CA1050976A - Compounds with prostaglandin type activity - Google Patents

Abstract

COMPOUNDS WITH PROSTAGLANDIN TYPE ACTIVITY

Abstract of the Disclosure The present invention concerns novel compounds of the formula, wherein D is one of the four carbocycles of formulae IIa, IIb, IIc or IId, II a II b IIc

Description

\
3S~97~

COMPOUNDS WITH PROSTAGLANDIN IYPE ACTIVITY
The present invention relates to novel cyclopropane derivatives.
In accordance with the invention there are provided new optically active compounds of ormula I, or racemic compounds of th-.s formula, ,/~\
D

.,, }~ .
wherein D is one of the four carbocycles of formulae IIa, IIb, IIc or IId, O
>~
: <

.. . . . . .
. '~ . O

II

. .
, o . . . ..

C
: '\~,~, J10' , ; :
~`, ' . ,. ' .

' ' . ~ -.

- 2 - 100-4042 O
`. ~_ , , ~ ~ ~I d .~, ~ ~ :
,'. il(:~' '-':
and Rl, R2 and R3independentlyare hydrogen or alkyl ~ groups of 1 to 4 carbon atoms.
:~, .... . ...

The invention also inclu~es pharmacologically accepta~le salt forms of the compounds of formula I, when Rl is hydrogen.
In the ~clopentane formula II the dotted oonnecting lines indicate that the substituents are linked with the cyclopentane ring in an a-configuration, i.e. they are situated below the level of the cyclopentane ring. The ~hicker solid connecting lines indioate that the substituents are linked with the cyclopentane ring in a ~-configurat-ion, i.e. they are situated above the level of thecyc~opentane ring. The wavy connecting line at C 15 in ormula I ~indicates that the hydroxyl group is present ,, ~ , .
as an a- or B-configuration.

In regard to formula I examples of alkyl -;:.. : .
groups of 1 to 8 carbon atoms are: methyl, ethyl, propyl, ~utyl, pentyl, hexyl, heptyl, octyl~ including the , isomeric forms of the same. Examples of cycloalkyl groups .;. . . .

. , .. ~.," ., .
... . .
. ,: . ^ .
'- . . ' . ' ~ ':
: . . .
.
, ~ ~f3 , . ' , S~g76 100-404:2 of i to 10 carbon atoms ~including alkyl-substituted cyclo-alkyl groups) are: cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-~iethylcyclopropyl, 2-butylcyclo-propyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4~triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclo-pentyl, 2-pentylcyclopentyl, 3-tert.butylcyclopentyl, cyclohexyl, 4-tert.butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimetllylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Examples of aralkyl groups of 7 to 12 carbon atoms are: benzyl, phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylhutyl, 3-phenylbutyl, 2-(1-n~phthyl)ethyl and 1- (2-naphthyl)methyl.
~ F'urther, in accordance with the invention a ; compound of formula I may be obtained by a process comprising a) hydrolysing a compound of formula III, A ~ 3 III

; ~ :
wherein R2 and R3 are as defined above, R4 is tert.~butyldimethylsilyl or 2-tetrahydro-pyranyl, R6 is hydrogen, an alkyl group of 1 to 4 carbon atoms, ' ~:
: ' ' ' , . ~ :
... .. .. ... ....... . .... ...... . . .. .... . . . ...
.. . - ~ , . . :
: . , ~ , . ,, ., .. ~

~5(~76 - 3a - 100-4042 or a tert.-butyl-dimethylsilyl group, and . .

A is a carbocyclic radical of formula IIa or ; IIb as defined above or of formula IIe or IIf~

~` ' ,,.
~ .

.

.'~ ' ;' .
~' :
.:
,'' ~-~ .
:.

"
.'~',~',':
,'.~' ' .
.~ ~
:
:~, ~''`' ~ .
~ .

5~76 ~ 4 100-40~2 .

~ ~ II e .
b) removing water from a compound of formula Ia, ~ ~ ~ COOR
D Ia . H

wherein D is a carbocycle of formula IId a~
defined above and Rl, R2 and R3 are as defined above to produce a compound of formula Ib, D~ UORl H
.~ . ' ~ .

'. ' .
:~

':
.

5~76 ~ 5 - 100-4042 wherein D is a carbocycle of formula IIb as defined above and : Rl, R~ and R3 are as defined above, c) hydrolysing a compound of formula Ic, / \ / \ OORl Ic whereln R i.s alkyl, cycloa~kyl or aralkyl and : R~, R3 and D are as defined ahove, to produce a compound of formula Id, /`\~--~ COORllI
Id H

wherei.n Rl is hydro~en and R2, R3 anù D are as de~ined abo~e, or d) esterifying a compound of ~ormula Id as defilled above to produce a compound of formula Ic.

' '~

.

~1~95(~7~

Process variant a)~ may be effected in conventional manner for the hydrolysis of 2-tetrahydro-pyranyl or tert.-butyldimethylsilyl protecting groups in prostaglandins For example the reaction may be carried out in solution, for example an organic acid/tetrahyaro-furan/water mixture, e.g. acetic acid/tetrahydrofuran/
water mixture.
A mineral acid is preferably present, e.g. hydro-chloric acid conveniently in methanol, or sulphuric acid.
The reaction is conveniently effected at from -10 to ~150C, preferably ~t from 30 ~ 60C.
Process variant b) may be effected in conventional manner for selectively dehydrating a 15-hydroxy-prosta-glandin E2 to obtain a 15-hydroxy-prostaglandin A2.
15Preferably 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 prostaylandin.
Process variant d) may be effected in conventional manner for the esterification of a 15-hydroxy-prostaglandin . . ~ .

.~ .
.1 .j ' .

::
'' ~3 . , , . ,, , , , , . :.

~50976 - 7 - 100-40~2 :, ~ to produce a 15-hydroxy-prostaglanc~in ester.
; The starting materials for the process variant . a), the compounds of formula IIIa, ~ ~ \ COQR6 A ~ ~ R~ IIIa wherein R2 to R4 and R6 are as deEined above, and A' is one of the carbocyclic radicals IIa, IIb, ; or IIf, are new and may be produced by oxi.dizing a compouncl of foxmula IV, ~ ' /\ ~\COO
~ B ~ ~ IV

.,-, .;. 0~4 wherein R2 to R4 and R6 are as defined above, and B is re~pectively one of the carbocyclic `;' radicals of formulae II~ or IIh, HO~
., > '' ., ~
HO

IIh , ~
. . . .
, ~"

- . . .: ..
,. : , . . : ~
.. .. . . ~ .. . .. ..

