IE41835B1

IE41835B1 - Prostadienoic acid derivatives

Info

Publication number: IE41835B1
Application number: IE1383/75A
Authority: IE
Original assignee: Roussel Uclaf
Priority date: 1974-06-21
Filing date: 1975-06-20
Publication date: 1980-04-09
Also published as: CH596163A5; GB1478262A; ES438725A1; CA1061338A; BE830475A; IL47437A0; DD118412A5; ZA753959B; SE7505967L; LU72786A1; NL7507431A; DK142171B; DK279475A; JPS5113751A; IE41835L; DE2526355A1; DK142171C; AU8211175A; FR2275443B1; IL47437A

Abstract

1478262 Prostaglandins ROUSSEL UCLAF 23 June 1975 [21 June 1974] 26591/75 Heading C2C The invention comprises a process for the preparation of prostaglandins of the Formula I wherein R is H or C 1-4 alkyl, R 1 is C 2-4 alkenyl which contains a group of the formula m is 3, 4 or 5 and n is 2, 3 or 4, by catalytically hydrogenating compounds of the above Formula I in which R 1 is C 2-4 alkynyl and the compounds methyl (5Z, 8RS, 12RS, 13E, 15SR) 15- hydroxy - 9 - oxo - 15 - vinyl - 5,13 - prostadienoate and methyl (5Z 8RS, 12RS, 13E, 15RS) 15 - hydroxy - 9 - oxo - 15 - vinyl - 5,13- prostadienoate. Pharmaceutical compositions, suitable for oral, parenteral, rectal or topical administration, contain the above named compounds together with pharmaceutical carriers or excipients. The compounds have hypotensive and anti-broncho-constrictive activities and stimulate contraction of the smooth muscles.

Description

The present invention relates to the preparation of novel derivatives of prostadlenoic acid.

‘Our Patent Specification No. 38875 describes and claims inter alia prostanoic acid derivatives having the general formula j 10 in · which R represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, R^ represents an alkenyl radical having from 2 to 4 carbon atoms and which'cbntains a group of formula -GH=CH-;m is an integer equal to 3, 4 or 5 and n is an integer equal to 2, 3 or 4..

As ' indicated in the said Specification, the compounds of formula I have valuable pharmacological properties, in particular, hypotensive and anfc£-broncho-constrictive ·/ 'S.. . of activities as well as stimulatingcontractions./ the smooth muscule. These properties,, ^render the compounds useful for example in the treatment of hypertension and circulatory disorders as well as in the treatment of respiratory disorders such as asthma.

It is an object of the present invention to provide a new and improved process for the preparation of compounds of formula I (as defined above).

According to one feature of the present invention we provide a process for the preparation of compounds of formula.I (as defined above) which comprises subjecting a compound of formula (II) t£ represents (in which R, ra-and n are as-defined above and Rg at alkynyl radical having from 2” to 4 carbon-atoms) to catalytic hydrogenation whereby the group of formula -C=C- in Rg is reduced to a group of formula -CH=CH-.

In formula I-above, R^ can thus represent a vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-btitenyl, 3-butenyl and 1-methyl-2-propenyl radical, corresponding groups for Rg in formula II being the ethynyl, 1-propynyl, 2-propynyl, l-butynyl, 2-butynyl, 3-butynyl and l-methyl-2-propynyl radicals respectively.

The process according to the present invention is especially applicable to 'the preparation of a compound of formulaί- ί la) by the catalytic hydrogenation of a compound of formula: In the catalytic hydrogenation the catalyst used is preferably a palladium catalyst, preferably palladium supported on barium sulphate, and the hydrogeni .. r atioh is advantageously carried ou-t in the presence of a trace of ' quinoline. Examples of other catalysts which may be used are palladium on ,1 calcium carbonate in the presence of lead acetate, palladium on carbon black in the presence of pyridine. Raney nickel can also be used.

