CA1094569A - Preparation process of novel lactone derivatives from cyclopentanol - Google Patents

Abstract

The subject of the invention is new lactones derived from cyclopentanol of general formula: I ′ in which the dotted line indicates the presence, where appropriate, of a second bond and A represents a single bond or a radical - (CH2) 2 -, as well as a process for the preparation of these new derivatives, which in particular manifests hypotensive activity.

Description

l9 ~ S ~ 9 The present invention has for object new lactones cyclopentanol derivatives of general formula I ':

~ ~~ r ~ I ' Rf R6 in which the dotted line indicates the presence, if where appropriate, of a second bond, A represents a single bond or a radical - (CH2) 2-, R represents a hydrogen atom or a alkyl radical, saturated or unsaturated, having from 1 to 4 atoms of carbon, R6 represents an OR'A radical in which R'A represents a hydrogen atom, a tetrahydropyrannyl radical, a radical alkyl having from 1 to 3 carbon atoms, a COR "A radical in which R "A represents either an alkyl radical having from 1 to 3 atoms of carbon, where appropriate, substituted by a carboxylic radical either a phenyl radical, where appropriate, substituted by a radical free carboxylic or protected by an acyl radical having from 2 to 4 carbon atoms or by a group easily removable by hydrolysis, where R and R6 together form a keto group, R7 represents a radical - (CH2) m -CH3 in which mA represents an integer equal to 3,4,5 or 6 or R6 and R7 together form a radical ~ (CE ~ 2) n -CH3 in which nA represents a number integer equal to 2,3,4 or 5, the wavy lines mean that the links can be in either configuration possible, it being understood that when A, represents a simple bond, the bond between the pentane ring and the oxygen atom is a bond ~.
The invention particularly relates to new lactones 3 ~ cyclopentanol derivatives of general formula I:.

-1- ~ d ~
B

o ~ = o AT
5 ~ R2 in which the dotted line indicates the presence, if where appropriate, of a second bond, A represents a single bond or a radical - (CH2) 2-, R represents a hydrogen atom or a saturated or unsaturated alkyl radical having from 1 to 4 atoms of carbon, Rl represents a radical OR 'in which R' represents a hydrogen atom, a tetrahydropyrannyl radical, a radical alkyl having from 1 to 3 carbon atoms, a COR "radical in which R "represents an alkyl radical having from 1 to 3 atoms of carbon or a phenyl radical, if appropriate, substituted by a carboxylic group or R and Rl together form a ketone group, R2 represents a radical - (CH2) m-CH3 in which m represents an integer equal to 3, 4 or 5 or Rl and R2 together form a radical ~ (CH2) n-CH3 in which n represents an integer equal to 2, 3 or 4, the wavy lines mean that the connections can be in one or the other of the possible configurations, it being understood that when A represents a single bond, the bond between the cycle pentane and the oxygen atom is a bond ~.
The radical R can in particular represent an atom of hydrogen or a methyl, ethyl, propyl, isopropyl radical, butyl, isobutyl, tert-butyl, vinyl, propenyl, butenyl, ethynyl or propargyl.
The radicals R ', R'A, R "and R" A can notably represent a methyl, ethyl, propyl, or isopropyl radical.
The acyl radical which can protect the hydroxyl radical carried by the phenyl radical can be an acetyl radical, propio-nyle, n-butyryl or isobutyryl ~
The group which can be easily removed by hydrolysis can 8tre for example, a tetrahydropyrannyl or tert-butyl radical -dimethyl silyl. ~.
The invention also particularly relates to the products of general formula I, in which the dotted line indicates the presence of a second bond, A represents a simple bond or radical - (CH2) 2-, R represents a hydrogen atom or an unsaturated alkyl radical having 2 or 3 carbon atoms, Rl represents a radical OR 'in which R' represents an atom of hydrogen, a tetrahydropyrannyl radical, a COR radical "in wherein R "represents a phenyl radical substituted by a group-carboxylic, R2 represents a radical - (CH2) m-CH3 in which m represents an integer equal to 3, 4 or 5, or Rl and R2 together form a radical / ~ \ (CH2) n-CH3) in which n represents an integer equal to 2, 3 or 4.
The invention also relates in particular to the products.
of general formula I in which the dotted line indicates the presence of a double bond, A represents a single bond, R represents a hydrogen atom or an unsaturated alkyl radical having 2 or 3 carbon atoms, Rl represents an OR 'radical in which R 'represents a hydrogen atom, R2 represents a radical (CH2) -CH3 in which m represents an integer equal to 4.
Among the products of general formula I or I ′, may in particular cite the products described below in the examples and in particular the acid lactone (lRS, 2SR, 5RS, 3'SR) (1 'E) 2-hydroxy 5- (3'-hydroxy l'-octenyl) cyclopentane carboxylic and the acid lactone (lRS, 2SR, 5RS, 3'SR) (1 'E) 2-hydroxy 5- (3'-hydroxy l'-d ~ cenyl) cyclopentane carboxylic.
Mention may also be made of the lactone of the acid (lRS, 2SR, 5RS, 3'SR) (1 'E) 2-hydroxy 5- / 3' - (2 "-hydroxy benzoyloxy) 1'-octenyl / cyclopentane carboxylic.
The subject of the invention is also a process for preparing ration of the products of formula I 'and in particular the products of formula I, as defined above, characterized in that subject to the action of a derivative-forming reagent acids, a product of formula IIa:

OH
CO2H IIa in which A, R, R6 and R7 have the meaning given above, with a view to obtaining a product of formula I 'and in particular a product of formula II:
OH

~ ACO2H II
~ R2 in which A, R, Rl and R2 have the meaning given above, with a view to obtaining a product of formula I, the functional derivative thus obtained in each case then reacting with the radical hydroxyl to form the lactonic ring, and thus obtain a product of formula I 'or I.
In a preferred embodiment of the process above the reagent for the formation of functional derivatives of acids to which the product of formula IIa or II is subjected is tosyl chloride to form a functional derivative which is mixed anhydride.
It is preferably carried out in the presence of triethylamine, but we can also use another base such as, for example, an alkali metal carbonate or an organic base such than methyl morpholine, pyridine or another trialkylamine.
We can also operate in the presence of diazabic ~ clo-109456 ~

octane.
We can also submit the product of formula IIa or II ~ the action of other anhydride forming reagents mixed. Mention may be made, for example, of isobutyl chloroformate or other alkyl chloroformates. We operate in this case in the presence of a basic agent chosen from the same groups as previously.
It is also possible to use other reagents such as dialcoylcarbodiimides or dicycloalcoylcarbodiimides such than dicyclohexylcarbodiimide.
Finally, reagents can be used to form acid chlorides such as thionyl chloride in the presence a basic agent chosen from the same group as above.
According to a preferred embodiment of the invention, the reagent for the formation of functional derivatives of acids which is used in the process of preparing the prodults of formula I 'and of formula ~ I, described above is chosen from the group formed by tosyl chloride, alkyl chloroformates, dicycloalcoylcarbodiimides, dialcoylcarbodiimides and thionyl chloride and in that the base that we use, the if applicable, is chosen from the group made up of alkali metal carbonates, triethylamine, methyl morpho-line, pyridine and diazabicyclooctane.
The invention also relates to a process for pre-paration of the products of general formula IB:

A IB

57 ~. (CM2) m-ClI3 R OH

in which the wavy and dotted lines, A and R have the meaning given above and corresponding to a product of formula I in which R1 represents a radical OR 'in which -` lO9 ~ S6 ~

R 'represents a hydrogen atom and R2 represents a radical - (CH2) mC ~ 3, characterized in that an agent is subjected of acid hydrolysis a product of formula IA:

O _ ~ 0 IA

~ 0 ~
in which A, R and m have the above-mentioned singularity and correspond corresponding to a product of formula I in which, Rl represents an OR 'radical in which R' represents a tetrahydro- radical pyrannyl and R2 represents a radical - (CH2jm-CH3.
The products of general formula IA used at the start of this process can be prepared by the process described above and which consists in activating a derivative formation reagent functional of acids on a product of formula:

OH

\ _I (CH2) m-CH3 ~ ~ J
in which A, R and m have the abovementioned meaning.
In a preferred embodiment of the method of preparation of products of formula IB, hydrolysis is carried out presence of acetic acid.
However, other mineral acids or organic such as aqueous hydrochloric acid, sulfuric acid, than or trifluoroacetic acid.
The invention also relates to a method of preparation of products of general formula IC:

~ `10945fi9 - ~ ' To IC

\ / ~ (CH2) m -CH3 o in which A, R, R "and m, have the meaning given initia-and corresponding to a product of formula I in which Rl represents a radical OR 'in which R' represents a radical COR "and R2 represents a radical - (CH2) -CH3, characterized in that which are treated with an acid of formula R "CO2H or with a chloride of formula R "COCl, or by an acid anhydride of formula (R "CO) 20, or by a mixed anhydride, a product of formula IB
as defined above.
In a preferred embodiment of the process above, the anhydride of formula (R "CO) 20 is used.
However, the acid chloride of formula R "COCl; one then operates in the presence of an acceptor hydrochloric acid such as, for example, a carbonate or a alkaline bicarbonate or a tertiary organic base such as for example triethylamine, pyridine or a picoline.
The invention also relates to a method of preparation of products of formula I'C:

~ 0 _ ~ O

AT
(2) mA 3 R O-lcl-Rlll-co2H

O
in which A, R and mA have the meaning given initially and R "'represents an alkylene radical containing from 1 to 3 atoms of carbon, corresponding to a product of formula I ', in which ~ `- 1094569 R7 represents a radical - (CH2) m -CH3 and R6 represents a radical ~ OCR "A, in which R" A represents an alkyl radical having l to 3 carbon atoms substituted by a carboxylic group, characterized in that one treats with an anhydride of formula (R "'CO) 2O a product of formula I'B:

I'B
'(CH2) m -CH3 R OH
in which the wavy and dotted lines, A, R and mA have the meaning given initially and corresponding to a product of formula I ', in which R7 represents a radical - (CH2) m CH

and R6 represents the hydroxyl group.
In a preferred embodiment of the process above, we operate in the presence of a tertiary organic base such as trieth ~ lamin, pyridine, dimethylamino pyridine, a picoline or a mixture of these bases.