~L~33S~9'7~

or of formula IIe as defined above.
A suitable reagent for the oxidation is Collins reagent (pyridine/chromium trloxi~e), Jones reagent ~CrO3/H /
acetone) or a sulphide reagent, e.g.

(~-S ~ 3, Z = Cl or Cl-~
Cl ~l The reaction may be ca~ried out in conventional manner for the oxidation of a prostaglandin ha~Ting an 9-hydxoY.y group. An inext solv~nt ls preferably used.
In the case of the sulphide rsagent t:he solvent l~ay ~e for example toluene and a suitable reaction temperature is from -30 to ~C. When a carbos~yl.ic acid is used as starting material, this is preferably protected in convent.ional manner wherl a sulphide reagent is us~d.
For the production of compoun~s oE Eormula IIIA wherein B i5 the carbocycle IIb, the oxidatlon may cllso be effected wlth dichlorodic~anohenzoquinorle or activa~ed manganese dioxide.
The compounds of formula IV are producea by, ~,g.
reacting a compound of formula V, ,: ~ . ... . .. . ..

~ 9 - 100-4042 E ~ ~ ~ ~ V

OR~ .

~herein R2, R3 and R~ are as defined above, and E is one of the three carbocycles of formulae Va, Vb or Vc, l~O
~, V ~
, ~,1, ..

~0 j ~' V
., ~.
.~ , ' , ,,' ' ~
I c S~ "

: ~4 ' ~ :

"
, ~' '' ~ .

.

s~g~
- 10 - 100-4042~

whereby the radical R4 in formula Vc has the above significance, with a compound of formula VI, X~3 ~ COOR
(R~)3P~3-C~I2-CIl2 --/ 1 :; .
wherein Rl is as defined above, R5 is naphthyl or ph~nyl, ea~h of which m~y be unsubstltuted or substituted by lower alkyl, or lower alkyl, and X is chl.oxine, iod.ine or bromlne.

~s it will be appreciated that the cornpound of formula IV wherein B is a carbocycle of forrnula IIe .is the same as a compound of formula III wherein A is a carbocycle of formula IIe, the present invention also provides a process for the production of a compound of formula III wherein A is a carbocycle of formula IIe comprising reacting a compound of formula V whexein B 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 WitticJ reaction. The reaction is preferably effected in dimethyl sulphox~ide .' ~ ' ' ' .; , .-, . . - . , . . ,. . , ... ,.. , ~ ,. .... . - ~ . .

S~7~;
~ 100-4042 or dimethylsulphoxide/tetrahydrofuran. A suitable temperature is between 20 and 80C conveniently room temperature.
The starting material, compounds of formula VI
wherein Rl, R5 and X are as defined above, are new and - may be produced, for example, by reacting a 4-halogen l-butene of formula VII, , X-c~2-c~l2-cH=cH2 VII

wherein X is chlorine, iodine or bromine, with a diazoacetic a~id alkyl ester of ~ormula VIII, N2CH-COOR] VIII

whe~eln Xl is alkyl.

The resulting isomers of cyclopropanecarboxylic acid alkyl esters of formula IX, X-CH~-CH2-C~I - CH-COORl IX
.~ .
wherein Rl and X are as deined above, may he separated. The ester ~roup may be hydrolyséd, e.g. und~
conventional acid conditlons. If desired the optical antipodes may be separated in conventional manner, e.g.
through diastereoisomex salt formation, e.g. with optically . .
~; ~ active ephedrine. The optically active acid .

.''~` , - ' --.

'' , ' ' ' ' ' ' '. " ' ' .

7~
- 12 - 100-~042 may be esterified in conventional ~anner and reacted Witil a phosphine compound of formula X, ( 5)3P X
wherein R5 is as defined abo~e. The phosphonium salt production may be effected in conventional manner, for example in an inert solvent, eOg. b~nzene. The reaction may be effected at the reflux temperature.
Free acld forms of compounds oE forrnula Id may be conver-ted into salt form in conventional m~nner and vice v~r~a. Compounds of Eormula I may be Ln 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. I-t is preferred to separa-te the individual optical isomers of compounds of formula IX as mentioned above.
In the following non-limitative Examples all temperatures are indicated ln degrees Centigrade.
Ether refers to diethyl ether. In the prostaglandin , nomenclature hereinafter, "trans or cis(~ or (-)-methylene"
refers to the optical rotation of the corresponding respective trans or cis-2-(2-bromoethyl)cyclopropanecarboxylic acid ., which can be converted by stereospecific procedures into the prostaglandin.
' ' ~ ' ,, I .

., , ,~
~ ~ ' . . . ..

- 13 - ~ ~ ~9~ 100-~042 EXAMPLE 1: 2,3-trans-methano-prostaqlandin -2 [process variant a)]

40 mg of 2,3-methano-tra.ns-11,15-bis-tetrahydropyranyl-prostagland.in F2 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 re-duced pressure, the resldue is separatecl on 3 g of silica gel w.ith chloro~orm containing ].7 /0 of methanol., wh~,reby the pure title compound is obta.inecl. M.P~ 108-112 .
~MR (CDC13t 90 megaoycles per sec.~ond) lnter ali.~ siynals at: 4 H (m) 5.45 ppm vinyl protons

3 H 3.8 - ~.2 ppm C~-OH
3 H (t) 0.9 ppm methyl 2,3~cis-maihano-prostaglarldin F2 and th~
following eskers are procluced in analoyous mannex:

2,3-cis-methano-pxostaglandin F2~ rnethyl estQr, 2,3-trans--methano-prostaglandin F2~ methyl ester, 2,3-trans-methano-prostaglandin F2a ethyl ester, ~. .
2,3-cis-methano-prostagl.andin F2a eth~l ester, 2,3-trans-methano-prostaglandin F2~ benzyl ester, 2,3-c.is-methano-pro~taglanclin F2 benzyl ester.
.~
:
,,~ ~' .
, . , .
::
, ,, , ~
!. .

