DE2752523A1 - NEW CYCLOPENTAN DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS THEREOF - Google Patents

Description

- 5 - Description

The invention relates to a new method for the production of Cyclopentane derivatives, new cyclopentane derivatives and compositions containing them.

The present invention relates to a new method for Preparation of compounds of the general formula

R is a hydrogen atom or a straight-chain or branched alkyl group with 1 to 12 (e.g. 1 to 4 or 7 to 12)

2 ^

Carbon atoms means that R and R · 'are identical or different

are and each denotes a hydrogen atom or a straight-chain or branched alkyl group with 1 to 4 carbon atoms, R ⁴ denotes a hydrogen atom or preferably a straight-chain or branched alkyl group with 1 to 10 (preferably 3, 6 or especially 4) carbon atoms and η denotes an integer of 4 to 8, preferably 6, denotes / and when R denotes a hydrogen atom, of their non-toxic salts.

In the compounds of the formula I, the vinylene group in the -CH = CH-CH (OH) -CR ² R ⁵ R ⁴ side chain is in the transfiguration.

As is apparent to the person skilled in the art, the structure shown in the general formula I has at least four chiral centers, three of these chiral centers being present on the ring carbon atoms to which the hydroxyl group and the side chains - (CHg) _n COOR ¹ and -CH = CH- CH (OH) -CR ² R ³ R ^{4 are} bonded and the fourth chiral center on the carbon atom in the hydroxymethylene group in the side chain -CH = CH-CH (OH) -CR ² R ⁵ R ⁴

809822/0833

is present. Further centers of chirality can be present in the group -CR ² R ⁵ R ⁴ or in alkyl groups represented by the symbols R ¹ , R ² , R ⁵ and R ^4. The presence of the centers of chirality is known to result in isomerism. However, all compounds of the formula I according to the invention have such a configuration that the side chains - (CH ₂ J _n COOR ¹ and -CH = CH-CH (OH) -CR ² R ³ R ⁴ with respect to one another are trans all isomers of the general formula I and mixtures thereof which _{carry such side chains - (CH 2} ) _n COOR ¹ and -CH = CH-CH (OH) -CR ² R ³ R ⁴ in the trans configuration with respect to one another are within the scope of the invention .

In addition to the new method of manufacture, the invention encompasses of compounds of the formula I per se new compounds within the formula I that have not been specifically described and have been characterized.

Compounds of the formula I fall into the range of compounds those described in the specification of British Patent 1,424,806 and corresponding patents such as U.S. Patent 3,923,872 and US Pat in U.S. Patents 3,933,890 and 4,045,467 and in DOS 23 07 793 are described.

In the published French patent application 2 162, inter alia, a certain class of compounds within of formula I described and claimed.

The nomenclature system described by Nelson, J _r Med. Chem., V7 (9), (1974), 911-918 is used here.

The compounds of formula I and when R ^{1 is} a hydrogen atom, their non-toxic salts have valuable pharmacological properties including, for example, the induction of hypotension, bronchodilation, the inhibition of gastric acid secretion and the stimulation of uterine contraction and a depressant effect in view of

809822/0833

2 7 5 2 b 2 3

- 7 on the central nervous system.

In laboratory tests, the (-) - (iOR and S, 15S) -11- deoxy-10-hydroxyprostaglandin E ^ methyl ester was found to be 0.3 times as active as the natural product prostaglandin E ₁ in stimulating uterine contraction in rats and its duration of action ranged from 3 to 7 minutes when administered intravenously.

In the anesthetized cat, (-) - (iOR and S, 15S) -11-deoxy-10-hydroxyprostaglandIn-E ₁ methyl ester was 0.2 times as active as prostaglandin E ₁ in causing a drop in diastolic blood pressure of 20 mm Hg when administered intravenously.

The compounds (±) - (10Rund S, 15S) -11-deoxy-10-hydroxyprostaglandin-E ₁ -methyl ester and (±) - (* RindS, 15l) -11-deoxy-10-hydroxy-prostaglandin-E ..- methyl ester and their mixtures and (i) - (10R and, S, 15S) -11-deoxy-10-hydroxyprostaglandin-E ₁ have not been specifically described and characterized up to now and they and their production process described below and compositions containing them represent further specific objects of present invention.

According to one object of the present invention, the compounds of the general formula

CR ² R ³ R *

II

(where R ^ is a straight or branched chain alkyl group with 1 to 12 carbon atoms and R, R, R and η are as defined above) within the general formula I

809822/0833

- 8 by reacting compounds of the general formula

(CH ₂ J _n COOR ⁵

III

/ wherein R and η are as defined above and R is a suitable one acid-labile protecting group means, with suitable acid-labile protecting groups are those which easily through acid hydrolysis can be removed and which do not cause side reactions, such as a 2-tetrahydropyranyl group (unsubstituted or substituted by at least one straight-chain or branched alkyl group with 1 to 4 carbon atoms) or a 2-tetrahydrofuranyl group or a trialkylsilyl group of the general formula

-SiR ⁷ R ⁸ R ⁹ IV

(where R and R, which can be the same or different, each represent a methyl or ethyl group and R ^ a straight-chain or branched alkyl group with 1 to 4 carbon atoms), e.g. a trimethylsilyl, dimethylisopropylsilyl or tert-butyldimethylsilyl group or a 1-alkoxyalkyl group of the general formula

-CH (CH ₂ R ¹⁰ ) OR ¹¹ V

(where R is a hydrogen atom or a straight-chain or denotes branched alkyl group with 1 to 4 carbon atoms and R denotes a straight-chain or branched alkyl group with Represents 1 to 4 carbon atoms), e.g. a 1-ethoxyethyl groupJ7 with a solution a compound of the general formula

