Thienyl-prostaglandins and process for their manufacture

The present invention relates to thienyl-prostaglandin derivatives and to a process for their manufacture. The compounds according to the invention have valuable pharmaceutical properties.

The present invention relates to thienyl-prostaglandins and to a process 
for their manufacture. 
Prostaglandins are a group of natural substances which have been isolated 
from various animal tissues. They are responsible for a large number of 
physiological effects in mammals. The natural prostaglandins have a carbon 
skeleton of generally 20 carbon atoms and differ chiefly in a major or 
minor content of hydroxyl groups or double bonds in the cyclopentane ring 
(the structure and action of prostaglandins are described, inter alia, in 
M. F. Cuthbert "The Prostaglandins, Pharmacological and Therapeutic 
advances", William Heinemann Medical Books, Ltd., London 1973). 
The synthesis of analogues of prostanoic acids which do not occur naturally 
and in which the large number of pharmacological actions of the natural 
prostanic acids are differentiated, acquires an increasing importance. 
The present invention provides prostanoic acid analogs which do not occur 
naturally of the general formula I 
##STR1## 
which comprises both the optically active compounds of the natural 
configuration and the racemic compounds and in which: 
R.sup.1 and R.sup.2 each is hydrogen or a hydroxyl group, R.sup.1 and 
R.sup.2 being different, 
R.sup.3 is a .alpha.- or .beta.-thienyl radical or a .alpha.- or 
.beta.-thienylmethyl radical which may be substituted 1 to 3 times in the 
nucleus by halogen, trifluoromethyl and/or alkyl or alkoxy having 1 to 6 
carbon atoms each and/or by a phenyl radical which is unsubstituted or 
substituted 1 to 3 times by halogen, trifluoromethyl and/or alkyl or 
alkoxy having 1 to 5 carbon atoms, or R.sup.3 is a benzo[b]thiophene 
radical which may be substituted 1 to 3 times by trifluoromethyl, or 
R.sup.3, is a cyclopentano-[b]-thiophene radical or a 
cyclohexano[b]thiophene radical, 
X is a straight-chain or branched alkylidene or alkylene group having 1 to 
7 carbon atoms or a straight-chain or branched alkoxyalkylene group of 2 
to 8 carbon atoms, 
and their physiologically acceptable salts with organic or inorganic bases 
and their esters with aliphatic, cycloaliphatic or araliphatic alcohols 
having 1 to 8 carbon atoms. 
The invention further relates to a process for the manufacture of the new 
analogs of prostanoic acids of the formula I, their physiologically 
acceptable salts with organic and inorganic bases and their esters as well 
as to pharmaceutical preparations containing these active compounds. 
The process is characterized in that 
(a) the aldehyde of the formula III 
##STR2## 
is reacted with a phosphonate of the formula IV 
##STR3## 
wherein X and R.sup.3 are defined as in the formula I, to an unsaturated 
ketone of the formula V 
##STR4## 
(b) the ketone of the formula V is reduced with a complex metal hydride to 
the epimer mixture of the alcohols of the formula VI 
##STR5## 
wherein X and R.sup.3 are defined as in the formula I, and the epimer 
mixture so obtained of the alcohols is separated into the S-epimer and the 
R-epimer optionally subsequently by means of column chromatography, 
(c) the alcohols (epimer mixtures or pure S-- or R--epimers) of the formula 
VI are converted, at room temperature, as epimer mixture or as S-- or 
R--epimer with an anhydrous alkali metal or alkaline earth metal carbonate 
in an alcoholic medium into a diol of the formula VII 
##STR6## 
wherein X and R.sup.3 are defined as in formula I, 
(d) the diol so obtained of the formula VII is converted by addition of 
2,3-dihydropyrane in the presence of acid catalysts into a 
di-tetra-hydropyranyl ether of the formula VIII 
##STR7## 
wherein X and R.sup.3 are defined as in formula I, 
(e) the di-tetrahydropyranyl ether so obtained of the formula VIII is 
reduced with a complex aluminum hydride in an aprotic solvent to a lactol 
of the formula IX 
##STR8## 
wherein X and R.sup.3 are defined as in formula I, 
(f) the lactol of the formula IX is reacted with the ylide of 
4-carboxy-butyl-triphenylphosphonium bromide in a solution of sodium 
hydride in dimethyl sulfoxide in an inert atmosphere to an acid of the 
formula X 
##STR9## 
wherein X and R.sup.3 are defined as in the formula I and 
(g) the tetrahydropyranyl protective groups in a compound of the formula X 
are split off by acid hydrolysis and the compound of the formula I so 
obtained is optionally converted into a physiologically acceptable salt or 
an alkyl ester. 