,. .

`~ 14 ~5~976 100-4042~

; The 2,3-trans-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2a, used as starting material, is produced as follows:

a) 2-bromoeth~l cyclopropane-car~oxylic acid eth-yl ester 40 cc of diazo-acetic acid lethyl ester are slowly added dropwise, while stirring vigorously, to a suspension heated to 100 of 2.48 g of copper powder in 22 g o 4-bromo-1-butene. After 2 hours at 1~0, filtration is effected and the isomeric cyclopropy].-: 10 carboxylic acid esters axe separated by chromato-graphy on ~00 g o~ silica gel with benzene as eluant.

trans-c~clo~ro~ane-1-(2-bromoethy.lL-2-carbox~lic - acid eth~1 ester _ _ _ _ _ , _ _ _ _ _ IR (~nethylene chloxide) inter alia bands at:
1710, 1420, 1200,~1~180 cm 1 ~MR (CDC13~ 60 meyacycles per second! inter alia si~nals at: 2 H 4.~17 ppm ~0 ~CH2-CX3) 2 EI 3.45 ppm (-cH2-cH2-Br) .
3 H 1.25 ppm (CH -OE12-) M = 220 ,, : . .
cis-cyclo~ro~ane-l (~-bromoeth~1)-2-carboxyl c acid~
thyl ester . ~
IR~ (methylene :ch~lcride) inter ~ alia bands ~ at: :
1715, 1395, 1180 cm~l~.

- 15 - 105~6 100-4042~

~MR (CDC13, 60 megac~cles per second ) inter alia signals at: 2 H 4.16 ppm (0-CH2-CH3~
, ~ 2 H 3.42 ppm (-CH2-CH2-Br) 2 H 2.15 ppm (-cH2-cH2-OEI) H 1.28 ppm tcH3-cH2-) b) trans-cyclopropane-],-(2-bromoethyl)-2-carboxylic , ~ acid 1 g of trans-cyclopropane-1-(2-brornoethyl)-2-carboxylic acid ethyl ester i5 added to a mixture cooled to 0 of 6.4 cc of 33 % hydrobromic acid and 1.7 cc o concentrated sulphuric acid while stirring vigorously. A~ter one hour at room temperat-lre, the soluti.on is heated to 100 for 15 minutes. The cooled solution is poured on 60 cc of a cold~
~, ~ saturated ammonium .sulphate solution and is extractad thrice with methylene chloride; the con~ined ex-tracts are washed with water, dried and concentrat~d by evaporation at reduced pressure. The residue is ~; 20 separat,ed on 40 g of silica gel with chloroorrn ,' containing 1 /0 o methanol (50 cc fractions), where-b~ the title compound is obtained.
IR (methylene chloride) inter alia bands at:
~; , 3450 - 2700, 1700, 1460, 1215 cm 1, ,~
'.' . - 16 - 1~976 100-~042 NMR (CDC13 , 60 megacycles per second) inter alia signals at: 1 H 10.5 ppm (-COOH) 2 H 3.42 ppm (-CH2-C~2~Br) 2 H 1.83 ppm (CH-CH2-OEI2-) cis-c~clo~ro~ane-1-~2_bromoethyl)~2-carboxylic acid Treatment as described above yields the corres-ponding cis-cyclopropane-1-(2-bromoethyl)-2-o carboxylic acid.
IR (methylene chlori.de) inter alia bands at:
3450 - 2470, 169S, 1220 cm 1.
NMR (CDC13, 60 megacycles per second) inter _lia .~ signals at: 9.5 ppm (1 I-I) -COOH
3.47 ppm (2 H) C~I2-Br 2.18 ppm (2 H~ -CH2-.
trans-cyclo~ro~ane-1-(2 bromoeth~ 2-carbo~ylic acid methyl ester 200 mg~of the trans acid are dissolved in 10 cc of "o methanol and treated with a solution o diazomethane : in ether at room temperature (20). After removlng the solvent at reduced pressure, the residue (200 mg) is chromatographed on silica gel with ~ ~ benzene whereby the corresponding methyl ester is .

~ ~ .

05iO976 loo-40a2 .:
obtained.
IR (methylene chloride) _ter alia bands at:
17'~0, 1210, 1120 cm 1, NMR (CDC13, 100 me~acycles per second) inter alia signals at: 3 H 3.68 ppm COOCH3 2 H 3.45 (t) CH~-Br ~ F~ 1.9 (m) CH2-CH2-Br The same com~ound is obtained by treating the trans acid with 3-methyl-1 ~-tolyl-triazine.

The followirlg esters are prod~ced i.n analo~ous mantler:
ci.s~cyclop.ropane-1-(2-bromoethyl)--2-carboxy.lic acid rnethyl ester, trans--cyclopropane~ (2-bromoethyl)-2-carbox-~lic acid ethyl ester, cis-c!yclopropane-1-(2-hromoethyl)-2-carboxylic aci~
ethyl ester, trans-cyclopropane~1-(2-bromoethyl)-2-carboxylic acid benzyl ester, cis-cyc].opropane-1-(2-bromoethyl)-2-car~oxylic acid benzyl ester.

c) triphenyl-~os~holl~urn salt of ethyl-trarls-cyclo~ro~ane-carboxyllc acid 10 g o~ triphenylphosphine are added to 5 cr o ~ trans-cyclrpropane-l-(2-bromoethyl)-2-;

- 18 ~ 6 100-4042 earbo~ylic acid in 100 ec 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 y of silica gel with mixtures of chloroform/methanc,l/acetic acid (300 cc fractions), whereby the title compound is obtained.
IR (methylene chloride) inter _ia bands at:
3400 3000, 1725, 1440, 1115 cm lo ~MR (CDC13, 60 megacycles per second) _ter alla signals at: 15 H 7.75 pprn (aromatic M) 2 H 3.8 ppm (CII2 - P -) ,, The phos~honium salts of the ~ollo~ling eompounds axe produced in analogous manner:
ethyl-cis-cyclopropane-carboxylie acid, ethyl-trans-cyclopropane-carb3x~1ic acid ethyl ester, ethyl-cis-cyclopropan~-carboxylic acid ethyl ester, : ethyl-trans-cyclopropane-carboxylic ae.id meth~l cst~r, ethyl-cis~cyclopropane-~carboxy:Lic acid methyl ester, ` 20 ethyl-trans-cyelo~ropane-carboxylic acid benzyl ; ester, , ~ ethyl-cis-cyclopropane-carboxylic acid be~nzyl ester.

d) ?, 3 trans-methano~ll,15-b]s-tetrah~dro~ran~l-prostaglandin F [Wittig reaction]
2~
70 mg o~ sodium hydride are dissolved in 0.7 ce of .:

.
. .