Li-CH = CH-CH (OR ⁶ ) -CR ² R ⁵ R ⁴ VI

(where R, r ', R ^ and R are as defined above) in

809822/0833

^ '/ b 2 b 2 3

an ether, e.g. diethyl ether or tetrahydrofuran in the presence of a copper compound, preferably a cupro compound, which is soluble in the ether solvent, under anhydrous conditions in an inert atmosphere "(e.g. nitrogen or argon) and at a low temperature (preferably between -10 and -80 ⁰ C, in particular between -15 and -25 ⁰ C) produced to products of the general formula

CR ² R ³ R * VII

OR ⁶

(in which R, R ^?, R ⁴ , R, R and η are as defined above, wherein the groups represented by the symbol R may be the same or different), whereupon hydrolysis of the compounds of the formula VII under * mildly acidic Conditions (for example in 60-80 # vol./vol. Aqueous acetic acid in the presence of an inert organic solvent, for example diethyl ether or tetrahydrofuran, preferably at a temperature between 15 and 50 ^° C.), in order to form compounds of the formula II .

Suitable copper compounds include complexes formed by an alkynyl copper, e.g., pentynyl copper, with a water soluble tertiary phosphine such as hexamethylphosphoric trisamide or in particular complexes formed by a cuprous halide, e.g., cuproiodide, with compounds of the general formulas VIII, IX or X

viii ix.

809822/0833

or with ligands of the general formulas XI, XII or XIII

XII XIII

1 ?
(wherein R is a straight or branched chain alkyl group having 1 to 4 carbon atoms
Phenyl group, means).

Is 1 to 4 carbon atoms and R ^ is an aryl, e.g.

The compounds of the formula VI and the copper compounds can by applying or adapting known methods, for example by methods described by Sih et al, J.A.C.S., 97: 857-874 (1975) and Corey et al, J.A.C.S., 94: 7210 (1972) are described.

According to a further feature of the invention there are compounds of the general formula

(CH ₂ J

cr ² rV

OH

(wherein R, R, R and η are as defined above) within of the general formula I by hydrolysis of compounds of the formula II by the action of yeast, preferably baker's yeast, produced under aqueous conditions.

The above novel process for the preparation of compounds of Formula I contains fewer reaction steps and gives better ones Results than previously known methods and thus represents an improvement.

Compounds of the formula III can be selected from compounds of the general formula

809822/0833

XV

(where B? and η are as defined above) by applying or adapting known methods.

For example, compounds of the formula III in which R is a 2-tetrahydropyranyl group (unsubstituted or substituted by at least one straight-chain or branched alkyl group having 1 to 4 carbon atoms) or a 2-tetrahydrofuranyl group or a 1-alkoxyalkyl group of the formula V (wherein R and R are as defined above) by reacting compounds of Formula XV with 2,3-dihydropyran or the suitable alkylated 2,3-dihydropyran or with 2,3-dihydrofuran or with a compound of the general formula

R ¹⁰ GH = CHORUS ¹¹ XVI

(wherein R and R are as defined above), e.g. ethyl vinyl ether, in the presence of a catalytic amount of an acid, e.g. a mineral acid (e.g. concentrated hydrochloric acid), or a strong organic acid (e.g. p-toluenesulphonic acid). The reaction is preferably conducted in the presence of an inert organic solvent, for example a halogenated hydrocarbon, eg dichloromethane, at a temperature between 15 and 75 ° C, preferably carried out between 20 and 40 ⁰ C.

Compounds of the formula III in which R is a trialkylsilyl group of the formula IV (in which R, R and R ^{9 are} as defined above) can be prepared by reacting compounds of the formula XV with a hexaalkyidisilazane of the general formula

SiR ⁷ R ⁸ R ⁹ -NH-SiR ⁷ R ⁸ R ⁹ XVII

809822/0833

2752b23

(wherein R ⁷ , R ⁸ and R ^{9 are} as defined above) in the presence of a compound of the general formula

SiR ⁷ R ⁸ R ⁹ Cl XVIII

(wherein R ⁷ , R and R ^{9 are} as defined above) or from gaseous hydrogen chloride under dry conditions, for example in dry tetrahydrofuran as solvent.

Compounds of the formula XV fall within the scope of the general formula

XIX

(where R ^{4 is} a hydrogen atom or a carboxylic acyl group, e.g. a straight-chain or branched alkanoyl group with 1 to 5 carbon atoms or a benzoyl group, R is a hydrogen atom or a straight-chain or branched alkyl group with 1 to 12 (e.g. 1 to 4 or 7 to 12) Denotes carbon atoms and η denotes 4 to 8, preferably 6).

The compounds of the formula XIX mentioned and, if R ¹ denotes a hydrogen atom, their salts are key intermediates for the preparation of compounds of the formula I and are described in DT-OS 27 01 455.

The compounds of the formula XIX are obtained by reacting a compound of the general formula

(CH ₂ J _n COOR ¹

809822/0833

2752b23

(where R and η are as defined above) with an acid, preferably as a reaction medium and preferably at an elevated temperature, for example at the reflux temperature of the reaction mixture. For making connections of the formula XIX, in which R is an acyl group (where R and η are as defined above), is daa the acidic or acid reagent used is the corresponding acid of the formula R -OH. When making the connections of the Formula XIX, where R is a hydrogen atom (where R and η are as defined above), the acidic reagent used is an inorganic acid, preferably one dilute inorganic acid, e.g., dilute sulfuric acid, preferably in the presence of an inert organic solvent, e.g., acetone or dioxane.

Compounds of the formula XX are obtained by epoxidation of a compound of the general formula

CH ₂ J _n COOR ¹

XXI

(where η and R are as defined above), preferably by reaction with hydrogen peroxide and an alkali metal hydroxide (e.g. sodium hydroxide) in an inert organic solvent, e.g. a lower alkenol (e.g. methanol), at a temperature near or below ambient temperature, preferably at 0 to 25 ^e C, made.

