IL45215A

IL45215A - 2,3-trans-methano pga2 pge2 and pgf2 derivatives their production and pharmaceutical compositions containing them

Info

Publication number: IL45215A
Application number: IL45215A
Authority: IL
Original assignee: Sandoz Ag
Priority date: 1973-07-09
Filing date: 1974-07-08
Publication date: 1977-07-31
Also published as: FR2318169A1; SE7512194L; GB1479964A; SE7408689L; IE41342L; FI58117C; FR2236490A1; ATA559874A; IL45215A0; DK352974A; ES428063A1; FR2318169B1; FI58117B; IE41342B1; DD113348A5; CA1050976A; FR2236490B1; DE2431930A1; GB1479965A; NO742378L

Description

2 ^ΪΛΪΚ &»^»3»n ηιπρη »n^« m :«->e*»e-»e-"-3*»sn-O »e«-»sat«»ee»SB»a 21 SGik2, ?(¾ and FS¾ deriva ives, their production and Jjti rm eeutlcai compositions containing them C. 43136 Case 100-4C 2 IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS The present invention relates to novel cyclopropane derivatives.

In accordance with the invention there are provided new optically active compounds of formula I, or raceitiic compounds of this formula, wherein D is one of the four carbocycles of formulae Ila, lib, lie or lid, - 2 - 100-4042 R^ is hydrogen or alkyl of 1 to 8 carbon atoms, or aralkyl of 7 to 12 carbon atoms , and R2 and R3 , independently, are hydrogen or alkyl of 1 to 4 carbon atoms.

The invention also includes pharmacologically acceptable salt forms of the compounds of formula I, when is hydrogen.

In the cyclopentane formulae Ila to lid the dotted connecting lines indicate that the substituents are linked with the cyclopentane ring in an σ-configura-tion, i.e. they are situated below the level of the cyclopentane ring. The thicker solid connecting lines indicate that the substituents are linked with the cyclopentane ring in a β-configuration , i.e. they are situated above the level of the cyclopentane ring. The wavy connecting line at C 15 in formula I indicates that the hydroxy1 group is present in an a- or "-configuration. 100-4042 Examples of aralkyl groups of 7 to 12 carbon atoms are: benzyl, phenethyl 1-phenethyl, 2-phenylpropyl , 4-phenyl-butyl, 3-phenylbutyl, 2- (1-naphthylethyl) and 1- (2-naphthylmethyl) .

Further, in accordance with the invention a compound of formula I may be obtained by a process comprising a) removing any protective group present in a can-pound of formula III, wherein R2 and R3 are as defined above , R6 is hydrogen, alkyl of 1 to 8 carbon atoms , cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, or tert .-butyldimethylsilyl , R^ is trialkylsilyl or tetrahydropyranyl , and A is a carbocycle of formula Ila or lib as defined above or of formula lie or - 4 - 100-40^*% b) removing water from a compound of formula la wherein D is a carbocycle of formula defined above and and R-> are as defined above to produce a compound of formula Ib 5 - 100-4042 wherein D is a carbocycle of formula lib as defined above and R^, and are as defined above, c) hydrolysing a compound of formula Ic, wherein R^ is alkyl, cycloalkyl or aralkyl and B.^, R^ and D are as defined above, to produce a compound of formula Id, wherein ^ is hydrogen and R2, ^ and D are as defined above, or d) esterifying a compound of formula Id as defined above to produce a compound of formula Ic. 6 100-4042 Process variant a) may be effected in conventional manner for the hydrolysis of tetrahydro-pyranyl or trialkylsilyl protecting groups in prostaglandins For example the reaction may be carried out in solution, for example an organic acid / tetrahydrofuran / water mixture, e.g. acetic acid / tetrahydrofuran / water mixture .

A mineral acid is preferably present, e.g. hydrochloric acid conveniently in methanol, or sulphuric acid. The reaction is conveniently effected at from -10 to +150°C, preferably at from 30-60°C.

The trialkylsilyl group preferably contains in each alkyl group thereof up to 6 carbon atoms/, e.g. tert-butyl dimethylsilyl .

Process variant b) may be effected in conventional manner for selectively dehydrating a 15-hydroxy prostaglandin Eg. to ob ain a 15-hydroxy prostaglandin E2« Preferably a dilute aqueous acid solution is used, e.g. acetic acid. The reaction is preferably carried out at from 0° to 60° .

Process variant c) may be effected in conventional manner for the hydrolysis of a prostaglandin ester to obtain a prostaglandin.

Process variant d) may be effected in conventional manner for the esterification of a 15-hydroxy prostaglandin - 7 - 100-4042 produce a 15-hydroxy prostaglandin ester.

The starting materials for the process variant , the compounds of formula Ilia, wherein R , R^ , R^ and R^ are as defined above, and A 1 is one of the carbocycles Ila, lib or IIf_, are new and may be produced by oxidizing a compound of formula IV, wherein R_. R_ , R. and R,. are as defined above, 2 3 4 B is respectively one of the carbocycles of formulae IIg_ or Ilh, II h 8 100-4042 or of formula lie as defined above.

A suitable reagent for the oxidation is Collins reagent (pyridine/chromium trioxide) , Jones reagent (Cr03/H+/ acetone) or a sulphide reagent, e.g.

The reaction may be carried out in conventional manner for the oxidation of a prostaglandin having an g-hydroxy group. An inert solvent is preferably used. In the case of the sulphide reagent the solvent may be for example toluene and a suitable reaction temperature is from -30 to -20°C. When a carboxylic acid is used as starting material, this is preferably protected i conventional manner when a sulphide reagent is used.

For the production of compounds of formula Ilia wherein B is the carbocycle lib, the oxidation may also be effected with dichlorodicyanobenzoquinone or activated manganese dioxide.

The compounds of formula IV are produced by e. reacting a compound of formula V, - 9 - 100τ4042 wherein R2 , and R^ are as defined above, and E is one of the three carbocycles of formulae Va, Vb or Vc, V c - 10 - 100-4042 whereby the radical R^ in formula Vc has the above significance, with a compound of formula VI, wherein R^ is as defined above, is naphthyl or phenyl, each of which may be unsubstituted or substituted by lower alkyl, or lower alkyl, and X is chlorine, iodine or bromine.

As it will be appreciated that the compound of formula IV wherein B is a carbocycle of formula lie is the same as a compound of formula III wherein A is a carbocycle of formula He, the present invention also provides a process for the production of a compound of formula III wherein A is a carbocycle of formula lie comprising reacting a compound of formula V wherein E is a carbocycle of formula Vc with a compound of formula VI.

The reaction is effected in accordance with known methods, for example by a Wittig reaction. The reaction is preferably effected in dimethyl sulphoxide - 11 - 100-4042 or dimethylsulphoxide/tetrahydrofuran. A suitable temperature is between 20 and 80°C conveniently room temperature.