. .
., . :, ,g ~LO~ 197~ 0-4042 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 bro~m solution. Stirring is then effected at room temperat.ure for 1 V2 hours and 145 mg of 2~-(3'~-tetrahydropyranyloxy-l'-trans-octenyl)-5a-hyaroxy-3a-te~:rahydropyranyloxy-cyclopentane-acetald~3hyde lactol are subsec~uently added to 1.2 cc of the ahove solution. The reaction mixture is allowecl t.o s~.and at: room temperature for 15 minutes, is heated to 7S for 3 hours, is subsequently poured on 20 g of ice, the pH is carefully adjusted to 3 ~nd ex-traction is effected with methylene chloride.
~-: Chromatography on 20 ~ of silica gel with chloroform~
containing 2 % OL methanol yialds t.he titl~ compound in pur6 form~
IR tmethYlene chloride) inter al.i.a band.s at:
3500, 1710 cm 1., ~MR (CDC13, 90 megacycles per second) inter alia signals a-t: 4 H (m) 5.4 p~m 1. 2 H 4.7 ppm ; 3 H (t) 0.9 ppm , . , .
~ .

- 20 - ~ ~5~76 100-4042 The, following compounds are produced in analogous manner:

2,3-cis-methano-ll,]5-bi.s-tetxahydropyranyl-prostaglandin F
2,3-trans-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2~ methyl ester, .:. 2,3-cis-methano-11,15-bis-tet:rahydropyranyl-prostaglandin F2a methyl ester, 2,3-trans-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2 ethyl ester, ' ~ 2,3-ci.s-methano-11,15-bis-~etrahydropyranyl-prostaglarldi.n F2~ ethyl ester, , 2,3- krans-methano-11,15~bis~tetrahydropyranyl-' '' pr~s~aglarldin F2a benzyl ester, 2,3-cis-rne~hano-11,15-bis-tetrahydropyr~nyl-prostaglarldin F2a berlzyl ester, whereby the es-ters may alternatively be obtained directly ~ro1.~ the corresponding acids.
~, .
~:, E~AMP~E 2~ 6-di et~_ 2,3-tr_n (~ methano_ p~o~ta:l~ di ~ ~ [pro~ess v~riarlt a)J
' 200 my of 16,16-dimethyl-2,3-(+)-methano-~ 15-bis-tetrahydropyranyl-prostaglandin F2~ are '.' dissol~ed in 7 cc of a rn.ixture of acetic acid,,, .

,' ' ., ,~ ', .
: , .

- 21 - ~50~76 ~oo 4oq2s tetrahydrofuran, water (3 : 1 : 1) and kept at 40 ~or 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.
[] D- +88 (c = 1.01, CMC13).
IR (methylene chlori.de) inter alia ~ands at 3600-3aoo, 1695 cm NMR (CDC13, 100 megacycles per second) _ter alia ban~s . . .
at: 4 ~I ~~ 5.5 ppm v.in~l H

6 H ~ ~ .ppm 3 x CI-I-OH

6 H 1.28 ~pm 2 ~ CH3-C

The following compounds are produced i.n analogous manner:

16,16-dimethyl-2,3-trans(+)-methano-prostagla7ldirl F2 methyl ester, 16,16~dimethyl~2,3-trans(-~-mechario-prostaglandin F2a ethyl ester, 16,16-dimethyl-2,3-trans(~ rnethano~prostaJland.in F2a . ~o benzyl ester, 2, 3-trans(+)-methano-Rrostaglandin F2~, 2,3-txans(-~)-methano-prostaglandin F2a methyl ester, 2, 3-trans(-~)-rnethano-prostaglandin F2a ethyl ester, ~: 2,3-trans(~)-methano-prc)staglandin F2a benzyl ester.

~ ~ .

~`' , ' ' ' :

- 22 - ~ ~5~9~ 100-~042 : The 16,16-dimethyl-2,3-trans(+)-methano-:, 11,15-bis-tetrahydropyranyl-prostaglandin F2~, used as . startin~ material, is produced as follows:

a) (-~l-trans-cycloero~ane-1-(2-bromoethyl)carboxylic acid 29 g of (-)-ephedrine in 200 cc of methylene : chloride are added to 66 g of trans-cycloPropane-l-(2-bromoethyl)ca.rboxylic acid in 200 cc of methylene chloride and the mixt~lre is allowed to stand at 20 ior 2 y2 hours. Upon adding n-hexane crystals are ormed. Filtration and recrystallization from methylene chloride/hexarle and methylene ch].oride/
~thy:l. aceta~e are e~ected.
M.P- 125-126~ 20 -1-22 (c -1.26, CHC13)-. lS Extr~ction w.ith methylene chloride/dilute hydro-chlocic acid yi~].ds the (-I-) acid:
~]20_ ~75,30 (c ~ 1.94, C~C13)~
. "
The ac.id i.~ converted into the fol.lowing esters as described in Example l:
... .
(-~)-trans-cyclopropane-1-(2--broII~oethyl)carboxylic acid methyl ester, ;, (-~)-trans-cyclopropa~ l (2-bromoethyllcarboxylic .~ a~id ethyl ester, ~ -trans--cyclopropane-1-(2-bromoethyl)carboxylic aci~ benæyl ester.
, .
:' ,' , . .;

. , -, - ' iL05097G o b) tri~henylphos~onium salt_of (-~)-trans-cyclo~ro~ane-1-(2-bromoethyl)carboxylic acid _ _ _ _ _ _ _ _ _ 10.3 g of triphenylphosphine are added to 6.3 g of (-~)-trans-cyclopropane-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.
M.P. 121-125; ~a]20= +17.5 (c = 1.18, C~3C13).
IR and NMR spectra correspond to those of the racemic compound.
The phosphonium salts oi th~ followirly compounds are produced in analoyous manner:

eth~l-trans(+)-cyclopropane~caxboxylic acid methyl ester, , 15 ethyl-trans(-~)-cyclopropane-carboxylic acid ethyl J ester, ethyl-trans(-~)-cyclopropane-carboxylic acid benz~Tl ester.