Compounds of the formula XXI in which R is a hydrogen atom (where η is as defined above); will be through Oxidation of a compound of the general formula

(CH ₂ J _n CH ₂ OH

XXII

809822/0833

(where η is as defined above), preferably by reaction with chromium trioxide and aqueous sulfuric acid in the presence an inert organic solvent, e.g. acetone, at a temperature close to or below room temperature, manufactured.

Compounds of the formula XXII are made by reacting a compound of the general formula

XXIII

(wherein R and R each represent an alkyl group or R ^ and R together form a 4- or 5-membered hydrocarbon chain form by one or two oxygen or

Nitrogen atoms - where such additional nitrogen atoms

17 17

of the form -N = or R, in which R is an alkyl group

-N-

means - can be interrupted, with the carbon atoms in this hydrocarbon chain, if appropriate, each carry one or two alkyl groups) with an aldehyde of the general type formula

4 O

R ^lo O (CH ₂ ) _n CHO XXIV

1 ft

(in which R denotes a hydrogen atom or a 2-tetrahydropyranyl group which can be unsubstituted or substituted, for example, by at least one alkyl group and η is as defined above). The reaction is carried out by heating in an inert organic solvent, for example an aromatic hydrocarbon (for example benzene) with continuous removal of water, preferably at 60 to 120 ° C _; carried out, whereupon a hydrolysis under aqueous acidic conditions (e.g. with hydrochloric acid), preferably at room temperature,

809822/0833

and then heating with an acid (e.g. concentrated hydrochloric acid), preferably at about 100 ° C, and preferably in an inert organic solvent such as an alcohol (e.g. butanol) to prevent migration of the double bond from the exocyclic to the endocyclic position to effect.

The compounds of the formula XDC, wherein R is an alkyl group with 1 to 12 carbon atoms (where R * and η are as defined above), are esterified by a Carboxylic acid of the formula XIX, in which R is a hydrogen atom, by using or adapting for the esterification produced by known methods of carboxylic acids.

The esterification can thus be carried out by reaction with an alcohol of the general formula

R ⁵ OH XXV

(wherein R ^ is as defined above), of which an excess can be used as a solvent medium, in the presence of an inorganic acid, for example hydrochloric acid or sulfuric acid, preferably at a temperature between 50 and 160 ⁰ C, and Advantageously, at the reflux temperature of the reaction

1 1Q? O

mixture, or when R is a group of the formula -CHR ^ R (wherein the symbols R ^ and R may be the same or different and each represent an alkyl group or, preferably, Denote hydrogen atom, the total number of carbon atoms in the group -CHR "r is at most 12), by reaction with a diazoalkane of the general formula

R ¹⁹ R ²⁰ C = N ₂ XXVI

(wherein R and R are as defined above) in one inert organic solvent medium, preferably a dialkyl ether (e.g. diethyl ether), preferably at room temperature.

809822/0833

Alternatively, a silver salt of such a carboxylic acid of the formula XIX with an alkyl halide of the general formula

R ^{5 line 1} XXVII

(represents wherein Z is a halogen atom and R is as defined above) optionally in the presence of an inert organic solvent, for example an aromatic hydrocarbon (eg benzene), at elevated temperature, for example, be implemented 40-110 ⁰ C and advantageously at the reflux temperature of the reaction mixture .

Compounds of the formula XXI, wherein R is an alkyl group with 1 to 12 carbon atoms (where η is as defined above), can by esterification of carboxylic acids of Formula XXI, where R is a hydrogen atom, by application or adaptation of methods described above for the esterification of carboxylic acids of formula XIX will.

Compounds of the formula XIX, in which R ⁴ denotes a hydrogen atom, are prepared by hydrolysis of compounds of the formula XIX in which R denotes a carboxylic acyl group, for example by the action of an alkali metal carbonate, for example sodium carbonate, in an aqueous alkanolic medium, for example aqueous methanol.

The salts of the carboxylic acids of the formula I and XIX, in which R is Hydrogen atom means are produced by applying or adapting methods relevant to the production of salts of carboxylic acids are known, for example by reacting stoichiometric amounts of acids of the formula I or XIX (where R is a hydrogen atom) and the appropriate base, e.g. an alkali or alkaline earth metal hydroxide or carbonate, ammonium hydroxide, ammonia or an amine in a suitable solvent, which is preferably water in the case of the production of alkali metal salts and water

809822/0833

or isopropanol in the case of amine salts. The salts can by lyophilizing the solution or, if they are sufficiently insoluble in the reaction medium, by filtration, if necessary after removing part of the solvent, isolated.

Just as they are valuable as such, these salts can be used for purposes of purifying the parent acids, for example by taking advantage of the differences in solubility between the salts and the parent acids in water and in organic solvents, according to techniques well known to those skilled in the art. You can get parent acids from their salts known methods, for example by treatment with an inorganic acid, e.g. dilute hydrochloric acid will.

It is understood that when present on compounds of the Formula I or XIX is referred to, it is intended, as well, insofar as the context permits, to these salts of the compounds of the formula I or x: material atom is to be referred to.

of the compounds of formula I or XIX, wherein R is a water

As is readily apparent to those skilled in the art, can the enantiomeric forms of the compounds according to the invention and the intermediate products that originate from the aforementioned chiral center or centers, be separated from known methods by application or adaptation. For example, the enantiomeric forms of acidic compounds of the formula I or XIX, in which R is a hydrogen atom, by forming salts with an optically active base, followed by a separation of the pair of diastereomers obtained, for example by fractional crystallization from a suitable solvent system, followed by a separate regeneration of the enantiomeric acids of the formula I or XIX.