The products of formula I'B can be for example prepared by the method described above from the products IIa or II corresponding according to the value of mA.
The invention also relates to a method of preparation of products of general formula ID:

O ~ c O
ID

~ (CM2) n -C ~ 13 in which A, R and n have the signification given initially and corresponding to a product of formula I in which R1 and R2 together form a radical ~~ "(CH2) n-CH3, characterized in that we treat with a dehydrating agent a product of .: .......

lOg4569 formula IA or IB as defined above.
In a preferred embodiment of the process below above, the acid para-toluenesulfonic but one can also use other strong aqueous acids such as concentrated sulfuric acid or phosphoric or polyphosphoric acid.
The invention also relates to a process for pre-paration of products of general formula IE:

0 _ ~ 0 ~ ~ A IE

~ ~ ~ (CH2) m CH3 in which A and m have the abovementioned meaning and correspond to a product of formula I in which R and Rl form together a keto group, and R2 represents a radical - ~ CH2) m-CH3, characterized in that one treats with an agent oxidizing a product of formula I "B:

--1 / ~ I 11 B
~ ~ A

~ (CH2) m-CH3 H

! in which A and m have the abovementioned meaning and correspond to a product of formula I in which R represents a hydrogen atom, Rl represents a radical OR 'in which R' represents a hydrogen atom and R2 represents a radical (2) m 3 In a preferred embodiment of the process above we use as an oxidizing agent dichlorodicyanoqui-none but silver silicate can also be used.
The products of formula I'B used from this , ~.

--`` 1094S69 process can be prepared from products of formula II using the method of the invention.
The invention also relates to a process for pre-paration of the products of general formula IF:
'~ r A IF

/ (C 2) m CH3 R3 ~ 0R ' in which R3 represents a hydrogen atom or a radical saturated alkyl and A and R 'have the above meaning and cor-corresponding to a product of formula I in which R represents a hydrogen atom or a saturated alkyl radical, Rl represents an OR 'radical and R2 represents a - (CH2) m-CH3 radical, characteristic laughed at in that it is treated with hydrogen in the presence of a catalyst a product of formula I'F:

~ ~ / 0 ~ ~ At I'F

~ (CH2) m-CH3 R Rl in which A, R, Rl and m have the meaning given initial-it being understood that R and Rl cannot represent together ble a ketone group and corresponding to a product of formula I in which R2 represents a radical - (CH2) m-CH3 and the dotted line indicates the presence of a double bond.
In a preferred embodiment of the process above, palladium on carbon is used as catalyst but it is also possible to use platinum or a platinum salt.
One can also use other supports such as sulfate barium ~

~ ,,.,; - 10 -.. ~.

~ 0 ~ 4S69 The products of formula I'F used from this process can be prepared from products of formula II
using the method of the invention.
The invention also relates to a method of preparation of products of formula IG:
~ ~

A IG
(CH2) mACH3 R ~ ~ 0-C _ o, ~ OR l ~ b in which A, R and mA have the meaning given above, and R "b represents a hydrogen atom, an acyl radical having from 2 to 4 carbon atoms or an easily removable group by hydrolysis, and corresponding to a product of formula I ', in which R7 represents a radical - (CH) m -CH3 and R6 represents a radical -OCOR "A in which R" A represents a phenyl radical substituted by a free hydroxyl group or protected by a radical acyl having 2 to 4 carbon atoms or protected by a group-easily removable by hydrolysis, characterized in that a product of formula I'B is treated, as defined above demment, by a functional derivative of an acid of formula:

~.
\) _ C02H
R "c '''~ \ === ~

in which R "represents an acyl radical having from 2 to 4 carbon atoms or a group easily removable by hydrolysis to obtain a product of formula I'G:

`iO9456 ~

o ~ o ',:
(CH2) mA-cH3 I'G

R ~ OC - ~ R "c in which R "has the abovementioned meaning, product which one treats, if necessary, with an acid or a base to form a product of corresponding formula IG, formula in which R "b re-has a hydrogen atom.
In a preferred embodiment of the process below above, a halide of acid:

We then operate in the presence of a hydrochloric acid acceptor or hydrobromic such as triethylamine, a picoline.
The halide is preferably chloride, but it is possible to use bromide.
It is also possible to use the mixed anhydride prepared for example by the action of oxalyl chloride on the acid, or the anhydride formed with ethyl or isobutyl chloroformate on the acid. One can also use an acid ester acti ~ é, an azide or an acid amide.
When R "c represents an acyl radical having from 2 to 4 carbon atoms, hydrolysis to pass products of formula I'G to products of formula IG, in which R "b represents a hydrogen atom, is a basic hydrolysis. We preferably use sodium carbonate, but you can use ~ -`` 1094569 other bases such as soda or potash in ethanol or methanol.
When R "represents an easily removable radical by acid hydrolysis, such as the tetrahydropyrannyl radical, the medium used is preferably oxalic acid. We can however use other acids such as acetic acid or trifluoroacetic.
The invention also relates to a process for pre-paration of products of formula IH:

IH

/ (2) mA-CH3 RIV J OH

in which A and mA have the abovementioned meaning and RIV represents has an alkyl radical having 2 to 4 carbon atoms and contains both a double bond, each of the carbon atoms doubly bound carrying at least one hydrogen atom, corresponding to a pro-duit of formula I ', in which R = R, R6 represents a group hydroxyl and R7 represents a radical - (CH2) mACH3, process characterized in that it is reduced by hydrogen, in the presence of a catalyst, a product of formula I'H:

~
At I'H

(CH2) m CH

Rlv OH

in which RlV represents an alkyl radical having from 2 to 4 carbon atoms and com ~ ortant a triple bond, corresponding to a product of formula I ', in which R = RlV, R6 represents a - ~ `1094S69 hydroxyl group and R7 represents a radical - ~ CH2) mA-CH3.
As the hydrogenation catalyst, preferably used of palladium on barium sulfate in the presence of a trace quinoline.
However, palladium on carbonate can be used calcium in the presence of palladium lead acetate on black carbon in the presence of pyridine or Raney nickel.
The products of formula I'H used from above process can be, for example, prepared according to the 10 ~, method described previously from products IIa or II
according to the value of mA.
The wavy lines that most the aforementioned formulas include the various possible conformations substituents around the carbon atoms to which they are linked.
The constituents of the mixtures possibly formed by these different products can be separated by methods usual physical in particular by chromatography.
The products of formula I 'and I can exist in racemic or optically active forms; active isomers can be separated by the usual methods.
These products show activity in pharmacology hypotensive.
We will find further in the experimental part, pharmacological results obtained with the invention.
Pharmacological properties of the products obtained by the process of the invention make them suitable for use as medicines, especially in the treatment of hypertension and circulatory disorders.
Thus, it is possible to use, as medicaments, the pharmaceutically acceptable compounds of formula I 'and I, such .