The starting material, compounds of formula VI wherein R^, and X are as defined above, are new and may be produced, for example, by reacting a 4-halogen-1-butene of formula VII, X-CH2-CH2-CH=CH2 VII wherein X is chlorine, iodine or bromine, with a diazoacetic acid alkyl ester of formula VIII, N2CH-C00R^ VIII wherein R is alkyl.

The resulting ΠΙ_«¾¾*ΓΟ of isomers of cyclopropanecarboxylic acid alkyl esters of formula IX, / 2\ X-CH2-CH2-CH CH-C00R IX • wherein R^ and X are as defined above, may be separated. The ester group may be hydrolysed,e.g. under conventional acid conditions. If desired the optical antipodes may be separated in conventional manner, e.g. through diastereoisomer salt formation, e.g. with optically active ■ ephedrine. The optically active acid - 12 - 100-4042 may be esterified in conventional manner and reacted with a phosphine compound of formula X, (R5) 3P X wherein R5 is as defined above. The phosphonium salt production may be effected in conventional manner, for example in an inert solvent, e.g. benzene. The reaction may be effected at the reflux temperature.

Free acid forms of compounds of formula Id may be converted into salt form in conventional manner and vice versa. Compounds of formula I may be in racemic form or in individual optical isomer form. Individual optical isomer forms may be obtained from racemic forms in conventional manner or by using appropriate starting materials in individual optical isomer form. It is preferred to separate the individual optical Isomers of compounds of formula IX as mentioned above.

Lower alkyl where not particularly defined otherwise preferably, has up to 8 carbon atoms.

In the following non-limitative Examples all temperatures are indicated in degrees Centigrade.

In the prostaglandin nomenclature hereinafter "cis or trans (+) or (-) methane" refers to the optical rotation of the corresponding respective trans- or cis-2- (2-bromo-ethyl ) cyclopropanecarboxylic acid which can be converted by stereospecific procedures into the named prostaglandin. - 12a- 100-4042 Where "methano" is unaccompanied by (+) or (-) then the compound is (*) mixture.

Hereinafter 2-bromoethylcyclopropanecarboxylic acid or cyclopropane-2-bromoethylcarboxylic acid refers to the appropriate compound of formula IX.

I.R. spectra are taken for CI^Clj solutions.

N.M.R. spectra are taken for CDC1- solutions at 90 MHz. - 13 - 100-4042 EXAMPLE 1 : 2 , 3-trans-methano-prostaglandin F^ [process variant a) ] 40 mg of 2 , 3-methano-trans-ll , 15-bis-tetrahydropyranyl-prostaglandin F2a are dissolved in 2 cc of a mixture of acetic acid, tetrahydrofuran, water (3 : 1 : 1) and the solution is heated to 60° for 2 hours.

After concentrating by evaporation at reduced pressure, the residue is separated on 3 g of silica gel with chloroform containing 17 % of methanol whereby the pure title compound is obtained. M.P. 108-112°.

MR (CDCl^, 90 megacycles per second) inter alia signals at: 4 K (m) 5.45 ppm vinyl protons 3 H 3.8 - 4.2 ppm CH-OH 3 H (t) 0.9 ppm methyl 2 , 3-cis-methano-prostaglandin F2 and the following esters are produced in analogous manner: 2 , 3-cis-methano-prostaglandin methyl ester, 2 , 3-trans-methano-prostaglandin F2a methyl ester, 2 , 3-trans-methano-prostaglandin ethyl ester, 2 , 3-cis-iaethano -prostaglandin F2a ethyl ester, 2 , 3-trans-methano-prostaglandin F2a benzyl ester, 2 , 3-cis-methano-prostaglandin F_ benzyl ester. - 14 - l00-40i42 The 2, 3-trans-methano-ll, 15-bis-tetrahydropyranyl-prostaglandin F2a, used as starting material, is produced as follows: a) 2-bromoe ΐ-eye1ogropane ar_oxy1ic_ac thy1_ester 40 cc of diazo-acetic acid ethyl ester are slowly added dropwise, while stirring vigorously, to a suspension heated to 100° of 2.48 g of copper powder in 22 g of 4-bromo-l-butene. After 2 hours at 100°, filtration is effected and the isomeric cyclopropyl- carboxylic acid esters are separated by chromatography on 900 g of silica gel with benzene as eluant. acid_eth_l_ester IR (methylene chloride) inter alia bands at: 1710, 1420, 1200, 1180 cm"1.

N R (CDCl^, 60 megacycles per second) inter alia signals at: 2 H 4.17 ppm (0-CH2~CH3) 2 H 3.45 ppm (-CH2-CH2-Br ) 3 H 1.25 ppm (CH3~CH2-) M+ = 220 ethy_l_ester IR (methylene chloride) inter alia bands at: 1715, 1395, 1180 cm"1.

NMR (CDC1-, 60 megacycles per second ) inter 2 H 4.16 ppm . (0-CH2-CH3) 2 H 3.42 ppm (-CH2-CH2-Br) 2 H 2.15 ppm (-CH2-CH2-CH) 3 H 1.28 ppm (CH3-CH2-).

M+ = 220 trans-eyelopropane-1- (2-bromoethyl^-2-carboxylic acid 1 g of trans-eyelopropane-1- (2-bromoethyl) -2-carboxylic acid ethyl ester is added to a mixture cooled to 0° of 6.4 cc of 33 % hydrobromic acid and 1.7 cc of concentrated sulphuric acid while stirring vigorously. After one hour at room temperature, the solution is heated to 100° for 15 minutes. The cooled solution is poured on 60 cc of a cold, saturated ammonium sulphate solution and is extracted thrice with methylene chloride; the combined extracts are washed with water, dried and concentrated by evaporation at reduced pressure. The residue is separated on 40 g of silica gel with chloroform containing 1 % of methanol (50 cc fractions), whereby the title compound is obtained.

IR (methylene chloride) inter alia bands at: 3450 - 2700, 1700, 1460, 1215 cm"1. - 16 - 100-4042 NMR (CDCl^ 60 megacycles per second) inter alia signals at: 1 H 10.5 ppm (-C00H) 2 H 3.42 ppm ( -CH2-CH2 -Br) 2 H 1.83 ppm (CH-CH2-CH2-) + = 193 cis-c clop_rop_ane-l- (2-bromoeth_Yl_) -2^carbo ^lic acid Treatment as described above yields the corresponding cis-cyclopropane-1- (2-bromoethyl) -2-carboxylic acid.

IR (methylene chloride) inter alia bands at: 3450 - 2470, 1695, 1220 cm"1.

NMR 60 megacycles per second) inter alia signals at: 9.5 ppm (1 H) -C00H 3.47 ppm (2 H) CH2 -Br 2.18 ppm (2 H) ~2¾~ trans-cyc1cp_rogane-l-_(2-bromoet y_1 ) -2 -carboxvlic acidjmethyl ester 200 mg of the trans acid are dissolved in 10 cc of methanol and treated with a solution of diazomethane in ether at room temperature (20°). After removing the solvent at reduced pressure, the residue (200 mg) is chromatographed on silica gel with benzene whereby the corresponding methyl ester is obtained.

