DE2711950A1 - NEW LACTONES DERIVED FROM CYCLOPENTANOL, THEIR MANUFACTURING PROCESS AND THE PHARMACEUTICAL COMPOSITIONS THESE CONTAINED - Google Patents

Description

ROUSSEL-UCLAF, Paris / France

New lactones derived from cyclopentanol, their manufacturing process and pharmaceutical compositions containing them

The present invention relates to new lactones derived from cyclopentanol, of the general formula

rO

where the dotted line indicates the possible presence of a second bond, A denotes a single bond or a radical - (CHg) ₂ -, R denotes a hydrogen atom or a saturated or unsaturated alkyl radical having 1 to 4 carbon atoms, R ^ denotes a radical OR ' _A wherein R ' _{A is} a hydrogen atom, a tetrahydropyranyl radical, an alkyl radical having 1 to 3 carbon atoms, a radical C0R " _A , in which R" _{A is} either an alkyl radical having 1 to 3 carbon atoms, which is optionally substituted by a carboxyl radical, or a phenyl radical , optionally by a carboxyl radical or by

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a hydroxyl group is substituted, which is free or is protected by an acyl radical with 2 to 4 carbon atoms or by a group easily removable by hydrolysis, or R and Rg together form a keto group, R "a radical - (CH _O ) _ - CH, where m. Is an integer,

c. Do ya

namely 3 * ^ * 5 or 6, or Rg and R ₇ together form a radical ^ \ (CH ₀ ) _ -CH, in which n. is an integer, namely 2, 3, 4 or 5, ^the wavy lines indicate that the bonds may be in one or the other of the possible configurations, it being understood that when A represents a single bond, the bond between the pentane ring and the oxygen atom is an alpha bond.

The invention relates in particular to new lactones which are different from cyclopentanol of the general formula I.

derive, in which the dotted line indicates the possible presence of a second bond, A represents a single bond or a radical - (CHp) p-, R a hydrogen atom or a saturated or unsaturated alkyl radical having 1 to 4 carbon atoms, R ₁ a radical OR ¹ , where R 'is a hydrogen atom, a tetrahydropyranyl radical, an alkyl radical having 1 to 3 carbon atoms, a radical COR ", in which R" is an alkyl radical having 1 to 3 carbon atoms or a phenyl radical which is optionally substituted by a carboxyl group, or R and R ₁ together form a keto group, Rg denotes a radical - (CHp) -CH, in which m is an integer, namely J _t k or 5, or R ₁ and R ₂ together form a radical «^ \. (CHg) _n -CH-, where η is an integer, namely 2, 3 or 4, where the wavy lines indicate that the bonds can be in one or the other of the possible configurations, whereof, of course, if A a

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Single bond represents the bond between the cyclopentane ring and the oxygen atom is an α-bond.

The radical R can in particular be a hydrogen atom, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Mean vinyl, propenyl, butenyl, ethynyl or propargyl radical.

The radicals R ¹ , R ' _A , R ″ and R ″ _A can represent a methyl, ethyl, propyl or isopropyl radical.

The acyl radical, which can protect the hydroxyl radical introduced by the phenyl radical, can be an acetyl, propionyl, be n-butyryl or isobutyryl radical.

The group which can easily be removed by hydrolysis can, for example, be a tetrahydropyranyl radical or a tert-butyldimethylsilyl radical be.

The invention relates in particular to products of the general formula I in which the dotted line represents the presence of a second bond angit> t, A represents a single bond or a radical - (CHp) ₂ -, R a hydrogen atom or an unsaturated alkyl radical having 2 to Z> carbon atoms R ₁ denotes a radical OR ', in which R ^{1 is} a hydrogen atom, a tetrahydropyranyl radical, a radical COR ", in which R" denotes a phenyl radical substituted by a carboxyl group, R _{0 represents} a radical "" (CHp) _1n -C ¹¹ - ** where m is an integer, namely 3, 4 or 5 or R "and R ₀ together are a radical ^ T \ (CHo) -CH-,

ic ^ tt η j

form, where η is an integer, namely 2, J> or 4.

The invention relates in particular to the products of general formula I wherein 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, R ₁ represents a rust OR ^1, wherein R 'represents a hydrogen atom, R _{0 represents} a radical (CHp) -CH ,, in which m represents an integer, namely 4.

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• / Μ.

Among the products of the general formula I or I ¹ , the products described below in the Beigjlelen can be mentioned in particular and, above all, the lactone of (1RS, 2SR, 5RS, 3 ¹ SR) (1'E) -2-hydroxy-5- (3'-hydroxy-1'-octenylj-cyclopentane-carboxylic acid and the lactone of (1RS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3'-hydroxy-1'- decenylj-cyclopentane-carboxylic acid.

The lactone of (1RS, 2SR, 5RS, 3 ¹ SR) (I ¹ E) -2-hydroxy-5- / 3 '- (2 "-hydroxy-benzoyloxy) -1'-octenyl / cyclopentanecarboxylic acid can be mentioned in particular.

The invention also relates to a process for the preparation of the products of the formula I ¹ and in particular the products of the formula I as defined above, which is characterized in that a product of the formula Ha

II «,

wherein A, R, Rg and R _{7 have} the meanings given above, to obtain a product of the formula I ¹ or a product of the formula II
OH

ACO ₅ H ²

II

wherein A, R, R ₁ and R _{2 have} the meanings given above, in order to obtain a product of the formula I of the interaction. kung of a reagent capable of forming functional acid derivatives, the functional derivative thus obtained in each case then being formed with the hydroxyl radical

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of the lactone ring and to obtain a product of the formula I ' or I responds.

According to a preferred embodiment of the above method is the reagent capable of forming functional acid derivatives, the action of which is called the product of the formula Ha or II subjects the tosyl chloride to form a functional derivative which is the mixed anhydride.

It is preferable to work in the presence of triethylamine, but a further base can also be used, for example an alkali carbonate or an organic base such as methylmorpholine, Pyridine or another trialkylamine.

You can also work in the presence of diazabicyclooctane.

Likewise, you can use the product of the formula Ha or II of the Subject to the action of other reactants capable of forming mixed anhydrides. For example, you can name the isobutyl chloroformate or other alkyl chloroformates. In this case one works in the presence of a basic one Agent selected from the same groups as above.

Other reactants such as dialkylcarbodiimides can also be used or use dicycloalkylcarbodiimides such as dicyclohexylcarbodiimide.

Finally, one can use reactants that lead to the formation of acid chlorides are capable such as thionyl chloride in the presence of a basic reagent selected from the same group as above, use.

The invention thus relates in particular to a process for the preparation of the products of the formula I ¹ and the formula I, the process being as described above and being characterized in that the reagent capable of forming functional acid derivatives is selected from the group consisting of tosyl chloride, the alkyl chloroformates, the dicyclo-

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alkylcarbodiimides, the dialkylcarbodiimides and thionyl chloride and that the base, which is optionally used, selected from the group consisting of the alkali metal carbonates ^ Triethylamine, methylmorpholine, pyridine and diazabicyclooctane.

The invention also relates to a process for the preparation of products of the general formula IB

IB H "" OH

in which the wavy and dotted lines A and R have the meaning given above, which correspond to a product of the formula I in which R _{1 is} a radical OR ¹ , in which R ^{1 is} a hydrogen atom and R _{2 is} a radical - (SHp) -CH -, ^as that is characterized in that a product of the formula IA

in which A, R and m have the meanings given above, which corresponds to a product of the formula I in which R _{1 is} a radical OR ¹ , in which R ^{1 is} a tetrahydropyranyl _{radical and R 2 is} a radical - ( ^CH ₂ ) _m -CH , subjected to the action of an acid hydrolysis agent.

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The products of the general formula IA used as starting materials for this process can be prepared according to the above Process described are prepared, which consists in that one capable of forming functional acid derivatives Reagent with a product of the formula

wherein A, R and m are as defined above.

According to a preferred embodiment of the manufacturing process for the products of the formula IB, the hydrolysis is carried out in the presence of acetic acid.

However, other mineral acids or organic acids can be used, such as aqueous hydrochloric acid, sulfuric acid or trifluoroacetic acid.

The invention also relates to a process for the preparation of the products of the general formula IC

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. / ff-

in which A, R, R "and m have the meanings given at the beginning, corresponding to a product of the formula I in which R _{1 is} a radical OR ', in which R ^{1 is} a radical COR" and Rp is a radical "(CHp) -CH, which is characterized in that a product of the formula IB as defined above with an acid of the formula R ¹¹ COpH or with an acid chloride of the formula R ¹¹ COCl or with an acid anhydride of the formula (R ¹¹ CO) «0 or with treated with a mixed anhydride,

According to a preferred embodiment of the above process, the anhydride of the formula (R ¹¹ CO) ₂ O is used.

The acid chloride of the formula R ¹¹ COCl can also be used. One then works in the presence of an acceptor for hydrochloric acid such as an alkali metal carbonate or bicarbonate or a tertiary organic base such as triethylamine, pyridine or a picoline.

