ANALOGUES OF PROSTANOIC ACIDS NOT OCCURRING IN NATURE AND PROCESS FOR PREPARING THEM

SYNTHESE D'ANALOGUES SYNTHETIQUES D'ACIDES PROSTANOIQUES

English Abstract

NOVEL ANALOGUES OF PROSTANOIC ACIDS NOT OCCURRING IN NATURE
AND PROCESS FOR PREPARING THEM
Abstract of the Disclosure:
The present invention relates to novel not naturally
occurring analogues of prostanoic acids of the formula
<IMG> (I)
as well as a process for their preparation. The compounds
of the invention have valuable pharmacological properties
similar to those of the natural prostaglandins and therefore
can be used as medicaments.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of the compound of the
formula I
(I)
<IMG>
wherein R1 and R2 together represent oxygen or each of them
separately represents hydrogen or a hydroxy group, R1 and R2
being different from each other, R3 represents a saturated,
straight chain or branched alkyl group of 1 to 10 carbon atoms,
which itself may be substituted by an O-alkyl group of 1 to 5
alkyl C-atoms, by an O-aryl group, by an O-furyl group or by
an O-benzyl group, which themselves may be substituted by one
or several halogen atoms, by trifluoromethyl or alkyl groups
of 1 to 3 carbon atoms or by the phenoxy group which may carry
one or several halogen atoms, or a saturated cycloalkyl group
of 3 to 7 ring members or an aryl or furyl group which itself
may be substituted by one or several alkyl groups of 1 to 3
carbon atoms, and the physiologically tolerated salts thereof
with organic and inorganic bases and the esters thereof with
aliphatic, cycloaliphatic or araliphatic alcohols of 1 to 8
carbon atoms,
in which
(i) the tetrahydropyranyl ether protective group in a compound
of the formula XXI
59

(XXI)
<IMG>
wherein Y2 represents a -CH2- or a -C(CH3)2-group or a single
bond and R3 is as defined above, is split off by mild acid
hydrolysis to produce an alcohol of the formula XXII
(XXII)
<IMG>
wherein Y2 and R3 are as defined above for formula XXI, the
ketal grouping in the alcohol of the formula XXII is re-
moved by mild acid-catalyzed hydrolysis or by trans-ketali-
zation in the presence of a large excess of a ketone, or
(ii) both protective groups are split off by mild acid hydrolysis
in one step, and the compound so obtained of the formula I,
in which R1 and R2 together represent oxygen is optionally be reduced
with a complex metal hydride to a compound of the formula I
wherein R1 and R2 represent hydrogen or hydroxyl and R1 is
not identical in meaning with R2, and, the compound of the
formula I is optionally be reacted with a physiologically acceptable
organic or inorganic base to produce a physiologically
tolerated acid or with an aliphatic, cycloaliphatic or arala-

phatic alcohol of 1 to 8 carbon atoms to produce a physio-
logically acceptable ester.
2. A process as claimed in claim 1 in which both protec-
tive groups are split off in one step by hydrolysis in the
presence of 10% aqueous oxalic acid to produce a compound of
the formula I wherein R1 and R2 together represent oxygen.
3. A process as claimed in claim 1 in which a compound
of the formula I wherein R1 and R2 represent hydrogen or hydroxyl
and R1 is not identical in meaning with R2 is reduced in the
presence of sodium boron hydride in an aqueous alcoholic
solution.
4. A compound of the formula I
(I)
<IMG>
wherein R1 and R2 together represent oxygen or each of them
separately represents hydrogen or a hydroxy group, R1 and R2
being different from each other, R3 represents a saturated,
straight chain or branched alkyl group of 1 to 10 carbon atoms,
which itself may be substituted by an O-alkyl group of 1 to 5
alkyl C-atoms, by an O-aryl group, by an O-furyl group or by
an O-benzyl group, which themselves may be substituted by one
or several halogen atoms, by trifluoromethyl or alkyl groups
of 1 to 3 carbon atoms or by the phenoxy group which may carry
61

one or several halogen atoms, or a saturated cycloalkyl group
of 3 to 7 ring members or an aryl or furyl group which itself
may be substituted by one or several alkyl groups of 1 to 3
carbon atoms, and the physiologically tolerated salts thereof
with organic and inorganic bases and the esters thereof with
aliphatic, cycloaliphatic or araliphatic alcohols of 1 to 8
carbon atoms, whenever obtained according to a process as
claimed in claim 1, claim 2 or claim 3 or by an obvious chemi-
cal equivalent thereof.
5. A process as claimed in claim 1 in which the compound
of the formula XXI is prepared by a process in which
(a) an acetal of the formula II
<IMG> (II)
wherein X represents oxygen or sulfur and Y represents a
-CH2- or
<IMG> group or a single bond, is reacted with a
Grignard compound of the formula III
<IMG> (III)
wherein Hal represents chlorine or bromine to produce an
acetal-ketone of the formula IV
62

<IMG> (IV)
wherein X and Y are as defined above,
(b) the acetal-ketone of the formula IV is converted into the
aldehyde-keton of the formula V
<IMG> (V)
(c) the aldehyde-ketone of the formula V is subjected to an aldol-
condensation under acid or alkaline catalysis, to produce the
unsaturated ketone of the formula VI
<IMG> (VI)
(d) the unsaturated ketone of the formula VI is reacted under
alkaline conditions with cyanide ions to produce the cyano-
ketone of the formula VII
(VII)
<IMG>
(e) the cyano-ketone of the formula VII is converted with
anhydrous alcoholic acid into the imino-ether salt of the
63

formula VIIa
<IMG> (VIIa)
wherein S represents an inorganic acid radical and R4 represents
lower alkyl of 1 to 5 carbon atoms, and by subsequent hydrolysis
into the ester of the formula VIII
<IMG> (VIII)
wherein R4 is as defined above
(f) the compound of the formula VIII is hydrogenated in the
presence of a catalyst to split off the benzyl-ether grouping
whereby an ester-alcohol of the formula IX
(IX)
<IMG>
wherein R4 is as defined above, is obtained,
(g) the ester-alcohol of the formula IX is oxidized to an
aldehyde of the formula X
64

<IMG> (X)
wherein R4 is as defined above,
(h) the aldehyde of the formula X is reacted selectively with
a dithiol of the formula XI
HS-CH2-Y1-CH2-SH (XI)
wherein Y1 represents a -CH2- group or a -C(CH3)2 group or a
single bond, in the presence of an acid catalyst to produce a
thio-acetal of the formula XII
<IMG> (XII)
wherein R4 is as defined above,
(i) the thioacetal of the formula XII is transformed by ketali-
zation under acid catalysis with a glycol of the formula XIII
HO-CH2-Y2-CH2-OH (XIII)
wherein Y2 has the meaning given for Y1 in formula XII into a
ketal-thioacetal of the formula XIV

<IMG>
( XIV)
Wherein Y1 and Y2 may be identical or different, and R4 is as
defined above,
(j) the ketal-thioacetal of the formula XIV is reduced with a
complex metal hydride in an aprotic solvent to an aldehyde of
the formula XV
<IMG>
(XV)
wherein Y1 and Y2 have the meanings given for formula XIV
(k) the aldehyde of the formula XI is reacted with a phosphonate
of the formula XVI
<IMG>
(XVI)
66

wherein R3 has the meaning given for formula I, to produce an
unsaturated ketone of the formula XVII
(XVII)
<IMG>
wherein Y1 and Y2 have the meanings given for formula XIV,
and R3 has the meaning given for formula I,
(1) the ketone of the formula XVII is reduced with a complex
metal hydride to the mixture of epimers of an alcohol of the
formula XVIII
<IMG>
(XVIII)
67

wherein Y1 and Y2 and R3 have the meanings given for formula
XVII
(m) the alcohol of the formula XVIII in the form of the mixture
of epimers or after having separated the epimers is transformed
by acid-catalyzed addition of 2,3-dihydropyrane into a tetra-
hydropyranyl ether of the formula XIX
(XIX)
<IMG>
wherein Y1 and Y2 and R3 have the meanings given for formula
XVII
(n) the ether of the formula XIX is converted by heating with
a C1 - C4-alkyl iodide in a polar aprotic solvent in the
presence of an acid acceptor, into an aldehyde ether of the
formula XX
68

<IMG> (XX)
wherein Y2 and R3 have the meanings given for formula XVII,
(o) the aldehyde ether of the formula XX is reacted with the
ylide from 4-carboxypropyl-triphenyl-phosphonium bromide in
a solution of sodium hydride in dimethyl-sulfoxide to produce
an acid of the formula XXI
(XXI)
<IMG>
wherein Y2 and R3 have the meanings given for formula XVIII.
69

6. A compound of the formula I
(I)
<IMG>
wherein R1 and R2 together represent oxygen or each of them
separately represents hydrogen or a hydroxy group, R1 and R2
being different from each other, R3 represents a saturated,
straight chain or branched alkyl group of 1 to 10 carbon atoms,
which itself may be substituted by an O-alkyl group of 1 to 5
alkyl C-atoms, by an O-aryl group, by an O-furyl group or by
an O-benzyl group, which themselves may be substituted by one
or several halogen atoms, by trifluoromethyl or alkyl groups
of 1 to 3 carbon atoms or by the phenoxy group which may carry
one or several halogen atoms, or a saturated cycloalkyl group
of 3 to 7 ring members or an aryl or furyl group which itself
may be substituted by one or several alkyl groups of 1 to 3
carbon atoms, and the physiologically tolerated salts thereof
with organic and inorganic bases and the esters thereof with
aliphatic, cycloaliphatic or araliphatic alcohols of 1 to 8
carbon atoms, whenever obtained according to a process as
claimed in claim 5 or by an obvious chemical equivalent thereof.

7. A process as claimed in claim 1 for the preparation of
7-[2-(3-hydroxy-3-pentyl-trans-1-propenyl)-5-oxo-cyclopentyl]-cis-4-
heptenoic acid, in which (i) the tetrahydropyranyl ether protective
group in the compound 7-[3,3-dimethy1-8-(3-pentyl-3-tetrahydropyranyloxy-
trans-1-propenyl)-1,5-dioxaspiro-[5,4]-dec-7-y1]-cis-4-heptenoic acid
is split off by mild acid hydrolysis to produce 7-[3,3-dimethyl-8-
(3-pentyl-3-hydroxy-trans-1-propenyl]-1,5-dioxaspiro[5,4]-dec-7-yl(-cis-
4-heptenoic acid and the ketal grouping in this compound is removed
by mild acid-catalyzed hydrolysis or by trans-ketalization in the
presence of a large excess of a ketone, or (ii) both protective
groups are split off by mild acid hydrolysis in one step.
8. A process as claimed in claim 7 in which 7-[3,3-dimethyl-
8-(3-pentyl-3-tetrahydropyranyloxy-trans-1-propenyl)-1,5-dioxaspiro-
[5,4]-dec-7-y1]-cis-4-heptenoic acid is prepared by a process in
which 3-(1,3-dithia-2-cyclopentyl)-propionitrile is reacted with
benzyloxybutylmagnesiumchloride, the resulting 7-benzyloxy-1-
(1,3-dithia-2-cyclopentyl)-heptane-3-one is transformed to 7-benzyl-
oxy-3-heptane carbaldehyde, this compound is subjected to an aldol-
condensation under acid or alkaline catalysis, the resulting 2-
(3-benzyloxypropyl)-2-cyclopentanone is reacted under alkaline
conditions with cyanide ions, the resulting 2-(3-benzyloxypropyl)-3-
cyano-cyclopentanone is converted with anhydrous alcoholic acid
into 3-ethoxycarbonyl-2-(3-benzyloxypropyl)-cyclopentanone, this
compound is hydrogenated in the presence of a catalyst, the resulting
3-ethoxycarbonyl-2-(3-oxypropyl)-cyclopentanone is oxidized to
produce the 3-(2-ethoxycarbonyl-5-oxo-cyclopentyl)-propionaldehyde,
this compound is reacted selectively with ethylene thioglycol to
71

produce 3-(2-ethoxy-carbonyl-5-oxo-cyclopentyl)-propionaldehyde-
ethylene-thioacetal, this compound is reacted under acid catalysis
with 2,2-dimethyl-1,3-propanediol to produce 7-[(1,3-dithia-2-
cyclopentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro-[5,4]-dec-8-yl-
carboxylic acid ethyl ester, this compound is reduced with a complex
metal hydride to 7-[(1,3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-
1,5-dioxaspiro-[5,4]-dec-8-yl-aldehyde, this compound is reacted
with dimethyl-2-oxo-heptyl-phosphonate to produce 1-[7-[(1,3-dithia-2-
cyclopentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro-[5,4]-dec-8-yl]-
trans-1-octene-3-one, this compound is reduced with a complex
metal hydride to 1-[7-[(1,3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-
1,5-dioxaspiro[5,4]-dec-8-yl]-trans-1-octene-3-ol, this compound is
transfored by acid-catalyzed addition of 2,3-dihydropyrane into 1-
[7-[(1,3-dithia-2-cyclopentyl)]-3,3-dimethyl-1,5-dioxaspiro-[5,
4]-dec-8-yl]-trans-1-octene-3-ol-tetrahydropyranylether, the compound
is converted by heating with methyl iodide in a polar aprotic
solvent in the presence of an acid acceptor into 3-[3,3-dimethyl-
8-[3-pentyl-3-tetrahydropyranyloxy-trans-1-propenyl]-1,5-dioxaspiro
[5,4]-dec-7-yl]-propionaldehyde and this compound is reacted with
the ylide of 4-carboxypropyl-triphenylphosphonium bromide in a
solution of sodium hydride in dimethyl sulfoxide to produce 7-[3,
3-dimethyl-8-(3-pentyl-3-tetrahydropyranyloxy-trans-1-propenyl)-
1,5-dioxaspiro[5,4]-dec-7-yl]-cis-4-heptenoic acid.
9. 7-[2-(3-Hydroxy-3-pentyl-trans-1-propenyl)-5-oxo-cyclopentyl]-
cis-4-heptenoic acid, whenever obtained according to a process as
claimed in claim 7 or claim 8 or by an obvious chemical equivalent
thereof.
72