Of the radicals mentioned for the substituent X, the methylene, the 
ethylene, the ethylidene as well as the isomeric isopropylene and 
methoxyethylene groups possible with regard to the bonds are preferred. 
Of the groups mentioned for the substituent R.sup.3 are preferred the 
unsubstituted .alpha.- or .beta.-thienyl as well as .alpha.- or 
.beta.-thienylmethyl radicals, further .alpha.- or .beta.-thienyl and 
thienylmethyl radicals which are substituted 1 to 3 times by chlorine, 
trifluoromethyl and/or methoxyl or methyl. Preferred substitutents of the 
thiophene radicals are also the phenyl group which is unsubstituted or 
substituted respectively 1 to 3 times by halogen, especially chlorine, by 
trifluoromethyl groups and/or by alkoxy having 1 to 3 carbon atoms, 
especially methoxyl or methyl. Preferred substituents R.sup.3 are 
furthermore the benzo[b]thienyl radical which is unsubstituted or 
substituted 1 to 3 times by the trifluoromethyl group, the 
cyclopentano[b]thienyl and the cyclohexano[b]thienyl radical. 
The following groups for R.sup.3 are especially preferred: 
3-thienyl, 2-(2'-methyl)-thienyl, 2-(3-methoxy)-thienyl, 
2-(3-methoxy)-thienylmethyl, 3-(2-ethoxymethyl)-thienyl, 
3-(2-methoxymethyl)-thienyl, 2-(3-chloro)-thienyl, 
2-(2-thienyloxy)-ethyl, 3-(2',3'-dimethyl)-thienyl, 
3-(3'-trifluoromethyl)-thienyl, 3-(3'-chloro)-thienyl, 
3-(3'-methyl)-thienyl, 3-(3'-phenyl)-thienyl, 
3-(2'(3-trifluoromethyl-phenyl))-thienyl, 3-(2'(4-methoxyphenyl))-thienyl, 
3-(2'-methyl)-thienyl, 
5-trifluoromethyl-3-benzo[b]thienyl, 
3-cyclopentano[b]thienyl, 2-cyclopentano[b]thienyl, 
2-cyclohexano[b]thienyl. 
The process according to the invention starts from the aldehyde of the 
formula III which is prepared according to German Offenlegungsschrift 
DT-OS No. 24 16 193 from the primary bicyclic alcohol of the formula II 
##STR10## 
by oxidation with an oxidizing agent, for example with a complex of 
thioanisol and chlorine or the complex compound of CrO.sub.3 and pyridine 
in an aprotic solvent at temperatures ranging between -50.degree. C. and 
room temperature, preferably -30.degree. C. and -5.degree. C. in an inert 
atmosphere. Suitable solvents are, in this case, for example aromatic 
hydrocarbons, such as benzene or toluene or for example chlorinated 
aliphatic hydrocarbons, such as carbon tetrachloride. 
The aldehyde of the formula III is reacted by the method of Horner, Wittig 
and Emmons with a phosphonic acid ester of the formula IV to give an 
unsaturated ketone of the formula V; a preferred embodiment of the 
reaction comprising preparing the sodium salt of the phosphonic acid ester 
by means of sodium hydride in glycol dimethyl ether, then adding the 
aldehyde of the formula III and allowing the reaction to take place at 
room temperature for 2 to 6 hours. 
A phosphonic acid ester of the formula IV may be prepared by reacting an 
ester of the formula R.sup.3 --OX--CO.sub.2 --alkyl in the presence of 
excess butyl-lithium and methylphosphonic acid dimethyl ester (for 
example, by the method of Corey, J. Am. Chem. Soc. 88, 5654 (1966)). 
The epimeric mixture of alcohols of the formula VI is obtained from the 
ketone of the formula V by reduction with a complex metal hydride, 
preferably with an alkali metal boranate or zinc boranate in ethereal 
solution, preferably at a temperature within the range of from 0.degree. 
C. to room temperature. The zinc boranate is preferably prepared in situ 
from zinc chloride and sodium borohydride in absolute ethereal solution. 