The invention also relates to a process for the preparation of products of the formula I ¹ C

. (CH ₂ ) _mA -C

H OCR " ¹ -CO ₂ H

in which A, R and m »have the meanings given initially and R" ^{1 is} an alkylene radical having 1 to 5 carbon atoms, corresponding to a product of the formula I ¹ , in which R_ is a radical - (CHp) -CH, and R ^ is a radical - OCR ". represents

wherein R " _{A represents} an alkyl radical having 1 to j carbon atoms which is substituted by a carboxyl group, the

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- • Τ-

characterized in that a product of the formula I ¹ B

R OH

in which the wavy and dotted lines ^ A, R and m. have the meanings given initially, corresponding to a product of the formula I ¹ , in which FL is a radical -

Formula (R ¹¹¹ CO) ₂ O treated

) -CH-, represents a hydroxyl group, with an anhydride of the

According to a preferred embodiment of the above The process is carried out in the presence of a tertiary organic base such as triethylamine, pyridine, dimethylaminopyridine Picoline or a mixture of these bases.

The products of the formula I ¹ B can be prepared, for example, by the method described above, starting from the products Ha or II corresponding to the value of m.

The invention also relates to a process for the preparation of the products of the general formula ID

ID

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in which A, R and η have the meaning given initially, corresponding to a product of the formula I in which R ₁ and R ₀

C.
together form a residue ^ \ (CHp) -CH, that thereby

is characterized in that a product of the formula IA or IB as defined above is treated with a dehydrating agent treated.

According to a preferred embodiment of the above method Paratoluenesulfonic acid is used as the dehydrating agent, but other strong aqueous acids such as conc. Sulfuric acid or phosphoric acid or polyphosphoric acid use.

The invention also relates to a process for the preparation of products of the general formula IE

IB

in which A and m have the meaning given above _> corresponding to a product of the formula I in which R and R ₁ together form a keto group and R _{2 is} a radical - (CHp) -CH, which is characterized in that a product of the Formula I ^W B

ο. ^ ο

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. Af.

where A and m have the meaning given above? corresponding to a product of the formula I in which R is a hydrogen atom, R _{1 is} a radical OR ¹ , in which R ^{1 is} a hydrogen atom and Rp is a radical "(CHp) -CH-, is treated with an oxidizing agent.

According to a preferred embodiment of the above method the oxidizing agent used is dichlorodicyanoquinone, however, silver silicate can also be used.

^{The products of the formula I 1} B used as starting materials for the process can be prepared starting from the products of the formula II by applying the process according to the invention.

The invention also relates to a process for the preparation of products of the general formula IF

IF

in which R represents a hydrogen atom or a saturated alkyl radical and A and R ^{1 have} the meanings given above _> corresponding to a product of the formula I in which R represents a hydrogen atom or a saturated alkyl radical, R _{1 represents} a radical OR ¹ and Rp a radical - (CHp) -CH, which is characterized in that a product of the formula I ¹ F

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I ¹ F

in which A, R, R ₁ and m have the meanings given at the beginning, it being understood that R and R ₁ together cannot form a keto group, corresponding to a product of the formula I in which Rp is a radical - (CH ₂ ) -CH ^ means and the dotted line indicates the presence of a double bond, treated with hydrogen.

According to a preferred embodiment of the above method the catalyst used is palladium on activated carbon. However, platinum or a platinum salt can be used in the same way turn around. Other carriers such as barium sulfate can also be used.

^{The products of the formula I 1} F used as starting materials for this process can be prepared starting from the products of the formula II using the process according to the invention.

The invention also relates to a process for the preparation of products of the formula IG

IG

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to-

in which A, R and m. have the meanings given above and R "represents a hydrogen atom, an acyl radical having 2 to 4 carbon atoms or a group which can be easily removed by hydrolysis, corresponding to a product of the formula I ¹ , in which R" represents a radical - ( CH ₀ ) -CH, and R, - is a radical -OCOR ¹¹ .

7 ^{2 m} A ^

denotes in which R "represents a phenyl radical which is optionally substituted by a hydroxyl group which is free or protected by an acyl radical having 2 to 4 carbon atoms or by a group which can be easily removed by hydrolysis and which is characterized in that a product of the formula I ¹ B as defined above with a functional acid derivative of the formula

wherein R "represents an acyl radical having 2 to 4 carbon atoms or a group which is easily removable by hydrolysis, treated to give a product of the formula I ¹ G

I ¹ G

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to obtain, wherein R "has the meaning given above, which product is optionally with an acid or treated with a base in order to obtain a corresponding product of the formula IG, in which R ". denotes a hydrogen atom,

According to a preferred embodiment of the above method an acid halide is used as the functional derivative

One then works in the presence of a hydrochloric or hydrobromic acid acceptor such as triethylamine or a picoline.

The halide is preferably the chloride, but the bromide can also be used.

A mixed anhydride can also be prepared, for example by reacting oxalyl chloride with the acid> or an anhydride formed by reacting ethyl chloroformate or isobutyl chloroformate with the acid. In the same way one can use an active acid ester, an azide or use an amide of the acid.

If R "is an acyl radical with 2 to 4 carbon atoms, so

is the hydrolysis, which allows the products of the formula I ¹ G to be converted into products of the formula IG, in which R "means a hydrogen atom, a basic hydrolysis. Sodium carbonate is preferably used, but other bases such as sodium hydroxide or potassium hydroxide can also be used in Use ethanol or methanol.

If R " _{c is} a residue such as the tetrahydropyranyl residue that can be easily removed by acid hydrolysis, the medium used is preferably oxalic acid. However, other acids such as acetic acid or trifluoroacetic acid can also be used.

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The invention also relates to a process for the preparation of the products of the formula IH

IH

OH

wherein A and m. have the meanings given above,

TV
and R is an alkyl radical with 2 to 4 carbon atoms which contains a double bond, each of the double bonded carbon atoms containing at least one hydrogen atom, corresponding to a product of the formula I ¹ , in which R = Rg is a hydroxyl group and R_ is a radical - (C represents, which is characterized in that in the presence of a catalyst, a product of the formula I ¹ H

, (CHp)

^m A ^CH 3

I ¹ H

wherein

Ty

an alkyl radical having 2 to 4 carbon atoms, the

contains a triple bond means corresponding to one

Product of the formula I ¹ , in which R = R

a hydroxyl group

and R_ is a radical - (CH ₀ ) -CH, reduced with hydrogen.

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The catalyst used for the hydrogenation is preferably palladium on barium sulfate in the presence of a trace of quinoline.

However, one can also use palladium on calcium carbonate in the presence of lead acetate, palladium on activated carbon in the presence use of pyridine or Raney nickel.

Those used as starting materials for the above process Products of the formula IΉ can, for example, according to according to the method described above, starting from the corresponding products Ha or II according to the value of m will.

The wavy lines that make up the vast majority of the foregoing Formulas containing give the various possible conformations of the substituents around the carbon atoms to which they are tied to.

The constituents of the mixtures, if any, formed by these various products can be determined with the aid of customary physical Methods, in particular by chromatography, separately will.

The products of the formulas I ¹ and I can exist in racemic or optically active forms. The active isomers can be separated by commonly used methods.

These products have hypotensive activity in pharmacology.

Below are the pharmacological ones in the experimental part Results given which were obtained with the products according to the invention.

The pharmacological properties of the products according to the invention make them for use in the form of drugs j in particular in the treatment of hypertension and circulatory

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Disturbances suitable.

Thus, the pharmaceutically acceptable compounds of the formulas I ¹ and I, as defined above, and in particular those described in the examples, can be used in the form of medicaments.

The invention thus also relates to pharmaceutical compositions which contain as active ingredient at least one of the pharmaceutically acceptable products of the formulas I ¹ and I, as defined above.

These pharmaceutical compositions can be administered by the buccal, rectal, parenteral or local routes.

They can be solids or liquids and they can be in the form of those commonly used in human medicine pharmaceutical preparations are available, such as simple or sugar-coated tablets, gel capsules, granules, Suppositories and injectable preparations. You will be after usual Methods made. The active ingredient (s) can usually be used in such pharmaceutical compositions Excipients such as talc, gum, arabic, lactose, Starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers.

The dose of administration is according to the disease to be treated, the particular individual, the mode of administration and the type in question pulled products variable. For example, it can be between 0.5 mg and 200 mg for those described in Examples 2 and 15 Products when administered by injection, for example by slow perfusion, in humans.

Finally, the invention relates as new industrial products and in particular as for the manufacture of products of the Formula I 'usable intermediates the products of the formula

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CO ₂ H

wherein the dotted line and the substituents R, R ₁ and Rp have the meanings given initially, the products of the formula

where the wavy line and η have the meanings given initially ^ and the products of the formula

II

wherein the wavy lines and the substituents A, R and R _{1 have} the meanings given at the beginning and R 'is a radical

represents or R. and R 'together form a radical -CH ₅ .

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IG-

The used as starting materials for the process Products of the formula II, in which A represents a single bond,

R. and Rp together cannot form a radical y ^ \ (CHp) -CH-, and m denotes the number k , can be prepared according to the process described in the French patent application number 75-26616 of August 29, 1975.

This process is characterized in that a product of the formula B

.CO ₂ R ₄

(B)

wherein R ^, denotes an alkyl radical having 1 to 12 carbon atoms and Rp. is a hydrogen atom or a 2-tetrahydropyranyl radical represents treated with an alkali hydride under mild conditions to give a product of formula C.