IR (methylene chloride) inter alia bands at: 1720, 1210, 1120 cm"1.

NMR (CDC13< 100 megacycles per second) inter alia signals at: 3 H 3.68 ppm C00CH3 2 H 3.45 (t) CH2-Br 2 H 1.9 (m) CH2-CH2-Br The same compound is obtained by treating the trans acid with 3-methyl-l-p_-tolyl-triazine.

The following esters are produced in analogous manner : cis-cyclopropane-1- (2-bromoethyl) -2-carboxylic acid methyl ester , trans-cyclopropane-1- (2-bromoethyl) -2-carboxylic acid ethyl ester, cis-cyclopropane-1- (2-bromoethyl) -2-carboxylic acid ethyl ester, trans-cyclopropane-1- (2-bromoethyl) -2-carboxylic acid benzyl ester, cis-cyclopropane-1- (2-bromoethyl) -2-carboxylic acid benzyl ester. tripJien l-phospJhonium_salt °^ eth^l-trans-c^clODropane-carboxylie _acid 10 g of triphenyl phosphine are added to 5 g of (-) -trans-cyclopropane-1- (2-bromoethyl) -2- - 18 - 100-4042 carboxylic acid in 100 cc of absolute benzene and the mixture is boiled at reflux for 42 hours.

After removing the solvent at reduced pressure, the residue is separated on 600 g of silica gel with mixtures of chloroform/methanol/acetic acid (300 cc fractions) , whereby the title compound is obtained. IR (methylene chloride) inter alia bands at: 3400 - 3000, 1725, 1440, 1115 cm"1.

MR (CDC13, 60 megacycles per second) inter alia signals at: 15 H 7.75 ppm (aromatic H) 2 H 3.8 ppm (CH_2 - P -) The phosphonium salts of the following compounds are produced in analogous manner: ethyl-cis-eye1opropane-carboxy1ic acid, ethyl-trans-cyclopropane-carboxylic acid ethyl ester, ethyl-cis-cyclopropane-carboxylic acid ethyl ester, ethyl-trans-cyclopropane-carboxylic acid methyl ester , ethyl-cis-cyclopropane-carboxylic acid methyl ester, ethyl-trans-cyclopropane-carboxylic acid benzyl ester, ethyl-cis-cyclopropane-carboxylic acid benzyl ester. 2 , 3-trans-methano-11^15-bis-tetrah drogyran l- Er°-!i:?i2i¾i i F2a fWitti9 reaction] 70 mg of sodium hydride are dissolved in 0.7 cc of - 19 - 100-4042 dimethyl sulphoxide and the solution is kept at 75° for 40 minutes in an atmosphere of nitrogen. After cooling, the triphenyl-phosphonium salt of (-) -ethyl-trans-cyclopropane-carboxylic acid in 1 cc of absolute dimethyl sulphoxide is added to the brown solution. Stirring is then effected at room temperature for 1 Y≥ hours and 145 mg of 2β-(3' -tetrahydropyranyloxy-11 -trans-octenyl) -5a-hydroxy-3a-tetrahydropyranyloxy-cyclopentane-acetaldehyde lactol are subsequently added to 1.2 cc of the above solution. The reaction mixture is allowed to stand at room temperature for 15 minutes, is heated to 75° for 3 hours, is subsequently poured on 20 g of ice, the pH is carefully adjusted to 3 and extraction is effected with methylene chloride.

Chromatography on 20 g of silica gel with chloroform containing 2 % of methanol yields the title compound in pure form.

IR (methylene chloride) inter alia bands at: 3500, 1710 cm"1.

NMR (CDCl^, 90 megacycles per second) inter alia signals at: 4 H (m) 5.4 ppm 2 H 4.7 ppm 3 H (t) 0.9 ppm The following compounds are produced analogous manner: 2 , 3-cis-methano-Il, 5-bis-tetrahydropyranyl-prostaglandin ?2α' 2 , 3-trans-methano-ll, 15-bis-tetrahydropyranyl-prostaglandin F2a methyl ester , 2 , 3-cis-methano-ll, 15-bis-tetrahydropyranyl-prostaglandin F2a methyl ester, 2 , 3-trans-methano-ll , 15-bis-tetrahydrcpyranyl-prostaglandin F^a ethyl ester, 2 , 3-cis-methano-ll , 15-bis—tetrahydropyranyl-prostaglandin F2a ethyl ester, 2 , 3- trans-methano-11, 15-bis-tetrahydropyranyl-prostaglandin F2(x benzyl ester, 2 , 3-cis-methano-ll, 15-bis-tetrahydropyranyl-prostaglandin F2 benzyl ester, whereby the esters may alternatively be obtained directly from the corresponding acids.

EXAMPLE 2: 16, 16-dimethyl-2 , 3-trans (+) -methano- prostaglandin F? [process variant a) ] 200 mg of 16, 16-dimethyl-2 , 3- (+) -methano-11, 15-bis-tetrahydropyranyl-prostaglandin F2a are dissolved in 7 cc of a mixture of acetic acid, - 21 - 100-4042 tetrahydrcfuran, water (3 : 1 : 1) and kept at 40° for 5 hours. After concentrating by evaporation at reduced pressure, the residue is chromatographed on 23 g of silica gel with chloroform containing 7 % of methanol, whereby the crude title compound is obtained, [a] p= +88° (c = 1.01, CHC13).

IR (methylene chloride) inter alia bands at 3600-3400, 1695 cm"1.

NMR (CDCl^, 100 megacycles per second) inter alia bands at : 4 H «~ 5.5 ppm vinyl H 6 H < 4 ppm 3 x CH-OH 6 H 1.28 ppm 2 x CH3-C The following compounds are produced in analogous manner : 16, 16-dimethyl-2 , 3-trans (+) -methano-prostaglandin F„ methyl ester, 16 , 16-dimethyi-2 , 3-trans (+) -methano-prostaglandin ethyl ester, 16, 16-dimethyl-2 , 3-trans (+) -methano-prostaglandin F2a benzyl ester, 2 , 3-trans (+) -methano-prostaglandin F2a' 2 , 3-trans (+) -methano-prostaglandin F2a methyl ester, 2 , 3-trans (+) -methano-prostaglandin F2a ethyl ester, 2 , 3-trans (+) -methano-prostaglandin F2a benzyl ester.

The 16, 16-dimethyl-2 , 3 -trans (+) -methane— 11, 15-bis-tetrahydropyranyl-prostaglandin F2a' use<^ as starting material, is produced as follows: acid 29 g of (-) -ephedrine in 200 cc of methylene chloride are added to 66 g of trans-cyclopropane-1- (2-bromoethyl) carboxylic acid in 200 cc of methylene chloride and the mixture is allowed to stand at 20° for 2 V2 hours. Upon adding n-hexane crystals are formed. Filtration and recrystallization from methylene chloride/hexane and methylene chloride/ ethyl acetate are effected.

.P. 125-126°; [a] J= +22° (c = 1.26, CHCl3) .