c) 16,16-dimethx1-~,3-trans(~)-methano-11,15-bis-_ _ _ . _ _ _ _ ~ _ _ ._ . . _ _ . _ _ _ _ _ _ . . _ _ . _ _ _ _ . . _ _ _ _ . _ _ _ _ _ _ .
tetrahydro~xran~ rosta~landin F2~[Wittig reaction]
600 m~ of sodium hydride are dissolved in 6 cc o~
absolute d methy~ sulphoxide and kept at 75 in an atmosphere of nitrogen for 55 minutes. After coolin~, 2.1 cc of this solution are slowly added ~ropwise to a prepared solution of 1.95 g of .

. .

: ., . . . . .. ~ ~ . , ., .. - . .

lCJ~S~
~ ~4 ~ 100-4042 the triphenylphosphonium salt of (+)-trans-cyclopropane-1-(2--bromoethyl)carboxylic acid in 5 cc of absolute dimethyl sulphoxide and the mix-ture is stirred in an atmosphere of nitrogen for 45 mi.nutes.

4.5 cc of the ylide ~olution described above are added at 20 to a prepared solution of 1 g of 2~(4',4'-dimethyl-3' a tetrahydropyranyloxy-l'-transo~tenyl)~5a-hydroxy-3a-tetrahyclropyranyloxy-c~rclopentane~acetaldehyde lactol in 1 cc of absolute dimethy]. ~;ulphoxide and the mixture i.Y
kept at 60 for 50 minutes. After the addition of a further 4.5 cc of the ylide solution, s-tirring is agairl effected at 60 for one hour. q'he cooi0d react:ion mixture i~ poured on ice, the p~ of the aqueous phase .is adjusted to 3--5 and extraction ls efected t.hrice with methylene c~hloride. The re.~ulti.ng crude product is chromatGgraphed on 140 g of silica gel with chloroform containi.ng 1 to 5 %
of methanol, whereby the pure t.itle compound is ob-- tained. [a~ 35.5~ (c = 1.07, CHC13).
IR (methylene chloride) inter alia bands at 3500, 1695 cm NMR (CDC13, 90 megacycles per second) inter alia :
-~6~5~9'76 - 25 ~ 100 -4042 signals at: 4 H ~ 5.5 ppm vinyl H
2 H 4.6 ppm THP H

The following cornpounds are produced in analogous manner:

16,16-dimethyl-2,3-trans (~ methano-ll,15-b.is-tetrahydrops~ranyl-prostaglandin F2a methyl ester, 16,16--dimethyl-2,3-trans (-~) -m~thano~ll,15-bis-tetrahydropyranyl-prostaglandin F2 ethyl ester, 16,16-di.methyl-2,3-trans (-~) -methano-ll,15-bis-tetrahydropyranyl-prostaglandin F2a henzyl estex.

T~hen the W:itticJ react:i on is e~t~d w.ith 2,~- (3 'a-tetrahyclropyranyloxy-l ' -trans-octenyl) -5a-hydroxy-3a-tetrahydrops~ranyloxy--cyclopentane a~e,.aldehyde lactol, then the following compounds :L 5 are pr:oduced in analogous manner:
2,3-t.rans (t-) -methano-ll,15-bis-tetrahydropyranyl-pr os taglandill F2a ~
2,3-trans (-~) -m~thano-ll,15-his -tetrahydropyranyl-prostaglandi.n F2a methyl ester, 2,3-trans(-~)-methano-11,15-bis-tetrahycLropyranyl-prostaglandin F21X ethyl ester, 2,3-trans ( ~) -methano-ll,15-~is-tetrahydropyranyl-prostaglandin F2 ~.enzyl ester.

.

. .
, - 26 ~ 76 100-4042~

EX~MP~E 3: 16,16-dimethyl~? ! 3-trans(+)-methano-r~osta~larlln r2 [prostq~landin acid group protection; oxidation; process vc~riant a)]
100 mg of 16,16-d:imethyl-2,3~rans(~)-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2a are dis-solved in 1 cc of absolute to:Luene, 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 trietllylamine are addedl st:irring is effected at 20 for 2 1/~ hours, the solution i5 cooled to -30 and slowly added dropwise to a sollltion of 108 m~
of N~chlorosuccinimicle in 4 cc of absolute toluene and 60 my oE climeth~l sulphide within 35 minutes. Ater a further 2 3/4 hours at 20, 220 mg of triethylamine in 1 CC OL pentane are added dropwise and workincJ up is e~fected with ether/water for a further 10 minutes. Th~
residue (100 mg) is chromatographed on 8 g of silica gel wlth chloroform containlng ~ % oE methanol.
16,l6-dimethyl-2,3-trans(-~)~methano-11,15-bis-tetrahydro-~o pyranyl prostac31andin E2 tert.butyl dimethylsilyl ester is obtained.
IR (methylsne chloride) inter alia bands at 1735, 16~5 cm 1.
50 mg of the ester described above are dis-solved 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 - ~ ~S~6 100-~042~

acetic acid are added at 0. Stirring is effected at 0 for 45 minutes, and at 25 for 1 1/2 hours, and sub-sequently working up is effected 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 concen~ratirlg by evaporation at re-duced pressure, the residue is chxomatographed on 2.5 g of sillca gel with chloroform containing 3 % of methanol.
The pure title cornpound is obtalned.
IR (methylene chlori.de) inter ali.a bands at 1735, 1695 cm 1, NMR tCDC13, 90 megacycles per second) int:er alia si.~nals at: 4 H 5.3 - 5.8 ppm (vLnyl protons)

5 H 3.7 - 4.2 ppm 2 x -CH-OH ~ COOH
2,3~krans(~)-rnethano-prostaglandin E2 i5 producPd i.n analogous manner.
The followin~ compounds are produced in anaLogous manner, using the esters described in ~ample 2 as starting materials:
; 20 16,16-dimethyl-2,3-trans(~)-methano-pros~agland:Ln E2 meth~l ester:, 16,16-dimethyl-2,3-trans(-~)-methano-prostaglandin E2 ethyl ester, 16,16-dLmethyl 2,3-trans(~)-methano prostaglandin E2 benz~l ester, 2,3-trans(~)-methano~prostaglandin E2 methyl ~ster, .: 2,3-~rans(+)-methano-prostaglandin E2 ethYl ester, ~ 2,3-trans(l)-meth2no~prostaalandin E2 benzyl ester.