10 ~ 4 ~ 69 as defined above and in particular those described in the examples.
Products of formulas I ~ and I pharmaceutically acceptable can be used for the preparation of composi-pharmaceuticals containing, as active ingredient, one at least of said products.
These pharmaceutical compositions can be administered very oral, rectal, parenteral, oral local.
They can be solid or liquid and present in pharmaceutical forms commonly used in medicine human, such as, for example, tablets, single or coated, capsules, granules, suppositories, preparations injectable, they are prepared according to the usual methods.
The active ingredient (s) can be incorporated therein excipients usually used in these pharmaceutical compositions ticks, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not.
The dose administered is variable depending on the condition treated, subject, route of administration and products considered. It can be, for example, between 0.5 mg and 200 mg with the products described in Examples 2 and 15, administered very injectable, for example, slow infusion, in the man.
The invention finally makes it possible to obtain, as products new industrialists and in particular as intermediate products useful for the preparation of the products of formula I ', the products of formula:
~ H
~ ~ ~ C02H

R Rl , "

10 ~ 4569 in which the dotted line and the substituents R, Rl and R2 have the meaning indicated initially, the products of formula:

~ H

(CH2) n - CH3 in which the wavy line and n have the indicated meaning initially, as well as the products of formula IIH:

~ H

- ~ ~ I IH

RR

in which the wavy lines and the substituents A, R and Rl have the meaning indicated initially, and R'2 represents a radical - (CH2) 6CH3, where Rl and R'2 together form a radical (2) 5 3 The products of formula II used from process and in which A represents a single bond, Rl and R2 cannot together form a radical ~ (CH) -CH and m represents the number 4, can be prepared according to the process described in the Canadian patent application, filed August 27, 1976 under number 260.079.
- This process is characterized in that:

- or else a product of formula B is treated:

CO2R4 (B) in which R4 represents an alkyl radical having from 1 to 12 carbon atoms and R5 represents a hydro atom or ne 2-tetrahydropyrannyl radical, by an alkali hydride in sweet conditions to obtain a product of formula C:

OEI
CO2R 4. (VS) ~~

product that is treated if desired, a) either with hydrogen, in the presence of a catalyst, to obtain a product of formula D:

O ~ H
CO2R4 (D) b) either by an alkaline base then an acid to obtain a pro ~
duit of formula E:

~ Oh C2 H (E) -. OR5 c) or, provided that R5 represents a hydrogen atom in formula C, with an oxidizing agent to obtain a product of formula F:

OH

~ C2 R4 (F) which are treated with an organometallic derivative of formula R'2-Mg X
in which R'2 represents a linear alkyl radical or branched, saturated or unsaturated with 1 to 4 carbon atoms and X a halogen atom, to obtain a product of formula G:

OH

(G) , ~

R'2 - or else we treat a product of formula B in which R5 represents a hydrogen atom by diazomethane to obtain.

a product of formula H:

C2 R4 (H) OH
that we treat with an oxidizing agent to obtain a product of formula H ':

~ CH3 ~ JC2 R4 (H ~) ~
~~.
o 1094S ~ i9 which are treated with an organometallic or organometallic derivative dique R'2 Mg X to obtain a product of general form J:

~ CH3 (J) \ "/ /

~ R ' which are treated with an acid to obtain a product of formula IC:

(K) HO 'R' that we are dealing with:
- either by a reducing agent under mild conditions for obtaining a product of formula G as described above, - or by dihydro 2,3-pyranne to obtain a product of formula Kl:

o ~~ C2 R4 \ I (K ') ) o R 2 ~ O
that are treated with a reducing agent under mild conditions to obtain a product of general formula L:

~ Oh ~ J C2 R4 R'2 and the products of formula D, F, G, L are treated with a base then an acid to obtain the acids entering into formula II.
Examples of the preparation of these products of formula II are given later in the experimental part.
The products of formula II in which Rl and R2 together form a radical // (CH2) 3-CH3 and A represents a single bond, can be prepared by the action of

2,4-dinitrobenzene sulfinyl on the product of formula B in which R5 represents a 2-tetrahydropyrannyl radical.
The products of formula II in which A represents a radical - (CH2 ~ 2, m represents the number 4 or Rl and R2 represented together feel a radical ~ (CH2) n - CH3 and n represent the number 3, can be prepared from the product of formula (M):, (M) on which we can perform the same reactions as those described above for the product of formula (B).
The product of formula M is obtained by the action of a alkyl acrylate on the product of formula (B) in which R5 represents a 2-tetrahydropyrannyl radical followed by a isomerization followed by decarboxylation. An example of such preparation is indicated later in the experimental part.
The products of formula II in which m represents the numbers 3 or 5 or n represents 2 or 4 can be prepared for from products of formula (B '):

~ C2 R4 (B ') _ (CH2) m, -CH3 :
in which m 'represents the number 3 or 5.
The preparation methods are identical to those used from the products of formula B. In particular, prepares the products of formula II in which A represents a radical - (CH2) 2- from the products of formula (M '):

O
2 4 (Ml) - ~ ~, (CH2) m ~ CH3 obtained from the products of formula B 'according to the scheme indicated above.
The products of formula IIa ':

IIa '(IIa, with ,OH
ACO2H R6 = OCOR "l, (H2) mACH3 7 (2) mACH3) R OCR "

, in which R and mA have the meaning given above, R "l represents either an alkyl radical having from 1 to 3 atoms of carbon substituted by a carboxylic group, ie a radical phenyl substituted by a free hydroxyl radical or protected by a acyl radical having from 2 to 4 carbon atoms or protected by a - group easily removable by hydrolysis, and A represents - a single bond can be prepared, as described below, from the product of formula A ':

o2alc A ' .
~ CHO
in which alk represents an alkyl radical having from 1 to 4 carbon atoms.
The product A ', itself, can be prepared according to a known process, characterized in that the product of formula:
H2C \ / CH-CH2OH

to the action of dihydropyran to obtain the product of formula:

H2 ~ --CH-CH2-0-1 ~

which are treated with an alkyl acetyl acetate of formula:

3 2 2 in the presence of a strong base, such as the hydride mixture of sodium-butyl lithium, to obtain a product of formula:

alcO2C ~ ~
o product which is treated with an oxidizing reagent, such as chromic acid-pyridine complex, to obtain the product of formula:

alcO2C ~

that we treat with a base, such as baking soda potassium, to obtain a product of formula:

10 ~ S ~ g ~ H2 ~) o ~
which is treated with hydrogen in the presence of a catalyst, such as than palladium on carbon, to obtain a farmule product:

1l ~ - ~ 2al ~ ~

that we treat with an acid, such as oxalic acid, to obtain a product of formula:

, C02alc ~ Oh that we submit to the action of diazomethane to obtain a product of formula:

co2alc that are treated with an oxidizing agent, such as the complex chromium-pyridine oxide, to obtain the product of formula.A ' sought ~:

~ co2alc A ' CHO

1094S ~ .9 To prepare the products of formula IIa ', the product A ', in the presence of a strong base, such as hydride sodium, for example, dimethyl (2-oxo nonyl) phosphonate to obtain a product of formula:

~ C02alC

o which is treated with a reducing agent such as borohydride of zinc to obtain a product of formula:

02alC
~ '.
OH
in the form of a mixture of its two constituents which are separated in its two constituents and whose function can be protected hydroxyl with a tetrahydropyrannyl radical and which is treated first with an acid such as hydrochloric acid, then with a reducing agent, such as the selective L, finally by a base such as the soda, followed, if necessary, by an acid treatment for example, with sodium phosphate to obtain a product (B1):

~ OH Bl ~ _, C 2 R 3 \ _ OH
in which R3 represents a hydrogen atom or a radical --` 1094S ~; 9 alkyl having 1 ~ 4 carbon atoms. We thus obtain final-ment, the products of formula (B2):
OH
A - co2H ~ ~

(2) mACH3 OEI
in which mA has the aforementioned meaning, applying the methods analogous to those leading to formula products Bl and E.
The products IIa 'in which A represents a simple bond are then prepared by action on B2 products, ie an anhydride of formula:

0 = 0 either an acid or a functional derivative R ~
of acid of formula:

~ "c ~ CO2H

followed by possible hydrolysis, under identical conditions to those indicated for the synthesis of I'C and IG products to from I'B products.
The products of formula IIA 'in which A represents te a radical - (CH2) 2- are obtained by action on the products B'2:

~ Oh ~, ~ 2 4 B'2 ~ ~ (2) mACH3 OH
of the same reagents as before.

10 ~ 4569 Finally, the products of formula IIA not comprising double bonds are obtained by hydrogenation of the products correspondents with a double bond.
The products of formula IIH can be prepared from the same fa, con as indicated above for the products correspondents of formula II but using as a product of departure, the product:

~ Oh ~ C02R3 OH
described above, or the products B'2 in which mA represents te the number 6, that is to say the products of formula:

~ H

~ ~ ~ 2 4 OH

Preparation methods can be summarized as following:
We can:
- either treat products B1 or B'2 with hydrogen in the presence of a catalyst to obtain the products that do not as long as no double bond, - either treat the same products by an agent oxidation so as to selectively oxidize allyl alcohol to obtain the products in which R and R1 represent a keto grouping then treat the products thus obtained by a organometallic derivative to obtain the products in which R
represents an alkylet radical ~ '~ J `

10 ~ 4569 - either treat the products of formula Bl or B'2 whose allylic hydroxyl function is protected by a radical tetrahydropyrannyl, by 2,4-dinitrobenzene sulfide chloride nyle to obtain the products in which Rl and R'2 represent a radical:
\ (CH2) 5CH3-The acids corresponding to the esters obtained are prepared by saponification according to the usual methods.
The following examples illustrate the invention without 10 however, give it no limiting character.
Example 1: Acid lactone (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hYdroxy 5- (3'o ~ -tetrahydropyrannyloxy l'-octenyl) cyclopentane carboxylic:
600 mg of acid are introduced (1 RS, 2 SR, 5RS, 3 'SR) (1 'E) 2-hydroxy 5- (3'o ~ -tetrahydropyrannyloxy 1'-octenyl) cyclo-carboxylic pentane, 12 cm3 of anhydrous chloroform, 1 cm3 of triethylamine and 402 mg of tosyl chloride. We shake four hours at 20C, pour into an acid phosphate solution of sodium, decant, methylene chloride extract and evaporates to 20 sec under vacuum.
700 mg of product are obtained which is chromatographed on silica gel with a cyclohexane-ethyl acetate mixture-triethylamine (75/25 / 0.1). 336 mg of ~ lactone are obtained expected.
Acid (1 RS, 2SR, 5RS, 3 'SR) (1' E) 2-hydroxy 5- (3'a-tetrahydropyrannyloxy l'-octenyl) cyclopentane carboxylic used ~ from Example 1 was prepared as follows:
Stage A: (1 RS, 2SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'u-tetra-hydropyrannyloxy l'-octényl) cyclo ~ entane ethyl carboxylate:

A mixture of 14 g of 3- (3 '~ -tetrahydropyrannyloxy trans l'-octenyl) cyclopentanone Ethyl 2-carboxylate, 200 cm3 of isopropyl alcohol, 20 cm3 ~ 0 ~ 4S6g of water and 5.6 g of sodium hydroboride, slowly add Acetone in the mixture then poured into a saturated aqueous solution monosodium phosphate.
Filtered, brought to dryness and taken up in ethyl acetate Wash with water and dry, then evaporate the solvent. We chromatograph remove the residue on silica, eluting with a cyclohexane-acetate mixture ethyl (8/2) with 0.1% triethylamine and obtains 3.4 g of isomer o ~ -OH (2 SR) expected.
Stage B: Acid (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'a ~ -tetrahydro ~ yrannyloxy l ~ -octenyl) cyclo ~ entane carboxyli ~ eu:
A mixture of 3.1 g of the ester obtained in stage A, 50 cm3 of methanol and 8.15 cm3 2N sodium hydroxide, then evaporates the solvents at 35 - 40C, resumes with water, washing with ether, saturating the solution with chloride sodium then acidified with hydrochloric acid. We extract at ether, wash with water, dry and evaporate the solvent. We obtain 2.6 g of expected product.
Example 2: Acid lactone (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) . _.
2-hYdroxy 5- (3'-hydroxy l'-octenyl) cyclopentane carboxylic:
336 mg of the ~ -lactone obtained is dissolved Example 1 in 10 volumes of acetic acid at 20% water in presence of 5 mg of sodium iodide. We leave sixteen hours at 20C, pour into water, extract of methylene chloride, wash with sodium bisulfite, dries and obtains 280 mg of product which is chromatography on silica gel with a cyclohexane mixture ethyl acetate (75/25). 160 mg of expected product are obtained.
~: Acid lactone (1 RS, 2SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3 'oc-hemiphtaloyloxy, l'-octén ~ l) cyclopentane carboxylic:
160 mg of ~ -lactone obtained in Example 2 are introduced, 1.6 cm3 of pyridine and 200 mg of phthalic anhydride. We let 9 days ~ room temperature. Pour into hydrochloric acid .. ~

,. lC) ~ 4S69 than normal iced, we extract ~ ether, wash, extract the phases organic with 10% bicarbonate, dries the ~ phases, evaporates dry vacuum. The alkaline aqueous phases are acidified with normal hydrochloric acid. Extract with ether and evaporates to dryness under vacuum. The acid fraction is chromatographed on silica gel with cyclohexane-ethyl acetate (1/1). We obtains 172 mg of expected product in the form of a colorless resin which crystallizes.

IR spectrum: ~ C = O: 1828 cm 1 ~ ~ lactone 10 1811 cm J

1725 cm 1 -1 ~ ester + acid 1708 cm aromatic: 1603 cm 1 1583 cm 1 1 ~ 91 cm 1 Example 4: Acid Lactone (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hvdroxy 5- (3'-hydroxy 3'-ethYnyl, l'-octenyl) cYclopentane 20 carboxylic:
530 mg of acid is placed (1 RS, 2SR, 5 RS, 3 'SR) (1 'E) 2,3'-dihydroxy 5- (3'-ethynyl, l'-octenyl) cyclopentane - carboxylic, 5.3 cm3 of chloroform, 0.78 cm3 of triethylamine and 430 mg of tosyl chloride. Shake at + 5C for thirty minutes then leave to return to 20C. We leave an hour, pour in water containing sodium acid phosphate, washed with water and extracted with methylene chloride. Dry, chromatography on silica gel with benzene-ethyl acetate (80/20) and obtains 106 mg of expected product. Rf. = 0.4.
Example 5: Acid lactone (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) 2-hydroxy 5- (3'-hydroxy 3'-ethynyl, l'-octenyl) cyclopentane carboxylic:

.

720 mg of acid is placed (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) 2-hydroxy 5- (3'-hydroxy 3'-ethynyl l'-octenyl) cyclopentane carboxylic, 7.2 cm3 of chloroform, 1.44 cm3 of triethylamine and 586 mg of tosyl chloride. The mixture is stirred at 20C under nitrogen. We pour on a water-sodium acid phosphate mixture. We wash at water, extract with methylene chloride, dry, evaporate to dryness and obtains approximately 1 g of product which is chromatographed on gel of silica with a benzene-ethyl acetate mixture 80/20. We obtains 128 mg of expected product. Rf. = 0.4.
Acid (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy ~ (3'-hydroxy 3'-ethynyl l'-octenyl) carboxylic cyclopentane used from Example 4 and the acid (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) 2-hydroxy 5- (3'-hydroxy 3'-ethynyl l'-octenyl) carboxylic cyclopentane used from Example 5 have been prepared as follows:
Stage A: 1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'-hydroxy _______ ___________ _______________________ ____ ________ ____ l'-octényl) cyclo ~ entane ethyl carboxylate -________ ____ ___ _____________ __________ __ 572 mg of 3- (3 '~ -hydroxy trans l'-octenyl) are mixed ethyl eyelopentanone 2-carboxylate, 23 cm3 ethanol, 2.3 cm3 water and 85 mg sodium hydroboride, stir for two hours at 5C, add a few drops of acetone then pour into a solution ~ saturated with monosodium phosphate.
Filtered, the solvent evaporated, taken up in acetate ethyl, washed ~ with water, dried and evaporated to dryness. We get 520 mg mixture of isomers 2 ~ -OH and 2 ~ -OH which are separated by chromatography on silica, eluting with methylene chloride at 2% methanol. 203 mg of the desired isomer are obtained.
Stage B: (1 RS, 2 SR, 5 RS) (1 'E) 2-hydroxy 5- (3'-oxo l'-octenyl) ethyl cyclopentane carboxylate:

1 g of product obtained in stage A is introduced into 20 cm3 of dioxane and adds 1.6 g of dichlorodicyanoquinone. We stir for twenty hours at room temperature. We spin and then rinse.

; -30-; .

-`109 ~ 5 ~, 9 Wash with cold soda N 10 to pH 9 ~ Filter, wash with water, dry and obtain 987 mg of crude product. We chromatograph phie on silica with an eluent (cyclohexane-ethyl acetate (1/1).
930 mg of expected product is recovered.
Stad ~ C: (1 RS, 2 SR, 5 RS, 3 'SR and RS) (1' E) 2-hydroxy 5- (3'-_______ _______________________________________________________, hydroxy 3'-ethyn ~ l l'-oc ~ enyl) cyclo ~ entane ethyl carboxylate ____ _______ _ __________ ____ ___ _____________ __________ __ 2.1 g of product obtained in stage B are introduced and 2.1 cm3 of tetrahydrofuran. We heat to 38C and introduce quickly 45 cm3 of a solution N of ethynyl magnesium bromide 10 in tetrahydrofuran heated to 40C. We stir for thirty minutes at 38C. Pour into an ammonium chloride solution in ice water extracted with methylene chloride, washed with water, dries, filters and evaporates to dryness.
By chromatography on silica we obtain with a eluent consisting of methylene chloride and ethyl acetate (85/15) 1.67 g of expected product.
Stage D: Acid (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'-hydroxy 3'-ethynyl l'-octenyl) cycloE ~ entane carboxyli ~ eu and ____ ___ - _--acid (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) 2-hydroxy 5- (3l-hydroxy 20 3'-ethynyl l'-octenyl) cycloE ~ entane carboxyli ~ eu Is introduced under nitrogen 1.67 g of ester obtained in ~ -stage C, 17 cm3 of ethanol and 8.5 cm3 of normal sodium hydroxide. We shake two hours at 20C, pour into water, extract with ether, wash -with N / 2 soda then with water, dry, filter and obtain 0.37 g of fraction consisting of impurities. ~ -We group the aqueous phases, acidify with phosphate monosodium, extract ~ ether, wash with water, dry, evaporate and obtains 1.33 g of product.

The two isomers are separated by chromatography under 30 pressure in isopropyl ether with 4% acetic acid.
530 mg of isomer OH ~ (3 ′ SR) Rf are obtained. = 0.15 and 720 mg of OH ~ (3 'RS) R isomer. = 0.10.