Extraction with methylene chloride/dilute hydrochloric acid yields the (+) acid: [a] +75.3° (0=1.94, CHC13).

The acid is converted into the following esters as described in Example 1: (+) -trans-cyclopropane-1- (2 -bromoethyl) carboxylic acid methyl ester, (+) -trans-cyclopropane-1- (2-bromoethyl) carboxylic acid ethyl ester, (+) -trans-cyclopropane-1- (2-bromoethyl) carboxylic acid benzyl ester. 100-4042 b) trip e ylshos h^ 1-^2 -bromoethyl)_carboxylic _acid 10.3 g of triphenylphosphine are added to 6.3 g of (+) -trans-eyelopropane-1- (2-bromoethyl) carboxylic acid in 150 cc of absolute benzene and the mixture is boiled at reflux for 65 hours. After cooling, the precipitated crystals are filtered off.

.P. 121-125°; [a] „= +17.5° (c =1.18, CHCl,).

IR and NMR spectra correspond to those of the racemic compound.

The phosphonium salts of the following compounds are produced in analogous manner: ethyl-trans (+) -cyclopropane-carboxylic acid methyl ester, ethyl-trans (+) -cyclopropane-carboxylic acid ethyl ester, ethyl-trans (+) -cyclopropane-carboxylic acid benzyl ester . "t®ti¾¾ ^2£ ^¾1∑ilS: 2 t¾2i¾ i?l_5!2a fWitti? reaction] 600 mg of sodium hydride are dissolved in 6 cc of absolute dimethyl sulphoxide and kept at 75° in an atmosphere of nitrogen for 55 minutes. After cooling, 2.1 cc of this solution are slowly added dropwise to a prepared solution of 1.95 g of - 24 - 100-4042 the triphenylphosphonium salt of (+) -trans-cyclopropane-1- (2 -bromoethyl) carboxylic acid in 5 cc of absolute dimethyl sulphoxide and the mixture is stirred in an atmosphere of nitrogen for 45 minutes. 4.5 cc of the ylide solution described above are added at 20° to a prepared solution of 1 g of 2β- (4 * , 4 ' -dimethyl-3 ' a - tetrahydropyranyloxy-1 * -transoctenyl) -5a-hydroxy-3cc-tetrahydropyranyloxy-cyclopentane-acetaldehyde lactol in 1 cc of absolute dimethyl sulphoxide and the mixture is kept at 60° for 50 minutes. After the addition of a further 4.5 cc of the ylide solution, stirring is again effected at 60° for one hour. The cooled reaction mixture is poured on ice, the pH of the aqueous phase is adjusted to 3-5 and extraction i effected thrice with methylene chloride. The resulting crude product is , chromatographed on 140 of silica gel with chloroform containing 1 to 5 % of methanol, whereby the pure title compound is ob tained. [a] J= 435.5° (c = 1.07, CHC13) .

IR (methylene chloride) inter alia, bands at 3500, 1695 cm"1.

N R (CDC1 , 90 megacycles per second) inter alia - 25 - 100-4042 signals at: 4 H 5.5 ppm vinyl H 2 H 4.6 ppm THP H The following compounds are produced in analogous manner : 16, 16-dimethy1-2 , 3-trans (+) -methano-11, 15-bis~ tetrahydropyranyl-prostaglandin F^ met*nY^ ester, 16, 16-dimethyl-2 , 3-trans (+) -methano-11, 15-bis-tetrahydropyranyl-prostaglandin F2a ethyl ester, 16, 16-dimethy1-2 , 3-trans (+) -methano-11, 15-bis-tetrahydropyranyl-prostaglandin benzyl ester. tthen the Wittig reaction is effected with 2β~ (3 'α-tetrahydropyranyloxy-l ' -trans-octenyl) -5a-hydroxy-3a-tetrahydropyranyloxy-cyclopentane-acetaldehyde lactol, then the following- compounds are produced in analogous manner: 2 , 3-trans {+) -methano-11, 15-bis-tetrahydropyranyl-prostaglandin 2 , 3-trans (+) -methano-11 , 15-bis-tetrahydropyranyl-prostaglandin methyl ester, 2 , 3-trans (+) -methano-11, 15-bis-tetrahydropyranyl-prostaglandin F2a ethyl ester, 2 , 3-trans (+) -methano-11, 15-bis-tetrahydropyranyl-prostaglandin benzyl ester. - 26 - 100-4042 EXAMPLE 3; 16 , 16-dimethyl-2 , 3-trans (+) -methano- prostaglandin E^ [prostaglandin acid group protection oxidation; process variant a) ] 100 mg of 16 , 16-dimethyl-2 , 3-trans (+) -methano- 11.15-bis-tetrahydropyranyl-prostaglandin F are dissolved in 1 cc of absolute toluene, and 26.7 mg of tert. butyl dimethylchlorosilane are added in an atmosphere of nitrogen. The reaction solution is cooled to 0°, 18 mg of triethylamine are added, stirring is effected at 20° for 2 1/2 hours, the solution is cooled to -30° and slowly added dropwise to a solution of 108 mg of N-chlorosuccinimide in 4 cc of absolute toluene and 60 mg of dimethyl sulphide within 35 minutes. After a further 2 3/4 hours at -20° , 220 mg of triethylamine in 1 cc of pentane are added dropwise and working up is effected with ether/water for a further 10 minutes. The residue (100 mg) is chromatographed on 8 g of silica gel with chloroform containing 2 % of methanol. 16.16-dimethyl-2 , 3-trans (+) -methano-11 , 15-bis-tetrahydro-pyranyl-prostaglandin tert. butyl dimethylsilyl ester is obtained.

IR (methylene chloride) inter alia bands at 1735, 1695 cm""1. 50 mg of the ester described above are dissolved in 0.7 cc of acetone, 0.2 cc of water are added dropwise, and 0.25 cc of a solution of 246 mg of sodium acetate in 3 cc of acetone, 1 cc of water and 180 mg of - 27 - 100-404_έ\ acetic acid are added at 0°. Stirring is effected at 0° for 45 minutes, and at 25° for 1 1/2 hours, and subsequently working up is effecte'd with ether.

The residue is dissolved in 2 cc of acetic acid/water/tetrahydrofuran (3:1:1) and kept at 38° for 2 1/2 hours. After concentrating by evaporation at reduced pressure, the residue is chromatographed on 2.5 g of silica gel with chloroform containing 3 % of methanol. The pure title compound is obtained.

IR (methylene chloride) inter alia bands at 1735, 1695 cm"1.

NMR (CDCI3/ 90 megacycles per second) inter alia signals at: 4 H 5.3 - 5.8 ppm (vinyl protons) 5 H 3.7 - 4.2 ppm 2 x -CH-OH + -C00H 2 , 3-trans (+) -methano-prostaglandin is produced in analogous manner.