The enantiomeric forms of the intermediates of formula VI

809822/0833

can, for example, from enantiomeric forms of compounds of the general formula

J-CH = CH-CH (OR ⁶ ) -CR ² R ³ R ⁴ XXVIII

O * K A f \

(wherein R, R, R and R are as defined above) by Application or adaptation of known methods, for example methods as mentioned above and from Sih et al (op.cit.) And Corey et al (op.cit.).

The enantiomeric forms of the compounds of formula XXVIII can by applying or adapting known methods, for example methods such as those described by Kluge et al, J.A.C.S., 94 (1972), 7827-7832.

The enantiomeric forms of the intermediates of the formula XIX can, for example, by formation of a derivative such as a Oxime, using an optically active reagent such as an optically active hydroxylamine analog to which a Separation of the pair of diastereomers obtained, for example by fractional crystallization or chromatography, followed by a separate regeneration of the enantiomeric intermediates of the formula XIX according to known methods Methods to be separated. Suitable methods can be found under Based on the methods described by Pappo et al, Tetrahedron Letters, (1973), 943-944.

The term "known methods", as used in the present case, means methods that have been used up to now or have been described in the literature.

The following examples explain the preparation of the new compounds according to the invention and the subsequent reference examples illustrate the preparation of a starting material used in Example 1.

809822/0833

example 1

13.0 ml of a 1.0M solution of tert-butyl-lithium in pentane were quickly added using a syringe to a stirred solution of 2.10 g of (i) -3- (1-ethoxy) -ethoxy-i- iodo-trans-oct-i-en in 50 ml of dry diethyl ether at -70 ⁰ C to -80 ⁰ C in an atmosphere of dry argon. The obtained mixture was stirred at -70 ° to -80 ⁰ C for a further 2 hours, obtaining the solution A.

In the meantime, 1.4 ml of freshly distilled tri-n-butylphosphine were added using a syringe to a solution of 2.22 g of tri-n-butylphosphine-copper-I-iodide complex in dry Diethyl ether under an atmosphere of dry nitrogen at room temperature to give solution B.

Solution B was transferred to solution A using a syringe and the resulting yellow mixture was _{stirred for 50 minutes at -70 to M} -8Q ° q and then added dropwise with a solution of 1.71 gVt -) - 7- ^ 4- (2-tetrahydropyranyloxy) -5-oxo-cyclopent-1-enyl7-heptanoate in 60 ml of dry diethyl ether using a syringe treated while keeping the temperature -70 to -80 ⁰ C. The obtained mixture was stirred for 1 hour -70 to -80 ⁰ C and then warmed to -18 to -23 ° C and stirred for 45 minutes between-48 and -23 ⁰ C. The mixture was then added dropwise with 50 ml of a 20 # w / v. aqueous ammonium sulfate solution using a syringe and the resulting mixture was poured into a mixture of 100 ml of diethyl ether and 50 ml of 20% w / v. poured cold aqueous ammonium sulfate solution. The aqueous layer was separated and extracted three times with diethyl ether. The extracts were combined with the ethereal layer and mixed with 20% w / v. aqueous ammonium sulfate solution and then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo (maintaining the temperature below 40 ⁰ C held) to 6.88 g of a pale brown oil yield. 6.70 g of this brown oil were mixed with 65 ml of glacial acetic acid,

809822/0833

55 ml of water and 10 ml of tetrahydrofuran are treated and the mixture is left to stand at 40 ^° C. for 20 hours. The mixture was evaporated in vacuo, the temperature being kept below 40 ^° C. 20 ml of toluene were added to the residue and the mixture was evaporated again to remove the last traces of acetic acid and water, leaving as residue 6.30 g of a pale brown oil.

Part of this residue (2.40 g) was chromatographed on a silica gel column (140 g) with a mixture of distilled ethyl acetate and distilled cyclohexane (1: 1 by volume) eluted to form two diastereomers Components of methyl 7- / 2- (3-hydroxyoct-trans-1-enyl) -4-hydroxy-5-oxocyclopentylT-heptanoate to build.

Analogously to known prostaglandins, the 25 mg of material which were closer to the original compound (component "la") were regarded as (±) - (10R and S, 15S) -H-deoxy-10-hydroxyprostaglandin-E ₁ -methyl ester. / NMR (approx. $ 5 w / v solution in deuterochloroform): Multiplets at 0.85 - 1.0 £, 1.05 - 1.95 cT, 2.0 - 2.5i, 2-5 - 2.9s, 3.8-4.4o and 5.4-5.8cf, singlet at 3.65 5 " J, 7? Ie 25 mg kenron duck Ia were further purified by thin-layer chromatography on silica gel, with one with a miscr: ar. " of methyl chloride and acetone (7: 3. to the volume be:; rve ~) eluted and the 7.3 mg of purified """! C-tct was examined on the basis of its mass spectrum (molecular ion at 368, ετ; ^: >;? ions at 2-7, 265 and 247).

the JO c <r::? ': . ■ -1 a 1 lid u ursn I'i'nr "i '" ■ - Ver "1b" : .- d.e hyl prop t α (τ 1 ι- ν '"" ,, - he Ko Since a I ¹ MR-; r ^; . " π oh 1b ν; (■; j t f; ϊ '' ■ bi Γ ■ et c τ

he: -ao? ench.ro:natograp ^: .i: .e from aer ■ rar erifertit were (component νιτκί Γ · 'i 5KJ-11 — Deo;: y-1 O-hydroxy— -a r.fiSR -'. en,

te Ir; > ar r: 11 '3 em, 1 on i; ~ f r: der τοί:; l /: t · -; d

mp} '- nter;':

/ Π 3 3

which were analogous to those used for component 1a and the 10.5 mg of purified product had a mass spectrum that was identical to that of the purified component 1a.