The alcohols of the formula VI are particularly suitable for separation 
into the S-epimers and R-epimers, preferably by means of column 
chromatography on silica gel, but the further reactions can also be 
carried out with the mixture of epimers and the separation of the epimers 
can be carried out at the stage of the end product. 
The subsequent hydrolytic splitting of the p-phenylbenzoyl group of the 
alcohol of the formula VI is carried out in an alcoholic medium with the 
aid of an alkali metal carbonate or an alkaline earth metal carbonate. An 
advantageous embodiment consists of treating the alcohol or the 
corresponding mixture of epimers in absolute methanol at room temperature 
with anhydrous potassium carbonate, a diol of the formula VII being 
formed. 
The di-tetrahydropyranyl ether of the formula VIII is prepared, generally 
in an ethereal or benzene solution of the alcohols of the formula VII, in 
the presence of a customary acid catalyst, such as, for example, 
toluenesulfonic acid. 
The resulting compound of the formula VIII is reduced to a lactol of the 
formula IX by means of a complex aluminum hydride in an aprotic solvent. 
It is preferable to use diisobutyl-aluminum hydride in toluene at 
-60.degree. C. to -70.degree. C. 
The resulting lactone of the formula IX can be reacted by the method of 
Wittig, without further purification, to give a carboxylic acid of the 
formula X. The preferred embodiment of this process follows the 
instructions given in J. Org. Chem. 28, 1128 (1963). 
The protective ether groups in a compound of the formula X are split off by 
mild acid hydrolysis of the tetrahydropyranyl ether groups by means of an 
aqueous organic acid, preferably in 2% strength aqueous-alcoholic oxalic 
acid solution at 20.degree. C. to 50.degree. C., or by heating for 1 to 2 
hours in 60% to 70% strength acetic acid at 40.degree. C., a carboxylic 
acid of the formula I being formed. 
If separation of epimers has not been carried out at the stage of the 
alcohols of the formula VI, a separation of the 15-S-epimer from the 
15-R-epimer is preferably carried out after formation of a compound of the 
formula I. In this process, the separation is preferably carried out on 
silica gel (Merck, 70-230 mesh), the 15-S-epimer usually being eluted 
after the 15-R-epimer. 
A suitable eluting agent for the separation by column chromatography of the 
compounds of the formula I is a mixture of chloroform and glacial acetic 
acid in the ratio of 97.5:2.5. 
The compounds of the formula I may optionally be converted according to 
usual methods into physiologically acceptable salts or esters. 
In a manner analogous to that described in the following Examples the 
following preferred compounds may be prepared: 
9S,11S,15-Trihydroxy-16-(3-thienyloxy)-5-cis-13-transtetranor-prostadienoic 
acid 
9S,11S,15-Trihydroxy-16-methyl,16-(3-thienyloxy)-5-cis,13-trans-tetranor-pr 
ostadienoic acid 
9S,11S,15-Trihydroxy-16,16-dimethyl-16-(3-thienyloxy)-5-cis,13-trans-tetran 
or-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(2-(2'-methyl)-thienyloxy)-5-cis,13-trans-tetranor- 
prostadienoic acid 
9S,11S,15-Trihydroxy-16,16-dimethyl,16-(2-(2'-methyl)-thienyloxy)-5-cis,13- 
trans-tetranor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(2-(3-methoxy)-thienyloxy)-5-cis,13-trans,-tetranor 
-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(2-(3-methoxy)-thienylmethyloxy)-5-cis,13-trans-tet 
ranor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(3-(2-ethoxymethyl)-thienyloxy)-5-cis,13-trans-tetr 
anor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(3-(2-methoxymethyl)-thienyloxy)-5-cis,13-trans-tet 
ranor-prostadienoic acid 
9S,11S,15-Trihydroxy-17-(2-(3-chlor)-thienyloxy)-5-cis,13-trans-trinor-pros 
tadienoic acid 
9S,11S,15-Trihydroxy-16-(2-(2-thienyloxy)-ethoxy)-5-cis,13-trans-tetranor-p 
rostadienoic acid 
9S,11S,15-Trihydroxy-16-(3-(2',3'-dimethyl)-thienyloxy)-5-cis,13-trans-tetr 
anor-prostadienoic 
9S,11S,15-Trihydroxy-16-(3-(3'-trifluormethyl)-thienyloxy)-5-cis,13-trans-t 
etranor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(3-(3'-chlor)-thienyloxy)-5-cis,13-trans-tetranor-p 