' :
'~ :
, . . . . . .
... , . , . ,: ., :, ... , :
.- : ., . . . . , : , ~.: , :

. ~ 28 - ~ ~5~g~ loo-40426 EXAMPLE 4: 16,16-dimethyl-2,~-trans~-~-methano- -[process variant a)]

:
109 mg of ~6,16-dimethyl-2,3-trans(-)-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2 are dissolved in 3.5 cc of a mixture of acet.c aci.d/
tetrahydrofuran/water (3:1:1) ancl kept at 40 for

6 hoursr After concentrating by e~aporation at reduced pressure, the residue is chromatographed on 5 g of ~ silica gel with chloroform containing 7 ~ of methanol, i ~ 10 whereby the pure title compound is ob'ained.
.~ ta]D = ~13.8 (c ~ 2, CHC13) XR (methylene ch~oride) inter alia bands at 3600, 3400, 169~ cm 1, NMR (CDC13, 90 megacycles per second) inter alia si~nals at: ~ E~ 5.3 - S.~ ppr~. vinyl ~

7 H 3.9 - 4 . 3 p~ 3 x _CH-~H . COOH
, C~ ~
1.28 pprn 3 ,,, , ' C~

:; The followin~ compounds are produced i.n analogous manner:
16,16-dimethyl-2,3-tran~( )-methano-prostagland~n F2 methyl ester, 16,16-dimethyl-2/ 3-trans (~) -methano-prostaglandin F2 . ethyl ester, .. : - 16,16-dimethyl-2,3-trans~-):-me~hano-prostaylc.ndin F2 : 25 benzyl ester, : . , , ~ -.

.. ~, .
, . :
;
,. ' : - :
.
- : ..

-- - 29 - ~S~976 l00-4042t 2t3-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.
~ 5 - The 16,16-dimethyl-2,3-trans(-)-methano-~11,15-bis-tetrahydropyranyl-Frostaglandin F2a, used as starting material, is produced as follo~Js:
a) ~ trans-cyclo~ro~ane-1-(2-bromoethyl)carboxylic acid The title compound is obtained in a manner analogous .
to that described in Example 2 a) ~ith (~)-ephedrine.
[a] -. -75.0 (c = 1.56, CHC13).
- - D
; The spectroscopic data o~ the title compound are identical with those of the (-~)-acid.
The acid is converted into the ~ollowing esters in a mannex analcgous to that described in Exa~.ple 1:
t-)-trans-cyclGpropane-1-(2-bromoethyl)carboxyli.c acid methy1 ester, trans-cyclopropane-1-(2-bromoethyl)carboxylic acid ethyl ester, ~ :
. ~ (-)-trans-cyclopropane-1-(2-bromoethyl)carboxylic . acld benzyl este.r.
; b~ Tri~h~nvl~hos~honiu~ salt of (-)-trans-c.~clo~ro~an6-_~2-bromoethyl)carboxylic acld 10 g of triphen~lphosphine are added to 61 g of : 25 ~-)-trans-cyclopropane-1-(2-bromoethyl)carboxylic ~ acld in 200 cc of absolute benzenel and the mixture ~ is boiled at re1ux for 63:hoursO After cooling the precipitated crystals are filtered of~f~

; ~ : . .

::

- ~ 30 - 100-4042 McP~ 120-122, ~]20= -17.3 ~c = lol9~ CHC13~.
The IR and NMR spectra correspond to those of the enantiomorphic compoundsO
The phosphonium salts of the following compounds are produced in analogous manner~
ethyl-trans(-)-cvclopropane-carboxylic acid methyl ester, ethyl-trans(-)-cyclopropane-carboxylic acid ethyl ester, ethyl-trans(-)-cyclopropane-carboxylic acid ben~yl ester.
c) 16116-dlmethyl-2L3-trans.~-)-methano-ll~,i5- :
__ _________ ___ _______ _________~.___._._ ; b~s~tetrah~dro~yranyl-~r~osta~andin_F2~WittiCJ reaction]
300 mg of sodium hydride are suspended ln 3 cc of absolute dimethyl sulphoxide, and the susp~.nsion is kept at 75 for 45 minutes in an atmosphere of nitrogen. After coolin~, 0.9 cc of this solution are slowly added dropwise to a prepared solution of 1 g of the tripher.ylphosphonium salt of ~ trans-cyclo~
propane~l-(2-bromoethyl)carboxylic acid in 2.5 cc of absolute dlmethyl sulphoxlde, and the mixture is stirred for 4S minutes under nitrog~n.~
.
1.9 cc of the yllde solution described above are slowly added dropwise to a solution of 500 mg of 2~(4',4'-dimethyl-3qa-tetrahydropyràn~yloxy~ trans-octenyl)-5a-hydroxy-3a-tetrahydxopyranyloxy-cyslo-pentane acetaldenyde lactol in 006 cc of absolute . .
. ~. .
, , ;
. , : ' - :

~ ~ , - .

., . , ,. , . ~ .

~~ o 31 ~ 100 4042 tetrahydrofuran~ After 40 minutes at 609 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 chiorideO The result:ing crude product ls purified by chromatography on 40 g of silica gel, whereby the title compound is obtained with chloro-form containing 2 % of methanol, IR (methylene chloride) inter alia bands at 3500, 1695 cm 1.
The follo~ing compounds are produced ln analogous manner:
16~16-dimethyl-2,3-trans(-)-methano-11,15-bis-'~ tetrahydropyranyl-prostaglandin F2a methyl es~er, 16,16-dimethyl~2,3--trans(-)-methano~ 5-bis~
- tetrahydropyranyl-prGstaglandin F2a ethyl ester, 16,16-dimethyl-2,3-trans(-)-methano-11,15-b.ts tetrahydropyranyl-prostaglandin F2~benzyl ester.
When the ~itti~ reaction is effected with 2B-~3'a-tetrahydropyranyloxy-1l-trans-octenyl)-5a-hydroxy-3a-tetrahydropyranyloxy-cyc1opentane , acetaldehyde lactol, the followinq compound.s .~ 25 are produced in analogous manner:~

-,.