The compounds of formula II employed as starting 5 materials may be prepared for example by the process described in our Patent Specification No. 38375. the compounds of formula II may be prepared by a which first comprises a) treating a compound of formula III: Thus, process (HI) (in which m and n are as defined above and ale and alCp which may be the same or different, each represent an alkyl radical having from one to four carbon atoms) with an acid to obtain a compound of formula IV: - 5 / (IV) ο (CH„) COOalc. 2 η 1 b) reacting the said compound of fonnula IV with a diazoalkane having from 1 to 4 carbon atoms to obtain a compound of formula V: (in which A represents an alkoxy radical having from 1 to 4 carbon atoms, and ale, alc-j, m and n are as defined above); c) saponifying the said compound of formula V with an alkaline base to obtain, after .acidification, a compound of formula VI: .- 6 41835 in which A, ra and n are as defined above; and d) heating the said compound of formula VI to effect decarboxylation on the cyclopentene ring and, if desired, reacting with a diazoalkane having from 1 to 4 carbon atoms to obtain a mixture of compounds having the formulae: 2>mCH3 (CH„) COOK Ζ n (VII) and (VII') OH - 7 41835 (in which A, m ahd n are as defined above and R' re^V'esents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms) which mixture can, if desired be separated into each of its constituent compounds;' The mixture Obtained in the last stage (or a constituent compound thereof) can then be treated with an oxidising agent to obtain a compound formula and/or a compound of formula (VIII') (in which A, R, m and n are as defined above). Where a mixture 10 is obtained this· can, .if desired,· be separated into its constituent compounds. This mixture.., (or a constituent - 8 41835 compound thereof) can then be treated with an organomagnesium derivative of formula: R2MgX (in which X represents a halogen atom and 5 Rg is as hereinbefore defined) to obtain a compound of formula: (αφΛ (CH2)nCOOR (IX) and/or a compound of. formula.

(CHjCOOR t n <CB2>,A (lx') (wherein A, R, Rg, in and n are as defined above), a mixture is obtained this can, if desired, be Where separated into its constituent compounds. This mixture (or a constituent compound thereof) may then be treated with an acid to obtain a compound of formula: and/or a compound of formula (wherein R, R2, m and n are as defined above). Where a mixture is obtained this can, if desired, be separated into its constituent compounds. .

The wavy lines shown -in certain of the above formulae indicate the substituents concerned may be disposed in either-stereochemical configuration. In the above processes therefore the compounds concerned can thus be in tha form of single stereoisomers or - 10 41835 mixtures from which the individual stereoisomers car, be ( separated, e.g. in conventional manner using physical methods such as chromatography.

We have found that mixtures of 'stereoisomers of the above-described starting materials of formula II can be easily resolved into the individual stereoisomers which can thus be used for the preparation of the corresponding stereoisomers of formula ϊ by the process according to the present invention. Ιθ Using the process according to the invention and starting from stereoisomers of formula Ila, individual stereiosmers of formula Ia above can be obtained as novel compounds, -According to a further feature of the present invention therefore we provide methyl (8RS, 12RS, 15SR) (5Z,, 13E) 15-hydroxy-9-oxo-15-vinyl-5,13-prostadienoate and methyl (8RS, 12RS, 15RS) (5Z, 13E) 15-hydroxy-9-oxo15-vinyl-5,13-prostadienoate, i.e. the stereoisomers of general formula Ia above. These stereoisomers may be used in medical therapy in an analogous manner to the above compounds of formula I.

According to a still further feature of the present ir invention therefore we provide pharmaceutical composition comprising, as active ingredient, at least one stereoisomer of general formula Ia, together with one or more pharmaceutical carriers or excipients, As for the compositions described in our aforesaid Specification, the pharmaceutical compositions «/ · according to the present invention may be administered by the parenteral, oral'or rectal route or by topical application, e.g, in the form of solutions, injectable suspensions, sterile powders for injectable preparations, tablets, coated tablets, capsules, syrups, suppositories, or aerosols.

The following Examples illustrate the invention. Example 1 -methyl (8 RS, 12 RS, 15 SR) (5 Z, 13 E) 15-hydroxy 9-oxo 15-vinyl 5,13-prostadienoate I 108 mg of methyl (8 RS, 12 RS, 15 SR) (5 2, 13. E) 15-ethynyl 15-hydroxy 9-oxo 5,13-prostadienoate, 10 cm3 of ethyl acetate, 20 mg of 5.25% palladium on barium •a sulphate and 0.1 cm.; of quinoline are mixed together.

The mixture is cooled to 0°Cand agitated in an atmosphere of hydrogen for 15 minutesj 6,5 cm3 of hydrogen are absorbed. The catalyst is filtered off, and the cold filtrate is washed with an ice·- /solution of normal hydrochloric acid, then with water. The organic solution is dried over magnesium sulphate and the solvent is evaporated under vacuum. Ihe residue obtained is purified by chromatography on silica, eluting with a 9:1 mixture of benzene and ethyl acetate, 60 mg of methyl (8 RS, 12 RS, 15 SR) (5 Z, 13 E) 15-hydroxy-9-oxo15-vinyl 5,13-prostadienoate are obtained in the form of a clear yellow oil.

