free the hydroxy function by means of an alkaline agent to produce a compound of formula I 21°- A process for producing a compound of formula Ipaccording to any of claims 1 to 30 which comprises the steps of blocking the reacting functions of a (hydroxy phenyl) ethanol of formula XIIA R R CH CHOH (Z)p x (XIIA) wherein Z and p are defined as above X is a hydroxy R and R1 are a hydrogen or a lower alkyl by means of a reagent which is easily split, contacting the thus *9 e blocked derivative with a phenol of formula XIIIA S' *HO I I wherein Y and n have the above-given definitions to produce a phenylethoxy phenyl of formula XIVA (Z)p (Y)n O R R CH CH-O (XIV) )hri (Z)p ()n i *e i* wherein Z, Y, n and p have the above-given definitions cl- t" V^ R and R 1 are hydrogen or a lower alkyl and X is a blocked phenolic group and making free the hydroxyl function by means of an alkaline agent to produce a compound of formula IA 220 As intermediate compounds the ethylenic derivatives of formula IXA R I C C H (Z)p (Y)n (IXA) wherein Y, Z, X, R, n and p have the above-given definitions 230 As intermediate compounds the ehtylenic derivatives of formula XIA (Z)p t r e e s r o o (XIA) wherein Z, Y, X, n and p defined as previously 240 The pharmaceutical composition which contains as active ingredient at least one compound of formula I according to any of claims 1 to 110 R R 1 I Ar-C-CH-O-Ar' (I) R' wherein Ar, Ar' R, R1 and R' are as hereinbefore defined, r z r I j lify~ 4 I. 56 in admixture or conjunction with an inert pharmaceutically acceptable carrier or vehicle. non-toxic A pharmaceutical composition according to claim 240 wherein the carrier or vehicle is one of those which are appropriate for the administration through parenteral, digestive, rectal, permucous or percutaneous ways. 26°- A pharmaceutical composition according to any of claims 24 and 250 wherein the content of active ingredient ranges from 1 to 200 mg per unit dosage. DATED this 22nd day of October 1990. LIPHA LYONNAISE INDUSTRIELLE PHARMACEUTIQUE ae e a4 0 0ees 0 **o0 0OO **00 000 WATERMARK PATENT TRADEMARK ATTORNEYS "THE ATRIUM" 290 BURWOOD ROAD HAWTHORN. VIC. 3122. 0 **e 400o Os S 0e 00
AU64869/90A 1989-10-18 1990-10-22 Novel aryloxy alcoyl benzenes, processes for their preparation as well as the pharmaceutical compositions containing them Ceased AU650429B2 (en)

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FR8913607 1989-10-18
CA002028031A CA2028031A1 (en) 1989-10-18 1990-10-19 Aryloxy alcoyl benzens, process for the preparation thereof and pharmaceutical compositions comprizing them

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JPH07179402A (en) * 1993-10-20 1995-07-18 Ishihara Sangyo Kaisha Ltd Substituted benzene derivative, its production and pest-controlling agent containing the same
EP0920306A2 (en) 1996-07-12 1999-06-09 Leukosite, Inc. Chemokine receptor antagonists and methods of use therefor
SE9801992D0 (en) 1998-06-04 1998-06-04 Astra Ab New 3-aryl-2-hydroxypropionic acid derivative I
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TWI262185B (en) * 1999-10-01 2006-09-21 Eisai Co Ltd Carboxylic acid derivatives having anti-hyperglycemia and anti-hyperlipemia action, and pharmaceutical composition containing the derivatives
CA2464770C (en) * 2001-11-21 2011-08-16 Sterix Limited Compound
FR2917084B1 (en) * 2007-06-05 2009-07-17 Galderma Res & Dev NOVEL 3-PHENYL PROPANOIC ACID DERIVATIVES OF PPAR-TYPE RECEPTORS, THEIR METHOD OF PREPARATION AND THEIR USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS
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