109 ~ 5 ~ 9 Example 6: Acid lactone (1 RS, 2 SR, 5 RS) (1 'E, 3' E) 2-hydroxy, 5- ~ 1 ', 3'-octadienYl) carboxylic cyclopentane:
150 mg of ~ -lactone prepared in Example 2 are introduced.
in 3 cm3 of benzene, 15 mg of paratoluenesulfo acid are added picnic and heat under nitrogen at 40C for three hours. We neutralizes with 150 mg of sodium carbonate, filters and evaporates the solvent. 139 mg of an oil are obtained, which is chromatographed.
on silica, eluting with cyclohexane-ethyl acetate (95/5).
36 mg of pure product are collected. Rf = 0.25, cyclohexane - ethyl acetate (90/10).
~ E ~ _e infrared ~ e (chloroform) ~ C = 0 1830 cm 1 1816 cm 1 shoulder 993 cm 1 Ultraviolet spectrum in ethanol Inflection = 227 nm E% = 1310 cm 1 cm Maximum = 232 nm E% = 1410 cm ~ = 31,000 1 cm Inflection = 239 nm E% = 1044 cm 1 cm EXAMPLE 7 Acid Lactone (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'-hydroxy l'-octenyl) propionic cYclopentane:
390 mg of acid are introduced (1 RS, 2 SR, 5 RS, 3 'SR) (1 'E) 2-hydroxy 5- (3'-hydroxy, l ~ -octenyl) cyclopentane propio-pic, 3 cm3 of anhydrous nitromethane, 0.3 cm3 of pyridine and 300 mg of dicyclohexylcarbodiimide. Agitation is carried out for sixteen hours at 20 ° C.
It is wrung, washed with ether, dried. We pour the organic phase in water, decant, ester with ether, wash with water and evaporate at dry ~ Chromatography on silica in cyclohexane-acetate ethyl (1/1) and obtains 173 mg of homogeneous product.

Example 8: Acid lactone (1 RS, 2 RS, 5 RS, 3 'SR) 11' E) 2-hydroxy 5- (3'-h ~ droxy l'-octenyl) propionic cyclopentane:
We start with 405 mg of acid (1 RS, 2 RS, 5 RS 3 'SR) (1 'E) 2-hydroxy 5- (3'-hydroxy l'-octenyl) cyclopentane propioni-that, 3 cm3 of nitromethane, 0.3 cm3 of pyridine, 300 mg of dicyclo-hexylcarbodiimide and by operating as ~ Example 7, we obtain 188 mg of pure product.
Acids (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydro-xy 5- (3'-hydroxy l'-octenyl) cyclopentane proplonique and (1 RS, 2 RS, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'-hydroxy l'-octenyl) propionic cyclopentane used respectively from Examples 7 and 8 were prepared as follows:
Stage A: (5 RS, 3 'SR) (1' E) 2-oxo ethyl l-carboxylate _______ _____________________________ __________ _ 5- (3'a-tétrahydro ~ yrannyloxy l'-octenyl) cyclo ~ entane pro ~ ionate _____________ ___ ____ ___ ___ ethyl:
_____ __ 1.113 g of 3- (3'-a-) are placed under a nitrogen atmosphere tetrahydropyrannyloxy trans (octenyl) cyclopentanone 2-carboxy-ethyl late and 3 cm3 of anhydrous ethanol. Then add 0.23 cm3 of sodium ethylate in 0.22 N ethanol, we add then 303 mg of ethyl acrylate. We leave two hours at 25C
then one hour at reflux. Cool to 0C then pour onto a frozen sodium phosphate solution. We extract with ether, wash with water, dry and evaporate the solvent under vacuum. The product obtained is chromatographed on silica gel with an eluent consisting of cyclohexane, ethyl acetate and triethylamine (80 /
20 / 0.1). 1.13 g of expected product are obtained.
- Stage s: (1 RS, 5 RS, 3 'SR) (1' E) 2-oxo 3-carbethoxy 5- (3'-a-_______ ______________________________________ _____ _________ tetrahydro ~ yrannyloxy l'-octenyl) cyclo ~ entane pro ~ ethyl ionate:

2.1 cm3 of a sodium ethylate solution are poured at 1.02 N in ethanol on 0.93 g of product prepared in stage A.

The mixture is brought to reflux for four hours, 10 cm 3 of toluene are added and distills ethanol. Cool to -20C, precipitate in a 109 ~ 569 Ice solution of monosodium phosphate, ether extract, washing organic phases with water, dry and obtain 940 mg of product crude which is purified on silica with an eluent consisting of cyclohexane-ethyl acetate (60/40). 680 mg of expected pure product.
Stage C: (l RS, 5 RS, 3 'SR (l' E) 2-oxo 5- (3'- ~ -tétrahydro-_______ _____________________________________________ ____ pyrannyloxy (octenyl) methyl cyclopentane propionate:
1.5 g of product prepared in stage B, 20 cm 3 are placed of methanol and add 9.6 cm3 of normal sodium hydroxide, leave to cool room temperature and then heats twelve hours at 40C. Concentrate dry, taken up in a mixture of water and ethyl acetate, ice, acidifies, extracted with ethyl acetate, washed with water, then concentrated to dryness and obtains 1.225 g of product, which is dissolved in 20 cm3 of benzene then reflux for an hour and obtain 1.2 g of product which is taken up in methylene chloride with a drop of triethylamine and esterified with diazomethane. We get a oil which is chromatographed on silica eluting with a ethyl acetate-cyclohexane mixture (50/50). We obtain 852 mg of expected product.
Stage D: The (l RS, 2 SR, 5 RS, 3 'SR) (the E) 2-hydroxy 5- (3'- ~ -_______ ________________________________ tetrahydro ~ yrannyloxy_l'-octenyl) _cyclo ~ entane-propionate de - methyl and (1 RS, 2 RS, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'- ~ -tetrahydropyrannyloxy l'-octenyl) cyclopentane-propionate methyl:
2.165 g of product obtained is placed under nitrogen.
stage C and 21 cm3 of methanol. Add to 0C in one hour 220 mg of sodium borhydride and stir for one hour, add 30 cm3 of water and 3 g of sodium phosphate, extracted with chloride methylene, washed with water and dried. 2014 g of product are obtained containing the two isomers which are separated on silica, eluting with a G gasoline mixture (boiling between 35 and 70C), ether (50/50), 10 ~ f ~ S ~ 9 329 mg of the 2 S ~ isomer are obtained, and 1.143 g of the 2 RS isomer.
Stage E. (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3 ~ -h ~ droxy _______ ___________________________________ ___________._ ____ l'-octen ~ l) cyclo ~ entane_propionate de methyl:

458 mg of the 2 SR isomer obtained in stage D are placed, ~, 6 cm3 of methanol, 0.46 cm3 of water and 46 mg of oxalic acid.
It is heated for four hours at 40C.
Stage F: Acid (1 RS, 2 SR, 5 RS, 3 'SR) (1' El 2-hydroxy 5-13'-hydroxy l'-oc ~ enyl) cyclo ~ entane ~ ro ~ ioni ~ eu:
____ _________ ____ ___ _______ __ ____ __ Is introduced at 40 ~ C under nitrogen 3 cm3 of normal sodium hydroxide in the solution of the 2 SR isomer obtained according to the process described at stage E. It is heated for two hours at 40C. We pour into the water containing sodium phosphate, extracted with ethyl acetate, wash with water, dry, filter, evaporate and obtain 390 mg of product gross expected.
Stage G: Acid (1 RS, 2 RS, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'-hydroxy l'-octényl) cyclopentane pro ~ ioni ~ ue:
_ _ ----------Om place 479 mg of the 2 RS isomer obtained in stage D, 5 cm3 of methanol, 0.5 cm3 of water and 50 mg of oxalic acid. We stir three hours at 40C, add 3 cm3 of normal sodium hydroxide and stirred again for three hours at 40C. It is acidified with phospha-monosodium, extract with ethyl acetate, wash with water, dry and obtains 405 mg of the expected product.
Example 9: Acid lactone (1 RS, 2 SR, 5 RS, 3'SR) (1 'E) 2-hydroxy-5- (3'-oxo-1'-octenyl) cyclopentane carboxylic.
15 cm3 of chloride are placed under a sweep of dry nitrogen dry methylene, 1.5 cm3 of anhydrous pyridine and add slowly at 20C by cooling 900 mg of chromic oxide. Shake 15 minutes then quickly add 358 mg of lactone acid (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2 hydroxy 5- (3'- ~ -hydroxy-1'-octenyl) cyclopentane carboxylic (obtained in Example 2) dissolved in 15 cm3 of methylene chloride.