The following compounds are produced in analogous manner, using the esters described in Example 2 as starting materials: 16 ,16-dimethyl-2 , 3-trans (+) -methano-prostaglandin methyl ester, 16 , 16-dimethyl-2 , 3-trans (÷) -methano-prostaglandin E2 ethyl ester, 16 , 16-dimethyl-2 , 3-trans (+) -methano-prostaglandin benzyl ester, 2, 3-trans (+) -methano-prostaglandin methyl ester, 2 , 3-trans (+) -methano-prostaglandin E2 ethyl ester, 2 , 3-trans (+) -methano-prostaglandin E_ benzyl ester. - 28 - 100-404 EXAMPLE 4; 16 , 16-dimethyl-2 , β-trans (-) -methano- prostaglandin F., [process variant a) ] 109 mg of 16 , 16-dimethyl-2 , 3-trans (-) -methano-11 ,15-bis-tetrahydropyranyl-prostaglandin are dissolved in 3.5 cc of a mixture of acetic acid/ tetrahydrofuran/water (3:1:1) and kept at 40° for 6 hours. After concentrating by evaporation at reduced pressure, the residue is chromatographed on 5 g of silica gel with chloroform containing 7 % of methanol, whereby the pure title compound is obtained.

IR (methylene chloride) inter alia bands at 3600, 3400, 1695 cm-1.

NMR (CDCl^, 90 megacycles per second) inter alia signals at: 4 H 5.3 - 5.7 ppm vinyl-H 7 H 3.9 - 4.3 ppm 3 x ^CK-CH + COOH CH 1.28 ppppmm J CH3- The following compounds are produced in analogous manner: 16, 16-dirnethy1-2, 3-trans (-) -methano-prostaglandin methyl ester, 16 ,16-dimethyl-2 , 3-trans (-) -methano-prostaglandin F?a ethyl ester, 16 , 16-dimethyl-2 , 3-trans (-) -methano-prostaglandin F2 benzyl ester, , 3-trans (-) -methano-prostaglandin F 2σ' , 3-trans (- ) -methano-prostaglandin F methyl ester, 2a , 3-trans (-) -methano-prostaglandin F ethyl ester, 2 , 3-trans (-) -methano-prostaglandin F 2a benzyl ester.

The 16 , 16-dimethyl-2 , 3-trans (-) -methano- , 15-bis-tetrahydropyranyl-prostaglandin , used starting material, is produced as follows: ) J-^-trans^cyclo^ropane-l^ 2-bromoet The title compound is obtained in a manner analogous to that described in Example 2 a) with (+) -ephedrine . ta]p = -75.0° (c = 1.56, CHCl3) .

The spectroscopic data of the title compound are identical with those of the (+)-acid.

The acid is converted into the following esters in a manner analogous to that described in Example 1 : (-) -trans-cyclopropane-1- (2-bromoeth l) carboxylic acid methyl ester, (-) -trans-cyclopropane-1- (2-bromoethyl) carboxylic acid ethyl ester, (-) -trans-cyclopropane-1- (2-bromoethyl) carboxylic acid benzyl ester. 1—J2—brgmoeth l)_ca box llc_ac±d 10 g of triphenylphosphine are added to 61 g of (-) -trans-cyclopropane-1- (2-bromoethyl) carboxylic acid in 200 cc of absolute benzene, and the mixture is boiled at reflux for 63 hours. After cooling the precipitated crystals are filtered off.

M.P. 120-122°, tal^ "17'3° (c = 1-19' CHC13> .

The IR and NMR spectra correspond to those of the enantiomorphic compounds.

The phosphonium salts of the following compounds are produced in analogous manner: ethyl-trans (-) -cyclopropane-carboxylic acid methyl ester, ethyl-trans (-) -cyclopropane-carboxylic acid ethyl ester, ethyl-trans (-) -cyclopropane-carboxylic acid benzyl ester. i2i§l£§-=£§-Y^£2EY--' DYilBE2staglandin_F2a [Wittig reaction] 300 mg of sodium hydride are suspended in 3 cc of absolute dimethyl sulphoxide, and the suspension is kept at 75° for 45 minutes in an atmosphere of nitrogen. After cooling, 0.9 cc of this solution are slowly added dropwise to a prepared solution of 1 g of the triphenylphosphonium salt of (-) -trans-cyclo-propane-1- (2~bromoethyl) carboxylic acid in 2.5 cc of absolute dimethyl sulphoxide, and the mixture is stirred for 45 minutes under nitrogen. 1.9 cc of the ylide solution described above are slowly added dropwise to a solution of 500 mg of 2β- (4 ' ,4 '-dimethyl-3 'σ-tetrahydropyranyloxy-l '-trans- octenyl) -5a-hydroxy-3a-tetrahydropyranyloxy-cyclo-pentane acetaldehyde lactol in 0.6 cc of absolute tetrahydrofuran. After 40 minutes at 60°, a further 1.9 cc of the ylide solution are added dropwise and the mixture is kept at 60° -for a further hour. The cooled reaction mixture is poured on 100 g of ice, the pH of the aqueous phase is adjusted to 3 - 4 and the aqueous phase is extracted thrice with methylene chloride. The resulting crude product is purified by chromatography on 40 g of silica gel, whereby the title compound is obtained with chloroform containing 2 % of methanol .

IR (methylene chloride) inter alia bands at 3500, 1695 cm"1.

The following compounds are produced in analogous manner : 16 , 16-dimethyl^-2 , 3-trans (-) -methano-11 , 15-bis-tetrahydropyranyl-prostaglandin methyl ester, 16 , 16-dimethyl-2 , 3-trans (-) -methano-11 , 15-bis-tetrahydropyranyl-prostaglandin et^ l ester, 16, 16-dimethyl-2, 3-trans (-) -methano-11 , 15-bis-tetrahydropyranyl-prostaglandin benzyl ester.

When the Wittig reaction is effected with 2β- (3 'α-tetrahydropyranyloxy-l ' -trans-octenyl) -5cc-hydroxy-3a-tetrahydropyranyloxy-cyclopentane acetaldehyde lactol, the following compounds are produced in analogous manner: - 32 - lO0-40¾ ""\ 2 ,3—trans (-) -methano-11 ,15-bis-tetrahydropyranyl- prostaglandin 2 , 3-trans (-) -methano-11, 15-bis-tetrahydropyranyl- prostaglandin methyl ester, 2 , 3-trans (-) -methano-11 , 15-bis-tetrahydropyranyl- prostaglandin F2a ethyl ester, 2 , 3-trans (-) -methano-11 , 15-bis-tetrahydropyranyl- prostaglandin benzYl ester.