Thin layer chromatography on silica (eluant 9:1 v/v benzene/ethyl acetate) Rf = 0.2. ' N.M.R. Spectrum (deuterochloroform) H of the hydroxyl at 15 : 146 Hz; H of the vinyl at 15 : quadruplet 517, 528, 535,5 and 546.5 Hz; H2 of the vinyl at 15: triplet 451.5, 461 '.5 and 479 Hz.

The methyl (8 RS, 12 RS, 15 SR) (5 Z, 13 E) -ethynyl-15-hydroxy-9-oxo-5,13-prostadienoate used as starting material in this Example is prepared according to the method described in Example 2. 13' 41835 Example 2 methyl (8 RS, 12 RS, 15 RS) (5 Z, 13 E) 15-hydroxy 9-oxo-15-vlnyl-5,13-prostadlenoate 108 mg of methyl (8 RS, 12 RS, 15 RS) (5 Z, 13 E) -ethynyl· 15-hydroxy 9-oxo 5,13-prostadienoat'a, 10 cm3 of ethyl acetate and 20 mg of 5,25% palladium on barium sulphate ate mixed together. The mixture is agitated in an atmosphere of hydrogen at ambient temperature for 3 minutes 6.5 cm of hydrogen are absorbed. The Catalyst is filtered off, the’filtrate is washed with art ice-cold solution of normal hydrochloric acid, then with water.

It is dried over magnesium sulphate and the solvent is evaporated under vacuum. The residue obtained is purified v/v by chromatography on silica, eluting with a 9:1/mixture of benzene and ethyl acetate, ItQ mg of methyl (8 RS, 12 RS, RS) (5 Z, 13 E) 15-hydroxy-9-oxo—15-viny 1-5,13I prostadienoate are obtained in the form of a clear yellow oil.

• Thin layer chromatography on silica (eluant 9:1v/v benzene/ethyl acetate ) Rf = 0.2.

N.M.R, Spectrum (deuteroChloroform) H of the hydroxyl at 15 : 145 Hz; H of the vinyl at 15 : quadruplet 521, 531, 538.5 and - 14 41835 549.5 Hz; Hg of the vinyl at 15 : triplet 453, 463.5 and 481 Hz.

The methyl (8 RS, 12 RS, 15 RS) (5 Z, 13 E) 15-ethynyl15-hydroxy-9-oxo-5,13-prostadienoate used as starting material in .this Example is prepared according to the method below; Stage A: ethyl (8 RS, 12 RS, 15 SR) (5 Z, 13 E) -ethoxycarbonyi-i5-hydroxy 9-oxo 5,13-prostadienoate 243 mg of ethyl (8 RS, 12 RS, 15 SR) (5 Z 13 E) - ethoxycarbonyl - 9 - oxo - 15 - (2 - tetrahydro; pyranyloxy - 5,13 - prostadienoate are introduced into □ cm of a 0.2% aqueous solution of oxalic acid and 4 cm3 of ethanol. The whole is kept at 48°C for eight hours, then the ethanol is evaporated under vacuum. The diethyl residue is extracted with/ether, and the ethereal phase diethyl is washed with/ether and dried over magnesium sulphate.

After evaporation of the diethyl ether, the oil obtained is v/v •chromatographed on silica gel using a 1:1/cyclohexane/ethyl acetate mixture. 93 mg of ethyl (8 RS, 12 RS, 15 SR) (5 Z, 13 E) 10-ethoxycarbonyl-l5-hydroxy-9-oxo-5,13-prostadienoate are thus obtained in the form of a pale yellow oil.