Example 2

By proceeding analogously to the manner described above in Example 1, except that the step of further purification of the crude (i) - (10R and S, 15S) -11-deoxy-10-hydropyprostaglandIn-E ₁ -methyl ester (obtained as ) replaced the material which was the original connection in the column chromatography in greater detail with the help of Dünnschichtchro ^ chromatography as described above by the step of crystallization of this material from a mixture of petroleum ether (bp. 60-80 ⁰ C) and ethyl acetate, to give ( £) - (10R and S, 15S) -11-Deoxy-10-hydroxyprostaglandin-E ^ -methylester in the form of a pesticide, p. = 114-117 ° C

Example 3

A mixture of 14 mg (±) - (10R and S, 15S) -11-deoxy-IO-hydroxyprostaglandin-E ^ -methyl ester, 2.0 g of active baker's yeast and 20 ml of aqueous phosphate buffer (pH = 7) was shaken together 18 Hours at 27 ° C. The mixture was then filtered and the residue washed exhaustively with ethyl acetate. The ethyl acetate phase was separated off and the aqueous phase was extracted exhaustively with ethyl acetate. The combined ethyl acetate phases were washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to give 10 mg of a pale yellow residue. The residue was purified by preparative thin-layer chromatography on silica gel, with a mixture of ethyl acetate, cyclohexane and 90 # w / w. aqueous formic acid (40: 40: 1 by volume) eluted and 1.7 mg (±) - (10R and S ₁ 15S) -11-deoxy-10-hydroxyprostaglandin-E ₁ .- / 5fMR (approx # W / V solution in deuteroacetone): Multiplets at 0.8 - 1.0 «, 1.1 - 1.80 *, 1.85 - 2.35 <f, 3.9 - 4.3d", 5.4 - 5.75 * 7.

609822/0833

Reference example 1

A solution of 3.0 g of (-) - 7- (1,2-epoxy-5-oxocyclopentyl) -heptanoic acid was heated in 75 ml of glacial acetic acid to reflux for 8 hours. The acetic acid was then removed in vacuo to give an oil which crystallized on standing. The recrystallization from a mixture of water and ethanol gave 1.4 g of (ί) -7- (4-Acθtoxy-5-oxocyclopent-1-enyl) -heptanoic acid, P. = 62-65 ° C.

Elemental analysis: C ₁₄ H ₂₀ O ₅ Calculated: C 62.7; H $ 7.5

Found: C, 62.9; H $ 7.8.

The nuclear magnetic resonance spectrum (NMR) of a 10 $ solution of (^^ - ^ - Acetoxy-S-oxocyclopent-i-eny ^ -heptanoic acid in deuterium oxide showed the following peaks: multiples at 2.45 and 3 , OS (J = 19 Hz) (ring methylene group), tiplett at 2.3Oi (chain metal group adjacent to the carboxy group), singlet at 2.1 <f (acetoxy group), multiplet at 2.0-2 , 5 S (chain methylene group adjacent to the ring).

The (ί) -7- (1,2-epoxy-5-oxocyclopentyl) -heptanoic acid used in the above preparation was obtained as follows:

A stirred solution of 16.5 g of 7- (5-oxocyclopent-1-enyl) -heptanoic acid in 400 ml of methanol was slowly treated with 32 ml of an aqueous hydrogen peroxide solution (100% by volume) and 28 ml of a 4N sodium hydroxide solution at 5 - 10 ⁰ C and ^ eB 18 hours at room temperature. The solution was concentrated in vacuo to a volume of approx. 100 ml and 100 ml of water were then added to the residue. The mixture was washed with chloroform and the chloroform discarded. The aqueous solution was then acidified to pH 3 using glacial acetic acid. The mixture was extracted with C ^ oroform and the Ctrtoroformextrakt was washed with water and dried over magnesium fat. The solvent was removed in vacuo and gave 16.0 g (ί) -7- (1 ^ -Epoxy-S-oxocyclopentylJ-heptanoic acid,

809822/0833

which was pure enough for use in the manufacture of (±) -7- (4-acetoxy-5-oxocyclopent-1-enyl) -heptanoic acid without further purification .

The 7- (5-oxocyclopent-1-enyl) -heptanoic acid used in the above preparation was obtained as follows:

90 ml of 8N-Jones reagent [prepared by dissolving 24 »O g of chromium trioxide in a small volume of water, careful treatment with 20.7 ml of concentrated sulfuric acid and dilution with water while cooling to 90 ml] to a stirred solution of 39, 2 g of 2- (7-hydroxyheptyl) cyclopent-2-enone in 400 ml of acetone, 10 - 22 ⁰ C at such a rate that caused by the addition of a drop of Jones reagent deep red coloration before adding the next drop changed to green. The mixture was then 90 minutes at 15 - 2O ⁰ C stirred. The reaction mixture was diluted with sufficient water to dissolve the precipitated chromium salts and then extracted four times with diethyl ether. The combined ether extracts were washed with water and then extracted three times with 2N aqueous sodium carbonate solution. The combined aqueous solutions were then acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid and extracted twice with diethyl ether. The combined essential extracts were dried over magnesium sulfate and evaporated in vacuo to give an oil which crystallized on standing. Recrystallization from a mixture of petroleum ether (bp. 40-60 ⁰ C) and diethyl ether gave 28 g of 7- (5-oxo-cyclopent-1-enyl) -neptansäure, P. = 41-43 ° C.

Elemental analysis: ° 12 ^H 18 ° 3 "Calc .: C 68.5; H 8.6%

Found: 68.1; $ 8.8.