' ~ :~ . .
,: ' .

.
. ~ , 32 - ~ ~ ~9~6 100-4042-.
2,3-trans(-)-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2~, 2,3-trans(-)-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2a methyl ester, 2,3 trans(-)-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2~ ethyl esterl 2,3~trans(-)-methano-11,15-bls-tetrahydropyranyl-prostaglandin F2 benzyl ester.

EXA~PLE 5: 16,16-dimethy~-2,3-trsns~-)-m~thano-prostagland;n E2 [prost~glandin acicl gro~p p~otection; c~idation; process variant a)]
177 mg of 16,16~dimeth~1-2,3~trans(-)-meth~no~ll,lS-bis tet:rahydropyranyl~prostacJlarldin F2~
ar~ dissolved in 1.5 cc of a~solute toluene. A solution of 4702 mg of tert~hutyldimethyl chlorosilane ir. toluene ; is added dropwise in an atmosphere of nitroyen. The re-action solutlon i5 cooled to 0, 32 mg of triethyl~mine ~re added and stirring is efected at 20 for 2 1/2 hours~ The reaction mi~ture is cooled to -30 and ls ! 20 slowl~ added dropwise to a solution of 191 mg of N-chlorosuccinimide in 6 cc of absolute toluene and 106.3 mg of dimeth~l sulphide. After 2 hours at ~30/-20 300 my o~ triethylamfne ln 1 cc of pentane are added, stir~ing is continued for 10 minutes anu working up i5 ~ ~5 efeeted with ether/water. The residue (19~ my) is ;- chromatographed on 12 g of silica gel with chloroform containi.ng 1 % o} m~thanol~ . ~

:`:

: . :

~ 33 ~ 76 100-~0~2 `.
The resu~ting silyl est:er ~IR in methylene ch~oride lnter alla bands at 1735, 1675 cm lj is dis-solved ln 2.7 cc of acetoneO 0.9 cc of water and 1.2 cc of a solutlon 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 react~on mixture is stirred at 0 for 30 minutes, at 25 30 for 1 1/2 nours, and is subsequently worlced up wi~h ether. The residue (IR in methylene chloride ~nter alla bands at 3500, 1735, 1695 cm 1) is dissolved in 3 cc of acetic acid/water/tetrahydrofuran (3~ and stirred at 40 for 6 hours. ~ter concentrat:ing by evaporat~on at redu~ed pressure, the residue i5 ChrOnlatO-graph~d on 4.5 g of silica gel with chloroform containin~
lS 2 % of methanol. The pure title co~pound ls obtained.
IR (methylene chloride) in~r alia bands at 3600, - 3400, 1735, 1695 cm 1, N~.R ~CDCli, 90 megacycles per second) inter alia signals ~t about: 0 ~.6 - 2.B5 ppm (1 ~

~H
s . 2 - 5, 6 ppm ~ 4 }3) HF

2,3-trans(-)-methano-prostaglanain E2 is pxoduced in ~nalogous manner.
The following compounds are produced in analogous manner, us~ng the esters described in s : ~ ~

.:', ~ ~ . : -~. , , , ~ .

~` 34 ~ ~ ~ ~9~6 100-4042 ~ Example 4 as starting materials:
: 16,16-dimethyl-2,3-trans(-)~methano-prostaglandin E2 methyl esterl . 16,16-di~ethyl-2,3-trans~ )-methano-prostaglandin E2 ethyl ester, 16,16-dimethyl-2,3-txans(-)-methanLo-prostaglandin E2 benzyl ester, 2,3 transl-)-methano prostaglandin E2 methyl ester, ~- 2,3-trans(-)-methano-pro3taglandirl E2 ethyl ester, 2,3-trans(-)-methano-prostaglandin E2 benzyl ester.

EXAMPLE 6: _,16-dimethyl-2,3-trans(t-)-methano-prosta~landin A2 [process vari~nt b)]
"
50 mg o 16,16-dimethyl-2,3-trans(+)-~thano-prostaglandin E2 o Example 3 are dissolve~ in :
1$ 2 cc of acet~c acid/water (9:1) and ~ept a~ 60~ for - 5 1/2 hours. After the addition of toluene, concentration ls 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. ~he pure title compound has the following characteristics:
~ IR ~methylene chloride) inter alia bands at 3600r . 1700, 1690, 1140 cm 1.
~ NMR (CDC13, 90 megacycles per second) inter alia : ~ignals at~
, ~ - :
i~ . : ' ~ ' , : , :. .

.. : , : .
, , :' :
j.
.. , . ~ .
.

~ 35 ~ ~05~9~6 100-4042' 1 H 7.5 ppm ~ 0.
, 1 H 6.15 ppm ~ 0 .
4 ~ 5.3 - 5.8 ppm -~

The following compouncls are produced in analo~ous manner:
- 16,16-dimethyl-2,3-trans~)-methano-prostaglandin A2, lS,16-dimethyl-2,3-trans(+)-methano-prostagland~n P~
methyl ester, 16,16-dimethyl-2,3-trans(~)-methano-prostaglandin A2 ~ 10 e~hyl ester, ' 16,16-di~lethyl-2,3-trans~)-methano-prostaglan~.in A2 ; benzyl ester, 2,3-trans(l)-methano-prostaglandin A2, : ~ :
2,3-~rans(*)-methano-pxostaglandin A2 methyl ester, :~
Z~3-trans(~?-methano-prostaglandin A2 ethyl ester, 2,3-trans(~)-methano-prostaglandin A~ benzyl ester.

- .
''` .' .

RX~MPI.E 7: 16,16-dimethvl-2,3-trans(-)-methano--. prosta~landin A2 [pro~ess varlant b)]
; .,,.,`

~ .120: mg of 16,16-aimethyl-2,3-trans(-)- . :;
: ~ 20 ~thano-pros~aglandin E2 of Example 5 are dissolved in ~ ~ 5 cc of acetlc acld/water ~9:1) and kept at ;S-60 .