10. A process as claimed in claim 1 for the preparation of
7-[2-(3-hydroxy-3-heptyl-trans-1-propenyl)-5-oxo-cyclopentyl]-cis-
4-heptenoic acid, in which (i) the tetrahydropyranyl ether protective
group in the compound 7-[3,3-dimethyl-8-(3-heptyl-3-tetrahydropyranyl-
oxy-trans-1-propenyl]-1,5-dioxaspiro-[5,4]-dec-7-y1]-cis-4-
heptenoic acid is split off by mild acid hydrolysis to produce
7-[3,3-dimethyl-8-(3-pentyl-3-hydroxy-trans-1-propenyl]-1,5-
dioxaspiro[5,4]-dec-7-y1]-cis-4-heptenoic acid and the ketal grouping
in this compound is removed by mild acid-catalyzed hydrolysis or
by trans-ketalization in the presence of a large excess of a ketone,
or (ii) both protective groups are split off by mild acid hydrolysis
in one step.
11. A process as claimed in claim 10 in which 7-[3,3-dimethyl-
8-(3-heptyl-3-tetrahydropyranyloxy-trans-1-propenyl]-1,5-dioxaspiro-
[5,4]-dec-7-y1]-cis-4-heptenoic acid is prepared by a process in which
3-(1,3-dithia-2-cyclopentyl)-propionitrile is reacted with benzyl-
oxybutylmagnesiumchloride, the resulting 7-benzyloxy-1-(1,3-dithia-
2-cyclopentyl)-heptane-3-one is transformed to 7-benzyloxy-3-heptane
carbaldehyde, this compound is subjected to an aldol-condensation
under acid or alkaline catalysis, the resulting 2-(3-benzyloxypropyl)-
2-cyclopentanone is reacted under alkaline conditions with cyanide
ions, the resulting 2-(3-benzyloxypropyl)-3-cyano-cyclopentanone is
converted with anhydrous alcoholic acid into 3-ethoxycarbonyl-2-
(3-benzyloxy-propyl)-cyclopentanone, this compound is hydrogenated in
the presence of a catalyst, the resulting 3-ethoxycarbonyl-2-(3-
oxypropyl)-cyclopentanone is oxidized to produce the 3-(2-ethoxycar-
bonyl-5-oxo-cyclopentyl)-propionaldhyde, this compound is reacted
73

selectively with ethylene thioglycol to produce 3-(2-ethoxy-carbonyl-
5-oxo-cyclopentyl)-propionaldehyde-ethylene-thioacetal, this compound
is reacted under acid catalysis with 2,2-dimethyl-1,3-propanediol
to produce 7-[(1,3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1,
5-dioxaspiro-[5,4]-dec-8-yl-carboxylic acid ethyl ester, this compound
is reduced with a complex metal hydride to 7-[(1,3-dithia-2-cyclo-
pentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro-[5,4]-dec-8-yl-aldehyde,
this compound is reacted with dimethyl-2-oxo-nonyl-phosphonate to
produce 1-[7-[(1,3-dithia-2-cyclopentyl)] -3,3-dimethyl-1,5-dioxa-
spiro-[5,4]-dec-8-yl]-trans-1-decene-3-one, this compound is reduced
with a complex metal hydride to 1-[7-[(1,3-dithia-2-cyclopentyl)-ethyl]-
3,3-dimethyl-1,5-dioxaspiro[5,4]-dec-8-yl]-trans-1-decene-3-ol, this
compound is transformed by acid-catalyzed addition of 2,3-dihydro-
pyrane into 1-[7-[(1,3-dithia-2-cyclopentyl)ethyl]-3,3-dimethyl-1,
5-dioxaspiro-[5,4]-dec-8-yl]-trans-1-decene-3-ol-tetrahydropyranylether,
the compound is converted by heating with methyl iodide in a polar
aprotic solvent in the presence of an acid acceptor into 3-[3,3-
dimethyl-8-[3-heptyl-3-tetrahydropyranyloxy-trans-1-propenyl]-1,5-
dioxaspiro[5,4]-dec-7-yl]-propionaldehyde and this compound is reacted
with the ylide of 4-carboxypropyl-triphenylphosphonium bromide in a
solution of sodium hydride in dimethyl sulfoxide to produce 7-[3,3-
dimethyl-8-(3-heptyl-3-tetrahydropyranyloxy-trans-1-propenyl)-1,5-
dioxaspiro[5,4]-dec-7-yl]-cis-4-heptenoic acid.
12. 7-[2-(3-Hydroxy-3-heptyl-trans-1-propenyl)-5-oxo-cyclopentyl]-
cis-4-heptenoic acid, whenever obtained according to a process as
claimed in claim 10 or claim 11 or by an obvious chemical equivalent
thereof. 74

13. A process as claimed in claim 1 for the preparation of
7-[2-[3-hydroxy-3-(1,1-dimethyl-3-oxa-pentyl)-trans-1-propenyl]-
5-oxo-cyclopentyl]-cis-4-heptenoic acid, inwhich (i) the tetrahydro-
pyranyl ether protective group in the compound 7-[3,3-dimethyl-8-
[3-(1,1-dimethyl-3-oxapentyl)-3-tetrahydropyranyloxy-trans-1-
propenyl]-1,5-dioxaspiro[5,4]-dec-7-y1]-cis-4-heptenoic acid
is split off by mild acid hydrolysis to produce 7-[3,3-dimethyl-8-
[3-(1,1-dimethyl-3-oxa-pentyl)-3-hydroxy-trans-1-propenyl]-1,5-
dioxaspiro[5,4]-dec-7-y1]-cis-4-heptenoic acid and the ketal grouping
in this compound is removed by mild acid-catalyzed hydrolysis or by
trans-ketalization in the presence of a large excess of a ketone, or
(ii) both protective groups are split off by mild acid hydrolysis
in one step.
14. A process as claimed in claim 13 in which 7-[3,3-dimethyl-
8-[3-(1,1-dimethyl-3-oxapentyl)-3-tetrahydropyranyloxy-trans-1-
propenyl]-1,5-dioxaspiro[5,4]-dec-7-y1]-cis-4-heptenoic acid is
prepared by a process in which 3-(1,3-dithia-2-cyclopentyl)-propionitrile
is reacted with benzyloxybutylmagnesiumchloride, the resulting 7-
benzyloxy-l-(1,3-dithia-2-cyclopentyl)-heptane -3-one is transformed
to 7-benzyloxy-3-heptane carbaldehyde, this compound is subjected to
an aldol-condensation under acid or alkaline catalysis, the resulting
2-(3-benzyloxypropyl)-2-cyclopentanone is reacted under alkaline
conditions with cyanide ions, the resulting 2-(3-benzyloxypropyl)-3-
cyano-cyclopentanone is converted with anhydrous alcoholic acid into
3-ethoxycarbonyl-2-(3-benzyloxy-propyl)-cyclopentanone, this compound

is hydrogenated in the presence of a catalyst, the resulting 3-
ethoxycarbonyl-2-(3-oxypropyl)-cyclopentanone is oxidized to produce
the 3-(2-ethoxycarbonyl-5-oxo-cyclopentyl)-propionaldehyde, this compound
is reacted selectively with ethylene thioglycol to produce 3-(2-
ethoxy-carbonyl-5-oxo-cyclopentyl)-propionaldehyde-ethylene-thioacetal,
this compound is reacted under acid catalysis with 2,2-dimethyl-1,
3-propanediol to produce 7-[(1,3-dithia-2-cyclopentyl)-ethyl]-3,
3-dimethyl-1,5-dioxaspiro-[5,4]-dec-8-y1-carboxylic acid ethyl ester,
this compound is reduced with a complex metal hydride to 7-[(1,3-
dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro-[5,4]-dec-
8-y1-aldehyde, this compound is reacted with dimethyl-2-(1,1-dimethyl-
3-oxa-pentyl)-2-oxapentyl-phosphonate to produce 1-[7-[(1,3-dithia-
2-cyclopentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro-[5,4]-dec-8-y1]-
3-(1,1-dimethyl-3-one-pentyl)-trans-1-propene-3-one, this compound is
reduced with a complex metal hydride to 1-[7-[(1,3-dithia-2-cyclo-
pentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-dec-8-y1]-3-(1,1-
dimethyl-3-oxapentyl)-trans-1-propene-3-ol, this compound is trans-
formed by acid-catalyzed addition of 2,3-dihydro-pyrane into 1-[7-
[(1,3-dithia-2-cyclopentyl)]-3,3-dimethyl-1,5-dioxaspiro-[5,4]-dec-8-
y1]-3-(1,1-dimethyl-3-oxapentyl)-trans-1-propene-3-ol-tetrahydro-
pyranylether, the compound is converted by heating with methyl iodide
in a polar aprotic solvent in the presence of an acid acceptor into
3-[3,3-dimethyl-8-[3-(1,1-dimethyl-3-oxapentyl)-3-tetrahydropyranyloxy-
trans-1-propenyl]-1,5-dioxaspiro[5,4]-dec-7-y1]-propionaldehyde
and this compound is reacted with the ylide of 4-carboxypropyl-tri-
phenylphosphonium bromide in a solution of sodium hydride in dimethyl
sulfoxide to produce 7-[3,3-dimethyl-8-(3-(1,1-dimethyl-3-oxa-pentyl)-
3-tetrahydropyranyloxy-trans-1-propenyl)-1,5-dioxaspiro[5,4]-dec-7-
yl]-cis-4-heptenoic acid.
76

15. 7-[2-[3-Hydroxy-3-(1,1-dimethyl-3-oxa-pentyl)-trans-1-
propenyl]-5-oxo-cyclopentyl]-cis-4-heptenoic acid, whenever obtained
according to a process as claimed in claim 13 or claim 14 or by an
obvious chemical equivalent thereof.
77

Description

104;~003
Prostaglandins represent a group of natural substances iso-
lated from various animal tissues. In mammals, they are respon-
sible for a great number of physiological activities. These na-
tural prostaglandins have a carbon structure of, in general, 20
carbon atoms and they are distinguished from each other essen-
tially by a higher or lower content of hydroxyl groups or double
bonds in the cyclopentane ring (regarding the structure and acti-
vity of prostaglandins, c.f., among others, M.F. Cuthbert "The
Prostaglandins, Pharmacological and Therapeutic Advances",
William Heinemann Medical Boods Ltd. 9 London 1973).
Therefore, the synthesis of analogues of prostanoic acids
not occurring in nature and which show differentiated actions of
the great number of pharmacological activities of the natural
prostanoic acids has become more and more important.
The present invention relates to novel analogues o~ pro-
stanoic acids not occurring in nature of the formula I
R1 \ ",'R2 ~ H
~ " CH2-(~H2-C =~- CH2 - CH2 C
¦ I (I)
H0
wherein
R1 and R2 together represent oxygen or each of them separately
hydrogen or a hydroxy group, R1 and R2 being different from each
--2-- ~1~
:
- . : ,

~04~003
~ other,
R3 represents a saturated, straight chain or branched alkyl group
of 1 to 10 carbon atoms, which itself may be substituted by an
O-alkyl group of 1 to 5 alkyl C-atoms, by an O-aryl group, by an
OLfuryl group or by an O-benzyl group, which themselves may be
substituted by one or several halogen atoms, by trifluoromethyl -
or alkyl groups of 1 to 3 carbon atoms or by the phenoxy group
which may carry one or several halogen atoms, or a saturated
cycioalkyl group of 3 to 7 ring members or an aryl or furyl group
which itself may be substituted by one or several alkyl ~roups
- of 1 to 3 carbon atoms,
and to their physiologically tolerated salts with organic
and inorganic bases and to their esters with aliphatic, cyclo-
aliphatic or araliphatic alcohols of 1 to ~ carbon atoms.
The present invention furthermore relates to a process for
preparing the novel analogues of pros~anoic acids of the general
formula I which do not occur in nature, their physiologically
~olerated salts with organic and inorganic bases, their esters `
- and pharmaceutical compositions which contain these compounds
as active substances. -
The process of the invention essentially comprises
- a) reacting an acetal of the formula II
- ~CH2 1 X
/
Y \ / CH - CH2 - CH2 - CN II
C~2 --X
in which
:~ . - 3 _
.. , .. . .. .. . , ~ . . . . . ~ .. ~ .
-- - : ~ , - - ~ . , - -.
- : : . ,
:

' '- 104Z003
X represents oxygen or sulfur, and Y represents a -CH2- or
~H3
- C - group or a simple bond,
C~13
with a Grignard compound of the formula III
H~l-M~-cH2-c~l2-cH2-cH2-o CH2 ~ III,
in which Hal represents chlorine or bromine, to an acetal--kstone
of the formula IV
~CH2 -~ X~
y ~ CH-cH2-cH2-c-cH2-cH2-cH2-c~2 C 2
CH2 X IV
'.
in which X and Y have the meanings given for formula II,
b) transforming the acetal-ketone of the formula IV so
obta1ned in a manner usual for acetals or thio-ae~tals into
the aldehyde-ketone of the formula V
CH2 CH2-C-CH2-CH2-CH2-CH2-0-CH2 ~ V
c) subjecting the aldehyde-ketone of the formula V ob-
tained to an aldol-condensation under acid or alkaline catalysis,
whereby the unsatura*ed ketone of the formula VI
~ , - . :, - : ~: :: : : .