`10 ~ 4Sfi9 Stir 2 hours at 20C, then add 4 g of celite and 15 cm3 of methylene chloride. We filter, concentrate the filtrate vacuum, flush the pyridine by nitrogen sweeping and obtain 375 mg of a brown oil. Chromatography on silica, eluting with a cyclohexane-ethyl acetate mixture (6-4). We obtain 329 mg of expected product - Rf = 0.45.
Infrared spectrum C = 0 ~ lactone 1826 cm (~ 696 cm 1 conjugate system, ~ ~~~ ~ ~ 1674 cm ¦1 ~ 630 cm Example 10_: Lactone of the acid (1 RS, 2 SR, 5 RS, 3 'SR) 2-hYdrox ~
5- (3'-hydroxy-octanYl) carboxYl cyclopentane.
105 mg of lactone are placed in a hydrogenator - acid (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'-a-hydroxy l'-octényl) cyclopentane carboxylic (obtained in the example 2) dissolved in 10 cm3 of ethyl acetate. 20 mg of 5% palladium on carbon.
Hydrogenated for 7 hours (absorption-10.4 cm3 hydrogen). The catalyst is drained, the filtrate is concentrated under vacuum and chromatography the residual oil on silica, in eluting with a cyclohexane-ethyl acetate mixture (50-50). We 97 mg of expected product is obtained. Rf = 0.35 IR spectrum: C = 0 1800 cm 1 absence of C = C trans OH 3600 cm Acid lactone (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) 2-hydroxy 5- (3'-hydroxy 3'-ethenYl l'-octényl? Cyclopentane carboxylic.
Saturated with hydrogen at atmospheric pressure ~ 45 mg of Palladium on barium sulfate at 4.75% in 5 cm3 of acetate ethyl. 150 mg of lactone of the acid are added (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'-hydroxy 3'-ethynyl l'-octenyl) cyclo-carboxylic pentane (obtained in Example 4), 10 mg of quinoline ~ "10945fi9 and 1 cm3 of ethyl acetate. We hydrogenate at 21C. At the end of 30 minutes 14.3 cm3 of hydrogen were ab ~ orbited. We filter the catalyst, wash the solution with hydrochloric acid ~, 1 N
then with salt water. The organic phase is dried, evaporated and obtains 153 mg of crude product.
The product is purified by chromatography on silica with a Benzene-ethyl acetate mixture (80-20) then by preparative plate chromatography with the same eluent. We obtains 110 mg of pure product Rf = 0.41.
The IR spectrum shows the absence of C-CH and the presence ~ lactone, ethenyl and hydroxyl groups.

NMR spectrum (CDCl 60 MHz).

(f) H, ~

~ H (d) / H (e) (c) HH () ~ ~ CH3 (a) (a): 0.88 ppm (b): 1.51 ppm ~ c): 3.1 ppm. (triplet J = 5Hz).
(d): doublet 3.8 ppm J = 4Hz (e): 5.16 to 6.2 ppm (f): 5 ppm. (triplet J = 3Hz) Example 12: Acid Lactone ~ 1 RS, 2 SR, 5 RS, 3 'SR3 (1' E) 2-hydroxy _- (3'-hydroxy 3'-ethenyl l'-octénYl) cyclopentane carboxylic.
By operating exactly as in Example 11 at the start 150 mg of acid lactone (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) 2-hydroxy 5- (3'-hydroxy 3'-ethynyl 1'-octenyl) cyclopentane carboxylic, (obtained in Example 5). 127 mg of B ~

lO ~ S ~ `, 9 pure product.
The infrared shows the absence of CC and the presence ~ lactone, ethenyl and hydroxyl group.
NMR spectrum (~ C ~ 3.60 MH2) (g) H ~ ~ o H (d) ~ ~ H (f) (c) H ~ ~ CH3 (a) (b) CH = CH2 (e) (e) (a): 0.88 ppm tb): 1.51 ppm (c): 3.1 ppm (d): doublet 3.8 ppm J = 4 Hz (e): 5.16 to 5.61 ppm (f): 5.16 to 6.2 ppm (g): 5 ppm (triplet) Example 13: Acid Lactone (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'-acetoxy l'-octénYl) cyclopentane carboxylic.
Stir at room temperature for two hours the mixture of 0.2 g of lactone of the acid (1 RS, 2 SR, 5 RS, 3 'SR) (li E) 2-hydroxy 5- (3'- ~ -hydroxy l'-octenyl) cyclopentane carboxylic (obtained in Example 2), 2 cm3 of methylene chloride 0.47 cm3 of triethylamine and 0.091 cm3 of acetic anhydride and some grains of dimethylamino pyridine.
3 cm3 of water are added, acidified to pH 5 with phosphate monosodium and extract with methylene chloride. We dry, evaporate dry under reduced pressure and obtains 266 mg of a crude oil which is purified by chromatography on silica, eluting with cyclohexane-ethyl acetate mixture (60- ~ 0). We get like this 211 mg of pure product. Rf = 0.5.

-3 ~ -Infra-red spectrum ~ C = O complex 1808 to 1824 cm ester 1725 cm 1 NMR spectrum (60 MGz CD 13) OO
(e) H, ~ \ ~
H (d) , l ~ CH3 (a) (c) HH ~ -C-CH3 (f) 0 (b) (a): 0.88 ppm (b): 2.03 ppm (c): triplet centered at 3.08 ppm J = 5Hz (d): doublet centered at 3.78 ppm J = 3.5 Hz (e): triplet centered on 5.01 ppm J = 3Hz (f): 5.15 ppm EXAMPLE 14 Acid Lactone Hemsuccinate (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (1'-octenyl 3'-hydroxy) cyclopen-tane carboxylic.
119 mg of the acid lactone are mixed (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'- ~ -hydroxy l'-octényl) cyclo-carboxylic pentane (obtained in Example 2), 2 cm3 of chloride anhydrous methylene, 100 mg of year ~ succinic ydride, 0.15 cm3 of pure triethylamine and 15 mg of 4-dimethylamino pyridine.
8 hours are brought to reflux and then the solvents are evaporated.

2 cm3 of absolute ethanol are added, left for 1 hour at temperature ambient. The excess succinic anhydride is eliminated in the form ethyl hemisuccinate. Evaporated under vacuum and obtained 226 mg 0 of gross product.
Chromatography on silica with pure ethyl acetate.
132 mg of pure product are isolated Rf = 0.3.

`" 10 ~ 45 ~ 9 NMR spectrum (CD 13 60 M ~ z) OO
(e) H
~ ''.
/ H (f) ~ // ~ CH3 ~ a) (c) H, H, (d) 'H ~ H ~ OH
b H (b, (a): 0.88 ppm (b): 2.63 ppm (c): 3.08 ppm (d): 5.2 ppm (e): 5.04 ppm (f): 5.33 to 5.58 ppm Example 15 Acid Lactone (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxv 5- (3'-h ~ droxy l'-decenyl) carboxylic cyclopentane.
0.15 g of acid is placed (1 RS, 2 SR, 5 RS, 3 'SR) (1 'E) 2-hydroxy 5- (3'-hydroxy l'-decenyl) cyclopentane carboxyli-that in 4 cm3 of chloroform, 0.315 g of triethylenediamine and 0.16 g of tosyl chloride. The reaction is instant. We pour into water and extract with ethyl acetate. After milking ment, we obtain 183 mg of an oil which is chromatographed on silica, eluting with a cyclohexane-ethyl acetate mixture (60-40). 41 mg of pure product are obtained. Rf = 0.25.
Infrared spectrum , C = 0 complex 1808 to 1824 cm, ~ C = C ~ 973 cm 1 NMR spectrum (CDC13 60 ~ Iz) ~ ~ /
/ ~ H (e) (b) ~ CH3 (a) (d) HHH
(g) OH (c) , - '.