(C)

0R5

to get which one you want

a) either treated by hydrogenation in the presence of a catalyst, a product of Formula D.

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(D)

to obtain,

b) or with an alkali base and then with an acid treated to a product of Formula E

(E)

to obtain,

c) or provided that FU is a hydrogen atom in formula C represents treated with an oxidizing agent to produce a product of formula F

(F)

to obtain, which is treated with an organometallic derivative of the formula R '-MgX, wherein R' is a linear or represents branched, saturated or unsaturated alkyl radical with 1 to 4 carbon atoms and X represents a halogen atom, a product of the formula G.

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(G)

HO R ¹

to obtain, or that a product of the formula B in which Rp. is a hydrogen atom means treated with diazomethane to give a product of formula H

OCH

to obtain, which is treated with an oxidizing agent to give a product of formula H ¹

OCH

CO ₂ R ₄

to obtain, which one with an organometallic or organometalloid derivative R'_MgX treated to be a product of general formula J

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OCH

(J)

HO Ί1

which is treated with an acid to obtain a product of formula K

HO R ¹

(K)

to get which one treats:

either with a reducing agent under mild conditions to give a product of formula G as described above was to get,

or with 2,3-dihydro-pyran to form a product of the formula K ¹

which is treated with a reducing agent under mild conditions to produce a product of the general formula L 709839/09 31

to obtain,

and the products of the formula D, F, G and L are treated with a base and then with an acid in order to obtain the acids, that enter Formula II. Preparation examples for these products of the formula II are given below stated in the experimental part.

The products of the formula II, in which R. and R ₂ together form a radical> ^ \ (CHp) -X-CH-, and A represents a single bond, can be prepared by reacting 2,4-dinitrobenzenesulfinyl chloride with the product of the formula B, in which R, - is a 2-tetrahydropyranyl radical, are prepared.

The products of the formula II in which A is a radical - (CHg) ₂ , m is the number 4 or R ₁ and R ₂ together form a radical (CH ^) -CH and η is the number 3, can

starting from the product of formula M.

(M)

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which can be used to carry out the same reactions as those described above for the Product of formula B have been described.

The product of the formula M is obtained by reacting an alkyl acrylate with the product of the formula B in which R ₁ - is a 2-tetrahydropyranyl radical, subsequent isomerization and finally * by decarboxylation. An example of such a production is given below in the experimental section.

The products of the formula II in which m denotes the numbers 3 or 5 or η denotes 2 or 4, starting from the products of the formula B ¹

where m ¹ denotes the numbers 5 or 5, are prepared.

The manufacturing methods are identical to those used starting with the products of formula B. In particular, the products of the formula II in which A is a radical - (CHp) p- are prepared starting from products of the; Formula M ¹
0

OR
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which are obtained starting from products of the formula B ¹ according to the scheme given above.

The products of the formula Ha ¹

Ila ¹ (Ha, with R ₆ = OCOR ". ,,

in which R and m. have the meanings given above, R "... denotes either an alkyl radical having 1 to 3 carbon atoms which is substituted by a carboxyl group or a phenyl radical which is substituted by a hydroxyl radical which is free or by an acyl radical having 2 to 4 carbon atoms or is protected by a group which can be easily removed by hydrolysis and A represents a single bond, as described below, starting from products of the formula A ¹

OCH

CO ₂ AXk

CHO

wherein Alk is an alkyl radical having 1 to 4 carbon atoms, are produced.

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73.

The product A ^{1, in} turn, can be prepared according to the process described in French patent application number 75-56161 of November 26, 1975, which is characterized in that the product of the formula

the action of dihydropyran to obtain the product of the formula

H ₂ C CH-CII ₂ -O

which product is subjected to an acetylalkyl acetate of the formula

CH ₅ COCH ₂ CO ₂ AIk

treated in the presence of a strong base such as a mixture of sodium hydride and butyllithium to give a product of the formula

. OH

to obtain which product is treated with an oxidizing agent such as the chromic acid pyridine complex to obtain the product of the formula

AlIcO ₂ C

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to get what product you can with a base like potassium bicarbonate treated to a product of the formula '

-CH ₂ -O

to obtain which product is treated with hydrogen in the presence of a catalyst such as palladium on charcoal a product of the formula

to obtain which product is treated with an acid such as oxalic acid to obtain a product of the formula

CO ₂ AlIc

to obtain which product is subjected to the action of diazomethane to obtain a product of the formula

OCH ₅

> ^ v ^, CO ₂ AIk

vT

^^ - CH ₂ OH

70983 970931

to obtain which product is treated with an oxidizing agent such as the chromium oxide-pyridine complex to give the desired product of the formula A ¹

OCH

CO ₂ AIk

CHO

to obtain.

To prepare the products of the formula Ha ¹ , the product A ^{1 is allowed to act} in the presence of a strong base such as sodium hydride, for example dimethyl (2-oxononyl) phosphonate, to give a product of the formula

OCH

to get which one with a reducing agent like
Zinc borohydride treated to form a product of the formula

OCH

MI

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in the form of a mixture of its two constituents, which is separated into its two constituents, the hydroxyl function of which can be protected with a tetrahydropyranyl radical and which is first with an acid such as hydrochloric acid, then with a reducing agent such as L-Selectride and finally with a base such as Treated sodium hydroxide solution, which is optionally followed by an acidic treatment, for example with monosodium phosphate, in order to obtain a product B ₁

to obtain, wherein R is a hydrogen atom or an alkyl radical means having 1 to 4 carbon atoms. The products of the formula B ~ are finally obtained in this way

B,

in which m. has the meaning given above by using the methods analogous _{to those leading to products of the formulas B 1 and E.}

The products Ha ¹ , in which A is a single bond, are then produced by the action of either an anhydride of the formula

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R "'

or an acid or a functional acid derivative of the formula

to products B ₂ , which is optionally followed by hydrolysis under the conditions identical to those for the synthesis of products I ¹ C and IG, prepared from products I ¹ B.

The products of the formula Ha ¹ , in which A is a radical - (CHg) ₂ -, are prepared by the action of the same reactants as above on the products of the formula B ' _o

B '

manufactured.

Finally, the products of the formula II which contain no double bond are obtained by hydrogenation of the corresponding products with a double bond.

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The products of the formula II “can be used in the same way

η
are prepared as indicated above for the corresponding products of the formula II, but using the product B

that has been described above, or the products B'p, wherein m. the number 6 means, i.e. the products of the formula

used.

The manufacturing methods can be summarized as follows: one can

hydrogenate either the products B ₁ or B 'with hydrogen in the presence of a catalyst to obtain products which do not contain a double bond

or the same products can be treated with an oxidizing agent in such a way that the allyl alcohol is selectively oxidized to obtain the products in which R and R _{1 represent} a keto group and then the products thus obtained with an organometallic derivative to obtain the products in which

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- ye. -

R is an alkyl radical, treat

or the products of the formulas B ₁ or B'g, whose allylic hydroxyl function is protected by a tetrahydropyranyl radical, can be treated with 2,4-dinitrobenzenesulfinyl chloride in order to obtain the products in which R ₁ and R'g are a radical

means.

The acids corresponding to the esters obtained are prepared by saponification using conventional methods.

The following examples illustrate the invention without restricting it.

Example 1 : Lactone of (1RS, 2SR, 5RS, 3 * SR) (I'E) -2-hydroxy-5- (3'a-tetrahydropyranyloxy-1'-octenyl) -cyclopentanecarboxylic acid.

600 mg of (1RS, 2SR, 5RS, 3 ¹ SR) (1'E) -2-hydroxy-5- (3'ct-tetrahydropyranyloxy-1'-octenyl) -cyclopentanecarboxylic acid, 12 enr anhydrous chloroform, 1 cmr triethylamine are added and 402 mg of tosyl chloride. It is stirred for 4 hrs. At 20 ⁰ C, poured into a solution of sodium acid phosphate, decanted, extracted with methylene chloride and evaporated to dryness in vacuo.

This gives 700 mg of product which was chromatographed on silica gel with a

.Cyelonexane-ethyl acetate-triethylamine mixture (75: 25: 0.1) eluted. 336 mg of the expected β-lactone are obtained.

The (iRS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3 ¹ a-tetrahydropyranyloxy-1'-octenyl) -cyclopentanecarboxylic acid used as starting material in Example 1 is prepared as follows: Step A: Ethyl- (1RS, 2SR.5R3,3'SR) (1 'E) -2-hydroxy-5- (3 ^f ct-tetrahydropyranyloxy-1'-octenyl) -cyclopentanecarboxylate:

A mixture of 14 g of ethyl 3- (3'octetrahydropyranyloxy-trans-1'-octenyl) cyclopentanone-2-carboxylate , 200 cnK of isopropyl alcohol, 20 cm ^ of water and 5.6 g of sodium is stirred for 2 hours -

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borohydride, slowly adds acetone to the mixture and then poured into a saturated aqueous solution of monosodium phosphate.

It is filtered, brought to dryness and taken up in ethyl acetate. It is washed with water and dried and then the solvent is evaporated. The residue is chromatographed on silica, eluting with a cyclohexane-ethyl acetate mixture (8: 2) with 0.1 % triethylamine, and 5.4 g of the expected α-OH (2SR) isomer is obtained.