104~1)03
~CH2-CH2-CH2-0-cH2
is formed,
d) reacting the unsaturated ketone of the formula YI so
obtained under alkaline conditions with cyanide ions, whereby the
cyano-ketone of the formula YII
O
- ~CH2-CH2-CH2-o-cH2- ~ -
CN
is obtained,
e j transforming the cyano-ketone of the formula VTI so ob- -
tained with anhydrous alcoholic acid over the imino-ether salt
of the formula VII a
O
CH2-CH2-CH2 _ 0-CH2 ~
_OR4 VII a
HS
in which S represents an inorganic acid radical, and ~4 repre-
sents lower alkyl of 1 to 5 carbon atoms, and subsequent hydro- -
lysis into the esters of the formula YIII
.
. .
: :
.
:
- :

1~4~'~3
,CH2-CH2-CH2-O-c~2 ~ VIII
COOR4
in which R4 has the meaning given for formula YII a,
f) hydrogenating in the presence of catalysts the ester
of the formula VIII so obtained under splittlng off the benzyi-
ether grouping, whereby an ester-alcohol of the formula IX
O
-CH2-CH2-OH IX
COOR4
r
in which R4 has the meaning given for formula VIII, is obtained,
g) oxidizing the ester-alcohol of the formula IX so ob-
tained to an aldehyde of the formula X
Q
CH2-CH2-CHO
I ~ X
~COOR4
in which R~ has the meaning given for formula VIII,
h) reacting the aldehyde of the formula X so obtained sele-
ctively with a dithiol of the formula XI
HS-CH2-Y1-CH2-SH XI
in which Y1 represents a -CH2- group or a -C~CH3)~ group or a
.
-- 6 ~
. . . . . . . . .. . .... . . . . . .. .
,,: "
- . .: . - ~. .,. :
. ~ ,

Ofl200;~
simple bond, in the presence of acid catalysts to a thio-acetal
of the formula XII
Q ~ S -CH2
,'CH2-CH2-CH ' CH2 Y1 XII
COOR~
in which R4 has the meaning given for formula X,
i) transforming the thioacetal of the formula XII ~o ob-
tained by ketalization under acid catalysis with a glycol of
the formula XIII
- HO-CH2~ Y2-CH2-OH XTII
in which Y2 has the meaning given for Y1 in formula XII, into
a ketal-thioacetal of the formula XIV
..
~Y~ ~S~CH2
COOR4
in which Yl and Y2 may be identical or different, and R4 has
the meaning given for formula X,
j) reducing the ketal-thioacetal of the formula XIV so
obtained with a complex metal hydride in aprotic solvents to an
aldehyde of the formula XV
. ....~,: .
.

104'~003
~ 2
IH2 ICH2
/S
" CH2 CH2-CH Yl - XV
.' . ,.
CHO
in which Y1 and Y2 have the meanings given for formula XIV,
k) reacting the aldehyde so obtained of the formula XI ~-
with a phosphonate of the formula XVI .
O O ~: '
CH~O \ ~
P-CH2-C-R~ XVI
C~O
-
in which R3 has the meaning given for formula I, to an unsatu-
rated ketone o~ the formule XVII
~Y2
f~H2 fH2
~ ,CH2-CH2-CH~ Y1 XVII
. .
,-. l
U
H O
~ . .
- 8 -
- ~ - ~ ... . . . ... .... ..
,
'.
~: , . . ' ;' :: . .' , '
', ~ . ' , : ', . .. -

lO~Z003
in which Yl and Y2 have the meanings given for formula XIV, and
R3 has the meaning given for formula I,
1) reducing the ketone obtained of the formula XVII with
a complex metal hydride to the mixture of epimers of the alco-
hols of the formula XVIII
.. . . . . .
- ~Y2
fH2 TH2
- ~ 9 ~s~ . . ...
~ ><r CH2-CH2-CX~ Y 1 . '
.. . ¦ . ¦ XVIII
C \ H
H
.
- in which Yl and Y2 and R3 have the meanings given for formula ~ -
XVII,
m) transforming the alcohol obtained of the formula XVIII
in the ~orm of the mixture of epimers or after having separated
the epimers~by acid-catalyzed addition of 2,3-dihydropyrane
: into a tetrahydropyranyl ether of the formula XIX
_ g _
,-
-

104'~003
.. . ~ ,
H2 ICH2
~112-CH2-CH Y XIX
R
in which Y~ and Y2 and R3 have the meanings given ~or formula XYII,
n) transforming the ether obtained of the formula XIX by
heating with a C1 - C4-alkyl iodide in a polar aprotic solvent
in the presence of an acid acceptor into an aldehyde ether of
the formula XX
~ 2
CH~ CH2 ~ - .
,1 . 1. , , , . ~ ,
. . ~ ,CH2-CH2-CHO
. , XX,
. I _ ~ 3 .-~.
.'' ' (~ o .'
,.. , ,, .,, _ _, . _ .. .
.
in which Y2 and R3 have the meanings given for formula XYII, : -
_ 10 --
-

104~0~3
o) reacting the aldehyde ether obtained of the formula XX
with the ylide from 4-carboxypropyl-triphenyl-phosphonium bromide
in a solutlon of sodium hydride in dimethyl-sulfoxide to an acid
of the ~ormula XXI
., , ~ , , .
~ . CH2
. ' . . 1. ..
. ><9 ,-' C~2 CH2-c~=cH-cl~2-cH2-cooH
, XXI
.
~ 3
r ~
'. .. .
in which Y2 and R3 haYe the meanings given for formula X~II,
p) splitting off in the compound obtained of the formula
XXI the tetrahydropyranol ether protective group by mild acid
hydrolysis, whereupon an alcohol of the formula XXII
~H2 ICH2
~D ", CHZ CH~-c~=cH-c~:2-cH2~cooH
_ _ ' XXII
. . ' .
. _
H
-
.:

104Z~03
in which Y2 and R3 have the meanings given for formula XVII, is
obtained and removing the ketal grouping in the alcohol of the
formula XXII either by mild acid-catalyzed hydrolysis or by trans-
ketali~ation in the presence of a large excess of a ketone,
or effecting splitting off of both protective groups in one step
by mild acid hydrolysis, and reducing optionally the compound so
obtained of the formula I, in which R1 and R2 together represent
oxygen, to a compound of the formula I, in which R1 and R2 re-
present hydrogen or hydroxyl, with a complex metal hydride,
and, if desired, converting the compounds of the formula I
into their physiologically tolerated salts or their esters. -.
Among the groups mentioned for the substituent R3, there
are preferred alkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 7
carbon atoms, and phenyl or phenyl which is substituted by one
or se~eral methyl groups. Furthermore, there are preferred, for
R3, groups of the formula -C(R')2-(CH2)n-0-R", in which R' re-
presents hydrogen or an alkyl group of 1 to 3 carbon atoms, in
particular the methyl group, with the proviso that both R' may
be identical or different, and in which n is zero or 1 and R"
represents an alkyl group of 1 to 5 carbon atoms, a phenyl or -
benzyl group which may be substituted once or several times in
the nucleus by halogen, in particular chlorine, trifluoromethyl
or alkyl of 1 to 3 carbon atoms, or. a diphenyl ether group, in
which the benzene in termi~al position may be substituted once
or several times by halogen,in particular chlorine, trifluoro-
methyl or alkyl of 1 to 3 carbon atoms. Particularly preferred
for R3 are group~ of the formula -C(R')2-(CH2)n-0-R" in which
n is zero and R" represents phenyl which is monosubstituted by
chlorine or trifluoromethyl or a diphenyl ether group in which
- 12 -
. . , :: -

~04Z0~3
the benzene nucleus in terminal position is mono-substituted
by chlorine.
The process of the invention starts with a ketone synthesis
from nitriles of the general formula II.
Such nitriles may be obtained, for example by converting
the 3-(2,5-dio~apentyl)-propyl-bromide, obtainable according to
G. Buchi and H. Wuest, J. Org. Chem. 34, (1969), page 112, by
- the reaction with KCN to the 3-(2,5-dioxapentyl)-propylnitrile.
This nitrile or its oxygen analogues (X = O) described by the
general formula II may be reacted directly with the suitable
Gri~nard compound of the general formula III-or may be converted
by acid-catalyzed trans-ketalization with thiols of the general
formula XI into the sulfur analogues (X = S) of the general
formula II.
In the following step, the nitriles of the general formula
II (X = O or S) are reacted with Grignard compounds of the general
formula III, whereupon the ketones of the general formula IV
are obtained by mild acid hydrolysis. The Grignard compounds
of the general formula III may be obtained in the usual manner
from 4-benzyloxybutyl-chloride or -bromide in one of the usual
solvents such as diethyl ether or tetrahydrofurane. In principle,
also other metal-organic compounds, for example 4-benzyloxy
butyl-lithium, may be used.
The components II and III are allowed to react for a period
of time of from 2 to 20 hours in the presence of a protective gas.
Advantageous solvents are diethyl-ether or tetrahydrofurane, the
preferred temperatures are in the range of from 30 and 70 C,
the reaction times in the range of from 12 to 16 hours are faYo-
rable.
- 13 -
:, .~ ''
,
,, ' :

0Q3
The reaction product is hydrolyzed under mild acid conditions
and the ketones of the general formula IV are isolated in pure
form by distillation or column chromatography. However, the raw
products of the general formula IV may also be used directly in
the next synthesis step, the split~tlng off of the acetal or thio-
acetal protective group.
In order to obtain the aldehyde-ketone of the formula V,
a usual acid-ketal splitting o~ is carried ou* in the case of
the oxygen acetals of the formula IV (X = 0). A particularly mild
mode of carrying out this stép of the process of the invention
comprises thoroughly mixing the solu~ion of-compounds of the
general formula IV, in which X = 0, in an ether, for example di-
isopropyl ether, at 40 to 80 C, in the presence of a protective
gas, for 3 to 6 hours, with aqueous oxalic acid and, after washing
to neutrality, removing the solvent by distillation. For the
sp~ itting or~of thio-acetals of the general formula IV, in which
X ~ S, the methods described in literature, for example those
described by Hsin-Lan l~ang Chan, Tetrahydron Lett. 1972, pages --
198g - 1990, are used. A preferred method of operation of the
process of the invention comprises the splitting dr with CuC12
and CuO as described in the Bll. Chem. Soc. Jap. 45, (1972),
page 3724.
The aldehyde of the formula V can be purified by chromato-
graphy or distillation; however, it is more advantageous to use
it directly without purification in the following reaction, the
more so since it is obtained in high purity if the above-mentioned
CuC12 - CuO method is used.
The aldehyde of the formula V is subsequently subjected to
. .
- 14 -
.
-
- . :, , , . . . :
.. . , . - ~

104Z003
a basically catalyzed aldol condensation, whereby the unsatu-
rated ketone of the formula VI is formed. In principle, also
acid catalysts may be used in the aldol condensation. A preferred,
particularly mild form of the aldol condensation consists in
working, while stirring thoroughly, under exclusion of oxygen,
in a two-phase system at 40 to 60 C, one phase constituting
the solution of the aldehyde of the general formula V in a not-
- hydrolyzable, water-insoluble solvent, for example di-isopropyl
ether or benzene, and the other phase consisting of aqueous lN-
sodium or potassium hydroxide solution. The unsaturated ketone
of the formula YI can be purified, as already mentioned, by chro-
matography or distillation. It is, however, also possible to use
the raw product in the further reaction.
Then, CN-ions are added in the usual manner to the ketone
of the formula VI in order to obtain the cyano-ketone of the for-
mula VII, this reaction being preferably carried out with aceto-
cyanohydrlne in a methanolic alkaline solution or with KCN in a
mixture of methanol and water at room temperature. In general,
the formation of cis-trans isomers must be expected in this reac-
tion step. Ho~ever, in view of the investigations carried out by
D. Varech et al., Bull. Soc. Chim. 6, 1622 (1965), the more stable
trans-configuration will preferably be formed under alkaline con-
ditions.
- The cyano-ketone of the general formula VII is reacted
with alcoholic acid, preferably with ethanolic hydrochloric acid,
over the imino-ether hydrochloride VIIa to th~ esters of the ge-
neral formula YIII.
In this step, the imino-ether hydrochloride VIIa is obtained,
after evaporation of the excess of alcohol, in the form oI an oil
_ 15 -
~ ........ . .
- . . ,
- - ' , ' ' ' -: :
,, ~
. . .
. ~:
~' ~' '- . -

~.04'~003
and can be freed from by-products by extraction with weakly
polar solvents, for example pentane or diethyl ether. A special
mode of operation of the process of the invention consists in
reacting the compounds of the general formulae V, VI and VII,
each time as raw product, and removing all the by-products formed
by extraction in the step VIIa.
The imino-ether hydrochloride VII a is then hydrolyzed in
the usual manner to the esters of the general formula VIII, pre-
ferably by providing the aqueous solution with a layer of ether
and stirring the whole at room temperature.
The ether solution then contains the esters oi the general
for~ula VIII which are purified in the usual way by distillation
or by chromatographic measures.
- From the esters of the general formula VIII, the ester al-
cohols of the general formule IX are obtained by splitting off
the benzyl-ether grouping by hydrogenation, preferably in the
presence of noble metal catalysts, for example 10% of palladium
on animal charcoal.
The oxidation of the ester-alcohols of the general formula
IX to the aldehydes of the general formula X is carried out
according to one of the methods usually applied for the oxi-
dation of primary alcohols to aldehydes, A preferred method is
the oxidation with chromic anhydride in the presence of pyridine,
optionally in the presence of methylene chloride aæ solvent,
as described by Collins in Tetrahedron Lett,, 3363 (1968). An-
other preferred method is the o~idation with chlorine in the
presence of thio-anisole (Corey and Kinn, J. Org. Chem. 3
(1973) 1233)
The aldehyde of the ormula X may be converted in the usual
.
. . : .
, :. .-
-. ,
.