`10945 ~ 3 (a): 0.88 ppm (b): 1.3 ppm (c): 1.53 ppm (d): 3.0 ~ ppm (e): 3.78 ppm (doublet J = 4Hz) (f): 4.05 ppm (g): 5.47 ppm (doublet J = 5Hz) (h): 5.01 ppm (triplet ~
Acid (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'-hydroxy l ~ decenyl) cyclopentane carboxylic used in The start of Example 15 was prepared as follows:
a) 1,2-e ~ oxy 3-a-tetrahydro ~ yrannyloxy ~ ro ~ donkey:
A solution of 3.9 g of glycidol is heated to 40C
(2,3-epoxy l-propanol), 18 5 cm3 of dihydropyran and 150 mg paratoluene sulfonic acid.
After 30 minutes, 150 mg of parato acid are added.
sulfonic luene, then after 15 minutes, neutralized at temperature ambient with potassium carbonate. We filter, wash with acé
ethyl tate, removes solvents under reduced pressure. We 8.48 g of expected product is obtained.
Rf = 0.6 (cyclohexane-ethyl acetate 8-2) b) 3-keto 6-hydroxy 7-a ~ tetrahydro ~ yrannyloxy __________ ____ ___________ ___ ____ ___ methyl heptanoate:
__ ______________ __ A solution containing 8 cm3 is added over 30 minutes acetyl methyl acetate and 16 cm3 of anhydrous tetrahydrofuran in a suspension maintained at 0C of 3.554 g of sodium hydride suspended at 50% in oil, in 16 cm3 of tetrahydrofuran anhydrous.
Are introduced in 30 minutes at 0C, 39 cm3 of butyl lithium in the mixture. We stir for half an hour, then maintain at -70C.
The solution is introduced in 45 minutes into a - 109 ~ S ~ g ~ 0C solution containing 5.8 g of 1,2-epoxy 3-a-tetrahydropyran-nyloxy propane prepared in stage a) and 16 cm3 of tetrahydrofuran.
It is stirred for 3 hours 30 minutes. It is poured into an excess of a solution concentrated and frozen with monosodium phosphate, stirred for 10 minutes, then extracted with ethyl acetate and washed until ~ itralité.
After evaporation of the solvent, 16.9 g of hufl are obtained, purifies then on silica (cyclohexane-ethyl acetate 6-4). We collects 8.02 g of pure product. Rf = 0.15.
c) 3,6-dioxo 7-a-tetrah ~ droeyrannyloxy he ~ tanoate methyl:
6 g of chromic acid are slowly introduced into a solution of 9.7 cm3 of pyridine, in 148 cm3 of chloride methylene. The mixture is stirred for 15 minutes. Then 1.1 g of product obtained in stage b) in solution in 10 cm3 of chloride methylene. After 15 minutes, 150 cm3 of ether are added, filter the precipitate, wash with ether and evaporate the solvents. We 1.3 g of crude product are obtained which are purified by chromatography on silica (methylene chloride-ethyl acetate 8-2.). We obtains 473 mg of pure product. Rf = 0.45.
d) 2- (a-tetrah ~ dro ~ yrannyloxy methyl) 5-oxo l-cyclo-E ~ entene carboxylate of meth ~ le:
___________ Vigorously stirred 291 mg of bicarbonate potassium in solution in 72 cm3 of distilled water and 220 mg of crude product obtained in stage c), dissolved in 2.4 cm3 of methylene chloride. After half an hour, acidify to pH 3 with oxalic acid, then saturates with sodium chloride and extracts with methylene chloride. After evaporation, we obtain 205 mg of expected product.
e) (1 RS, 5 SR) 2-oxo- 5- (a-tetrahydroE? yrannyloxy methyl) cyclo ~ entane methyl carboxylate:
___ ____ ___ _____________ ____________ __ Stirred under a hydrogen atmosphere, a solution containing 215 mg of product obtained in stage d), 10 cm3 of - 10 ~ 4569 methanol and 21 mg of 10% palladium on carbon. Volume theoretical is absorbed in 40 minutes, filtered, washed with acetate ~ -of ethyl, evaporates the solvents and obtains 172 mg of an oil which chromatography on silica (cyclohexane-ethyl acetate 50-50). 122 mg of expected product are obtained.
f) (1 RS, 5 SR) 2-oxo 5-hydroxymethyl cycloeentane _______________________________ ___ ___ ______ methyl carboxylate ______ ____________ __ It is brought to 60C with stirring for 3 hours, a mixture of 43 g of product obtained in stage e), 860 cm 3 of methanol, 86 cm3 of water and 12.7 g of oxalic acid. We concentrate under pressure reduced to 40C, taken up in chloroform, washed with water and dry. The solvent is evaporated and 29.2 g of product are obtained crude which is chromatographed on silica (cyclohexane-acetate ethyl 2-8). 14 g of pure oil are recovered.
g) (5 RS) 2-methoxy 5-hydroxymeth ~ c ~ clo ~ entene methyl carboxylate:
______ ____________ _ Stir at room temperature for 4 hours, 4 g of ~ -keto ester obtained in stage f), 10 cm3 of methylene chloride, 50 cm3 of diazomethane in solution in methylene chloride.
The solvent and the excess diazomethane are evaporated and obtains 4.3 g of a crude yellow oil used in the reaction next.
h) (5 RS) 2-methoxy 5-formyl l-cyclo ~ entene carboxy-______________ _______ _____ ___ _____________ methyl late ____________ __ 25.5 g of oxide are introduced in small portions of chromium in a solution, maintained at 15 ~ 20C, of 41 cm3 of pyridine in 400 cm3 of anhydrous methylene chloride. We shake a quarter of an hour, then cools the solution obtained to -15C and -add the 4.3 g of product obtained in the previous stage, dissolved in 10 cm3 of methyl chloride ~ ne. After an hour and a half, we introduced 50 g of celite and 100 cm3 of ether, filtered, washed with ether and evaporates the solvents ~ 30C.

~ Q ~ 4569 i) (5 RS) (1 'E) 2-methoxy 5- (3'-oxo 1' decenyl) methyl l-cyclopentene carboxylate:
___ ___ _____________ ____________ __ A solution of 9.674 g is introduced over 10 minutes dimethyl (2-oxo nonyl) phosphanate in 20 cm3 of glyme, in a suspension of 1.85 g of 50% sodium hydride in oil. After solidification, 5 g are added in 20 minutes aldehyde prepared in stage H, in solution in 30 cm3 of glyme.
The reaction is complete after 20 minutes. We pour into a solution saturated monosodium phosphate and acetate extract ethyl. 13.2 g of oil are obtained which is purified by chroma-tography on silica eluting with cyclohexane = ethyl acetate (60-40) and 1% triethylamine. This gives 4.652 of oil pure. Rf = 0.25.
Infrared spectrum: `C = 0 max: 1651 cm `` Conjugated CC 1623 cm 1 j): (5 RS, 3 'SR) (1' E) 2-methoxy 5- (3'hydroxy 1'-decenyl) -l-cyclo ~ methylene carboxylate and (5 RS, 3 'RS) _____ ______ ___ _____________________________________________ (1 'E) 2-methoxy 5- (3lhydroxy l'-decenyl) 1-cyclopentene carboxy-_______________ _______ ____ ____________________ _______________ methyl late:
__________----4.6 g of ketone obtained at the stage are cooled to 0C
dissolved in 100 cm3 of glyme distilled over sodium, then intro-add in 45 minutes 200 cm3 of a 0.13 M / l solution of borohydride of zinc in the glyme. Leave to return to room temperature and continues agitation for 4 hours. Pour into a saturated solution of sodium phosphate and extracted with ethyl acetate. After treatment, 7.3 g of oil are obtained. Two chromatographies are carried out.
successive spellings on silica eluting with a benzene mixture-ethyl acetate (60-40) and (1% triethylamine).
901 mg of isomer ~ (3'SR) are obtained and 810 mg of isomer ~ (3'SR) as well as 503 mg of the mixture.
K): Acid_ (l RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy `` lO9 ~ Sfi9 5- (3'-hydroxy l'-décén ~ l) cyclopentane carboxyli ~ eu.
_______ ___ ~ _________ ~ ___ ___ _____________ __ __ ~) hydrolysis of enol ether We have a solution for 15 hours at room temperature 8.49 mg of the 3'SR isomer prepared in stage J, in 3 cm 3 of methanol and 2 cm3 of hydrochloric acid 0.1 lN. We neutralize by 2 cm3 of sodium hydroxide 0.1 l extract the aqueous phase with ether. We obtain 763 mg of pure oil in chromatography. Rf = 0.32 (benzene-ethyl acetate (60-40).
~) Reduction of the ketone.
, The previous 763 mg in solution is added, in 4 cm3 of tetrahydrofuran and 5.14 cm3 of a molar solution of L selectride in tetrahydrofuran maintained at -60C.
It is stirred for 2 hours 30 minutes at this temperature, then hydrolysis by pouring into a ~ saturated phosphate solution monosodium, extract with ethyl acetate. 1.7 g are obtained crude oil.
Rf = 0.25 (cyclohexane-ethyl acetate 40-60).
~) Saponification.
The oil obtained above is stirred for 2 hours while presence of 3 cm3 of ethanol, 2.4 cm3 of normal sodium hydroxide. We hunt ethanol and extracted with ethyl acetate. The aqueous phase is acidified to pH 5 with monosodium phosphate and extracted at ethyl acetate. The organic phases are washed with water, then dried. After removing the solvent under pressure reduced, 365 mg of pure colorless oil are obtained by chromatography.
Rf = between 0.1 and 0.36 (ethyl acetate).

NMR spectrum (CDCl 60 MHz) OH

(d) H ' ~ H (b) 30 ~ ~ - ~ O2H CH3 OH

109456 ~

(a): 0.88 ppm (b): two doublets centered on 2.4 and 2.59 ppm (J = 5Hz) (c): 4.06 ppm (d): 4.5 ppm.
Example 16: Lactone of the acid (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3 ~ hydroxy l'-octényl) cyclopentane carboxyli ~ eu.
By operating in a similar manner ~ that described in example 1, but replacing triethylamine with diazabi-cyclooctane, the lactone of the acid is obtained (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy 5- (3'- ~ -tetrahydropyrannyloxy l'-octenyl) caxboxylic cyclopentane which is treated as in Example 2 to obtain the expected product.
Pharmacological study .
In this study, we will designate:
- By product A: the acid lactone (1 RS, 2 SR, 5 RS, 3 'SR) (1 'E) 2-hydroxy 5- (3'-hydroxy l'-octenyl) cyclopentane carboxyli than.
- By product B: the acid lactone (1 RS, 2 SR, 5 RS, 3 'RS) (1 'E) 2-hydroxy 5- (3'-hydroxy 3'-ethynyl l'-octenyl) cyclopentane carboxylic.
- By product C: the acid lactone (1 RS, 2 SR, 5 RS, 3 'RS) (1 'E) 2-hydroxy 5- ~ 3'-hydroxy 3'-ethenyl l'-octenyl) cyclopentane carboxylic.
- By product D: the acid lactone (1 RS, 2 SR, 5 RS, 3 'SR) (1 'E) 2-hydroxy 5- (3'-acetoxy l'-octenyl) cyclopentane carboxy-lique.
- By product E: the acid lactone (1 RS, 2 SR, 5 RS, 3 'SR) (1 'E) 2-hydroxy 5- (3'-hydroxy l'-decenyl) cyclopentane carboxyli-than.
1) hYpotenslve activity in anesthesia dogs a) method:

The study was done on adult bastard dogs of both sexes weighing from 14 to 20 kg, with closed chest. Animals are anesthetized with chloralose (125 mg / Kg IV). The trachea has was intubated and the animals were ventilated artificially with a pump.
The blood pressure expressed in mm of Hg was carotid artery using a pressure head. The effects cardiovascular on average blood pressure: (pressure diastolic + 1/3 of the difference: systolic pressure-diastolic pressure) were studied at doses of 10 to 1000 r / Kg IV for product A, and 30 to 1000 r / Kg IV for product B.
The table below indicates the maximum variations of average blood pressure and the time required so that the pressure returns to its initial state.
b) Results:

DOSE PRODUCT TO PRODUCT B

2 ~ in r / Kgvarlation duration varlation duration IV average action average action Go. avg. in minutes p. art.moy. in minutes n% 8 in% _ 100 -17 18 0 _ 30300 25 l ~, 30 1000 -31 37 -17 _ .