Level B; (1RS, 2SR, 5RS, 5'SR) (1'E) -2-hydroxy-5- (3'a-tetrahydropyranyloxy-1'-octenyl) -cyclopentanecarboxylic acid:

The mixture is stirred for 5 hrs. At 2O ⁰ C a mixture of 5.1 g of the ester obtained in Stage A, 50 cnr methanol and 8.15 cnr 2N sodium hydroxide solution, then the solvent is evaporated off at 55 to 40 ⁰ C, decreases with Water, washes with ether, saturates the solution with sodium chloride and then acidifies with hydrochloric acid. Extract with ether, wash with water, dry and evaporate the solvent. 2.6 g of the expected product are obtained.

Example 2: Lactone of (1RS, 2SR, 5RS, 5'SR) (1'E) -2-hydroxy-5- (5 * -hydroxy-1 «octenyl) -cyclopentanecarboxylic acid:

556 mg of β-lactone obtained in Example 1 are dissolved in 10 volumes of acetic acid with 20 % water in the presence of 5 mg of sodium iodide. It is left for 16 hours at 20 ° C., poured into water, extracted with methylene chloride, washed with sodium bisulfite and dried, and 280 mg of product is obtained, which is chromatographed on silica gel with a cyclohexane-ethyl acetate mixture (75:25). 16O mg of the expected product are obtained.

709839/0931

Example 3: Lactone of (1RS, 2SR, 5RS, 3 ¹ SR) (I ¹ E) -2-hydroxy-5- (3 * -ot-hemiphthaloyloxy-1'-octenyl) -cyclopentanecarboxylic acid:

One brings 16O mg of the ß-lactone obtained in Example 2, 1.6 cnr pyridine and 200 mm phthalic anhydride. It is left for 9 hours at room temperature. It is poured into ice-cold hydrochloric acid, extracted with ether, washed, extracted the organic phases with 10 tiger bicarbonate, dried the ethereal phases and evaporates to dryness in a vacuum. The alkaline aqueous phases are acidified with η-hydrochloric acid. Extract with ether and evaporates to dryness in a vacuum. The acidic fraction is chromatographed on silica gel with cyclohexane-ethyl acetate (1: 1). 172 mg of the expected product are obtained in the form of a colorless resin that crystallizes.

IR- . ^ C-
Spectrum "- ^ = 0 : 1828
1811 cm
cm -1
-1. j β-lactone - 1725
1708 cm"
cm" - 1
. 1 I. Ester + acid. aromatic: : 1603
1583
1491 cm
cm"
cm" - 1
• 1
■ 1 •

Example 4 : Lactone of (1RS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3'-hydroxy-3'-ethyl-1'-octenyl) -cyclopentane-carboxylic acid:

530 mg (1RS, 2SR, 5RS, 3'SR) (1Έ) -2,3'-dihydroxy-5- (3'-At ^ TIyI-I ¹ -octenyl) -cyclopentane-carboxylic acid, 5.3 em - * chloroform, 0.78 cnr triethylamine and 430 mg tosyl chloride. The mixture is stirred for 30 min. At +5 ⁰ C and leaves at 20 ⁰ C return. It is left for 1 hour, poured into water mixed with acidic sodium phosphate, washed with water and extracted with methylene chloride. It is dried and chromatographed on silica gel with benzene-ethyl acetate (80:20) and 106 mg of the expected product are obtained.

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Rf. = 0.4.

Example 5 : Lactone of (1RS, 2SR, 5RS, 3'RS) (1'E) -2-hydroxy-5- (3'-hydroxy-3 ^1- ethinyl-1'-octenyl) -cyclopentane-carboxylic acid:

720 mg (1RS, 2SR, 5RS, 3 ¹ RS) (1 ^f E) -2-hydroxy-5- (3'-hydroxy-3'-ethinyl-1 '-octenylj-cyclopentane-carboxylic acid, 7 * 2) are added CRRR chloroform, 1.44 cnr triethylamine and 586 mg tosyl chloride a. the mixture is stirred at 20 ⁰ C under nitrogen. pour mixture sodium phosphate to a water treating. It is washed with water, extracted with methylene chloride, dried and evaporated to dryness to obtain ca 1 g of product which is chromatographed on silica gel with a benzene-ethyl acetate mixture (80:20) to give 128 mg of the expected product, Rf = 0.4.

The (1RS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3 ¹ -hydroxy-3 ^1- ethinyl-1'-octenyl) -cyclopentane-carboxylic acid used as the starting substance of Example 4 and the (1RS, 2SR, 5RS, 3'RS) (1'E) -2-hydroxy-5- (3 * -hydroxy-3 ¹ -äthinyl-1 ¹ -octenyl) -cyclopentan- carboxylic acid were made as follows:

Level A: Ethyl- (1RS, 2SR, 5RS, 3 'SR) (I' E) -2-hydroxy-5- (3'-hydroxy-1 ¹ -octenyl) -cyclopentane-carboxylate:

572 mg of ethyl 3- (3'-a-hydroxy-trans-1'-octenyl) cyclopentanone-2-carboxylate, 23 cm of ethanol, 2.3 cm of water and 85 mg of sodium borohydride are mixed in, and the mixture is stirred for 2 hours 5 ⁰ C, adds a few drops of acetone and then pours into a saturated monosodium phosphate solution.

It is filtered, the solvent is evaporated off, taken up in ethyl acetate, washed with water, dried and evaporated to dryness. 520 mg of a mixture of the 2oc-OH and 2ß-OH isomers are obtained, which are chromatographed by chromatography on silica, eluting with methylene chloride containing 2% methanol. 203 mg of the desired isomer are obtained.

709839/0931

Level Bt Sthyl- (iRS _f 2SR, 5RS) (rE) -2-hydroxy-5- (3'-oxo-1 ^l -octenyl) -cyclopentane-carboxylate:

Bring 1 g of the product obtained in stage A in 20 cn? Dioxane and adds 1.6 g of dichlorodieyanochihon. The mixture is stirred for 20 hours at room temperature. It is suctioned off and then rinsed. It is washed with N / 10 ice-cold sodium hydroxide solution until a pH of 9 is achieved. It is filtered, washed with water and dried, and 987 mg of crude product is obtained. It is chromatographed on silica, eluting with cyclohexane-ethyl acetate (1: 1). 930 mg of the expected product are obtained.

Level C : Ethyl- (1RS, 2SR, 5RS, 3'SR and RS) (I ^f E) -2-hydroxy-5- (3 * -hydroxy- '-äthinyl-1'-octenyl) -cyclopentane-carboxylate:

2.1 g of the product obtained in stage B and 2.1 cnr * tetrahydrofuran are introduced. The mixture is heated at 38 ⁰ C and has a rapid and 45 cnr an N-Äthinylmagnesiumbromidlösung in tetrahydrofuran is heated to 40 ⁰ C, a. The mixture is stirred for 30 minutes at 38 ^° C. It is poured into an ammonium chloride solution in ice-cold water, extracted with methylene chloride, washed with water, dried, filtered and evaporated to dryness. Chromatography on silica using an eluent consisting of methylene chloride and ethyl acetate (85:15) gives 1.67 g of the expected product.

Level D: ( 1RS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3'-hydroxy-3'-ethinyl-1 ^l -octenyl) -cyclopentane-carboxylic acid and (1RS, 2SR, 5RS, 3 ¹ RS) (i'E) -2-hydroxy-5- (3'-hydroxy-3 * -ethinyl-1'-octenyp-cyclopentane-carboxylic acid:

1.67 g of the ester obtained in stage C, 17 cnr ethanol and 8.5 cnr N sodium hydroxide solution are introduced under nitrogen. The mixture is stirred 2 hrs. At 20 ⁰ C, poured into water, extracted with ether, washed with N / 2 sodium hydroxide solution, then with water, dried, filtered, and obtained 0.37 g of a group consisting of impurity fraction.

709839/0931

The aqueous phases are collected, acidified with monosodium phosphate, extracted with ether, washed with water, dried and evaporated to dryness, and 1.33 g of product are obtained. The two isomers are separated by chromatography under pressure in isopropyl ether containing 4% acetic acid.

530 mg of 0H-a- (3 ¹ SR) -isomer with an Rf. = 0.15 and 720 mg of 0H-ß- (3'RS) -isomer with an Rf. = 0.10 are obtained.

Example 6: Lactone of (1RS, 2SR, 5RS) (1'E, 3'E) -2-hydroxy-5- (1 ', 3'-octadienyl) -cyclopentane-carboxylic acid;

150 mg of the β-lactone prepared in Example 2 are added in 3 cnr benzene, add 15 mg paratoluenesulphonic acid and heat to 40 ° C. for 3 hours under nitrogen. You neutralize with 150 mg sodium carbonate, filtered and evaporated the Solvent off. One receives 139 mg of an oil, which one to Chromatographed silica, eluting with cyclohexane-ethyl acetate (95: 5).

36 mg of pure product are obtained. Rf. = 0.25, cyclohexane-stylacetate (90:10).