Stage B: ethyl (8 RS, 12 RS, 15 SR) (52, 9, 13 E) - ethoxyearbonyl - 15 - hydroxy - 9 - methoxy - 5,9,13 prostatrienoate 550 mg of product prepared according to the previous stage are dissolved in 4 cm of methylene chloride, 1 n The,solution is cooled to 0° and 15 cm0 of a methylene chloride'solution containing 15 g/1 of diazomethane are added. The whole, is allowed to return to ambient temperature, and the reaction is continued for five hours, , The excess diazomethane and the methylene chloride are then evaporated off under vacuum, 564 mg of ethyl (8 RS, RS, 15 SR) (5 Z, 9, 13 E) 10-ethoxycarbonyl-.l5-hydroxy9-meth'oxy-5,9,13-prostatrienoate are thus obtained in the form of a pale yellow oil, Stage G: (8 RS, 12 RS, 15 SR) (5 Z, 9,'13 E) -carboxy-15-hydroxy-9-methoxy - 5,9,13 - prostatrienoic acid 2,16 g of product prepared according to the 1 3 previous stage are dissolved in 21 cm of ethanol, 14,4 cm3 of normal aqueous sodium hydroxide, and the whole is heated .at 70°C for six’hours; 4,8 eta of formal aqueous sodium hydroxide are again added and the.whole is heated at 70°C for ten hours,' The ethanol is then, evaporated off and the residue is dissolved in a water/ diethyl ether mixture. The aqueous phase separated is acidified with 2N hydrochloric acid, then saturated with sodium chloride.

The whole is extracted with diethyl ether, and the ethereal phase is dried over magnesium sulphate and concentrated under vacuum. 1.89 g of (8 RS, 12 RS, 15 SR) (5 Z, 9, 13 E) -5,9,13- . . -carboxy-15-hydroxy-9-methoxy/prostatneitOic acid are thus obtained in the form of a thick yellow oil.

Stage D: methyl (8 RS, 12 RS, 15 SR) (5 Z, 9, 13 E) -hydroxy—9-methoxv-5,9,13-prostatrienoate and methyl (12 RS, 15 SR) (5 2, 8, 13 E) -hydroxy-9-methoxy-5,8,13-prostatrienoate 2.35 g of the diacid prepared according to the 3 previous stage are introduced into 183 cm of xylene.

The mixture is refluxed for eight hours, then the xylene is evaporated under vacuum. The thick oil obtained is dissolved in 10 cm of methylene chloride, The solution is cooled to 0°, and 30 cm3 of methylene chloride solution containing 15 g/1 of diazomethane are added. After the addition, the excess diazomethane and the methylene chloride, are evaporated under vacuum. A yellow oil is chromatographed obtained which is / on silica using an 8:2 v/v benzyl/ -,17 ethyl acetate mixture as eluant. 1.95g.of oil are obtained which is found, by N.M.R. Spectrography, to be mixture of methyl (8 RS, 12 RS, 15 SR) (5 Z, 9,13 E) 15-hydroxy-9-methoxy5,9,13-prostatrienoate and methyl (12 RS, 15 SR) (5 Z, 8,13 E) 15-hydroxy-9-methoxy-5,8,13-prostatrienoate in the approximate proportion of 3/5 to 2/5, Stage Ei methyl (8 RS, 12 RS) (5 Z, 9, 13 E) 9-methoxy-15-oxo-5,9,13-protatrienoate and methyl (12 RS) (5 Z, 8, 13 E) 9-methoxy -oxo 5,8,13-prostatrienoate 180 mgOf the mixture obtained in the previous stage are introduced into 13 cm3 of benzene. 580 mg of J silver silicate are added-and the whole is taken to reflux for three hours thirty minutes, After cooling, it is filtered and the * - · residue is washed with benzene.