EXAMPLE 5: 16 , 16-dimethyl-2 , 3-trans (-) -methano- prostaglandin [prostaglandin acid group protection; oxidatio process variant a) ] 177 mg of 16 , 16-dimethyl-2 , 3-trans (-) -methano-11, 15-bis-tetrahydropyranyl-prostaglandin F2a are dissolved in 1.5 cc of absolute toluene. A solution of 47.2 mg of tert.butyldimethyl chlorosilane in toluene is added dropwise in an atmosphere of nitrogen. The reaction solution is cooled to 0° , 32 mg of triethylamine are added and stirring is effected at 20° for 2 1/2 hours. The reaction mixture is cooled to -30° and is slowly added dropwise to a solution of 191 mg of N-chlorosuccinimide in 6 cc of absolute toluene and 106.3 mg of dimethyl sulphide. After 2 hours at -30°/-20° 300 mg of triethylamine in 1 cc of pentane are added, stirring is continued for 10 minutes and working up is effected with ether/water. The residue (192 mg) is chromatographed on 12 g of silica gel with chloroform containing 1 % of methanol. - 33 - 100-4043^ The resulting silyl ester (IR in methylene chloride inter alia bands at 1735, 1675 cm-1) is dissolved in 2.7 cc of acetone. O*.9 cc of water and 1.2 cc of a solution of 246 mg of sodium acetate in 3 cc of acetone, 1 cc of water and 180 mg of acetic acid are added to the solution which has been cooled to 0° . The reaction mixture is stirred at 0° for 30 minutes, at 25-30° for 1 1/2 hours, and is subsequently worked up with ether. The residue (IR in methylene chloride inter alia bands at 3500, 1735, 1695 cm"1) is dissolved in 3 cc of acetic acid/water/tetrahydrofuran (3:1:1) and stirred at 40° for 6 hours. After concentrating by evaporation at reduced pressure, the residue is chromato-graphed on 4.5 g of silica gel with chloroform containing 2 % of methanol. The pure title compound is obtained. IR (methylene chloride) inter alia bands at 3600, 3400, 1735, 1695 cm""1.

N R (CDC1_, 90 megacycles per second) inter alia signals at about: 2,3-trans (-) -methano-prostaglandin is produced in analogous manner.

The following compounds are produced in analogous manner, using the esters described in Example 4 as starting materials: 16 , 16-dimethyl-2 , 3-trans (-) -methano-prostaglandin E methyl ester, 16 , 16-dimethyl-2 , 3-trans (-) -methano-prostaglandin E ethyl ester, 16 ,16-dimethyl-2 , 3-trans (-) -methano-prostaglandin E benzyl ester, 2 , 3-trans (-) -methano-prostaglandin methyl ester, 2 , 3-trans (-) -methano-prostaglandin ∑2 ethyl ester, 2 , 3-trans (-) -methano-prostaglandin E_ benzyl ester.

EXAMPLE 6 : 16 , 16-dimethyl-2 , 3-trans (+) -methano- prostaglandin [process variant b) ] 50 mg of 16 , 16-dimethy1-2 , 3-trans (+) -methano-prostaglandin of Example 3 are dissolved in 2 cc of acetic acid/water (9:1) and kept at 60° for 5 1/2 hours. After the addition of toluene, concentration is effected by evaporation at reduced pressure and the residue is chromatographed on 0.5 g of silica gel with chloroform containing 0.5 % of methanol. The pure title compound has the following characteristics: IR (methylene chloride) inter alia bands at 3600, 1700, 1690, 1140 cm"1.

NMR (CDCI3, 90 megacycles per second) inter alia signals at: - 35 - 100-404 The following compounds are produced in analogous manner: 16 , 16-dimethyl-2 , 3-trans (+) -methano-prostaglandin A2 , 16 , 16-dimethyl-2 , 3-trans (+) -methano-prostaglandin A2 methyl ester, 16 , 16-dimethyl-2 , 3-trans (+) -methano-prostaglandin A2 ethyl ester, 16 , 16-dimethyl-2 , 3-trans (+) -methano-prostaglandin A2 benzyl ester, 2 ,.3-trans (+) -methano-prostaglandin A2 , 2 , 3-trans (+) -methano-prostaglandin A2 methyl ester, 2 , 3-trans (+) -methano-prostaglandin A2 ethyl ester, 2 , 3-trans (+) -methano-prostaglandin A2 benzyl ester.

EXAMPLE 7: 16 , 16-dimethyl-2 , 3-trans (-) -methano- prostaglandin A2 [process variant b) ] 120 mg of 16 , 16-dimethyl-2 , 3-trans (-) -methano-prostaglandin E2 of Example 5 are dissolved 5 cc of acetic acid/water (9:1) and kept at 55-60° - 36 - 100-4042^ for 15 hours. The reaction mixture is concentrated by evaporation at reduced pressure and the residue is chromatographed on 5 g of silica gel. The pure title compound is isolated with a mixture of chloroform/methanol. IR (methylene chloride) inter alia bands at 3600, 1700, 1690, 1590, 1065, 1030 cm"1.