IR spectrum (chloroform ^

1830 cm "]

1816 cm "shoulder - -'- - -

993'cm " ¹

UV spectrum in ethanol. ^ V ₅ -

1 % -1

Inflexion = 227 nm E. = I3IO cm

ι cm

Maximum = 232 nm E ¹ ^ = 1410 cm £ = 31,000

1 cm

Inflexion = 239 nm E ¹ * = 1044 cm * " ¹

1 cm

709839/0931

Example 7 : Lactone of (IRS ^ SR ^ RS,? ¹ SR) (I 'E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) -cyclopentane-proplonic acid:

Add 390 rag (1RS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3'-hydroxy-1'-octenylj-cyclopentane-propionic acid, 3 cnr anhydrous nitromethane, 0.3 cnr pyridine and 300 mg of a dicyclohexylcarbodiimide. the mixture is stirred 16 Stdn.bei 20 ⁰ C. It is suctioned off, washed with ether and dried. the organic phase is poured into water, decanted, extracted with ether, washed with water and evaporated to dryness It is chromatographed on silicon dioxide in cyclohexane-ethyl acetate (1: 1) and 173 mg of homogeneous product is obtained.

Example 8 : Lactone of (1RS.2RS.5RS.VSRU1 'E) -2 -Hydroxy - ^ - (V-hydroxy-1' -octenyD-cyclopentane-proplonic acid ;

One starts from 405 mg (1RS, 2RS, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) -cyclopentane-propionic acid, 3 cnr nitromethane, 0.3 cnr pyridine and 300 ng dicyclohexylcarbodiimide, whereby one as works in Example 7 and receives 188 mg of pure product.

The (iRS, 2SR, 5RS, 3 ^l SR) (i ^l E) -2-hydroxy-5- (3'-hydroxy-i'-octenyl) -cyclopentane propionic acid and (1RS, 2RS, 5RS, 3 ¹ SR ) (1'E) -2-Hydroxy-5- (3'-hydroxy-1'-octenyl) -cyclopentane-propionic acid, which were used as starting materials in Examples 7 and 8, respectively, were prepared as follows:

Stage A: ( 5RS, 3'SR) (I'E) -1-ethyl carboxylate-2-oxo-5- (3 ^f -a-tetrahydropyranyloxy-1'-octenyl) -cyclopentane-proplonate:

1.113 B 3- (3'-a-tetrahydropyranyloxy-trans-1'-octenyl) -cyclopentanone-2-carboxylic acid ethyl ester and 3 cnr anhydrous ethanol are brought under a nitrogen atmosphere. Is then added to 0.23 ⁵ cnr sodium ethylate in ethanol (0.22 N), and then added 303 mg of ethyl acrylate to. The mixture is left for 2 hrs. At 25 ⁰ C and then for 1 h. Under reflux. It is cooled to ⁰ ° C. and then poured onto an ice-cooled solution of monosodium phosphate. It is extracted with ether, washed with water, dried and the solvent is evaporated off in vacuo. The product obtained is on

709839/0931

-η.

Silica gel using an eluent consisting of cyclohexane-ethyl acetate and triethylamine (80: 20: 0.1) _? chromatographed. 1.13 g of the expected product are obtained.

Level B: (1RS, 5RS, 3'SR) (1'E) -2-0xo-3-carbethoxy-5- (3'-q-tetrahydropyranyloxy-1 '~ octenyl) -cyclopentane-propionic acid ethyl ester:

2.1 cnr of a 1.02 N sodium ethylate solution in ethanol is poured over 0.93 g of the product prepared in step A. The mixture is refluxed for 4 hours, 10 cnr toluene is added and the ethanol is distilled off. The mixture is cooled to -20 ⁰ C., falls out of monosodium sulfate in an ice-cooled solution, extracted with ether, the organic phases are washed with water, and dried to give 940 mg crude product which was on silica using a cyclohexane-ethyl acetate (6θ: 4θ) cleans the existing eluent. 680 mg of the expected pure product are obtained.

Level C: CiRS _t 5RS _> 3'SR) (i'E) -2-0xo-5- (3'-a-tetrahydropyranyloxy-1'-octenyl) -cyclopentane-propionic acid methyl ester:

Bringing 1.5 g of the product prepared in Step B 20 cnr methanol and adds 9.6 cnr η-sodium hydroxide solution, leaving at room temperature and then heated for 12 hrs. At 40 ⁰ C. The mixture is concentrated to dryness, taken up in a mixture of water and ethyl acetate, cools, acidifies, extracted with ethyl acetate, washed with water, then evaporated to dryness and obtained 1.225 g of product, which was dissolved in 20 cnr benzene. One then brings

t hrs. to reflux and get 1.2 g of product, which one takes up in methylene chloride with a drop of triethylamine and esterified with diazomethane. An oil is obtained that has silicon dioxide chromatographed while eluting with an ethyl acetate-cyclohexane mixture (50:50). 852 mg of the expected product are obtained

709839/0931

<ff-

Stage Dt (iRS, 2SR, 5RS, 3'SR) (i'E) -2-hydroxy-5- (3'-tt-tetrahydropyranyloxy-1'-octenylj-cyclopentane-propionic acid methyl ester and (1RS, 2RS, 5RS, 3'SR) (I'E) -2-hydroxy-5- (3'-oc-tetrahydropyranyloxy-1 '-octenyD-cy'clopentanproplonic acid diethyl ester;

2.165 g of the product obtained in step C and 21 cnr of methanol are placed under nitrogen. 220 mg of sodium borohydride are added at ⁰ ° C. over the course of 1 hour and the mixture is stirred for 1 hour, 30 cnr of water and 3 g of monosodium phosphate are added, the mixture is extracted with methylene chloride, washed with water and dried. This gives 2.014 g product containing the two isomers are separated on silica eluting with a mixture of Essence G (petroleum ether fraction with bp. Between 35 and 70 ⁰ C) and ether (50:50).

329 mg of 2SR isomer and 1.143 g of 2RS isomer are obtained.

Stage E: (1RS, 2SR, 5RS, 3'SR) (I'E) -2-hydroxy-5- (3'-hydroxy-1 ^f -octenyl) -cyclopentane-proplonic acid methyl ester;

458 mg of the 2SR isomer obtained in stage D are added, 4.6 cnr methanol, 0.46 cnr water, and 46 mg oxalic acid. Man heated to 40 ° C for 4 hours.

Stage Ft (iRS, 2SR, 5RS, 3'SR) (i ^t E) -2-hydroxy-5- (3'-hydroxy-1 ^l -octenyl) -cyclopentane-propionic acid

Bringing at 40 ⁰ C under nitrogen for 3 cnr * N sodium hydroxide solution to the resulting solution of the 2SR isomer according to the procedure described in Step E, a. The mixture is warmed to 40 ° C. for 2 hours, poured into water containing monosodium phosphate, extracted with ethyl acetate, washed with water, dried, filtered and evaporated. 390 mg of the expected crude product is obtained.

709839/0931

-44-

Level G: (1RS, 2RS, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) -eyelopentane-propionic acid:

479 mg of the 2RS isomer obtained in stage D are added, 5 cnr methanol, 0.5 cnr water and 50 mg oxalic acid. Man Stir for 3 hours at 40 ° C and add 3 cnr η-sodium hydroxide solution and stir again for 3 hours at 40 ° C. It is acidified with monosodium phosphate on, extracted with ethyl acetate, washed with water, dried and obtained 405 mg of the expected product.

Example 9: Lactone of (1RS, 2SR, 5RS) (1 ^l E) -2-hydroxy-5- (3'-oxo-1'-octenyl) -cyclopentane-carboxylic acid;

Bringing while purging with dry nitrogen for 15 cnr dry methylene chloride and 1.5 cnr of anhydrous pyridine and added slowly at 20 ⁰ C, with cooling to 900 mg chromium oxide. The mixture is stirred for 15 minutes and then 358 mg of lactone of (1RS, 2SR, 5RS, 3 ¹ SR) (T ¹ E) -2-hydroxy-5- (3'-α-hydroxy-1'-octenyl) - cyclopentane-carboxylic acid (obtained in Example 2), dissolved in 15 cnr methylene chloride.

The mixture is stirred for 2 hours at 20 ° C. and then 4 g of C elite and 15 cnr methylene chloride added. It is filtered, the filtrate is concentrated in vacuo and the pyridine is driven off by rinsing with it Nitrogen and receives 375 mg of a brown oil. It is chromatographed on silica using a mixture eluted by cyclohexane-ethyl acetate (6: 4). 329 mg are obtained of the expected product. Rf. = 0.45

^ C = O β-lactone '1826 cm
conjugated system

709839/0931

Example 10; Lactone of (iRS, 2SR, 5RS, 3'SR) -2-hydroxy-5- (3'-hydroxyoctenyl) -cyclopentane-carboxylic acid:

105 mg of lactone are introduced into a hydrogenation apparatus (1RS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3'-a-hydroxy-1'-octenyl) -cyclopentane-carboxylic acid (obtained in Example 2), which is dissolved in 10 cm of ethyl acetate. 20 mg of 5% palladium are added towards activated charcoal.

■ x

It is hydrogenated for 7 hours (absorption of 10.4 cmr of hydrogen), The catalyst is filtered off with suction, the filtrate is concentrated in vacuo and the remaining oil is chromatographed on silicon dioxide, with it is eluted with a mixture of cyclohexane and ethyl acetate (50:50). 97 mg of the expected product are obtained. Rf. = 0.35.