The· filtrate is evaporated under vacuum, which gives 160 mg of oil which is found bv N.M.R. spectrography, to be a mixture of methyl (,8 RS, 12 RS) (5 Z, 9, 13 E) 9-methoxy15-0X0-5,9,13-. prostatrienoate and methyl (12 RS) (5 Z, 8,13 E) 9-methoxy-15-oxo-5,8,13-prostatrienoate in the approximate proportion of 4/5 to 1/5. - 18 41835 Stage F: methyl· (8 RS, 12 RS, 15) (5 Z, 9, 13 E) 15-cthynyl-15-hydroxy-9-methoxy-5,9,13prostatrienoate and methyl (12 RS, 15) (5 Z, -· 8t 13 E)-il5-ethyftyl-15-hydroxy-9-methoxy 5 - 5,9,13-prostatrienoate 500 mg of mixture obtained in the previous stage 3 are dissolved in 3 cm of tetrahydrofuran, 3.6 cm of a 0.5 N solution of ethynyl magnesium bromide in tetrahydrofuran are added. This is agitated for one hour at ambient 'temperature, ll1611 a further 1.4 cm of the ethynyl magnesium bromide solution are added, and the whole is agitated again for one hour thirty minutes at ambient temperature. The reaction mixture is poured into an ice-cold saturated aqueous solution of ammonium chloride and extracted with diethyl ether. After washim (several times) and drying the organic phase, it is evaporateG under vacuum, and an oil is obtained which is ourified by chromatography on silica gel using a 95j5 benzene/ethyl acetate mixture as eluant, which gives 139 mg of a mixture of methyl (8 RS, RS, 15) (5 Z„ 9, 13 E) 15-ethynyl-15-hydroxy-9-methoxy— ,9,13-prostatrienoate and methyl (12 RS, 15) (5 Z, 8, 13 E) -ethynyl-15-hydroxy-9-methoxy-$,9,13-prostatrienoate. - 19 41835 Stage G: methyl (8 RS, 12 RS, 15SR) (5 Z, 13 E) -ethynyl 15-hydroxy 9-oxo 5,13-prostadienoate ' a~nd methyl (8 RS, 12 RS, 15 RS) (5 Z, 13 E) 15-ethynyl—l5-hydroxy-9-oxo-5,13-prostadienoate 139 mg of the mixture obtained in the previous ' 1 3 ο stage are dissolved in 5 cm. of ethanol. 5 cm of a 1:1 ’o.l N aqueous hydrochloric acid/ethanol solution are added. The whole is left in contact for forty-five minutes, then the ethanol is evaporated under vacuum, The residue is dissolved in diethyl ether, and the ethereal phase is washed with brine then dried over magnesium sulphate. After evaporation of the, diethyl ether, a yellow oil is· obtained, which is chromatographed on silica gel using an 8:2 v/v benzene/ ethyl acetate mixture. 38 mg of methyl (8 RS, 12 RS, RS) (5 Z, 13 E) 15-ethynyl 15-hydroxy 9-oxo 5,13prostadienoate and 24 mg of methyl (8 RS, 12 RS, 15 SR) • (5 Z 13 E) 15-ethynyl -15-hydroxy-9 -oxo-5,13-prostadienoate are thus separated· out, · ·

Claims

1. A process for preparing compounds of the general formula (CH„) COOR 2 n (CH 2 ) A (I) (in which R represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, R 1 represents an alkenyl radical having from 2 to 4 carbon atoms and which contains a group of formula -CH = CH-; m is an integer equal to 3, 4 or 5 and n is an integer equal to 2, 3 or 4,) which comprises subjecting-compound of formula:- R (CH„) COOR 2 n 2 represents an alkynyl radical having from 2 to 4 carbon atoms) to catalytic hydrogenation whereby the group of formula -C s C- in R 2 is reduced to a group of formula -CH = CH-. - 21 41835

2. Ά' process as claimed in claim 1 for the preparation of a compound of the formula:- of formula to catalytic hydrogenation. .

3. A process as claimed in either claim 1 or claim 2 wherein the hydrogenation is effected in the presence of a palladium catalyst: 10

4. A process asclaimed 1n claim 3 wherein the palladium is supported on barium sulphate.

5. A process as claimed in claim 3 or claim 4 wherein the hydrogenation is carried out in the presence of a trace of quinoline. 15

6. A process as claimed in claim 3, wherein the palladium is supported on calcium carbonate.

7. A process as claimed in claim 3 wherein the palladium is supported on carbon black.

8. A process as claimed in claim 1 substantially as 20 herein described.

9. A process for the preparation of compounds of formula I (as defined in claim 1) substantially as herein described with reference to either of the Examples.

10. Compounds of formula I (as defined in claim 1) whenever prepared by a process as claimed in any of the preced- ing claims. 11. A compound of formula Ia (as defined in claim 2) 5 whenever prepared by a process as claimed in. claim 2.

11. 12. Methyl (8 RS, 12 RS, 15 SR) (5 Z, 13 E) 15 - hydroxy - 9 - oxo - 15 - vinyl - 5,13 - prostadienoate.

12. 13. Methyl (8 RS, 12 RS, 15 RS) (5 Z, 13 E) 15 - hydroxy - 9 - oxo - 15 - vinyl - 5,13 - prostadienoate. 10

13. 14. Pharmaceutical compositions comprising, as active ingredients, at least one compound as claimed in either claim 12 or claim 13, together with at least one pharmaceutical carrier or excipient.

14.

15. Compositions as claimed in claim 14 in the form 15 of injectable solutions or suspensions, sterile powders for injectable preparations, tablets, coated tablets, capsules, syrups, suppositories, or aerosols