NMR (CDC13, 90 megacycles per second) inter alia signals at: H ■ .1 H 7.5 ppm / \ 0 5 H 5.2 - 6.3 ppm 0.7 - 0.95 ppm CH3~ The following compounds are produced in analogous manner: 16 , 16-dimethyl-2 , 3-trans (-) -methano-prostaglandin , 16 , 16-dimethyl-2 , 3-trans (-) -methano-prostaglandin methyl ester, 16 , 16-dimethyl-2 , 3-trans (-) -methano-prostaglandin ethyl ester, 16 ,16-dimethyl-2 , 3-trans (-) -methano-prostaglandin benzyl ester, 2 , 3-trans (- ) -methano-prostaglandin A , 2 , 3-trans (-) -methano-prostaglandin A2 methyl ester, 2 , 3-trans (-) -methano-prostaglandin A2 ethyl ester, 2 , 3-trans {-) -methano-prostaglandin benzyl ester. 100-4O4 Physical data;- 2,3-cis-(+) or (-) -methano-pErosta-Zlandin F2_n 7H 1.9 - 2.4 ppm aliphatic H 3H 3.51 - 4.16 ppm CHOH 4H 5.15 - 5.75 ppm vinyl H I.R. 3580, 3400, 1710 - 1695 cm"1 2,3-cis-(+) or (-) -methano-prostaglandin ^ methyl N.M.R. 7H 1,9 - 2,4 ppm aliphatic H 3H 3,58 ppm ~°~C¾ 3H 3,58 - 4,15 ppm ^CHOH 4H 5,2 - 5,2 ppm Vinyl H IR 3580, 3400, 1725 - 1710 cm" 100-4042 2,3-cis-(+) or ( -methano-prostaglandin NMR 7H 1,88 - 2,38 ppm aliphatic H 5H 3,6 - 4,4 ppm ^CHOH, -C00CH 4H 5,1 - 5,7 ppm Vinyl H IR -1 3580, 3400, 1725 - 1705 cm ethyl ester F2a- NMR 7H 1,88 - 2,38 pm aliph tdc H 3H 3,6 - 4,1 ppm cHOH 2H 4,1 - 4,4 ppm . -COOCH2- 4H 5,1 - 5,7 ppm Vinyl H IR 3580. 3400f 1725-1705 cm"1 100-4042 2, 3-trans- (+) or (-) -methano-prostaqlandin F^ ethyl ester NMR 7H 1,88 - 2,38 ppm aliphatic H 3H 3,6. - 4,1 ppm /CHOH 2H 4,1 - 4,4 ppm -C00CH2- 4H 5,1 - 5,7 ppm Vinyl, H IR 3580, 3400 , 1725 - 1705 cm -1 2 , 3-trans- (+) or (-) -methano-prostaqlandin ^ methyl ester NMR 7H 1,88 - 2,38 ppm aliphatic H 3H 3,6 ppm -0-CH3 3H 3,58 - 4,15 ppm CH0H 4H 5,1 - 5,7 ppm Vinyl H IR -1 3580, 3400, 1725 - 1705 cm 100-4042 2 , 3-trans- (+) or (-) -methano-prostaglandln methyl ester NMR 3H 3,65 ppm -C00CH3 4H 5,1 - 5,65 ppm Vinyl H IR 3600, 3400, 1740 - 1705 cm' 2> 3-trans- (4) or (-) -methano-prostaglandin E ethyl ester NMR 4H 5 , 2 - ppm IR 3400, 1740 - 1705 cm 100-4042 16 , 16-dimethyl-2, 3-trans- (+) or ( -) -methano-prostaglandin A_ methyl ester NMR -H 0 H 0,8 - 1,0 ppm -CH3, 3H 3,6 ppm -C00CH3 4H 5,1 - 5,6 ppm Vinylprotonen 1H 5,9 - 6,2 ppm Vinylproton 1H 7,35 - 7,55 ppm Vinylproton IR -1 3600 , 3400, 1740 - 1705 cm 16 ,16-dlmethyl-2 , 3-trans- (+) or (-) -roethano-prostaglandin ethyl ester NMR 2H 4,1 - 4,3 ppm -COOCH2- 4H 5,15 - 5,6 ppm Vinylprotonen 1H 6,0 - 6,25 ppm Vinylproton 1H 7,35 - 7,55 ppm Vinylproton IR 3600, 3400, 1740 - 1705 cm 100-4042 16,16-dimethyl-2,3-trans-(+) or (-) -methano-prostaglandin E methyl ester 2H 2,56 - 3,2 ppm COCH2~ 3H 3,6 ppm -COOCH3 4H 5,1 - 5,7 ppm Vinylprotonen IR -1 3600, 3400, 1745 - 1705 cm 16,16-dimethyl-2,3-trans-(+) or (-) -methano-prostaglandin E„ ethyl ester NMR 2H 4,1 - 4,3 ppm -COOCH2- 4H 5,15 - 5,7 ppm Vinylprotonen IR -1 3600, 3400, 1745 - 1705 cm 100-4042 2 , 3-trans- (+) or (-)-methano-prostaglandin R, NMR 4H 5,3 - 5,8 ppm Vinylprotonen IH 6,15 ppm Vinylpro on IH 7,5 ppm Vinylproton IR 3600, 1710 - 1690 cm' 1 ,3-trans- (4·) or (-) -methano-prostaqlandin A methyl ester NMR 4H 0,7 - 0,9 ppm -CH3, ^- — 3H 3,65 ppm -COOCH3 4H 5,1 - 5,6 ppm . Vinylprotonen IH 5,9 - 6,2 ppm Vinylproton IH 7,3 - 7,55 ppm Vinylproton IR -1 3600, 3400, 1745 - 1705 cm 100-4042 ,3-trans- (+) or (-) -methano-prostaglandin A? ethyl ester NMR H 7H 0,8 - 1,1 ppm •CH3, 2H 4,1 - 4,25 PPm -COOCH2- 4H 5,2 - 5,7 ppm Vinylprotonen 1H 5,9 - 6,25 ppm Vinylproton 3H 7,35 - 7'5 ppm Vinylproton IR -1 3400, 1745 - 1705 cm 100-4042 EXAMPLE 8; l zl§l^meth^l^2z3-trans- Obtained by methylating 16 ,16-dimethyl-2 , 3-trans-f»V (-) -methylene-prostaglandin F2a in ether/methanol at 0°C with diazomethane .

I.R. 3580, 3400, 1725 - 1705 cm"1.

N.M.R. 90 MHz 3H 3.6 - 36.5 ppm -0CH_3 EXAMPLE 9 : 16 16-dimethy.l-2j.3-t ans; +^_or_ l lBethy_lene- E∑2 !=§9i§i ^iil_5!2a-----^------- Obtained by benzylating 16 ,16-dimethyl-2 , 3-trans-i+) *** (•r I -methylene-prostaglandin in ether with phenyldiazo-methane obtained from N-benzyl-N-nitroso-tolyl-4-sulphon-amide.

I.R. 3580, 3400, 1735 - 1715 cm"1 N.M.R. 1.9 - 2.5 ppm aliphatic H 5.2 - 5.7 ppm vinylprotons .

EXAMPLE 1° : iIl^ S2-i ~-i-L2lt----- -.lillO}St ∑i^ SZE£°≥t22-:2Q^i-i _?2 This is obtained in analogous manner to Example 1.

I.R. 3350, 1750 - 1705 cm -1 100-4042 EXAMPLE 111 16x16=dimethyl=9 χ11αΛ15Βztrihy_dro trans-^+^-methanogrosta-5c acid Obtained in analogous manner to Example 1.

I.R.: 3600, 3500, 17lO, 1695 cm"1.

N.M.R.: 4H ca. 5.5 ppm vinyl H 3H ca. 4 ppm 3 CH OH EXAMPLE 12: 16x16-dimeth l-llax15ezd^hYdrox^-g-keto-^IJ;; tran§ ^+}.:. ethanoErosta::5cis^ acid_ Obtained in analogous manner to Example 1.

I.R.: 3600, 1740, 1695 cm"1.

EXAMPLE 13: 16x16-dimethv^l50-hvd^^ acid Obtained in analogous manner to Example 1.

I.R.: 3600, 1705, 1695 cm"1.

EXAMPLE 14; The following compounds are also obtained in analogous manner to Example 1. (a) (5Z,9e,ll6,13E,15S)-9,ll,15-trihydroxy-2 ,3-(+)-trans methylene-8,12-epi-prosta-5 ,13-dienoic acidf 1O0-4042 [α]β = +17.0° (c = 0.9) . (b) 5Z ,118 ,13E ,15S ) -11 ,15-dihydroxy-2 , 3- (+) -trans- niethylene-9-oxo-8,12-epi-prosta-5 ,13-dienoic acid, [cc]D = +107.85° (c = 0.56) (c) (5Z ,13E ,15S)-15-hydroxy-2 , 3- (+) -trans-methylene-8 , epi-prosta-5 ,10-13-trienoic acid, ta]D = -98.6° (c = 1.43) The specific rotations are given for the free acid in CHC1-/CH-0H 9:1.

The compounds of formula I exhibit prostaglandin-like pharmacological activity. In particular the compounds of formula I exhibit bronchodilatory activity and lower arterial blood pressure as indicated in standard tests, for example, both by their effect on the smooth muscles of the rat stomach and colon in accordance with the principles of N. Gilmore et al, Nature 218, 1135-40 (1968) and by their effect on the guinea pig ileum in accordance with the principles of . Ruegg et al, Exper. 28, 1525 (1972) , R. Jaques, Kelv. Physiol. Acta, 17, 255 (1959) and 2_3, 156 (1965) .