-•1 - ·

.IR spectrum C = O 1800 cm -j absence of C = C-trans

OH 5600 cm "*

Example 111 Lactone of (1RS, 2SR, 5RS, 3'RS) (1'E) -2-hydroxy-5- (3 * -hydroxy-3 ^1- ethenyl-1'-octenyl) -cyclopentane-carboxylic acid:

45 mg of 4.75% palladium on barium sulfate in 5 cm of ethyl acetate are saturated with hydrogen at atmospheric pressure. 150 mg of Laeton of (1RS, 2SR, 5RS, 3'SR) (1 ^l E) -2-hydroxy-5- (3 ^t -hydroxy-I'-ethinyl-i'-octenylJ-cyclopentane-carboxylic acid (obtained in Example 4), 10 mg of quinoline and 1 cn of ethyl acetate are added, and the mixture is hydrogenated at 21 ° C. After 30 minutes, 14.3 cn * of hydrogen is absorbed, the catalyst is filtered off, the solution is washed with 0.1 N hydrochloric acid and then with salt water The organic phase is dried and evaporated, and 153 mg of crude product is obtained.

709839/0931

The product is chromatographed on silica with a mixture of benzene and ethyl acetate (80:20) and purifying by preparative chromatography on plates using the same eluent. Man receives 110 mg of crude product. Rf. = 0.41.

The IR spectrum shows the absence of CsCH and its presence of the ß-lactone of ethenyl and hydroxyl groups.

NMR spectrum U) H _n (CDcI, 6OiAH ₁ 6.2 ppm s). = ^CH 2 (egg ) 5 ppm (triplet J = 5Hz) y ^ u) 4Hz / .H ( e) ■■ - : 0.88 (a) . 1.51 PPra (e) /? N ⁰ * "" ^ (b) 5.1 ppa _(e) CH (c) s ppm (triplet J = (d): Düblet tr- 3.8 ppm J = (e) '. 5.16 (f) s 3Hz

Example 12 : Lactone of (1RS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3 ^f -hydroxy-3'-ethenyl-1'-octenyl) -cyclopentane-carboxylic acid;

By working exactly as in Example 11 and adding 150 mg of lactone of (1RS, 2SR, 5RS, 3'RS) (1 'E) -2-hydroxy-5- (3'-hydroxy-} ¹ ethinyl-1'- octenyl) cyclopentane carboxylic acid (obtained in Example 5), 127 mg of pure product are obtained.

709839/0931

The IR spectrum shows the absence of C = C and its presence of ß-lactone and of ethenyl and hydroxyl groups.

NMR spectrum ( OP C ^ , 60 IiIIz )

(β) Η

(b) (c) (a) (e) (f) (ß)

CH, (a)

(a): 0.88 ppm 1.51 ppm 3.1 ppm doublet, 3.8 ppm 5.16 to 5.61 ppm, 5.16 to 6.2 ppm 5 ppm (triplet)

\ JHH (e) (e)

= 4 Hz

Example 13: Lactone of (1RS, 2SR ₁ 5RS, 3 ¹ SR) (I. ¹ E. ) -2-Hydroxy- ^ - (3 ^f -acetoxy-1'-octenyl) -cyGlöpentan-oarboxylic acid:

A mixture of 0.2 g of lactone of (1RS, 2SR, 5RS, 3 ^f SR) (I'E) -2-hydroxy-5- (3'-a-hydroxy-1 'is stirred at room temperature for 2 hours. -octenylj-cyclopentane-carboxylic acid (raise in Example 2), 2 cnr methylene chloride, 0.47 cnr triethylamine and 0.091 cnr acetic anhydride as well as some dimethylaminopyridine grains.

3 cnr of water are added and the mixture is acidified with monosodium phosphate a pH of 5 and extracted with methylene chloride. One dries evaporated to dryness under reduced pressure and obtained 266 mg

709839/0931

of a crude oil obtained by chromatography on silica eluting with a mixture of cyclohexane and Ethyl acetate (60:40) purifies. This gives 211 mg of pure Product. Rf. = 0.5.

IR spectrum : \ -.

^ CJ = 0 complex 1808 "to 1824 cmr- \ . '

Ester 1725 cm-1 · NMR spectrum ■ ( 60 MHz

(e) H.

(c) Η

(a) (b) Cc) (d) (e) (f)

Ö-C-CH, ■ 0 (b

CH ₅ (a)

0.88 ppm

2.03 ppm

centered triplet at 3.08 ppm J = 5Hz centered doublet at 3.78 ppm J »

centered triplet at 5.01 ppm J = 5.15 ppm

709839/0931

Example 14 ; Hemlsuccinate of the lactone of (1RS, 2SR, 5RS.3 * SR) (1'E) -2-hydroxy-5- (i'-octenyl-3'-hydroxyj-cyclopentane-carboxylic acid;

119 mg of lactone of (1RS, 2SR, 5RS, 5 ¹ SR) (1 * E) -2-hydroxy-5- (3'-a-hydroxy-1'-octenyl) -cyclopentanecarboxylic acid (obtained in Example 2), 2 cnr anhydrous methylene chloride, 100 mg succinic anhydride, 0.15 cnr pure triethylamine and 15 mg 4-dimethylaminopyridine.

The mixture is refluxed for 8 hours and the solvents are then evaporated off. Add 2 cnr abs. Ethanol and leaves for 1 hour. at room temperature. Excess succinic anhydride is removed in the form of ethyl hemisuccinate. It is evaporated in vacuo and 226 mg of crude product are obtained.

Chromatograph on silica using pure ethyl acetate. 1-2 mg of pure product are isolated. Rf. = 0.5.

NMR spectroscopy

(C) H.

(a)
M.
(c)
(d)
(e)

CH ₅ (a)

OH

: 0.88 ppm: 2.63 ppm : 3.08 ppm: 5.2 ppm: 5.04 ppm

(f): 5.33 ~ 5.58 ppm

709839/0931

Example 15 : Lactone of (1RS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3'-hydroxy-1'-decenyl) -cyclopentane-carboxylic acid:

0.1-5 g (1RS, 2SR, 5RS, 3 ¹ SR) (1 'E) -2-hydroxy-5- (3'-hydroxy-1'-decenylj-cyclopentane-carboxylic acid in 4 cnr chloroform, 0.315 g of triethylenediamine and 0.16 g of tosyl chloride in. The reaction takes place immediately. It is poured into water and extracted with ethyl acetate. After the treatment, 183 mg of an oil is obtained which is chromatographed on silica using a mixture of cyclohexane and Ethyl acetate (60:40) eluted, giving 41 mg of pure product, Rf. = 0.25.

IR ^ 3pek-trum

^ = O complex 1808 bis

NMR- (CDCl

1824 c

ra- ^.

973 cm-

(
spectrum

.CH, CaJ

α jn. H
(ß) (f) V, _N
OH (c) ^: (a) '. 0.88 PPm (b) j • 1.3 ppm (c) « i 1.53 PPm (d): - 3.08 ppm 4Hz) (e): 3.78 PPm (Doublet J = U): 4.05 PPm 5Hz) (ß) s 5.47 PPm (Doublet. J = (h) i 5.01 PPm (Triplet)

709839/0931

The (1RS, 2SR, 5RS, 3'SR) (I ¹ E) -2-hydroxy-5- (5'-hydroxy-1'-decenyl) -cyclopentane-carboxylic acid used as starting material in Example 15 was prepared as follows:

a) 1,2-epoxy-3-a-tetrahydropyranyloxy-propane ;

A solution of 3.9 g of glycidol (2,3-epoxy-i-propanol), 18.5 cnr dihydropyran and 150 mg of para-toluenesulfonic acid is warmed to 40 ⁰ C.

After 30 minutes, another 150 mg of paratoluenesulfonic acid are added and then neutralized after 15 minutes at room temperature with potassium carbonate. It is filtered and washed with ethyl acetate and the solvents are driven off under reduced pressure. 8.48 g are obtained of the expected product. Rf. = 0.6 (cyclohexane-ethyl acetate 8: 2).

b) 3-Keto-6-hydroxy-7-α-tetrahydropyrarfyloxy-heptanoic acid methyl ester

An 8 cnr Acetylessigsäuremethylester and 16 enr of anhydrous tetrahydrofuran solution containing one added during 30 min. In a maintained at 0 ⁰ C. A suspension of 3.554 g of sodium hydride (50 # suspension in oil) in 16 cnr of anhydrous tetrahydrofuran is added.

One brings 39 cm- 'butyllithium into the mixture ^{at 0 ° C. over a period of 30 minutes.} It is stirred for 1.2 hrs. And then leaves at -70 ⁰ C.