- 104~003
manner in its pure form, but it is of advantage to react it in
its raw form in the presence of acid catalysts in inert solvents
with thiols of the general formula XI to to thioacetals of the
general formula XII.
A preferred mode of operation of the process of the inven-
tion consists in reacting the aldehyde of the general formula X,
which is obtained with a purity of about 90%, with the equi-
molar quantity of a thiol of the general formula XI, for example
ethylene-thioglycol, in the presence of acid catalysts, prefe-
rably boron-trifluoro-di-etherate, in the presence of an oxygen-
free protective gas such as nitrogen or argon in an aprotic sol-
vent, for example benzene or toluene, for a period of time of
from 30 minutes to 5 hours at temperatures in the range of from
15 C to 50 C. In this step, the aldehyde function in the com-
pounds of the general formula XII is protected selectively.
The remaining keto-function in the thio-acetals of the ge-
neral formula XII is then protected by ketalization with the
glycols of the general formula XIII in aprotic solvents in the
presence of aoid catalysts, whereby the ketal-thio-acetals of
the general formula XIV are obtained. A particularly preferred
method is the ketalization of XII with glycols of the general
formula XIII, for exaMple ethylene-glycol or neopentyl-glycol,
in which the reactioncomponents are heated for 3 to 5 hours in
benzene or toluene on a water-separator, whereby the ketal--thio-
acetals of the general formula XIV are obtained.
The compounds of the formulae IX, X, XII and XIV each may
be converted into their pure forms; however, in the process of
the invention it is of advantage to further process the compounds
of the general formulae IX, X and XII, which are obtained in
- 17 -
.. ..
:

10~;~00~
high yields in the respectiYe reaction steps as crude products
and to purify the compounds of the general formula XIV in the
usual manner, preferably by column chromatography.
In the ketal-thioacetals of the general formula XIV, the
ester functions are reduced with a complex metal hydride, pre-
ferably di-isobutyl-aluminium hydride, in an inert sol~ent such
as toluene, at temperatures below 0 C, preferably at -40 to
-80 C, to the aldehydes of the general formula XV.
The aldehydes of the general formula XV are then reacted
according to ~Iorner, Emmons and Wittig with the phosphoni- acid
esters o~ the general formula XVI to the unsaturated ketones
of the general formula XVII, a preferred mode of carrying out
the reactio ~ onsisting in preparing the sodium salt of the
phosphonic acid esters of the general formula XVI with sodium
hydride in glycol-dimethylether and subsequently adding the al-
dehydes of the general formula XV and allowing the whole to
react for ~ to 6 hours. The phosphonic acid esters of the gene-
ral formula XVI are prepared according to methods known in li-
terature -(c.f. for example Corey, J. Am. Chem. Soc. 88, 5654
(1966)).
The alcohols of the general formula :XYIII are obtained in
the form of their epimeric mixtures, by reducing the ketones of
the general formula XVII with a comple~ metal hydride, preferably
an alkali metal boranate. The alcohols of the general formula
XVIII are-particularly suitable for a separation of the epimers, J
but the further reaction may also be carried out with the epi-
meric mixture a~d the sep~ration of the epimers may be effc-cted
at the stage of the final products.
.
- 18 ~
.,, ' ~' ` '~ ' . .
.. . . ~
-. - - : .
- : ..

104Z003
The addition of dihydropyrane to the tetrahydropyranyl
ether of the general formula XI is carried out in an ether or
benzene solution of the alcohols of the general formula XYIII,
in the presence of the usual acid catalysts~ for example p-tolu-
ene-sulfonic acid. In general, it is advantageous to purify at
this stage by chromatography the tetrahydropyranyl ether obtained
of the general formula XVIII.
Owing to the preparative difficulties involved, the libe-
ration of aldehydes and ketones from thio-acetals or thio-ketals
has been the subject of many publications (c.f. among others
Chang in Tetrahydron Letters No. 19, page 1989 (1972)). In par-
ticular, the preparation of the relatively sensitive aliphatic
aldehydes is very difficult, the more so if particularly unstable
protective groups, for example the tetrahydropyranyl ether group,
are present in the same molecule. It is surprising that upon addi-
tion of acid-binding agents, preferably calcium carbonate, to a
solution of the thioacetals of the general formula XIX in polar
~protic solvents, preferably dimethylformamide or acetone, the
aldehydes of the general formula XX are formed in practically
quantitative yield under maintenance of the tetrahydropyranyl
protective group after heating for 1 to 5 hours to a temperature
in the range of from 30 to 70 C, preferably 50 C, with C1-C4-
alkyl iodide, preferably methyl iodide.
The aldehyde ethers so prepared of the general formula XX
may be reacted without purification to the carboxylic acids of
the general formula XXI. The preferred form of operation us-ng
the Wittig reaction is effected in accordance with the method
described in J. Org. Chem. 28, 1128 (1963).
-- 19 --
: . ,
:. . , ; -
- :. , : ,
.. : : -

1042003
The splitting of~ of the ether protective groups is effected
by mild acid hydrolysis of the tetrahydropyranyl ether grouping,
preferably in a 2% aqueous alcoholic oxalic acid solution at 20
to 50 C or by heating for 1 to 2 hours in 60 to 70% acetic acid
to 50 C, whereby the carboxylic acids of the general formula
XXII are obtained.
The last step of the synthesis of this invention comprises
the mild acid hydrolysis of the ketal grouping of the compounds
of the formula XXII to compounds of the general formula I in
which R1 and R2 together represent oxygen. Another method for
the ketal separation comprises the trans-ketalization of XXII to
I in which Rl and R2 together represent oxygen, in the presence
of a large excess of a ketone, preferably acetone, in the pre-
sence of acid catalysts such as p-toluene-sulfonic acid.
HoweYer, in a preferred method of the process of the inven-
tion, both protective groups in the carbo~ylic acids of the
formula XXI may be split off in one step by acid hydrolysis,
for which purpose 10% aqueous oxalic acid has proved particularly
advantageous. Thereby, the compounds of the general formula I
are obtained in which R1 and R2 together represent oxygen.
The reduction to compounds of the formula I in which R1
and R2 represent hydrogen or hydroxyl is carried out witll a com-
plex metal hydride, preferably with a metal boranate, for example
sodium boron hydride, in an aqueous-alcoholic solution. A mixture
of the 9~,~-epimeric alcohols is obtained. The epimers can be
~eparate-d in the usual manner, for example by thin-layer chro-
matography or by partition chromatography.
If no separation of the epimers at the stage of the alcohols
of the general formula XVIII has been effected, it is possible
~. .
~ 20 -
,'~

104Z003
to subject the compounds of the general formula I in which R1
and R2 represent oxygen to an epim~r dissociation of the alcohols
in 15-position (15-OH according to the prostaglandin nomenclature
(cf. Andersen, Ann. New Yor. Acad. Sci. Acad. Sci., Vol. 1&0,
page 14) corresponding to 3-OH of the IUPAC nomenclature).
Furthermore, a racemate resolution may be carried out at
the stage of the acids of the general formula XXI or of the for-
mula I in the usual manner by salt formation with optically ac-
tive bases.
The compounds of the formulae IV, V, VI, VII, VIII, IX, X,
XII, XIV, XV, XVII, SYIII, XIX, XX, XXI and XXII are valuable
intermediate products for the synthesis of the compounds of the
formula I.
The compounds o~the invention are distinguished by sPasmoeenic
as well as spasmolytic, in particular bronchodilating and blood-
pressure lowering properties. They are furthermore therapeutically
active in thc case of gastro-intestinal disorders and have an
anti-fertility action. In comparison to the natural prostaglan-
dins E, F and E, they have an essentially better stability.
They may, therefore, be used as medicaments.
In this respect it is surprising that the compounds of the
formula I which are epimeric with regard to the 15-OH group
possess the mentioned pharmacological properties at about the
same degree.
The compounds of the invention may be used as free acids,
in the ~orm of their physiologically tolerated salts or of
their esters with aliphatic, cycloalipha~ic- or araliphatic al-
cohols of 1 to 8 carbon atoms. As salts, there may be used, ~or
example the benzylammonium, triethanolammonium or morpholine
- 21 -
: . . . ,- .-. : :. . - - . . ~ . .
- . . . , , :: : , :
~ ::: :. . : : . . :

lO~Z003
salts, in particular the tris-(hydroxymethyl)-aminomethane salt,
as well as the alkali metal salts such as the Na- and K-salts,
as esters there are preferably used the esters of lower saturated
aliphatic al~ohols such as the methyl, ethyl, propyl, isopropyl,
butyl or pentyl ester, and the benzyl ester.
The acids, salts or esters may be administered in the form
of their aqueous solutions or suspensions or even as solutions
in pharmacologically tolerated organic solvents, for example
mono- or polyhydric alcohols, dimethyl-sulfoxide or dimethyl-
formamide, or also to~ether with pharmacologically tolerated
polymeric carrier substances, for example polyvinyl-pyrrolidon~.
The pharmaceutical compositions may be the usual galenic
infusion or injection solutions, or tablets; preferably, however,
there are used locally applicable compositions such as creams,
emulsions, suppositories or aerosols. -
The compounds may be used as such alone or together with
other pharmacologically ac~ive substal~ces, for example diuretic
agents or anti-diabetic agents.
Bronchodilating active medicaments with a surprisingly strong
action are obtnined by mixing the compounds of 7-~2-(3-hydroxy-
3-pentyl-trans-1-propenyl)-5-oxo-cyclopentyl]-cis-~-heptenoic
acid, epimeric with regard to the 15-OH-group, either in the
form of a free acid or in the form o~ their physiologically
tolerated inorganic or organic salts or of their esters of ali-
phatic, cycloaliphatic or araliphatic alcohols of 1 to 8 carbon
atoms, at a weight proportion of 0.75 to 1 to 1.25 to 1; such
mixtures have the greatest actlvity when applied in the form of
an aerosol.
Surprisingly, such mixtures show an activity which is se-
veral times higher th~n the activities of the in~ividual isomers.
- 22 -
- ., - , :
-,. . , -~ , . .

~04'~003
Particularly advantageous is a mixture of the isomers in a
weight proportion o~
In the medicinal compositionsof the invention, the isomers
are likewise used in the form of the free acids, in the form of
the Na- or K-salts or of salts with organic bases such as benzyl-
ammonium, triethano]ammonium or morpholine salts, in particular
of the tris-(hydroxymethyl)-aminomethane salt or in the form of
- the esters of lower, saturated, straight-chain or branched ali-
phatic alcohols such as the methyl, ethyl, propyl, isopropyl,
butyl or pentyl ester or benzyl ester.
Particularly preferred are corresponding mixtur~ of the iso-
meric~free acids and of the methyl, ethyl, propyl and isopropyl
esters of the mentioned acids.
For administ~ration in aerosol form, the mi~ture of the in-
vention may be dissolved in the usual physiologically tolerated
solvents which are not irritating with regard to taste, for
example water or ethanol, or suspended, for example in lower
alkyl esters of higher fatty acids, for example the myristic
acid isopropyi ester, if desired with the addition of surface-
active agents as stabilizers, for example sorbitane- or penta-
erythritol fatty acid ester, and filled, together with one of
the usual inert propellant gases in aerosol containers, However,
the ~entioned compositions may also be administered by means of
a conventional atomizer with the aid of compressed air.
The following dosage units or daily doses may be administered
for the various possible indications:
- , ' : ~ . ' ~ : ~, . .. .

:104~00;~
Bronchodilating action (as aerosol):
Dosage unit: 0.1 - 1000 ~g
preferred: 1 - 200~ug ~per single spray
output)
Daily dose: 0.1 - 10 mg
Blood-pressure-lowering action:
.
Dosage unit: 1 - lOOO)ug
preferred: 1 - lOOJug parenterally (i.v.)
- Daily dose: 1 10 mg
Dosage unit: 0.5 - 11000 ~g
preferred: 1 - 500JUg orally
Daily dose: 1 mg - 10 mg
The doses in the administration against gastro-intestinal
disorders correspond to those indicated for the application as
blood-pressure-lowering agents. ~
The ~ollowing Examples illustrate the invention.
_ 24 -
- ,, - ~ . .
- ~ : ., ,.- : :
: ' ' , ' ' .-
. ' .
- : : ::: . .
: ' : , , - ~ ,

' 104Z003
EXAMP1ES:
Starting materials:
3-(2,5-dioxapentyl)-propyl bromide was prepared according
to G~ Buchi and H. Wuest (J. Org. Chem. 34 (1969) page 1122)
and heated in a manner analogous to that described by r~ohl,
Chem. Ber. 39 (1906(), page 1952, for 3 hours under reflux
in a mixture of 60 parts of ethyl alcohol and 40 parts of H20
with 2 molar equivalents of KCN in the presence of catalytical
amounts of potassium iodide. The 3-(2,5-dioxapentyl)-propyl-
cyanide (B~p~o 6 mm 68-69 C) was heated under reflux in ben-
zene with ethylene-thioglycol in the presence of boron-tri-
fluoride-etherate, whereupon~after the usual working up,3-(2,5~
dithiapentyl)-propylcyanide having a B~p~o 5 m~ of 124 - 126 C
was obtained.
4-Benzyloxybutanol was obtained according to the method
described by Butler, Reufrew and Clapp (Am. Soc. 60 (1938)
1~72) and transformed according to Bennett and Hock, J. Chem.
Soc. (Lond.) 1927, page 476, into the 4-benzyloxybutyl-chloride.
EXAMPLE 1:
7-Benzyloxy-1-(2,5-dithiapentyl)-heptane-3-one
The Grignard compound was prepared by a 5 hours' heating
of ~0.103 mole] = 2.5 g of ~g and [0.101 mole] = 20 g of 4-
benzyloxybutyl chloride in 50 ml of diethyl ether.
To this Grignard solution, there was added dropwise the
solution of 12 g = ~0.076 mole] of 3-(2,5-dithiapentyl)-propyl-
cyanide in 50 ml of diethyl ether and the whole was heated for
18 hours under argon and under reflux. After cooling, ~9 ml
of methylene chloride and ice vater were added, the mixture
was acidified to pH 1 by means of H~l and stirred fol 15 minutes.
,
- 25 - -
.. : - - , . - . . . , ~ : . ................... . . . .
;~

10~00~
The or~nic phase was separated, washed with water and concen-
trated. The residue was dissolved in 200 ml of acetone and 50 ml
of methanol and stirred with 25 ml of 2N-HCl for 4 hours at room
temperature, The solvent was concentrated under reduced pressure,
the residue was dissolved in methylene chloride, washed once
with a 2N-sodium carbonate solution and twice with water, dried
over Mg S04 and concentrated. The residue was distill~dunder
reduced pressure. B.pØ3 mm
EXAMPLE 2:
7-Benzyloxy-3-oxoheptanal:
.. _ . _ .. . ... . .. _ _ _
-~- - 0.135 mole = 44 g of 7-benzyloxy-1-(2,5-dithiapentyl)-
heptane-3-one were heated for 1 hour under nitrogen and under
reflux in 1 liter of acetone with [0.275 mole] = 47 g of CuC12 .
2 H20 and tO.57 mole] = 44 g of CuO, the copper salts were fil-
tered o~f and the filtrate was concentrated under reduced pressure.
The residue was dissolved in ether, washed twice with 2N- HCl
and thrice with water, dried and the solvent was removed by
distillation under reduced pressure. The residue was distilled
under reduced pressure. B~p~o 5 mm 185 - 192 C.
EXAMPLE 3:
2-(3-Benzyloxypropyl)-2-cyclopentanone:
30.8 g of crude 7-benzyloxy-3-oxoheptanal were dissolved
in 100 ml of di-isopropyl ether and well mixeA with S00 ml of
lN-sodium hydroxide solution at 50 C under nitrogen with the
aid of a vibromixer. The organic phase was separated, the aque-
ous phase was extracted with 200 ml of ether and the combined
ether extracts were washed with water, dried, concentrated and
distilled under reduced pressure. B~p~o 5 ~m 175 - 1~0 C.
. '
- 26 -
- - . . .
. - . .:

104~00~
EXA~IPLE 4:
2-(3-Benzyloxypropyl)-3-cyano-cyclopentanone:
47.8 g =~0.208 mole ~ of 2-(3-benzyloxypropyl)-2-cyclo-
pentanone were di$solved in 200 ml of methanol, 41.5 g =~0.64
molel of KCN were added and then 15 g = [0.25 mole~ of glacial
acetic acid in 25 ml of methanol were added dropwise within one
hour. After having stirred for 1 hour, 4 g =[0.066 mole~ of
~lacial acetic acid were again added and the whole was stirred
for a further hour. After this time, no starting material could
be detected in the thin-layer chromatogram. 100 ml of 2N NaOH
and gOO ml of ice-water were added and the mixture was extracted
thrice with 200 ml of diethyl ether, the combined ether extracts
were washed until neutral, dried and the solvent was removed by
distillation under reduced pressure. The residue was distilled.
B~p~o 5 mm 210 - 215 C. ---
EXA~LE 5:
3-Ethoxycarbonyl-2-(3-benzyloxy-propyl)-cyclopentanone:
10.02 mole~ = 5.1 g of 2-(3-benzylo~ypropyl)-3-cyanocyclo-
pentanone were dissolved in 25 ml of absolute benzene with ~0.022
mole] = 1 g of absolute ethyl alcohol while stirring, at 20 C,
and HCl gas was introduced slowly within 4 hours. The reaction
mixture was a~lowed to stand for 16 hours at room temperature.
The solvent was removed under reduced pressure and the residue
was stirred thrice with each time 75 ml of absolute di-ethyl
ether and these ether extracts were rejected.
The oily residue was dissolved in 20 ml of water, provided
with a layer of 100 ml of dî-ethyl ether and stirred for 30 mi-
nutes at room temperature, the organic phase was separated and
.
~ ; . :
,

10~2~03
the aqueous phase was extracted with 200 ml of di-ethyl ether.
The combined ether extracts were washed with 2N-sodium carbonate
solution and water, dried and the solvent was removed under re-
duced pressure. An oil was obtained.
An analytically pure sample was eluted by chromatography on
silica gel with a mixture of cyclohexane and glacial acetic acid
in a proportion of 9 : 1 and showed the following spectroscopic
data:
N.M.R. 7.3 ppm singulett 5 H,/4.2 (c) ppm
4,4 ppm singulett 2 H,/ quartett 2H.
EXAMPLE 6:
3-Ethoxycarbonyl-2-(3-oxypropyl)-cyclopentanone
5 g of 3-ethoxycarbon~1-2-(3-benzyloxy-propyl)-cyclopentanone
were hydrogenated in 50 ml of 80% acetic acid with 1 g of palla-
dium black at room temperature and a pressure of 50 atmospheres
gauge. The reaction mixture was combined ~vith 100 ml of wate~
and 100 ml of methylene chloride, the catalyst was filtered off,
the whole was combined with an aqueous soda solution until pH
8 to 9, the methylene chloride was separated, the remainder was
washed, dried and distilled under reduced pressure. The oily
residue was heated for 1 hour to 50 C at 0.02 mm Hg.
I.R. 3500 cm 1.
EXAMPLE 7:
3-(2-Ethoxycarbonyl-5-oxo-cyclopentyl)-propionaldehyde:
3.07 g = [0.014 mole] of 3-ethoxycarbonyl-2-(3-oxypropyl)-
cyclopentanone were dissolved in 3 ml of methylene chloride and
added dropwise to the oxydation reagent of 11.95 g of CrO3 and
19.15 g of pyridine in 300 ml of methylene chloride at 0 C.
After stirring for 35 minutes at 0 C, 61.8 g of sodium hydrogeno-
, .
- 28 -
' ~ . , - ''~: . :
'~ ' :

104Z003
sulfate-monohydrate in solid form were added and the whole was
further stirred for 30 minutes at 0 C. The suspension was
filtered through a clarifying filter and the filter residue
was washed six times with each time 50 ml of methylene chloride.
The combined methylene chloride filt~ates were dried over MgS04
and concentrated. An oil was obtained.
I.R. no OH~band at 3500 cm
wide carbonyl band at 1730 - 1740 cm 1.
EXAMPLE 8:
3-(2-Ethoxycarbonyl-5-oxo-cyclopentyl)-propionaldehyde-
- ethylene-thioacetal:
3 g = [0.014 mole) of oily 3-(2-ethoxycarbonyl-5-oxo-cyclo- -~
pentyl)-propionaldehyde were stirred for 3 hours at room tempe-
rature with 1.29 g - tO.ol37 molel of ethylene thioglycol, 0.5 ml
oi boron-trifluoro-di-etherate and 50 ml of anhydrous benzene,
diluted with 150 ml of ether and washed with ice-cold lN-NaOH - - -
and water. The mixture was dried over sodium sulfate and the
solvent was evaporated under reduced pressure. An oil was ob-
tained.
I.R. = 1740 cm 1.
EXA~LE 9 a:
7-~(1,3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1,5-
dioxaspiro -r 5.~1-dec-8-yl-carboxylic acid ethyl ester
3.35 g = ~0.0116 mole) of 3-(2-ethoxycarbonyl-5-oxocyclo-
pentyl)-propionaldehyde-ethylene-thioacetal were heated for 3 -
hours on a water separator under reflux with 2.1 g = [0.02 mole~
of 2,2-dimethyl-1,3-propane-dioI, 0.2 g of p-toluenesulfonic
acid and 50 ml of benzene. After cooling, the reaction mixture
was diluted with ether, washed with ice-cold 2N-sodium carbonate
29 -
- : ~, . . . . . .

104200;~
solution, dried over Na2S04 and concentrated. From the oil that
had formed, there was obtained an analytically pure product by
chromatography on silica gel and elution with cyclohexane/ethyl
acetate in a ratio of 95:5.
N.M.R. 4.2 ppm (c)-quartett 2H
3,5 ppm singulett 4H.
EXA~LE 9 b:
In a manner analogous to that described above, there was
obtained with ethylene glycol the 6-[(1,3-dithia-2-cyclopentyl)-
ethyl]-1,4-dioxaspiro-14,4]-none-7-yl-carboxylic acid ethyl ester.
N.M.R. 3.8 - 45 ppm singulett + multiplett 7H
3.2 ppm singulett 4H.
EXAMPLE 10:
7-~(1,3-dithia-2-cyclopentyl)-ethyl] 3,3-dimethyl-1,5-di-
oxaspiro ~[5,41-dec-8-yl-aldehyde
1.3 g = [3.5 mmoles] of 7-[(1,3-dithia-2-cyclopentyl)-ethyl]-
3,3-dimethyl-1,5-dioxaspiron-15,4]-dec-8-yl-carboxylic acid ethyl
ester were dissolved in 50 ml of absolute toluene, then 0.7 ml z
3.85 mmoles] of di-isobutyl-aluminium-hydride in 10 ml of ab~
solute toluene were added dropwise within 20 minutes at -70 C
and the whole was stirred for 2 hours at -70 C. 1 ml of methanol
and 0.5 ml of glacial acetic acid were added dropwise, then
20 ml of water were added and finally 50 ml of diethyl ether were
added~ The turbid solution was filtered through a clarifying fil-
ter and the re~idue was washed with ether. The ether phase was
washed with a solution of sodium bicarbonate, dried and concen-
trated under reduced pressure. The oil that had formed showed
the following spectral data: -
- 30 -
.. . . .
,
- , - - , :
.
: . ~
......
~,..,.. ~ .

~04Z003
N.M,R. 9.35 ppm dublett lH
4.4 ppm triplett 1 H
3.5 ppm singulett 4 H
3.2 ppm singulett 4H
EXA~LE 11 a:
1-~4-l(1,3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1,5-
dioxaspiro-~5,41-dec-8-yll-trans-1-octene-3-one
0~1 g a ~3.3 mmolesl of 80% sodium hydride ~ere stirred
for 15 minutes at room temperature in 25 ml of glycol-dimethyl
ether and then 0.89 g = [4 mmoles] of dimethyl-2-oxo-hept~l-
phosphonate were added dropwise. After a 25 minutes' stirring,
a white emulsion had formed. To this emulsion, a solution of
1.06 g =~3.2 mmoles] o~ 7-[1,3-dithia-2-cyclopentyl)-ethyl]- -
3,3-dimethyl-1,5-dioxaspiro~5,4~-dec-8-yl-aldehyde was added
dropwise and the whole was stirred for 2 1/2 hours at roorn tem-
perature. After this t~me, the solution was only weakly turbid.
Some drops o~ glacial acetic acld and 2 spatula points of char-
coal were added and the whole was filtered. The filtrate was
concentrated under reduced pressure, whereupon a light oil was
obtained. Chromatography on silica gel and elution with cyclo-
hexane/ethyl acetate 95:5 and 90:10 yielded the analytically
pure sample.
N.M.R. 5.8 - 6.8 ppm multiplett 2 H
4.4 ppm triplett 1 H
3.5 ppm singulett 4 H
- 3.2 ppm singulett 4 H
- 31 -
,: . - - -:

1042003
EXAMPL~ 11 b:
In analogous manner, there was prepared by the reaction with
dimethyl-2-oxo-nonylphosphate, the 1-~7-~1,3-dithia-2-cyclopentyl)-
3,3-dimethyl-1,5-dioxaspiro~5,4~-dec-8-yl~-trans-1-decene-3-one.
EXAMPLE 11 c:
In analogous manner, there was prepared by the reaction with
dimethyl-2-cyclohexyl-2-oxo-ethyl-phosphonate, the 1-~7-~1,3-di-
thia-2-cyclopentyl)-ethy ~ -3,3-dimethyl-1,5-dioxaspiro~5, ~ -dec-
8-y ~-3-cyclohexyl-trans-1-propene-3-one.
EXAMPLE 11 d:
In analogous manner, there was prepared by the reaction with
dlmethyl-2-(1,1-dimethyl-3-oxa~pentyl)-2-oxopentyl-phosphonate,
~he 1-~7-~ 1,3-dlthia-2-cyclopentyl)-ethyl7-3,3-dimethyl-1,5-
dioxaspiro~5,4~dec-8-yl~-3-(1,1-dimethyl-3-ox~-pentyl)-trans-1-
propene-3-one.
EXAMPLE 11 e:
In analogous manner, there was prepared by the reaction with
dimethyl-2-cycloheptyl-2-oxo-ethyl-phosphonate, the 1-~7-~ 1,3-
dithia-2-cyclopentyl)-ethyl~-3,3-dimethyl-1,5-dioxaspiror5,4~-
dec-8-y ~-3-cycloheptyl-trans-1-propene-3-one.
N.M.R. 5.8 - 6.8 ppm multiplett 2 H
EXAMPLE 11 r:
In analogous manner, there was prepared ~y the reaction with
dimethyl-2-oxo-pent ylphosphonate~ the 1-~7-(1,3-dithia-2-cyclo-
pentyl)-ethyl~-3,3-dimethyl-1,5-dioxasplro~5, ~ -dec-8-yl~-trans-
1 hexene-3-one.
N.M.R. 5,8 - 6,8 ppm multiplett 2 H
EXAMPLE 11 g:
In analogus manner, there was prepared by the reaction with
- 32 -
-' ,; '' '' ' '
,
: ,, ~ .

03
dlmethyl-2~ ethyl-l-~p-(p-chloro-phenoxy)-phenoxy~ -methy ~ -
2-oxo-ethyl-phosphonate, the 1-/6-/(~,3-dithia-2-cyclope ~yl)-
ethyl7-1,4-dioxaspiro~4,4~none-7-y 17 -3 -~1 -methyl-l-~p-(p-chloro-
phenoxy)-phenoxy7methyl7-trans-1-propene-3-one.
N.M.R. 6.3 - 7.4 ppm multlplett 10 H
4.5 ppm (c) " 1 H
3.9 ~m singulett 4 H
3.15 ppm singulett 4 H
EXAMP1E 11 h:
In analogous manner, there was prepared by the reaction with ~-
dimethyl-2-~1,1-dimethyl-1-~p-(p-chlorophenoxy)-phenox ~ -methyl~- -
2-oxo-ethyl-phosphonate, the 1-~6-~ 1,3-dithia-2-cyclopentyl)-
ethyl~-1,4-dioxaspiron~ , ~ none-7-yl~-3-~1,1-dimethyl-1-~p-~p-
chlorcphenoxy)-phenoxy7-methy ~ -trans-1-propene-3-one.
N.M.R. 6.8 7.4 ppm multiplett 10 H
4.5 ppm " 1 H
3.9 ppm singulett 4 H
3.15 ppm singulett 4 H
EXAMPLE 11 i:
In analogous manner, there was prepared by the reaction with
dimethyl-2-phenoxymethyl-2-oxo-ethyl-phosphonate, the 1-~6-/(1,3-
dithia-2-cyclopentyl)-ethy ~ -1,4-dioxaspiro~ , ~ none-7-yl7-3-
phenoxymethyl~trans-l-propene-3-one.
~.M.R. 6.8 - 7.5 ppm multiplett 5H
EXAMPLE 11 J:
In analoguus manner, there was prepare~ by the reaction with
dimethyl-2-(4-fluorophenoxy)~methyl-2-oxo-ethyl-phosphonate, the
1-~ -~ 1,3-dithla-2-cyclopentyl)-ethyl7-1,4-d~o~spiro~ , ~ -none-
7-y ~ 3-(4-fluorophenoxy)-methyl-trans-1-propene-3-one.
- 3~ -
.
- .
- , . ~, . . .
, - - :. - . :, - . :