The 2- (7-hydroxyheptyl) -cyclopent-2-enone used as the starting material in the above preparation was prepared as follows:

809822/0833

A mixture of 22 g of 7- (2-tetrahydropyranyloxy) -heptanal and 21.4 g of I-morpholinocyclopentene, ie the morpholine amine of cyclopentanone, in 25 ml of benzene was refluxed for 12 hours under nitrogen and the released water was continuously removed with a Dean - Strong-head. 10 ml of benzene and then 28 ml of 18% hydrochloric acid were added dropwise, and the mixture was stirred for 2 hours. The organic layer was separated and evaporated. 72 ml of concentrated hydrochloric acid and 500 ml of butanol were added to the residue. The mixture was ^{heated to 100 °} C. for 1 hour and the solution was then evaporated to give an oil. Diethyl ether was added and the ethereal solution was washed with aqueous sodium bicarbonate and then with water and dried over sodium sulfate. The solvent was evaporated and the residue was distilled under reduced pressure to give 11.7 g of 2- (7-hydroxyheptyl) cyclopent-2-enone. Bp = 125-17O ° C / 0.15 mm Hg. N ^ ⁵ = 1.490, ^ _max 228 mp (ethanol).

Reference example 2

A solution of 1.0 g of (-) - 7- [4-acetoxy-5-oxocyclopent-1-enyl] -heptanoic acid (prepared as described above in reference example 1) in 10 ml of dry diethyl ether was treated with a solution of 0, 32 g of diazomethane in 5 ml of dry diethyl ether. The reaction mixture was allowed to stand at room temperature for 2.5 hours. The diethyl ether and excess diazomethane were removed in vacuo to yield 1.06 g / T -) - 7- [4-acetoxy-5-oxocyclopent-1-enyl] heptanoate. [\) _mö ^ 1740 cm " ¹ , 1720 cm" ¹ , 1625 cm " ¹ , 1380 cm" ¹ , 1240 cm "¹;

/ I _111n , (ethanol) 232 mu; NMR (about 10 $ solution in Deutero-

Ui CLJL '

Chloroform): Multiplets at $ 7.28, 3.35-2.76, 2.7-2.25, 2.5-2.06 ", 2.0-1.05 c", doublet of doublet at 5 , 15 S (J = 3 Hz and 7 Hz), sigulets at 3.7 S ^and 2, U].

809822/0833

Reference Example 3 Methyl-j

Treated 7-66 gVT ^) - 7- [4-acetoxy-5-oxocyclopent-1-enyl] heptanoate (prepared as described above in reference example 2) with a mixture of 200 mg sodium carbonate and 1 ml water in 100 ml methanol and left the mixture to stand at room temperature for 20 hours. One then the methanol was removed in vacuo keeping the temperature at about 20 ⁰ C. 30 ml of water was added to the residue and the mixture was extracted three times with dimethyl ether. The ethereal extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to give an oil which solidified on standing. The pest was recrystallized from a mixture of petroleum ether (bp. 40-60 ⁰ C) and diethyl ether to 2.21 g of methyl (±) -7- [4-hydroxy-5-oxocyclopent-1-enyl] -heptanoat vom F. = give 62.5 to 63.5 C ^0.

Elemental analysis ^{: c -j3 H} 20 ⁰ 4 Calc .: C 65.0; H 8.4%

Get.ι 65.0 8.5 #.]

Reference example 4

The methyl (i) -7- [4- (2-tetrahydropyranyloxy) -5-oxocyclopent-1-enyl] heptanoate used as the starting material in Example 1 was made as follows:

A solution of 20 mg of p-toluenesulfonic acid in 5 ml of dry methylene chloride was added dropwise to a stirred mixture of 1.2 g of methyl (i) -7- [4-hydroxy-5-oxocyclopent-1-enyl] heptanoate (prepared as described above in reference example 3) and 0.48 g of 2,3-dihydropyran in 20 ml of dry methylene chloride with cooling and maintaining a temperature below 30 ^° C. After 1 hour, a further amount of 0.3 g of 2,3 was added -Dihydropyran was added dropwise and the mixture was stirred for a further hour. 100 mg of pyridine were added and the mixture was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo, finally at 0.1 mm Hg and 50 ^° C., for 4 hours, to give 1.9 g of methyl (±) - 7- [4- (2-tetrahydropyranyloxy) -5-

809822/0833

oxocyclopent-1-enylJ-heptanoate in the form of a brown oil obtained which was pure enough for use as a starting material in Example 1 without further purification.

The present invention also includes pharmaceutical compositions, the at least one compound of the above new cyclopentane derivatives of the general formula I together contained with a pharmaceutical carrier or coating. In clinical practice, the new invention Compounds normally administered orally, rectally, vaginally, or parenterally.

Solid compositions for oral administration include compressed tablets, pills, dispersible powders and granules. In such solid compositions, one or more of the active compounds are with at least one inert diluent, such as calcium carbonate, potato starch, alginic acid or lactose mixed. The compositions can also accordingly it is common practice to contain substances other than inert diluents, e.g. lubricants such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, Syrups and elixirs, the inert diluents commonly used in the art, such as water and contain liquid paraffin. In addition to the inert diluents, compositions of this type can also contain adjuvants, such as wetting and suspending agents and sweetening, flavoring, fragrance-imparting and preservatives. The invention Compositions for oral administration also include capsules of absorbable material such as gelatin, which contain one or more of the active ingredients with or without the addition of diluents or excipients.

Solid compositions for vaginal administration include pessaries formulated in a manner known per se and a or contain more of the active compounds.

809822/0833

Solid compositions for rectal administration include suppositories formulated in ways known per se and containing one or more active compounds.

Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions can also use adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersants. For example, by filtering through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions; sterilized by irradiation or by heating will. They can also be made in the form of sterile solid compositions that are immersed in sterile water or a other sterile injectable medium can be dissolved immediately prior to use.