The solution is for 45 min. In a solution of ^{0 0} C, which contains 5.8 gi ^ -Epoxy ^ -cc-tetrahydropyranyloxy-propane, prepared in stage a)> and 16 cnr tetrahydrofuran. The mixture is stirred for 3 hours and 30 minutes. It is poured into an excess of a conc. and ice-cold solution of monosodium phosphate, stir for 10 min., then extracted with ethyl acetate and washed until neutral. After evaporation of the solvent, 16.9 g of oil are obtained and then purified on silicon dioxide (cyclohexane

709839/0931

Ethyl acetate 6: 4). 8.02 g of pure product are obtained. Rf. = 0.15

c) ^ jä-Dioxo-Tg-tetrahydropyranyloxy-heptanoic acid methyl ester:

6 g of chromic acid are slowly brought into a solution of 9.7 cnr Pyridine in 148 cnr methylene chloride. Stir for 15 minutes then brings 1.1 g of the product obtained in step b) in solution in 10 cnr methylene chloride. After 15 minutes you add Add 150 cm ^ ether, filter the precipitate, wash with ether and evaporates the solvents. 1.} g of crude product is obtained, which is obtained by chromatography on silicon dioxide (methylene chloride-ethyl acetate 8: 2) cleanses. 473 mg of pure product are obtained. Rf. = 0.45.

d) g- (q-Tetrahydropyranyloxy-methyl) -5-oxo-1-cyclopentene-carboxylic acid methyl ester:

291 mg of potassium bicarbonate in solution in 72 cm- ^{5 of} distilled water and 220 mg of crude product obtained in stage c) in solution in 2.4 cm of methylene chloride are stirred vigorously. After 1/2 hour the mixture is acidified to pH 3 with oxalic acid, then saturated with sodium chloride and extracted with methylene chloride. After evaporation, 205 mg of the expected product are obtained.

e) (iRS, 5SR) -2-0xo-5- (cc-tetrahydropyranyloxymethyl) -cyclopentanecarboxylic acid methyl ester:

A 215 mg of the in stage d) is stirred under a hydrogen atmosphere solution containing the product obtained, 10 cnr of methanol and 21 mg of 10% palladium on activated charcoal. The theoretical volume is absorbed after 45 minutes. It is filtered, washed with ethyl acetate, the solvent evaporates and 172 mg of an oil is obtained which is chromatographed on silica (cyclohexane-ethyl acetate 50:50). 122 mg of the expected product are obtained.

709 8 3 9/0931

f) ( iRS, 5SR) -2-Oxo-5-hydroxymethyl-cyclopentane-carboxylic acid methyl ester:

A mixture of 43 g of the product obtained in step e), 860 ml of methanol, 86 ml of water and 12.7 g of oxalic acid is added with stirring to 60 ° C. for 3 hours. One constricts under reduced Pressure at 40 ° C., taken up with chloroform, washed with water and dried. The solvent is evaporated and obtained 29.2 g of crude product, which is on silicon dioxide (cyclohexane-ethyl acetate 2: 8) chromatographed. 14 g of pure are obtained oil.

g) (5RS) -2-methoxy-5-hydroxymethyl-1-cyclopentene-carboxylic acid methyl ester;

The mixture is stirred at room temperature for 4 hours. 4 g of the in stage f) obtained ß-ketoester, 4 cnr methylene chloride and 50 cnr Diazomethane in solution in methylene chloride.

The solvent and the excess diazomethane are evaporated off and 4.3 g of a yellow oil are obtained, which is obtained with the following Implementation is used in raw form.

h) (5RS) -2-methoxy-5-formyl-1-cyclopentene-carboxylic acid methyl ester;

In small portions 25.5 g of chromium oxide are brought into solution, which is maintained at 15 to 20 ⁰ C, 41 ⁵ cnr pyridine in 400 * cnr anhydrous methylene chloride. It is stirred for 1/4 hr., The solution obtained is cooled to -15 ⁰ C., and add the 4.3 g of the product obtained in the preceding step product dissolved in methylene chloride 10 cnr to. After 1 hr. 30 min. Brings 50 g celite and 100 * cnr a ether, filtered, washed with ether and the solvents evaporated at 30 ⁰ C from.

i) ( 5RS) (i ^t E) -2-methoxy-5- (3 ^> -oxo-1'-decenyp-i-cyclopentene carboxylic acid methyl ester

A solution of 9.674 g of dimethyl (2-oxononyl) phosphonate in 20 cm ^{5 of glyme is suspended in the course of 10 minutes}

709839/0931

of 1.85 g of 50% sodium hydride in oil. After the introduction, 5 g of aldehyde prepared in step h) in solution in 30 cnr of glyme are added over a period of 20 minutes. The reaction is complete after 20 minutes. It is poured into a saturated monosodium phosphate solution and extracted with ethyl acetate. 13.2 g of oil are obtained, which are purified by chromatography on silica while eluting with cyclohexane-ethyl acetate (60:40) and 1 % triethylamine. 4.652 g of pure oil are obtained in this way. Rf. = 0.25.

-1

IR spectrum : ^ C = O max: 1651 cm
conjugated) C = C (1623 cm " ¹

J) ( 5RS, 3'SR) (1 ^t E) -2-methoxy-5- (3'-hydroxy-i'-decenyl) - i-cyclopentene-carboxylic acid methyl ester and (5RS, 3'RS) (1 ' E) -2-methoxy-5- (3'-hydroxy-1'-decenyl) -1-cyclopentene carboxylic acid methyl ester;

It is cooled to 0 ^° C. 4.6 g of the ketone obtained in stage i) in

-κ
Solution in 100 cnr glyme distilled over sodium and then add 200 cnr of a 0.13 M / l solution of zinc borohydride in glyme over 45 minutes. The mixture is allowed to return to room temperature and stirred for a further 4 hours. It is poured into a saturated monosodium phosphate solution and extracted with ethyl acetate. After the treatment, 7 * 3 g of oil are obtained. Two successive chromatographies are carried out on silica, eluting with a mixture of benzene-ethyl acetate (6O: 4O) and 1 % triethylamine.

901 mg of a- (3'SR) -isomer and 810 mg ß- (3'RS) -isomer and 503 mg mixture.

709839/0931

k) (1RS, 2SR, 5RS , 3'SR) (1'E) -a-hydroxy-S- (3'-hydroxy-1'-decenyl) -cyclopentanecarboxylic acid ;

α) hydrolysis of the enol ether

The mixture is stirred for 15 minutes. at room temperature a solution of 8.49 mg in step j) prepared 3'SR isomer in 3 cnr methanol and

2 cnr 0.1N hydrochloric acid. It is neutralized with 2 cnr 0.1N sodium hydroxide solution and extracted the aqueous phase with ether. After chromatography, 763 mg of a pure oil are obtained. Rf. = 0.32 (Benzene-ethyl acetate 60:40).

ß) Reduction of the ketone

Is added the above 763 mg dissolved in 4 cnr of tetrahydrofuran and 5 * 1 ^ cnr a molar solution of L-selectride to tetrahydrofuran, which is kept at ⁰ C -6O.

The mixture is stirred for 2 hours and 30 minutes at this temperature and hydrolyzed then by placing in a saturated monosodium phosphate solution poured and extracted with ethyl acetate. 1.7 g of a crude oil are obtained. Rf. = 0.25 (cyclohexane-ethyl acetate 40:60).

Saponification

The oil obtained above is stirred for 2 hours in the presence of

3 cnr ethanol and 2.4 cnr sodium hydroxide solution. You drive that out Ethanol and extracted with ethyl acetate. The aqueous phase is acidified to pH 5 by adding monosodium phosphate and extracted with ethyl acetate. The organic phases are washed with water and then dried. After the eviction of the solvent under reduced pressure, 365 mg of a colorless oil which is pure on the basis of chromatography are obtained. Rf. = Between 0.1 and 0.36 (ethyl acetate).

709 839/0931

NMR spectrum ( C3) Cl ~ 6O MHz)

• * · OH

■ (d) H.S.

H (b)

(a): 0.88 ppm.

(b): two centered J doublets at 2.4 and 2.59 ppm (J = 5Hz)

(c): 4.06 ppm

(α): 4.5 ppm. _. · · ·

Example 16; Lactone of (1RS _t 2SR, 5RS, 3 ¹ SR) (I'E) -2-hydroxy- ^ - (3'-g-hydroxy-1'-octenyl) -cyclopentane-carboxylic acid;

By working analogously to the manner described in Example 1, but replacing the triethylamine with diazabicyclooctane, the lactone of (1RS, 2SR, 5RS, 3 ¹ SR) (I'E) -2-hydroxy-5- ( 3'-a-tetrahydropyranyloxy-1'-octenyl) cyclopentane carboxylic acid which is treated as in Example 2 to obtain the expected product.

Pharmacological studies

The following terms were used in these investigations:

Product A : Lactone of (1RS, 2SR, 5RS, 3'SR) (I'E) -2-hydroxy-5- (3 ^1- hydroxy-1'-octenyl) -cyclopentane-carboxylic acid.

Product B: lactone of (1RS, 2SR, 5RS, 3 ¹ RS) (1'E) -2-hydroxy-5- (3 ¹ -hydroxy-3'-ethinyl-1'-octenyl) -cyclopentane-carboxylic acid.

Product C; Lactone of (1RS, 2SR, 5RS, 3 ¹ RS) (I'E) -2-hydroxy-5- (3 ¹ -hydroxy-3 ^1- ethenyl-1 · ', -octenyl) -cyclopentane-carboxylic acid.

Product D : lactone of (1RS, 2SR, 5RS, 3'SR) (1 ^f E) -2-hydroxy-5- (3 ¹ -acetoxy-1'-octenylJ-cyclopentane-carboxylic acid.