104Z003
N.M.R. 6.9 - 7.3 ppm multiplett 4 H
EXAMPLE 11 k:
In analogous manner, there was prepared by the reaction with
dlmethyl-2-(3-chlorophenoxy)-methyl-2-oxo-ethylphosphonate, the
~ 1,3-dithia-2-cyclopentyl)-ethy ~-1,4-dioxaspiro r , ~-none-
7-yl7-3-(3-chlorophenoxy)-methyl-trans-1-propene-3-one.
N.M.R. 6.7 - 7.5 ppm multiplett 4 H
EXAMPLE 11 1:
In analogous manner, there was prepared by the reactlon with
dimethyl-2-(3-trifluoromethyl-phenoxy)-methyl-2-oxo-ethyl-phos-
phonate, the 1-~ -~ 1,3-dithia-2-cYClopentYl)-ethyl7-1,4-d~.oxa-
spiro~4,47-none-7-yl7-3-(3-trifluoromethylphenoxy)methyl-1-trans-
l-propene-3-one.
N.M.R. 7.0 - 7.6 ppm multiplett 4 H
EXAMPLE 11 m:
In analogus n~anner, there was prepared by the reaction with
dimethyl-2-isobutyl-2-oxo-ethyl-phosphonate, the 1-~ -~ 1,3-di-
thia-2-cyclopentyl)-ethyl7-1,4-dioxaspiro~4, ~ none-7-y ~ -3-iso-
butyl-trans-l-propene-3-one.
N.M.R. 5.9 - 7 ppm multiplett 2 H
4.5 ppm multiplett 1 H
3.95 ppm singulett 4 H
3.2 ppm singulett 4 H
EXAMPLE 11 n:
- In analoguus manner, there was prepared ~y the reaction with
dimethyl-2-(1,1-dimethylpentyl)-2-oxo-ethyl-phosphonate, the
1-/6-~ 1,3-dithia-2-cyclope~nyl)-ethy ~ -1,4~-dio~aspiro~ ,47none-
7-y~7-3-(1,1-dimethylpentyl)-trans-l~propene-3-one.
34
.
-

" -` 104Z003
EXAMPLE 12 a:
1-/7-/(1,3-dlthla-2-cyclopentyl)-ethyl~-3,3-dimethyl-1,5-
dioxaspiro~5,47-dec-8-yl7-trans-1-Oc tene-3~01 _ __
0.12 g of NaBH4 /3.2 mmole ~ were dissolved in 1 ml o~ H20 +
10 ml Or CH30H, cooled to 0 C and 1.28 g (3 mmoles) of 1-~7-~ 1,3-
dithia-2-cyclopentyl)-ethy ~ -3,3-dimethyl-1,5-dioxaspiron~5,4~- ` -
dec-8-yl7-trall~l-octene-3-one in 15 ml o~ methanol were added
dropwise; the whole was stirred ror 1 hour at room temperature.
The solution was neutralized with glacial acetic ac1d, concen-
trated under reduced pressure and the residue was dissolved in
diethyl ether and washed with water. Arter removal of the ether
by evaporation, an oil remained which showed the following spectral
data:
I.R. 3500 cm 1; no carbonyl band
N.M.R. 5.3 - 5.7 ppm multiplett 2 H
EXAMPLE 12 b:
In analogous manner there was prepared from 1 r7-~ 1,3-di-
thia-2-cyclopentyl)-ethy~7-3,3-dimethyl-lJ5-dioxaspiro~ ,4J-dec-
8-y ~ -trans-1-decene-3-one, the 1-~7- ~ 1,3-dithia-2-cyclopentyl)-
ethy~ -3,3-dimethyl-1,5-dloxaspiro~5,4~dec-8-y ~-trans-l-decene-
3-ol.
I.R. 3500 cm 1
N.M.R. 5.3 - 5.7 ppm multlplett 2 H
EXAMPLE 12 c:
Analogously, from 1- ~-~1,3-dithla-2-cyclopentyl)-ethY ~ -
3,3-dlmethyl-1,5-dioxasplro~5,4~-dec-8~yjl~-3-cyclohexyl-trans-1-
propenone-5-one, the 1-~7-~ 1,3-dithia-2-cyclopentyl)-et~v ~ -3,3-
dimethyl-1,5-dioxaspiro~ ,~-dec-8-y ~ -3-cyclohexyl-trans-1-pro-
- pene -3 - ol.
- 35 -
- ,
- - :, , . .- - ~. ,, . . -

lQ4Z003
I.R. 3500 cm
N.M.R. 5.3 - 5.7 ppm multiplett 2 H
EXAMPLE 12 d:
from
1-/7-~ 1,3-dithia-2-cyclopentyl)-ethyl~ -3,3-dimethy1-1,5-dioxa-
spiro~5,4~-dec-8-y~ -3-(1,1-dimethyl-3-oxapentyl)-trans-1-propene-
3-one,
the 1-~7-~ 1,3-dlthla-2-cyclopentyl)-ethyl7-3,3-dimethyl-1,5-dioxa-
splro~ , ~ -dec-8-yl7-3-(1,1-dimethyl-3-oxapentyl)-trans-1-propene-
3-ol.
--1
I.R. 3500 cm
N.M.R. 5.3 - 5.7 ppm multiplett 2 H
EXAMPLE 12 e:
rrom
1-~7-~ 1,3-dithia-2-cyclopentyl)-ethy ~ -3,3-dimethyl-1,5-di~a-
spiro~5,4J-dec-8-y ~-3-cycloheptyl-trans-1-propene-3-one,
the 1-~7-~ lJ3-dithia-2-cyclopentyl)-ethy~7-3,3-dimethyl-1,5-di-
oxaspiro~5,47-dec-8-yl7-3-cycloheptyl-trans-1-propene-3-ol.
I.R. 3500 cm 1
N.M.R. 5.3 - 5.7 ppm multiplett 2 H
EXAMPLE 12 f:
In a manner analogous to that described in Example 12 a, there
was prepared from 1-~7-~ 1,3-dlthia-2-cyclopentyl)-ethyl~-3,3-
dimethyl-1,5-dioxaspiro~5, ~ -dec-8-yl7-trans^l-hexene-3-one,
the 1-~7-~ 1,3-dithia-2-c~clopentyl)-ethy ~-3,3-dimethyl-1,5-di-
oxaspiro~5,~7-dec-8-yl7-trans-1-hexene-3-ol.
I.R. 3500 cm 1
N.M.R. 5.3 - 5.7 ppm multiplett 2 H
- 3 6 -
.
;:
:
. . .
-
.

104'~0l;);~
EXAMPLE 12 g:
In a manner ana]o~ous to that descrlbed in Example 12 aJ
there was prepared from 1~ 1,3-dithia-2-cyclopentyl)-ethy ~ -
1,4-dioxaspiro~4,4~-none-7-y~7-3-~1-methyl-1-~p-(p-chlorophenoxy)-
phenoxy~methyl7-trans-1-propene -3-one,
the l-r6-~ 1,3-dithia-2-cyclopentyl)-ethy ~ -1,4-i~oxaspiro~r4, ~ -
none-7-yl~-3~1-methyl-1-~p-(p- chlorophenoxy)-phenox ~ methy ~ -
trans-l-propene-3-ol.
I.R. 3500 cm 1
N.M.R. 5.3 - 5.7 ppm multiplett 2 H
EXAMPLE 12 h:
In a manner analogous to that described in Example 12 aJ
there was prepared from 1-~6-~ 1,3-dithia-2-cyclopentyl)-ethY ~ -
1,4-dioxaspiro~4, ~ -none-7-y~ -3-~1,1-dimethyl-1-~p-(p-chloro-
phenoxy)-phenoxy~-methyl7-trans-1-propene-3-one,
the 1-~ -~(1,3-dithia 2-cyclopentyl)-ethy ~ -1,4-dioxaspiro~ ~4~-
none-7-y ~-3-~ ,1-dimethyl-1-~p-(p-chlorophenoxy)-phenoxy~-methy~7-
trans-l-propene-3-ol.
I.R. 3500 cm 1
N.M.R. 5.3 - 5.7 ppm multiplett 2 H
EXAMPLE 12 i:
In a manner analogous to that descrlbed in Example 12 aJ
there was prepared from 1-~ -~ 1,3-dlthia-2-cyclopentyl)-ethy ~ -
1,4-dloxaspiro~4,4~-none-7-y ~ -3-phenoxymethyl-trans-1-propene-
3-one,
thej~ 6-~ 1,3-dithia-2-cyclopentyl)-ethy ~-1,4-dioxaspiro/4,4~ -
none-7-y ~-3-phenoxymethyl-1-trans-propene-3-ol.
I.R. 3500 cm 1
N.M.R. 5.3 - 5.7 ppm multiplett 2 H
- 37 -

~04Z003
EXAMPLE 12 ~
In a manner analogous to that described in Example 12 a,
there was prepared from 1-~6-~(1,3-dithia-2-cyclopentyl)-ethy ~ -
1,4-dioxaspiro~4,4~-none-7-y ~-3-(-4-fluorophenoxy)-methyl-trans-
l-propene-3-one,
the 1-~6-~ 1,3-dlthia-2-cyclopentyl)-ethy~ -1,4-dioxasplro/4, ~ -
none-7-yl7-3-(4-fluorophenoxy)-methyl-trans-1-propene-3-ol.
I.R. 3500 cm 1
N.M.R. 5.3 - 5.7 multiplett 2 H
EXAMP~E 12 k:
In a manner analogous to that described in Example 12 a,
there was prepared from 1-~ - ~ 1,3-dithia-2-cyclopentY17-ethY17-
1,4-dioxaspiro~ J4~-none-7-y~ -3-(3-chlorophenoxy)-methy~ -trans-
l-propene-3-one,
the 1-~6-~ 1,3-dithia-2-cyclopentyl)-ethy ~-1,4-dioxaspiro~ , y -
none-7-yl~-3 f3-chlorophenoxy)-methy ~ -trans-1-propene-3-ol.
; I.R. 3500 cm 1
N.M.R. 5.3 - 5.7 ppm multiplett 2 H
EXAMPLE 12 1:
In a manner analogous to that described in Example 12 a,
there was prepared from 1-~6-~ 1,3-dithia-2-cyclopentyl)-ethy ~ -
1,4-dioxaspiro~ ,4~-none-7-y ~-3~(3-trlfluoromethylphenoxy)-methyl -
trans-l-propene-3-one,
the 1-~6-~ 1,3-dithia-2-cyclopentyl)-ethyl7-1,4-dioxaspiro/~, ~ -
none-7-y ~-3-(3-trifluoromethylphenoxy)-methyl-trans-1-propene-
3-ol.
I.R. 3500 cm 1
N.M.R 5.3 - 5.7 ppm multiplett 2 H
- 38 -
,, ,

~04'~003
EXAMPLE 12 m:
In a manner analogous to that described in Example 12 a,
there was prepared from 1~ -dithia-2-cyclopentyl)-ethy ~ -
1,4-dioxaspiro/4,47-none-7-y ~ -3-isobutyl-trans-1-propene-3-one,
the 1-~ -~ 1,3-dithia-2-cyclopenty~-ethyl7-lJ4-dioxaspiro~4,4~-
none-7-y~ -3-isobutyl-trans-1-propene-3-ol.
I.R. 3500 cm 1
~.M.R. multiplett 2 H
EXAMPLE 12 n:
In a manner analogous to that described in Example 12 a,
there was prepared from 1-~6~ lJ3-dithia-2-cyclopentyl)-ethy ~ -
1,4-dioxaspiro~ ~47-none-7-y ~ -3-(1,1-dimethylpentyl)-trans-1- -~-
propene-3-one,
the l-f6-~ 1,3-dithia-2-cyclopentyl)-ethy ~ -1,4-dioxasplro/4,4~-
none-7-yl7-3-(l,l;dimethylpentyl~-trans-1-propene-3-ol.
I.R. 3500 cm -
N.M.R. 5.3 - 5.7 ppm multiplett 2 H
EXAMPLE 13 a:
1-~7-~ 1,:3-Dithia-2-cyclopentyll,7-3,3-dimethyl-1,,5-dioxaspiro-
5,47-dec-8-yl7-trans-1-octene-3-ol-tetrahydro~yranyl ether.
1.1 g ~2.5 mmole ~ o~ 7-~ 1,3-dithia-2-cyclopentyl)-ethyl~-
3,3-dimethyl-1,5-dioxaspiro~5,4~-dec-8-ylJ7-trans-1-octene-3-ol
were dissolved ln 20 ml Or absolute ether, 20 mg of p-toluene-
sulfonic acid were added, 1.2 ml ~13 mmole ~ of dihydropyrane
in 10 ml Or absolute ether were added dropwise and the whole was
stirred for 4 hours at room temperature. 0.2 ml Or dihydropyrane
were again added. The reactlon mixture was allowed to stand over-
night and was then stirred for 30 minutes with 0.5 g of solid
- 39 -
-: : .
~ . ;~ - :
~'. ~ :,. : . ;

104Z003
Na2CO3. The suspension was ~iltered, the filtrate was concentrated
under reduced pressure and the oil that had formed was eluted
with cyclohexane-ethyl acetate (9:1) over a silica gel column.
In the infrared spectrum, the analytically pure sample showed
no OH-band at 3500 cm 1.
Thin-layer chromatography R~ = o.64 on silica gel in cyclo-
hexane/ether 4 : 6,
N.M.R. 4.5 - 4.8 ppm multiplett 2 H
In analogous manner, there were prepared from the above-des-
cribed alcohols the following tetrahydropyranyl ethers:
EXAMPLE 13 b:
1- ~-~ 1,3-Dithia-2-cyclopentyl)-ethyl7-3,3-dimethyl-1,5-dioxa-
spiro~5,4~-dec-8-yl7-trans-1-decene-3-ol-tetrahydropyranyl ether.
N.M.R. 4.5 - 4.8 pp~ multiplett 2 H.
EXAMPLE 13 c:
1-~7~1,3-Dithia-2-cyclopentyl)-ethyl7-3,3-dimethyl-1,5-dioxa-
spiro~5,4~-dec-8-yl~-3-cyclohexyl-trans~l-propene-3-ol-tetrahydro-
pyranyl ether.
N.M.R. 4.5 - 4.8 ppm multiplett 2 H
EXAMPLE 13 d:
1-~7-~ 1,3-Dithia-2-cyclopel~tyl)-ethyl7-3,3-dimethyl-1,5-diox~-
spiro~,4~-dec-8-yl~-3-(1,1-dimethyl-3-oxapentyl)-trans-1-properle-
3-ol-tetrahydropyranyl ether.
N.M.R. 4.5 - 4.8 ppm multiplett 2 H
EXAMPLE 13 e:
1-~7-~ 1,3-Dithia-2-cyclopentyl)-ethyl~-3,3-dimethyl-1,5-dioxa-
spiro~5,47-dec-8-y ~ -3-c~clopentyl-trans-1-propene-3-ol-tetra-
hydropyranyl ether.
N.M.R. 4.5 - 4.8 ppm multiplett 2 H.
- 40 -
.
, -: , . .~ . . , ;
. ~ ' ' '
. ' " . .
.