1 ~ 9 ~ 569 .,.

Prodults show hypotensive activity interesting from the dose of 0.1 mg / kg for the product A and 1 mg / Kg for product B.
A second study was done on adult mongrel dogs from two sexes weighing 14 ~ 20 kg with closed chest. Animals are anesthetized with a mixture of barbiturates.
The trachea is intubated and the animals are ventilated artificially with a pump.
Blood pressure was taken at the carotid using a pressure head. We determined the dose ~ ui determines a decrease in average blood pressure of at least minus 20% for at least 20 minutes.
The results were as follows:
Product C: 0.5 mg / kg Product D: 1 mg / kg Product E: 1 mg / kg.
2) Hypotensive activity in rabbits The products are used in solution in the serum physiological ~ 10% ethanol. These solutions are administered by intravenously to rabbits anesthetized with urethane and measures carotid pressure. The dose that lowers by 30%
this pressure was found to be 20 ~ g / kg with product E
and equal to 50 ~ g / kg with product C.

!
~ * ...

.

Claims (17)

The embodiments of the invention, about which an exclusive right of property or privilege is claimed, are defined as follows: 1. Process for the preparation of the products of formula general I:

I

in which the dotted line indicates the presence, if where appropriate, of a second bond, A represents a single bond or a radical - (CH2) 2-, R represents a hydrogen atom or a alkyl radical, saturated or unsaturated, having from 1 to 4 atoms of carbon, R6 represents an OR'A radical in which R'A represents a hydrogen atom, a tetrahydropyrannyl radical, a radical alkyl having from 1 to 3 carbon atoms, a COR "A radical in which R "A represents either an alkyl radical having from 1 to 3 carbon atoms, if any, substituted by a radical carboxylic or a phenyl radical, where appropriate, substituted by a free carboxylic radical or protected by an acyl radical having 2 to 4 carbon atoms by an easily grouped eliminable by hydrolysis, where R and R6 together form a group ketone, R7 represents a radical - (CH2) mA-CH3 in which mA
represents an integer equal to 3,4,5 or 6 or R6 and R7 form together a radical in which nA represents a whole number equal to 2,3,4 or 5, the wavy lines mean that the connections can be found in one or the other of the possible configurations, it being understood that when A represents a single bond, the bond between the pentane cycle and the oxygen atom is an .alpha. bond, characterized in that one submits a product of formula IIa:
IIa in which A, R, R6 and R7 have the abovementioned meaning, except the action of a reagent for the formation of functional derivatives of acids. 2. Method according to claim 1, of preparation products of general formula I:

I

in which the dotted line indicates the presence, if where appropriate, of a second bond, A represents a single bond or a radical - (CH2) 2-, R represents a hydrogen atom or a saturated or unsaturated alkyl radical before 1 to 4 atoms of carbon, R1 represents a radical OR 'in which R' represents a hydrogen atom, a tetrahydropyrannyl radical, a radical alkyl having from 1 to 3 carbon atoms, a COR "radical in which R "represents an alkyl radical having from 1 to 3 atoms of carbon or a phenyl radical, where appropriate, substituted by a carboxylic group, or R and R1 together form a group-ketone, R2 represents a radical - (CH2) m-CH3 in which m represents an integer equal to 3.4 or 5, or R1 and R2 form together a radical in which n represents a whole number equal to 2, 3 or 4, the wavy lines mean that the connections can be found in one or other of the configu-possible rations, it being understood that when A represents a single bond, the bond between the pentane ring and the atom oxygen is an .alpha. bond, process characterized in that one submits a product of formula II:

II

in which A, R, R1 and R2 have the abovementioned meaning, to the action of a reagent for the formation of functional derivatives of acids. 3. Method according to claim 2, characterized in that products of general formula I are prepared such as defined in claim 2 in which the dotted line indicates the presence of a second bond, A represents a simple bond or radical - (CH2) 2-, R represents a hydrogen atom or an unsaturated alkyl radical having 2 or 3 carbon atoms, R1 represents a radical OR 'in which R' represents an atom of hydrogen, a tetrahydropyrannyl radical, a COR radical "in wherein R "represents a phenyl radical substituted by a group-carboxylic, R2 represents a radical - (CH2) m-CH3 in which m represents an integer equal to 3, 4 or 5, or R1 and R2 together form a radical in which n represents an integer equal to 2, 3 or 4. 4. Method according to claim 2, characterized in that products of general formula I are prepared such as defined in claim 2 in which the dotted line indicates the presence of a double bond, A represents a single bond, R represents a hydrogen atom or an alkyl radical unsaturated having 2 or 3 carbon atoms, R1 represents a radical OR 'in which R' represents a hydrogen atom, R2 represents a radical (CH2) m-CH3 in which m represents an integer equal to 4. 5. Method according to claim 1, for preparation acid lactone (IRS, 2SR, 5RS, 3'SR) (1'E) 2-hydroxy 5- (3'-hydroxy 1'-decenyl) cyclopentane carboxylic acid, characterized in that one submits the acid (1RS, 2SR, 5RS, 3'SR) (1'E) 2-hydroxy 5- (3'-hydroxy 1'-decenyl) cyclopentane carboxylic action a reagent for the formation of functional acid derivatives. 6. Method according to claim 2, of preparation acid lactone (1RS, 2SR, 5RS, 3'SR) (1'E) 2-hydroxy 5- (3'-hydroxy 1'-octenyl) cyclopentane carboxylic acid, characterized in that we submit the acid lactone (1RS, 2SR, 5RS, 3'SR) (1'E) 2-hydroxy 5- (3'.alpha.-tetrahydropyrannyloxy 1'-octenyl) cyclo-carboxylic pentate to the action of a formation reagent functional derivatives of acids. 7. Method according to claim 1, characterized in that that the reagent for the formation of functional derivatives of acids is chosen from the group formed by tosyl chloride, alkyl chloroformates, dicycloalkylcarbodiimides, dialcoylcarbodiimides and thionyl chloride. 8. Preparation process according to claim 2, characterized in that the reagent for the formation of functional derivatives nels of acids is selected from the group formed by chloride tosyle, alkyl chloroformates, dicycloalcoylcar-bodiimides, dialkoylcarbodiimides and thionyl chloride. 9. Method according to claim 7, characterized in that that we operate in the presence of a base chosen from the group formed by alkali metal carbonates, triethylamine, methylmorpholine, pyridine and diazabicyclooctane. 10. The method of claim 2 for preparing general formula IB products: IB
in which the wavy and dotted lines, A and R have the meaning given to claim 2, characterized in that that a product obtained is subjected to an acid hydrolysis agent of formula IA:
in which A, R and m have the meaning given in the claim 2. 11. The products of formula I 'as defined in claim 1, each time they are obtained by a process according to claim 1, 7 or 9 or its equivalents manifest chemicals. 12. The products of formula I as defined in claim 2, each time they are obtained by a process according to claim 2 or 8 or its chemical equivalents manifestos. 13. The products of formula I, as defined in claim 3, each time they are obtained by a process die according to claim 3 or its chemical equivalents manifestos. 14. The products of formula I, as defined in claim 4, each time they are obtained by a process according to claim 4 or its chemical equivalents manifestos. 15. The acid lactone (1RS, 2SR, 5RS, 3'SR) (1'E) 2-hydroxy 5- (3'-hydroxy 1'-decenyl) cyclopentane carboxy-lique, each time it is obtained by the process according to the claim 5 or its obvious chemical equivalents. 16. The acid lactone (1RS, 2SR, 5RS, 3'SR) (1'E) 2-hydroxy 5- (3'-hydroxy 1'-octenyl) cyclopentane carboxy-lique, each time it is obtained by the process according to the claim 6 or its obvious chemical equivalents. 17. Products of formula IB, as defined to claim 10, each time they are obtained by a method according to claim 10.