The compounds are, therefore, indicated for use as bronchodilator agents and agents for lowering arterial blood pressure.

The activity of the compounds in the above tests also indicate a nasal decongestant effect, and a blood platelet aggregation inhibition effect.

The compounds of formula I wherein D is a or lid carbocycle of formula lie/, exhibit activity in the above tests and also in the rat uterus in situ according to the principles of Bisset G.W. , et al, in Memoirs of the Society for Endocrinology No. 14 - Endogenous substances affecting the myometrium. Edited by V.R. Pickles and R.J. Fitzpatrick. Cambridge University Press 1966, p.185-198 and the rat uterus in vitro in accordance with the - .38"'- 100-4042 principles of P. Holton, Brit. J. Pharmacol., 3_, 328 (1948).

These compounds of formula I wherein D is a or lid carbocycle of formula lie/ are therefore further indicated for use as uterus-stimulating agents.

The compounds of formula I wherein D is a or lid carbocycle of formula lie/additionally inhibit gastric secretion as indicated in standard tests, for example, by an inhibition of pentagastrin- and histamine-induced gastric secretion in rats according to the principles of M.N. Gosh et al . , in Brit. J. Pharmacol., 13, 54 (1958) and F. Kalter et al., in Helv. med. Acta Suppl. , 50, 113 (1971) .

These compounds of formula I wherein D is a or lid carbocycle of formula lie/ are therefore further indicated for use as gastric secretion inhibiting agents. 16 , 16-dimethyl-2, 3-trans (+) -methano-prosta- and 16, l6 dimethyl-2,3-trans(-)-methano-prostaglandin E? glandin F2a/show especially interesting properties.

For all the above uses an indicated daily dose is from about 0.1 to about 20 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.02 to about 10 mg, or in sustained release form. 100-4042 The compounds of formula Id may be administered in pharmaceutically acceptable salt form. Such salt forms exhibit the same order of activity as the free acid forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I in pharmaceutically acceptable form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.

Claims

100-4042

1. A process for the production of a compound of formula I, wherein D is one of the four carbocycles of formulae Ila, lib, lie or lid, 45215/2 100-4042 R^ is hydrogen or alkyl of 1 to 8 carbon atoms , or aralkyl of 7 to 12 carbon atoms , and R2 and R^ , independently , are hydrogen or alkyl of 1 to 4 carbon atoms, comprising a) removing any protective group present in a compound of formula III, wherein 2 and R^ are as defined above, R^ is trialkylsilyl or tetrahydropyranyl, R- is hydrogen, alkyl of 1 to 8 carbon b atoms , , aralkyl of 7 to 12 carbon atoms or tert .-butyldimethylsilyl , and A is a carbocycle of formula Ila or lib as defined above or. of formula lie or Ilf 100-4042 b) removing water from a compound of formula la, wherein D is a carbocycle of formula lid as defined above and R.. , R and R-. are as defined above to produce a compound of formula lb, lb R 2YR1 100-4042 herein D is a carbocycle of formula lib as defined above and R^, and are as defined above, c) hydrolysing a compound of formula Ic, wherein is alkyl, cycloalkyl or aralkyl and R^, and D are as defined above, to produce a compound of formula Id, wherein R 1 is hydrogen and and D are as defined above, or d) esterifying a compound of formula Id as defined above to produce a compound of formula Ic. 45215/2 - 55 - 100-4042

2. A process for the production of a compound of formula I, as stated in Claim L, substantially as hereinbefore described with reference to any one of the Examples. ,

3. A compound of formula I whenever produced by a process according to Claim 1 or 2.

4. A compound of formula 1 as defined in Claim 1.

5. 2 , 3-trans- (+) or (-) -methano-prostaglandin F2a«

6. 2,3-cis-(+) or (-) -methano-prostaglandin 2a

7. 2,3-cis-(+) or (~) -methano-prostaglandin F2ot methyl ester.

8. 2,3-cis-(+) or (-) -methano-prostaglandin ethyl ester.

9. 16 ,16-dimethyl-2 , 3-trans- (+) or (-) -methano-prostaglandin F2a*

10. 16 ,16-dimethyl-2 , 3-trans- (+) or (-) -methano-prostaglandin methyl ester.

11. 16 ,16-dimethyl-2 , 3-trans- (+) or (-) -methano-prostaglandin ethyl ester.

12. 2 , 3-trans- (+) or (-) -methano-prostaglandin F_ methyl ester. 45215/2 - 56 - 100-4042

13. 2 , 3-trans- (+) or (-) -methano-prostaglandin ?2a etnyl ester.

14. 16 ,16-dimethyl-2 , 3-trans- (+) or (-) -methano-prostaglandin F2a benzyl ester.

15. 16 ,16-dimethyl-2 , 3-trans- (+) or (-) -methano-prostaglandin E^.

16. 2 , 3-trans- (+) or (-) -methano-prostaglandin E 2*

17. 2 , 3-trans- (+) or (-) -methano-prostaglandin ∑2 methyl ester.

18. 2 , 3-trans- (+) or (-) -methano-prostaglandin E2 ethyl ester.

19. 16,16-dimethyl-2, 3-trans- (+) or (-) -methano-prostaglandin methyl ester.

20. 16, 16-dimethyl-2 , 3-trans- (+) or (-) -methano-prostaglandin E2 ethyl ester.

21. 16 ,16-dimethy1-2 , 3-trans- (+) or (-) -methano-prostaglandin A2-

22. 16 ,16-dimethyl-2 , 3-trans- (+) or (-)-methano-prostaglandin A2 methyl ester.

23. 16 ,16-dimethyl-2 , 3-trans- (+) or (-) -methano-prostaglandin A2 ethyl ester.

24. 2, 3-trans- (+) or (-) -methano-prostaglandin V

25. -A compound of any one of claims 3 to 24 in the individual optical isomer form, having the same = 57 - 45215/2 100-4042 absolute configuration at C2 and C3 as 16 , 16-dimethyl- 20 2, 3-trans- (+) -methano-prostaglandin having [α]β = +88

26. (C 5= 1.01, CHC13) .

27. A compound of any one of claims 3 to 24 in the individual optical isomer form, having the same absolute configuration at C2 and C3 as 16 ,16-dimethyl - 20 2 , 3-trans- (-) -methano-prostaglandin F^ having [ot- D = +13 (c = 1.02, CHC13) .

28. 16 ,16-dimethy1-2 , 3-trans- (+) -methano- prostaglandin F2a*

29. . 16 ,16-dimethyl-2 , 3-trans- (-) -methano-prostaglandin ·

30. A pharmaceutical composition according to any one of claims 3 to 29 in pharmaceutically acceptable form in association with a pharmaceutical carrier or diluent. 3700/RR/IL For the -p licants DRo RE! QLI COHN AND PARTNERS B : . J