rostadienoic acid 
9S,11S,15-Trihydroxy-16-ethyl-16-(3-(3'-methyl)-thienyloxy)-5-cis,13-trans- 
tetranor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(3-(3'-phenyl)-thienyloxy)-5-cis,13-trans-tetranor- 
prostadienoic acid 
9S,11S,15-Trihydroxy-16-(3-(3'-(3"-chlor-phenyl))-thienyloxy)-5-cis,13-tran 
s-tetranor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(3-(2'-(3"-trifluormethyl-phenyl))-thienyloxy)-5-ci 
s,13-trans-tetranor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(3-(2'-(4"-methoxy-phenyl))-thienyloxy)-5-cis,13-tr 
ans-tetranor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(3-(2'-methyl)-thienyloxy)-5-cis,13-trans-tetranor- 
prostadienoic acid 
9S,11S,15-Trihydroxy-16-(4-methoxy)-3-benzo[b]thienyloxy)-5-cis,13-trans-te 
tranor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(5-trifluoromethyl)-3-benzo[b]thienyloxy)-5-cis,13- 
trans-tetranor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(5-chlor)-3-benzo[b]thienyloxy)-5-cis,13-trans-tetr 
anor-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(3-cyclopentano[b]thienyloxy)-5-cis,13-trans-tetran 
or-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(2-cyclopentano[b]thienyloxy)-5-cis,13-trans-tetran 
or-prostadienoic acid 
9S,11S,15-Trihydroxy-16-(2-cyclohexano[b]thienyloxy)-5-cis,13-trans-tetrano 
r-prostadienoic acid 
The compounds of the invention of the formula I are analogs of prostanoic 
acids which do not occur naturally and which can be used as medicaments by 
virtue of their pharmacological effects. 
The natural prostaglandins PGE.sub.1.alpha., PGE.sub.2.alpha. or PGA.sub.2 
have the disadvantage that they are so quickly deactivated in a living 
body that their pharmacological action cannot be maintained for the time 
required for therapy. 
In contrast to this, the compounds of the invention are distinguished by a 
longer duration of action and a stronger effect. 
The compounds of the invention have a hypotensive and diuretic action, and 
may be used as abortifacients and contraceptives, as agents for inhibiting 
secretion of the gastric juices, and as agents against gastric ulcers and 
asthma. The compounds of the invention are especially suitable 
contraceptives for human beings and especially suitable agents for 
synchronization of the estrus in different animal species. 
The compounds of the invention may be used in the form of the free acid, 
physiologically tolerable inorganic or organic salts, or as esters with an 
aliphatic, cycloaliphatic or araliphatic alcohol. Examples of suitable 
salts are benzylammonium, triethanolammonium or morpholine salts and 
alkali metal salts, and the preferred esters are those with saturated, 
branched or straight-chain, lower aliphatic alcohols, for example, methyl, 
ethyl, propyl, butyl or pentyl esters, and benzyl esters. 
The acids and salts as well as the esters may be used in the form of 
aqueous solutions or suspensions, or solutions in pharmacologically 
suitable organic solvents, for example, monohydric or polyhydric alcohols, 
dimethylsulfoxide or dimethyl formamide. A pharmaceutically suitable 
polymeric carrier, for example, polyvinylpyrrolidone, may also be used. 
The preparation of the invention may be in a form suitable for 
administration, for example, infusion solutions or injection solutions, 
tablets, as well as preparation which can be applied locally, for example, 
creams, emulsions, suppositories and aerosols. 
The preparations of the invention may comprise compounds of the formula I, 
salts or esters thereof, as the only active substance, or may also 
comprise one or more other pharmacologically active substances, for 
example, diuretics or antidiabetics. 
The single dose to be administered to animals, especially to cattle, horses 
or sheep is 0.05 to 50 mg, preferably 0.5 to 30 mg. The daily dose is 0.1 
to 100 mg, preferably 1 to 60 mg. For human beings, infusion solutions are 
especially suitable. The dose is, for example, 0.2 to 0.5 mg per 2 hours. 
The compounds of the formulae V, VI, VII, VIII, IX and X are intermediate 
products for the synthesis of the compounds according to the invention, of 
the formula I.