104Z003
EXAMPLE 13 f:
1-~7-/(1,3-Dithia-2-cyclopentyl)-ethyl7-3,3-dimethyl-1,5-
dioxasplro~5,4~-dec-8-yl~-trans-1-hexene-3-ol-tetrahydropyranyl
ether.
N.M.R. 4.5 - 4.8 ppm multiplett 2 H
EXAMPLE 13 g:
From 1-~ -~ 1~3-dithia-2-cyclopentyl)-ethY17-1,4-dioxaspiro-
~4,47-none-7-yl7-3-~1-methyl-1-~p-(p-chlorophenoxy)-phenox ~ -
methyl~-trans-l-propene-3-ol,
the 1-~ -~ 1,3-dithia-2-cyclopentyl)-ethYl~-1>4-dioXaspiro~ ,4~- -
none-7-y~7-3-~1-methyl-1-r~-(p-chlorophenoxy)-phenoxy7-methy~7-
trans-l-p~opene-3-ol-tetrahydropyranyl ether.
N.M.R. 4.1 - 5.0 ppm broad multiplett ~ H
EXAMPLE 1~ h:
From the alcohol of Example 12 h, there was obtained in a
manner analogous to that of Example 13 a
the 1-~6-~ 1,3~dithia-2-cyclopentyl)-ethy ~ -1,4~d~oxaspiro/4,4~ -
none-7-yl~-3-~rl,l-dimethyl-1-~p-(p-chlorophenoxy)-phenox ~ -methyl~-
trans-l-propene-3-ol-tetrahydropyranyl ether.
N.M.R. 4.5 - 4.8 ppm multiplett 2 H.
EXAMPLE 13 i:
From the alcohol Or Example 12 i, there was prepared ln a
manner analogous to that of Example 13 a
the 1-~ 1,3-dithia-2-cyclopentyl)-ethyl~-1,4-dioxaspiro-~ ,4~ -
none-7-y ~ -~-phenoxymethyl-trans-1-propene-3-ol-tetrahydropyranyl
ether.
N.M~R. 4.5 - 4.8 ppm multiplett 2 H
EXAMPLE 13 J:
From the alcohol of Example 12 ~, there was prepared in a
- 41 -
':.' ' ' , ~ ; : ,.
, . :: . .

`` ~042003
manner analogous to that of Example 13 a,
the l-r6~ 1,3-dithia-2-cyclopentyl~-ethyl~ -1,4-dioxaspiro~ ,4~-
none-7-y ~-3-(4-fluorophenoxy)-methyl-trans-1-propene-3-ol-
tetrahydropyranyl ether.
N.M.R. 4.5 - 4.8 ppm multiplett 2 H
EXAMPLE 1~ k:
From the alcohol of Example 12 k, there was prepared in a
manner analogous to that of Example 13 a,
the 1- ~ -~ -dithia-2-cyclopentYl)-ethyl7-1,4-dioxaspiro~4,4J-
none-7-y~ -3-(3-chlorophenoxy)-methyl7-trans-1-propene-3-ol-
tetrahydropyranyl ether.
N.M.R. 4.5 - 4.8 ppm multiplett 2 H
EXAMPLE 1~ 1:
From the alcohol of Example 12 1, there was prepared in a
manner analogous to that of Example 13 a,
the 1- ~ - ~ 1,3-dithia-2-cyclopentyl)-ethy ~ -1 J 4-dioxaspiro~ ,4~ -
none-7-yl7-3-lsobutyl-trans-1-propene-~~ol-tetrahydropyranyl ether.
N.M.R. 4.5 - 4.8 ppm multiplett 2 H.
EXAMPLE 13 m:
From the alcohol of Example 12 m, there was obtained in a
manner analogous to that of Example 13 a,
the 1~ 1,3-dithia-2-cyclopentyl)-ethyl7-1,4-dioxaspiro~ , ~-
none-7-y ~ -3-isobutyl-trans-1-propene-3-ol-tetrahydropyranyl ether.
N.M.R. 4.5 - 4.8 ppm multiplett 2 H.
EXAMPLE 13 n.
From the alcohol of Example 12 n, there was prepared in a
manner analogous to that of Example 13 a,
the 1- ~ -~ -dithia-2-cyclopentyl)-ethylj~-1,4-dioxaspiro/~,4~-
- 42 -
.: . ; -
- :.

104;Z003
none-7-y ~-3-(1,1-dimethylpentyl)-trans-1-propene-3-ol-tetra-
hydropyranyl ether.
N.M.R. 4.5 - 4.8 ppm multiplett 2 H
EXAMPLE 14 a:
3-~3,3-Dimethyl-8~-3-pentyl-3-tetrahydropyranyloxy-trans-1-
propenyl7-1,5-dioxaspiror ,47-dec-7-yl7-propionaldehyde
1.05 g ~2.05 mmolesJ of 1-~7-~ 1/3-dithia-2-cyclopentyl)7-
3,3-dimethyl-1,5-dioxaspiro~5,47-dec 8-yl7-trans- 1-octene-3-ol-
tetrahydropyranyl ether was stirred for 2 hours at 50 C in 100 ml
of DMF with 0.7 ml (10.3 mmoles) of methyl iodide, 1.4 g (14 moles)
Or CaCo3 and 0.4 ml o~ H20. The solution was cooled, combined with
50 ml of acetone, ~iltered with suction to remove the precipitate
and the filtrate was evaporated to dryness at 0.1 mm Hg. The re-
sidue was dissolved in ether, washed with H20, dried over MgS04
and the solvent was removed by distillation under reduced pressure.
The oily residue which was not further purified showed in the
in~rared spectrum a strong carbonyl band at
1730 cm 1.
Thin-layer chromatography R~ value 0.51 on sllica gel in
cyclohexane/ether 4 : 6.
In analogous manner, there were obtained from the thioacetals
13 b - 13 n, the following propionaldehydes of the general rormula
EXAMPLE 14 b:
3-~3,3-dimethyl-8-~3-heptyl-3-tetrahydropyranyloxy-trans-1-
propenyl~-1,5-dioxaspiro~5,4~-dec-7-y ~ -propionaldehyde.
I.R. 1730 cm 1
EXAMPLE 14 c:
3-~3,3-Dimethyl-8-~3-cyclohexyl~3 te~rahydropyranyloxy-trans-
.i
~ 43 -
. ~ , . ~: - . . .:
--. .: ' ' : . ' -

104Z003
ropeny~ dioxaspiro~5~4~-dec-7-yl7-propionaldehyde.
I.R. 1730 cm
EXAMPLE 14 d:
3-~3,3-Di~ethyl-8-~3-(1,1-dimethyl-3-oxapentyl-3- tetrahydro-
pyranyloxy-trans-l-propeny ~ -1,5-dioxaspiro~5,47-dec-7-Y17-pro-
pionaldehyde.
I.R. 1730 cm 1
EXAMPLE 14 e:
In a mannner analogous to that described in Example 14 al there
was prepared rrom the tetrahydropyranyl ether of Example 13 e,
the ~-~3,3-dimethyl-8-(3-cycloheptyl-3-tetrahydropyranyloxy-
trans-l-propenyl)-1,5-dioxaspiro~5,47-dec-7-yl7-propionaldehyde.
I.R. 1730 cm 1
EXAMPLE 14 f:
In a manner analogous to that descrihed in Example 14 a, there
was prepared from the tetrahydropyranyl ether o~ Example 13 f,
the 3-~3,3-dimethyl-8-(3- tetrahydropyranyloxy)-trans-l-hexenyl)-
1,5-dioxaspirof5 J 4J-dec-7-ylJ-propionaldehyde.
; I.R. 1730 cm 1
EXAMPLE 14 g:
In a manner analogous to that described in Example 14 a, there
was prepared ~rom the tetrahydropyranyl ether o~ Example 13 g,
the 3-~7-(3-tetrahydropyranyloxy-3-~1-methyl ~ p-(chlorophenoxy)-
phenoxy7-methyl~-trans-1 propenyl7-1,4-dloxasplro~ ,47-none-6-yl~-
propionaldehyde.
I.R. 1730 cm 1
EXAMPLE 14 h:
In a manner analogous to that described in Example 14 a, there
was prepared ~rom the tetrahydropyranyl ether o~ Example 13 h,
~,
- 44 -
:- , .

: 104Z003
the 3-~7-(3-tetrahydropyranyloxy-3 -fi,l-dimethyl-l-rp-(p-chloro-
phenoxy)-phenox~/-methyl~-trans-l-propenyl~ 4-dioxaspiro~4,4~-
none-6-yl~-propionaldehyde.
I.R. 1730 cm 1
EXAMPLE 14 i:
In a manner analogous to that described in Example 14 a, there
was prepared from the tetrahydropyranyl ether Or Example 13 i,
the 3-~7-(3-tetrahydropyranyloxy-3-phenoxymethyl-trans-1-propeny1~7
1,4-dioxaspiro/~,4~-none-6-yl~-propionaldehyde.
EXAMPLE 14 ~:
In a manner analogous to that described in Example 14 a, there
was p~epared ~rom the tetrahydropyranyl ether of Example 1~ ~,
the 3-~7-(3-tetrahydropyranyloxy-3 (4-~luorophenoxy)-n^,ethyl-trans-
l-propenyl~-1,4-dioxaspiro/4,4/-none-6-yl~ -propionaldehyde.
I.R. 1730 cm 1
EXAMPLE 14 k:
In a manner analogous to that descr~bed in Example 14 a, there
was p~epared rrom the tetrahydropyranyl ether of Example 13 k,
the 3-~7-(3-te~rahydropyranyloxy-3-(3-chlorophenoxy)-methyl-trans-
l-propenylJ-1~4-dioxaspiro~,4~none-6-yl7-propionaldehyde.
I.R. 1730 cm 1
EXAMPLE 14 1:
In a manner analogous to that described in Example 14 a, there
was prepared rrom the tetrahydropyranyl ether of Example 13 1,
the 3-~7-(3-tetrahydropyranyloxy-3-(3-trifluoromethylphenoxy)-
methyl-trans-l-propenyl7-1,4-dioxaspiro~4,1~-none-6-y ~-pro-
pionaldehyde.
I.R. 1730 cm 1
- 45 - .
- - . - - ~ ' ' . ~ ~ ' ,: . ., , ' . ' -:
.. ~ . ~ , :
: , ' ~ - ~ . , - .

lO~ZOQ3
EXAMPLE 14 m:
In a manner analogous to th~t described in Example 14 a, there
was prepared from the tetrahydropyranyl ether of Example 1~ m,
the 3-/7-(3-tetrahydropyranyloxy-~-isobutyl-trans-1-propeny ~ -1,4-
dioxaspiro~4,4~-none-6-yl~-prop1Onaldehyde.
I.R. 1730 cm 1
EXAMPLE 14 n:
In a manner analogous to that described in Example 14 a, there
was prepared from the tetrahydropyranyl ether of Example 13 n,
the 3-~7-(3-tetrahydropyranyloxy-3-(1,1-dimethylpentyl)-trans-1-
propenylJ-1,4-dioxaspiro~4,4~-none-7-y ~ -propionaldehyde.
I.R. 1730 cm
EXAMPLE 15 a:
7-~ ,3-Dimethyl-8-(3-pentyl-3-tetrahydropyranyloxy-trans-1-
propenyl~-1,5-dioxaspiro 5,47-dec-7-yl7-cls-4-heptenoic_acid
0.3 g ~-10 moles~ of 80~ sodium hydride were heated for 1 hour
under argon to 60 - 65 C in ~ ml of absolute dimethyl-sulfoxide
and then 2.15 g ~5 moles7 of 4-carboxypropyltriphenylphosphonium
bromide in 12 ml o~ DMS0 were added. The solution whose color had
change to red was stirred for 40 minutes at rocm temperature, and
then o.88 g of~2~ -dimethyl-8-~ -pentyl-3-tetrahydropyranyloxy-
trans-l-propeny ~ -1,4-dloxaspiro~-4~-dec-7-yl7-propionaldehyde
in 5 ml of DMS0 was added dropwise. The solution was stirred for
16 hours at room temperature. It was diluted at 0 C with 50 ml
of ether, ac~dified to pH 1 - 2 with 5 % NaHS04 solution, the or-
ganic phase was separated and the aqueous phase was extracted
thrice with each time 75 ml of diethyl ether. The combined ether
extracts were washed ~ith water, dried over MgS04 and concentrated
~, , .: ~ . : . ,