.

,, AUSTRAL!'` CAN~ )A
36 ~ 76 10~4042 for 15 h~ur^~ The re2ction mixture ls conc~ntrated by evaporation at reduced pressure and the resld~le ls chro~atographed on 5 g of sili~a qlel. The pure ti~le ~ompound is isolated with a mixture of chloroform/~e~.ol.
IR (methylene chloride) intex alia bands at 3600, 1700, - 1690, 15gO, 1065~ 1030 c~ lo NMR tcDcl3~ 90 megacycles per second) inter alia s~gnals at~
1 ~ 7.5 ppm ~ ~ _ 0 S ~1 5.2 - 6.3 ppm ~=~--H
0.7 - 0.95 p~m CH3-The follo~ng compounds a~e produced in analogous manr.er:
16,16-dimethyl-2,3-trans(-)-methano-prostagland n A2, ; 15 16,16-dim~thyl 2/3-trans(-)-methano-prost~land-n A2 methyl ester, 16,16-dirrethyl-2,3-trans(-~-methano-prost~landi~ A2 ethyl ester, 16,16-dimethyl-2,3-trans(-)-methano prost~landin A2 benzyl ester, 2,~-t~ans(-1-methano-prostag~andin ~2r 2,3-trans(-)-methano-prostaglandin A2 methyl-ester, ; 203-trans(-)-methano-prostaglandin ~2 ethyl ester, 203-trans(-~-methano-prostaglar.din ~2 benzyl ester.

,~ :
`: . ' ~ . ' .
. . , ~ .

.. .

-~L~5C~976 - 37 ~ 100-~042 The compounds of formula I exhibit prosta~landin-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 M. Ruegg et al, Exper. 28, 1525, (1972), R. Jaques, IIelv. Physiol. Acta, 17, 255 ~1959) and 23, 156 (1965).
The compounds are, thereFore, indicated for use as bronchodilator agents and agents for lowering arterial , blood pressure.
~ 15 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 carbo-:`
1 cyclic radlcal of formula IIc or IId, 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. ~dited by V.~. Pickles and R.J. Fitzpatrick. Camhridge University Press 1966, p. 185-' ~ 25 198 and the rat uterus in vitro in accordance with the r , ., . . ~
' S' , ~

- 38 ~ ~ ~5~76 100-4042 principles of P. Holton, Brit. J. Pharmacol. 3, 328 (1948).
These compounds of formula I wherein D is a carbo-cyclic radical of formula IIc or :[Id are therefore further indicated for use as uterus-stimu:Lating a~ents.
The compounds of formula I wherein D is a carbo-cyclic radical of formula IIc or lId 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. Halter et al., in Helv. med. ~cta Suppl~, 50, 113 (1971).
These compounds of formula I wherein D is a carbo-cycloc radical of formula IIc or IId are therefore further i indicated for use as gastric secretion inhibitin~ agents.
16,16-dimethyl-2,3-trans-(+)-methylene-prosta-glandin F2a shows especially interesting uterotonic properties, and 16,]~-dimethyl-2,3-trans-(-)-methylene-Z0 prostaglandin E2 shows especially interesting propertles as a gastric secretion inhibitor.
For all the above uses an indicated daily dose is from 0.1 to 20 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing l 25 from 0.0~ to 10 mg, or in sustained release form.
:.
.,, ,..

- . ~ . . : . .

ASJ ~;TP.ALl 1-\
CANADA
~ 39 - 100-~042 The compounds of formula Id may be administerea in pharmaceutically acceptable salt form. Such salt forms exhibit the same order of activity as the free aci.d forms and are readily prepared in conventional manner. The present invention also provides a pharma-ceutical composition comprising a compound of formula I
ln pharmaceutically acceptable form, i.n association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.

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Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows

1. A process for the production of a compound of formula I, wherein D is one of the four carbocycles of formulae IIa, IIb, IIc or IId, II a II b II c II d R1, R2 and R3 are, independently, hydrogen or alkyl groups of 1 to 4 carbon atoms, comprising a) hydrolysing a compound of formula III, III
wherein R2 and R3 are as defined above, R4 is tert.butyl-dimethylsilyl or 2-tetrahydro-pyranyl, R6 is hydrogen, an alkyl group of 1 to 4 carbon atoms, or a tert.-butyl-dimethylsilyl group, and A is a carbocyclic radical of formula IIa or IIb as defined above or of formula IIe or IIf.

II e II f b) removing water from a compound of formula Ia, Ia wherein DI is a carbocycle of formula IId as defined above and R1, R2 and R3 are as defined above to produce a compound of formula Ib, Ib wherein DII is a carbocycle of formula IIb as defined above and R1, R2 and R3 are as defined above, c) hydrolysing a compound of formula Ic, Ic wherein R1 is alkyl, cycloalkyl or aralkyl and R2, R3 and D are as defined above, to produce a compound of formula Id, Id wherein R1II is hydrogen and R2, R3 and D are as defined above, or d) esterifying a compound of formula Id as defined above to produce a compound of formula Ic.

2. A compound of formula I as defined in claim 1, whenever produced by a process according to claim 1.

3. A process fox the production of 16,16-dimethyl-2,3-trans-(+)-methanoprostaglandin F2.alpha. which comprises hydrolysing 16,16-dimethyl-2,3-trans-(+)-methanoprostaglandin F2.alpha.
11,15-bis-tetrahydropyranyl ether in the presence of acid and water at a temperature of from 30° to 60°C, or an obvious chemical equivalent thereof.

4. 16,16-dimethyl-2,3-trans-(+) -methanoprostaglandin F2 .alpha., whenever produced by a process according to claim 3.

5. A process for the production of 16,16-dimethyl-2,3-trans-(-)-methanoprostaglandin E2 which comprises hydrolysing the tert.-butyldimethylsilyl ester of 16,16-dimethy1-2,3-trans-(+)-methanoprostaglandin E2 11,15-bis-tetrahydropyranyl ether in the presence of acid and water at a temperature of from 30° to 60°C, or an obvious chemical equivalent thereof.

6. 16,16-dimethyl-2,3-trans-(-)-methanoprostaglandin E2, whenever produced by a process according to claim 5.