The percentage of the active ingredient in the inventive Compositions can be varied, it being necessary that it should be in such a proportion that one appropriate dosage for the desired therapeutic effect is obtained. Obviously you can at about the same time various unit dosage forms can be administered. in the in general, the preparations should normally contain at least 0.025% by weight of active ingredient if required for administration by injection. For oral administration, the preparations normally contain at least 0.1 wt .- # active ingredient. The dose used depends on the desired therapeutic effect, the route of administration and the duration of treatment. In adults, the doses are generally between 0.02 and 2.0 mg by aerosol administration for compounds of formula I as bronchodilators between 0.0002 and 2.0 mg / kg body weight by intravenous administration, preferably by intravenous infusion, with

809822/0833

a rate between 0.0001 and 1.0 mg / kg body weight / minute for compounds of the formula I as hypotensives, between 0.001 and 0.3 mg / kg of body weight for the oral Administration for compounds of the formula I as inhibitors of gastric acid secretion and between 0.01 and 1.0 mg / kg of body weight by intravenous administration, preferably by intravenous infusion, at a rate between 0.02 and 20yUg / kg body weight / minute for compounds of formula I. as stimulators of uterine contraction. If necessary, can these doses are repeated as required.

The compounds of general formula I can be administered orally as bronchodilators after each one for administration Inhalation of active ingredients which are not themselves gaseous under normal conditions of administration, known per se Method to be administered. Thus, a solution of the active ingredient in a suitable pharmaceutically acceptable solvent, e.g., water, can be atomized by a mechanical atomizer such as a Wright atomizer to form an aerosol of finely divided liquid particles suitable for inhalation. Advantageously, is to be atomized Diluted solution and aqueous solutions containing 0.2 to 20 mg and preferably 0.2 to 5.0 mg of active ingredient per ml of solution are particularly suitable. The solution can contain stabilizing agents such as sodium bisulfite and buffer substances to achieve an isotonic character, e.g. sodium chloride, sodium citrate and citric acid.

The active ingredients can also be taken orally by inhalation in the form of aerosols obtained from self-propelling pharmaceutical compositions are formed, administered. Suitable compositions for this purpose can be obtained by the active ingredients in finely divided form, preferably after a radiation mill treatment to achieve an average Particle size less than 5 microns, in pharmaceutically acceptable solvents, e.g., ethanol, the Are co-solvents and dissolve the active ingredients

809822/0833

assist in the volatile liquid propellants described below or pharmaceutically acceptable suspending or dispersing agents, for example aliphatic Alcohols, such as oleyl alcohol, are dissolved or suspended and the resulting solutions or suspensions together with pharmaceutically acceptable volatile liquid propellants in conventional, pressurized packings or containers, which is made of any suitable material, e.g. metal, plastics or glass, which are capable of passing through to withstand the pressures caused by the volatile fuel in the container. Pressurized pharmaceutically acceptable gases, such as nitrogen, can also be used as Propellants are used. The pressurized container is preferably provided with a metering valve which dispenses a controlled amount of the self-propelling aerosol composition a single dose releases.

Suitable volatile liquid propellants are known in the art and include fluorochlorinated alkanes containing 1 to 4 and preferably 1 or 2 carbon atoms such as dichlorodifluoromethane, dichlorotetrafluoroethane, trichloromonofluoromethane, dichloromonofluoromethane and monochlorotrifluoromethane. The vapor pressure is preferably the volatile liquid propellant is between about 1.8 and 4.6 atm (25 and 65 psig) and more preferably between about 2.1 and 3.9 atm (30 to 55 psig) at 21 ⁰ C. As Known in the art, the volatile liquid propellants of various vapor pressures can be mixed in varying proportions to yield a propellant having a suitable vapor pressure for the formation of a satisfactory aerosol suitable for the container selected. For example, dichlorodifluoromethane be [steam pressure 6.0 atm (85 psig) at 21 ⁰ C] mixture and dichlorotetrafluoroethane [steam pressure 2.0 atm (28 psig) at 21 ⁰ C] in varying proportions to propellant to yield steam pressures between those of the two components, for example a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane in a ratio of 38:62,

809822/0833

by weight, a vapor pressure of 3.7 atm has (53 psig) at 21 ⁰ C.

The self-propelling pharmaceutical compositions can be prepared by adding the required amount of the active ingredient dissolves in the co-solvent or the required Amount of the active ingredient combined with a measured amount of the suspending or dispersing agent. A measured one Amount of this composition is then placed in an open container designed for that to be pressurized Pack is used. The container and its contents are then brought to a temperature below the boiling point of the to be used volatile propellant cooled. The required amount of the liquid, at a temperature below Propellant cooled to its boiling point is then added and the contents of the container mixed. That The container is then closed with the required valve closure without raising the temperature to a temperature lets rise above the boiling point of the propellant. The temperature of the sealed container is then left rise to room temperature, shaking to ensure complete homogeneity of the contents, with it a pressurized pack suitable for the formation of aerosols for inhalation is obtained. Alternatively becomes the co-solvent solution of the active ingredient or the combination the active ingredient and the suspending or dispersing agent introduced into the open container, the container closed with a valve and introduced the liquid fuel under pressure.

Agents for forming self-propelling compositions for the generation of aerosols for the delivery of medicaments are described in detail in U.S. Patents 2,868,691 and 3,095,355, for example.

The self-propelling pharmaceutical compositions according to the invention preferably contain 0.2 to 20 mg and in particular

809822/0 8 33

especially 0.2 to 5.0 mg of active ingredient per ml of solution or suspension. It is important that the pH is kept of the present invention for the production of aerosols solutions and suspensions used within the range of 3 to 8 and preferably these should be stored at or below 4 ⁰ C to a pharmacological avoid deactivation of the active ingredient.

In practicing the present invention, the means should selected to form an aerosol for inhalation according to the physicochemical properties of the active ingredient will.

Under the term "pharmaceutically acceptable" as used herein is used with regard to solvents, suspending or dispersing agents, propellants and gases are solvents, To understand suspending or dispersing agents, propellants and gases that are non-toxic when in Aerosols suitable for inhalation therapy can be used.