709839/0931

Product E ; Lactone of (1RS, 2SR, 5RS, 3 ^f SR) (1'E) -2-hydroxy-5- (5 ¹ -hydroxy-1'-decenylJ-cyclopentane-carboxylic acid.

ti, 1 ·) Hypotensive activity in the anesthetized dog

a) Method:

The study was carried out on adult bastard dogs of both sexes weighing 14 to 20 kg with closed Torax carried out. The animals are anesthetized by chloralose (125 mg / kg I.V.). The trachea is intubated and the animals were artificially ventilated via a pump.

Arterial pressure, expressed in mmHg, was measured on the Carotid removed with the help of a print head. The cardiovascular effects on the mean arterial were determined Pressure (diastolic pressure + 1/3 of the difference: systolic pressure - diastolic pressure) at doses from 10 to 1000 y / kg I.V. for the product A and from 30 to 1000 y / kg I.V. for the Product B.

The table below shows the maximum changes in mean arterial pressure and the time required was for the pressure to reach its initial value.

709839/0931

b) Results

Cans in PRODUCT A we
kungs
duration
in min. PRODUCT B 0 We-
kungsr-
duration
in
Min. . y / Kg
IV average
change
of the middle
arterial
Pressure
in % 8th average
changes
tion of the
middle
arterial ■
Pressure in % ^: 0 10 -4 5 - -8th - 50 -5 18th -17 - 100 -17 16.50 8.50 500 -25 57 20th 1000 -51

The products show interesting hypotensive activity at doses of 0.1 rag / kg for the product A and 1 mg / kg for the Product B.

A second study was carried out on adult bastard dogs of both sexes weighing between 14 and 20 kg closed torax. The animals are anesthetized by a mixture of barbituric acid.

709839/0931

The trachea is intubated and the animals are artificially ventilated with a pump.

The arterial pressure was taken from the carotid with the aid of a pressure head. You determined the dose, the one
Reduced the average arterial pressure of at least 20 % for at least 20 minutes.

The results are 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 physiological serum with 10 % ethanol. These solutions are administered intravenously to rabbits anesthetized with urethane and the carotid pressure is determined. The dose that lowers this pressure by 50 # became 20 jug / kg and for product E

found for product C to be 50 μg / kg.

709839/0931

Claims (1)

.Patent claims. 1.)! Products of the general formula I ¹ where the dotted line indicates the possible presence of a second bond, A represents a single bond or a radical - (CHp) ₂ -, R represents a hydrogen atom or a saturated or unsaturated alkyl radical with 1 to 4 carbon atoms, FL- represents a radical 0R ' _A » wherein R ' _{A is} a hydrogen atom, a tetrahydropyranyl radical, an alkyl radical having 1 to 3 carbon atomsj a radical COR "., in which R". either an alkyl radical having 1 to 3 carbon atoms, which is optionally substituted by a carboxyl radical, or a phenyl radical which is optionally substituted either by a carboxyl radical or by a hydroxyl radical which is free or by an acyl radical with 2 to 4 carbon atoms or by a slightly group removable by hydrolysis can be protected, or R and Rg together form a keto group, R "represents a radical - (CH ₀ ) -CE, in which m whole number, namely 3 »4» 5 or 6 means or R, - and R "together ^ \ () a radical ^ \ (CH ₀ ) -CH- ,, where n. is an integer, namely * ⁿ A ' ^A 2, 3, 4 or 5 means "form ^ the wavy lines indicate that the bonds may be in one or the other of the possible configurations, it being understood that when A represents a single bond, the Bond between the pentane ring and the oxygen atom is an α bond. 709839/0931 ORIGINAL INSPECTED 2.) Products of the general formula I where the dotted line indicates the possible presence of a second bond, A is a single bond or a radical - (CH ₂ ) ₂ -, R is a hydrogen atom or a saturated or unsaturated alkyl radical having 1 to 4 carbon atoms, R _{1 is} a radical OR ', wherein R ^{1 is} a hydrogen atom, a tetrahydropyranyl radical, an alkyl radical having 1 to 3 carbon atoms, a radical COR ", in which R" is an alkyl radical having 1 to 3 carbon atoms or a phenyl radical which is optionally substituted by a carboxyl group, or R and R ₁ together form a keto group, Rp is a radical - (CHp) -CH, where m is an integer, namely 3, 4 or 5, or R ₁ and Rp together are a radical , ^ X (CH ₂ J _n -CH, Mlden, where η is an integer, namely 2.3 one, the wavy lines indicate that the bonds can be in one or the other of the possible configurations, it being understood that when A is a single bond, the bond between the pentane ring and the oxygen atom is an α-bond. 3.) Products of the general formula I according to claim 2, wherein the dotted line indicates the presence of a second bond, A is a single bond or a radical - (CH ₂ J ₂ -, R is a hydrogen atom or an unsaturated alkyl radical having 2 or 3 carbon atoms R _{1 represents} a radical OR ¹ , in which R ^{1 represents} a hydrogen atom, a tetrahydropyranyl radical, a radical COR ", in which R" represents a phenyl radical substituted by a carboxyl group, R _{2 represents} a radical - (CH ₂ ) -CH, in which 709839/0931 m is 3> ^ or 5 is an integer, representing, or R. and R p together are a radical <^ \. ^(CH p ^ n ~ ^CH '5' ^form wherein η is an integer 'is 2,3 or 4 means. 4.) Products of general formula I according to claim 2, wherein the dotted line indicates the presence of a double bond, A is a single bond, R is a hydrogen atom or an unsaturated alkyl radical having 2 or 3 carbon atoms, R is a radical OR ¹ in which R ¹ is a hydrogen atom, R _{2 is} a radical ^(CH p) _m ~ ^C S ^represents> wherein m is an integer of 4 represents. 5.) Lactone of (1RS, 2SR, 5RS, 3 ^! SR) (1'E) -2-hydroxy-5- (3'-a-hydroxy-1'-octenyl) -cyclopentane-carboxylic acid. 6.) Lactone of (1RS, 2SR, 5RS, 3'SR) (I'E) -2-hydroxy-5- (3'-hydroxy-1'-decenylj-cyclopentane-carboxylic acid. 7.) Process for the preparation of products of the general formula I ¹ according to claim 1, characterized in that a product of the formula Ha Ha wherein A, R, Rg and R ~ have the meaning given in claim 1, exposed to the action of a reagent capable of forming functional acid derivatives. 8.) Process for the preparation of products of general formula I according to claim 2, characterized in that one is a Product of formula II 7,098 39/0 931 II wherein A, R, R ₁ and R _{2 have} the meaning given in claim 2, exposed to the action of a reagent capable of forming functional acid derivatives. 9.) The method according to claim 7 *, characterized in that the Reagent capable of forming functional acid derivatives is selected from the group consisting of tosyl chloride, alkyl chloroformates, Dicycloalkyl carbodiimides, dialkyl carbodiimides and thionyl chloride. 10.) The method according to claim 8, characterized in that the reagent capable of forming functional acid derivatives is selected from the group consisting of tosyl chloride, alkyl chloroformates, Dicycloalkyl carbodiimides, dialkyl carbodiimides and thionyl chloride. 11.) Method according to claim 7 or. 9, characterized in that one works in the presence of a base selected from the _group> consisting of the alkali metal carbonates, triethylamine, methylmorpholine, pyridine and Diazabicyclooctane. 12.) Process for the preparation of products of the general formula IB R 'OH 709839/0931 in which the wavy and dotted lines A and R have the meanings given in claim 2, corresponding to a product of the formula I in which R _{1 is} a radical OR ¹ , in which R 'is a hydrogen atom, and Rp is a radical - (CHp) - CH, means, characterized in that a product of the formula IA in which A, R and m have the meanings given above, corresponding to a product of the formula I in which R _{1 is} a radical OR ¹ , in which R ^{1 is} a tetrahydropyranyl radical and Rp is a radical "(CHp) -CH, the action of an acidic Undergoes hydrolysis reagent. 13 ·) Pharmaceutical compositions, characterized in that they contain at least one of the pharmaceutically acceptable products of the formula I ¹ according to the definition given in claim 1 as active ingredient. H.) Pharmaceutical compositions, characterized in that they as active ingredient at least one of the pharmaceutical acceptable products of the formula I according to the definition given in claim 2. 15.) Pharmaceutical compositions, characterized in that they are at least one of the pharmaceutical as active ingredient acceptable products of the formula I according to the definition given in claims 3 or 4. 709839/0931 16.) Pharmaceutical compositions, characterized in that they contain the product according to claim 5 as the active ingredient. 17) Pharmaceutical compositions, characterized in that that they contain the product according to claim 6 as active ingredient. 18.) Products selected from the group consisting of: a) the products of the formula CO ₂ H wherein the dotted line and the substituents R, R ₁ and have the meaning given in claim 2; b) deji products of the formula CH ₂ ) _n -CH ₃ wherein the wavy line and η have the meaning given in claim 2 and c) the products of the formula OH ., ACO ₀ H 70983.9 / 093 1 ^R in which the wavy lines and the substituents A, R and R _{1 have} the meanings given in claim 2, R ' _{2 is} a radical - (CH ₂ ) ^ CH, or R ₁ and R' ₂ together are a radical = CH- ( Form CH ₂ J ₅ CH ₃ . 709839/0931