It is highly desirable that the aerosols be particle size less than about 10 microns and preferably less than 5 microns, e.g. between 0.5 and 3 microns, to ensure an effective distribution to the very narrow bronchi oils. Administration is preferably carried out with the help of devices that allow the administration of controlled amounts of the active ingredients, for example with the aid of the above-mentioned measuring valves.

The following example illustrates pharmaceutical compositions according to the invention.

Example 4

300 mg of (£) - (iOR and S, 15S) -11-deoxy-10-hydroxyprostaglandin-E _{1 were dissolved} in 1 ml of ethanol and the resulting solution was then added to 12 ml of an aqueous solution containing 50 mg of sodium carbonate 2 ml 0.9 # w / v. aqueous

809822/0833

Sodium chloride solution to obtain a final volume of 15 ml. The solution was then sterilized by passage through a bacteria-retaining filter and dissolved in 1.5 ml Portions placed in 5 ml ampoules to 30 ng heptanoic acid derivative (in the form of their sodium salt) per ampoule. The contents of the ampoules were freeze-dried and the ampoules locked. The contents of one ampoule in a suitable volume, for example 2 ml, of sterile water or physiological saline gave a solution ready for administration by injection.

809822/0833

Claims (1)

80OO Munich 2 - BrauhausstraOe 4 - Telephone Semmel No. 22 53 41 - Telegram Zumpat - Telex 529979 Case 848 14 / bs MAY & BAKER LIMITED, Dagenham, Essex / Great Britain. Claims 1. Process for the preparation of compounds of the general formula II (where Br is a straight-chain or branched alkyl radical with 2 "5 denotes 1 to 12 carbon atoms, R and R, which can be identical or different, each denote a hydrogen atom or a straight-chain or branched alkyl group with 1 to 4 carbon atoms, R * denotes a hydrogen atom or a straight-chain or branched alkyl group with 1 denotes up to 10 carbon atoms and η denotes an integer from 4 to 8), characterized in that compounds of the general formula III (wherein R and η are as defined above and R is ge suitable, unstable in an acidic medium, means protecting group) with a solution of a compound of the general formula _VI 809822/0833 2 7 b 2 b 2 3 (in which R, R, R ^ and R have the meanings given above own) in the presence of a copper compound converts to products of the general formula Q, . (CH ₀ ) COCR ⁵ : ² rV VII (in which R ² , R ⁵ , R ⁴ , R ⁵ , R and η are defined as above, where the groups represented by the symbols R may be the same or different) and then hydrolyzed the compounds of the formula VII in a moderately acidic medium to form the compounds of Formula II. 2. The method according to claim 1, characterized in that the compound of general formula III with the solution of the compound of general formula VI in an ether, in particular diethyl ether or tetrahydrofuran in an anhydrous medium under an inert atmosphere, in particular under nitrogen or argon and at lower Temperature, in particular at -10 to -80 ⁰ C and in particular in the presence of a soluble in the ether used as a solvent cupro compound. 3. The method according to claim 1 or 2, characterized in that the group R which is labile in an acidic medium is an unsubstituted one or by at least one straight-chain or branched alkyl group 2-tetrahydropyranyl group substituted by 1 to 4 carbon atoms or a 2-tetrahydrofuranyl group, a trialkylsilyl group of the general formula -SiR ⁷ R ⁸ R ⁹ IV (wherein R 'and R, which may be the same or different, each denotes a methyl or ethyl group and R denotes a straight-chain or branched alkyl group having 1 to 4 carbon atoms 809822/0833 means) or a 1-alkoxyalkyl group of the general formula -CH (CH ₂ R ¹⁰ ) OR ¹¹ V wherein R represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms and R represents a straight-chain or branched
Represents carbon atoms, 1st. R is a straight-chain or branched alkyl group with 1 to 4 4 «The method according to any one of claims 1 to 3, characterized in that the hydrolysis of the compounds of formula VH in aqueous acetic acid medium with a concentration of 60 to 8O5 & by volume in the presence of an inert organic solvent, in particular diethyl ether or tetrahydrofuran a temperature between 15 and 50 ⁰ C carries out. 5. The method according to any one of claims 1 to 4, characterized in that the copper compound is a complex which is formed by an alkynyl copper, in particular pentynyl copper, with a water-soluble tertiary phosphine, in particular hexamethylphosphorus trisamide or by a cuprous halide, in particular cuproiodide the compounds of the general formulas VIII ₁ ^- S or X: (R ¹² ) / [(R ^) ₂ N VIH IX or with ligands of the general formulas XI, XII or XIII XI XII XIH 12th
wherein R is a straight-chain or branched alkyl group having 1 to 4 carbon atoms and R ^{3 is} an aryl group. 6. Prev / end of the compounds of the general formula II according to Claim 1 for the preparation of compounds of the general 809822/0833 formula (CH.) COCH c. η XIV (wherein R, R, R and η are as defined in claim 1) or of their salts, characterized in that the action of yeast, in particular baker's yeast, in an aqueous medium a compound of the general formula II, wherein R, R, R ^, R ^ and η are as defined in claim 1, hydrolyzed, after which the product of the formula XIV obtained is optionally converted into one of its salts by methods known per se. (7J (i) _ (iOR and S, 15S) -11-Deoxy-10-hydroxy-prostaglandin-E ₁ -methyl ester. 8. (±) _ (1OR and S, 15R) -11-deoxy-IO-hydroxy-prostaglandin-E. methyl ester. 9. (±) - (iOR and S, 15S) -11-Deoxy-10-hydroxy-prostaglandin-E _<( . 10. Pharmaceutical compositions, characterized in that they contain at least one compound according to one of the active ingredients Claims 7 to 9, or a non-toxic salt of the compound according to Claim 9, together with a pharmaceutical carrier or contain coating agents. P09822 / 0833