~042003
under reduced pressure.
The oil that had formed was chromatographed on sillca gel
and an analytically pure substance was obtained by elution with
cyclohexane/ethyl acetate in a ratio of ~ : 2.
N.M.R. 8.5 ppm broad signal 1 H
5.3 - 5.7 ppm broad signal 4 H
4.7 ppm broad signal 1 H
3.5 ppm duplett 4 H
.
EXAMPLE 15 b;
In analogous manner, there were obtalned rrom the aldehydes
Or the general ~ormula XX described in Examples 14 b - 14 nJ the
following acids: -
7-~3,3-dimethyl-8-~3-heptyl-3-tetrahydropyrany~oxy-trans-1-
propenyl7-1,5-dioxaspiror5,47-dec-7-yl~-cis-4-heptenoic acid.
N.M.R. 5.3 - 5.7 ppm broad signal 4 H
EXAMPLE 15 c:
7-f3-,3-Dimethyl-8-~3-cyclohexyl-3-tetr~hydropyranyloxy-trans-
1-propenyl_7-1,5-dioxaspiro~5,4~-dec-7-y ~ -cis-4-heptenoic acid.
N.M.R. 5.3 - 5.7 ppm broad signal ~ H
EXAMPLE 15 d,
7-~3,3-Dimethyl-8-~3-(1,1-dimethyl~3-oxa-pentyl)-3-tetrahydro-
py~anyl-oxy-trans-l-propenyI7-1,5-dioxaspiro~5 J 47-dec-7-yl7-cis-
4-heptenoic acid.
EXAMP1E 15 e:
In a manner analogous to that described in Ex~ample 15 aJ there
was obtained from the propionaldehyde of Example 14 e,
the 7-~3,3-dimethyl-8-(3-cycloheptyl-3-tetrahydropyranyloxy-trans-
~ 47 -
- . . ~ . .
.. - . . , . . .
: : ~ , , ~ :: .
. .
-: ' ', ' ' :

109~Z003
l-propenyl )-1,5-dioxaspiro~5,47-dec-7-y ~-cis-4-heptenoic acid.
N.M.R. 5.3 - 5.7 ppm broad signal 4 H
EXAMPLE 15 f:
In a manner analogous to that described in Example 15 a, there
was prepared from the propionaldehyde of Example 14 f,
the 7-~ ,3-dimethyl-8-(3-tetrahydropyranyloxy-trans-1-hexenyl)-
1,5-dioxaspiror5,4~-dec-7-ylJ-cis-4-heptenoic acid.
N.M.R. 5.~ ppm b~ad signal 4 H
EXAMPLE 15 g:
In a manner analogous to that described in Example 15 a, there
was obtained from the propionaldehyde of Example 14 g,
the 7-~7-(3-tetrahydropyranyloxy-3-~1-methyl-~p- (p-chlorophenoxy)-
phenox ~ -methyl~-trans-l-propeny ~ -1,4-dioxaspiro~4,4~-none-6-y ~ -
cis-4-heptenoic acid.
N.M.R. 5.3 - 5;7 ppm broad signal 4 H
EXAMPLE 15 h:
In a manner analogous to that described in Example 15 a, there
was obtained from the pr~pionaldehyde of Example 14 h,
the 7-~7-(3 ~etrah~dropyranyloxy-~ dimethyl-~p-~p-chloro-
phenoxy)-phenoxy~-methyl7-trans-1-propeny ~ -1,4-dioxaspiro~ ,4~-
none-6-y ~ -cis-4 heptenoic acid.
N.M.R. 5.~ - 5.7 ppm broad signal 4 H
EXAMPLE 15 i:
In a manner analogous to that described in Example 15 aj there
was prepared from the propionaldehyde of Example 14 i,
the 7-~7-(3-tetrahydropyranyloxy-3-phenoxymethyl-trans-1-propeny ~-
1,4-dioxaspiro~ ,4~ -none-6-yl7-cis-4-heptenoic acid.
N.M.R. 5.3 - 5.7 ppm broad signal 4 H
.
48 -
- . - . - . ... . . . . . . . .
.. .. . . . . .. ~ . . . ~. . - . . .

.
~04~003
EXAMPLE 15 ~: -
In a manner analogous to that described in Example 15 a, there
was prepared ~rom the propionaldehyde of Example 14 ~,
the 7-j7-(3-tetrahydropyranyloxy-3-(4-fluorop~enoxy)-methyl-trans-
l-propeny1~-1,4-dioxaspiro~4,47-none-6-ylJ-cis-4-heptenGic acid.
N.M.R. 5.3 - 5.7 ppm broad signal 4 H
EXAMPLE 15 k:
In a manner analogous to that described in Example 15 a, there
was prepared from the propionaldehyde of Example 14 k,
the 7-~7-(3-tetrahydropyranyloxy-3-(3-chlorophenoxy)-methyl-trans~
l-propenylJ-1,4-dioxaspiror4~47-none-6-yl~-cis-4-heptenoic acid.
N.M.R. 5.3 - 5.7 ppm broad signal 4 H
EXAMPLE 15 1:
In a manner analogous to that described in Example 15 a, there
was prepared from the propionaldehyde of Example 14 1,
the 7-~7 (3-tetrahydropyranyloxy-3-(3-trifluoromethylphenoxy)-
methyl^trans-l-propeny ~ -1,4-dioxaspiro~ ,47-none-6-y ~ -cis-4-
heptenoic acid.
N.M.R. 5.3 - 5.7 ppm broad signal 4 H
EXAMPLE 15 m:
In a manner analogous to that described in Example 15 a, there
was prepared from the proplonaldehyde of Example 14 m,
the 7-~7-(3- tetrahydropyranyloxy-3-isobutyl-trans-1-propenyl)-
1,4-dioxaspiro~4,4J-none-6-y ~ -cis-4-heptenoic acid.
N.M.R. 5.3 - 5.7 ppm broad si~nal 4 H
EXAMPLE 15 n:
In a manner analogou~ to that described in Example 15 a, there
was prepared rrom the propionaldehyde of Example 14 n,
- 49 -
,
.

00;~
the 7-/7-(~-tetrahydropyranyloxy-3-(1,1-dimethylpentyl-trans-1-
propenyl~-1,4-dioxaspiro~ ,47-none-7-y ~ ~cis- 4-heptenoic acid.
N.M.R. 5.3 - 5.7 ppm broad signal 4 H
EXAMPLE 16 a:
7-~2-(~-Hydroxy-~-pentyl-trans-l-propenyl)-5-oxo-cyclopenty ~ -
cis-4-heptenoic acld
0.41 g ~1 mmole~ of 7-~ ,3-dimethyl-8-(3~p~ntyl-3-tetrahydro-
pyranyloxy-trans-l-propenyl)-1,5-dioxaspiro~5,4~-dec-7-yl7-cls-
4-heptenoic acid was dissolved in 25 ml of ethyl alcohol and
stirred with 5 ml of 2% aqueous oxalic acid solution for 20 hours
at room temperature under nitrogen. The solvent was partially re-
moved by distillation under reduced pressure, the residue was com-
bined with 20 ml of a saturated NaCl solution and extracted twice
with 100 ml of diethyl ether. The combined ether extracts were
washed thrice with each time 20 ml of H20, dried and concentrated.
3~7 mg of a light oil were obtained: 7-~ ,3-dimethyl-8-
(3-pentyl-3-hydroxy-trans-1-propenyl~ -1,5-dioxaspiro~5,4~-dec-
7-yl)-cis-4-heptenoic acid.
These 337 m~ from the first stage were stirred in 30 ml of
acetone with 20 mg o~ p-toluene-sulfonic acid monohydrate for -
5 hours at 50 C under nitrogen and allowed to stand overnight
at room temperature. The mixture was then concentrated, the re-
sidue was dlssolved in ether, washed with water and concentrate~.
The residue was chromatographed on silica gel and the analytically
pure substances were obtained by elution with a solvent mixture
o~ 80 parts of cyclohexane, 20 parts of ethyl acetate and 1 part
of glacial ace~ic acid. 2 Isomers were isolated which were found
to distinguish in their Rf-values on sllica gel (Or Messrs. Merck)
- 50

0()3
in the solvent mixture cyclohexane/ethylacetate/glacial acetic
acid 80/20/1 as ~ollows:
isomer B 0.41
isomer A 0.36.
After HD exchange, the N.M.R spectrum of both isomers was
practically identical.
Before HD exchange:
5.2 - 6.o ppm broad signal 6 H
4.05 ppm broad signal 1 H
After HD exchange:
- - 5,2 - 5.4 ppm broad signal 2 H
5,5 - 5.7 ppm broad signal 2 H
4,05 ppm broad signal 1 H.
In analogous manner, there were prepared from compounds of
the general ~ormula XXI, as those described in Example 15 b - 15 n,
the following carboxylic acids o~ the general formula I, in which
Rl and R2 together represent oxygen:
EXAMPLE 16 b:
7-~2-(3-hydroxy-3-heptyl-trans-1-propenyl)-5-oxo-cyclopenty ~ -
cis-4-heptenoic acid.
N.M.R. 5.2 - 6~o ppm broad signal 6 H
EXAMPLE 16 c:
7-~2-(3-Hydroxy-3-cyclohexyl-trans-~-propenyl)-5-oxocyclo-
pentyl7-cis-4-heptenoic acid.
N.M.R. 5.2 - 6.5 ppm broad signal 6 H
EXAMPLE 16 d:
7-~2-r3-Hydroxy-3-(1,1-dimethyl-3-oxa-pentyl)-trans-1-pro-
pen$ ~ -5Oxo-cyclopenty ~ cis-4-heptenoic acid.
N.M.R. 5.2 - 6.o ppm broad signal 6 H
~-
- 51 -
, . .... . .
- . . - . ,..... . : :
-: . ' . - ~.... :

104Z00~
EXAMPLE 16 e:
In a manner analogous to that described in Example 16 a,
there was prepared rrom the heptenoic acid o~ Example 15 e,
the 7-/2-(3-hydroxy-3-cycloheptyl-trans-1-propenyl)-5-oxocyclo-
pentyl~-cis-4-heptenoic acid.
N.M.R. 5.2 - 6.2 ppm broad signal 6 H.
EXAMPLE 16 ~:
- In a manner analogous to that described in Example 16 a,
there was prepared ~rom the heptenoic acid of Example 15 e,
the 7-~2-(3-hydroxy-trans-1-hexenyl)-5-oxycyclopentyl7-cls-4
heptenoic acid.
N.M.R. 5.2 - 6.5 ppm broad signal 6 H
EXAMPLE 16 g:
In a manner analogous to th~ described in Example 16 a,
there was prepared from the heptenoic acid of Example 15 gJ ~ -
the 7-~2-(3-hydroxy-3-~1-methyl-~p-(p-chlorophenoxy)-phenox ~ -
methy ~ -trans-l-propeny ~ -5-oxocyclopentyl7~cis-4-heptenoic acid.
N.M.R. 5.2 - 6.1 ppm broad signal 6 H
EXAMPIE 16 h:
In a manner analogous to that descrlbed in Example 16 a,
there was prepared ~rom the heptenoic acid o~ Example 15 hJ
the 7-~2-r3-hydroxy-3-~lJl-dlmethyl-l-~p-(p-chlorophenoxy)-
phenoxy7-methyl7-trans-1-propenyl-5-oxocyclopenty ~ ~cls-4-hep-
- tenoic acid.
N.M.R. 5.2 - 6.o ppm broad signal
- ~ EXAMPLE 16 i:
In a manner analogous to that described in Example 16 aJ
there was prepared from the heptenoic acid o~ Example 15 i,
:
- 52 ~
- . , . : , . :
. : ,: . , ~. ~: :

10~2()03
the 7-~2 (~- hydroxy-3-phenoxymethyl-trans-1-propenyl)-5-oxo-
cyclopentyl~-cis-4-heptenoic acid.
N.M.R. 5.2 - 6.1 ppm broad signal 6 H
EXAMPLE 16 ~:
In a mannar analogous to that described in Example 16 a,
there was prepared from the heptenoic acid of Example 15 ~,
the 7-~2-~3-hydroxy-3-(4-fluorophenoxy)-methyl-trans-1-propenyl~-
5-oxocyclopentyl~-cis-4-heptenoic acid.
N.M.R. 5,2 - 6.5 ppm broad signal 6 H
EXAMPLE 16 k:
In a manner analogous to that described in Example 16 a,
there was prepared from the heptenoic acid of Example 15 k,
the 7-~2-r3-hydroxy-3-(3-chlorophenoxy)-methyl-trans-1-propenyl7-
5-oxocyclopentyl7-cis-4- heptenoic acid.
N.M.R. 5.2 - 6.o ppm broad signal 6 H
EXAMPLE 16 1:
In a manner analogo~s to that described in Example 16 a,
there was prepared from the heptenoic acid of Example 15 1,
the 7-~2-~3-hydroxy-3-(3-trifluoromethylphenoxy)-methyl-trans-1-
propeny ~ -5-oxocyclopentyl7-cis-4-heptenoic acid.
N.M.R. 5.2 - 6.3 ppm
EXAMPLE 16 m:
In a manner analogous to that described in Example 16 a,
there was prepared from the heptenoic acid o~ Example 15 m,
the 7-~2-(3-hydroxy-3-isobutyl-trans-1-propenyl)-5-oxocyclo-
pentyl7-cis-4-heptenoic acid.
N.M.R. 5.2 - 6.1 ppm broad signal
,
"~

~Q4ZO(~3
EXAMPLE 16 n:
In a manner analogous to that descrlbed in Example 16 a,
there was prepared from the heptenoic acid of Example 15 n,
the 7~ 3-hydroxy-3- (1,1-dlmethylpentyl)-trans-1-propenY17-
5-oxocyclopenty ~-cis-4-heptenoic acid.
N.M.R. 5.2 - 6.5 broad signal 6 H
EXAMPLE 17 a:
7-~2-(3-Hydroxy-3-pentyl-trans-1-propenyl)-5-hydroXy-cycle-
pentyl~-cis-4-heptenoic acid
- - :
150 mg of 7-~2-(3-hydroxy-3-pentyl-'rans-1-propenyl)-5~oxo-
cyclopenty ~ -cis-4-heptenoic acid were dissolved in 20 ml of
methanol and three times each time 150 mg of NaBH4 were added
within the course 1 1/2 hours. The reactlon solution was adJusted
to pH 7 by means of glacial acetic acid, the solvent was removed
by distillation under reduced pressure, the residue was acidified
with 2N-HCl to pH 1 and extracted thrice with 150 ml Or ether.
After washing, the organic phase was concentrated.
I.R. 3500 cm 1 -~
1720 - 1700 cm 1
In analogous mannerJ there were prepared from the carboxylic
acids of the general formula I, in which R1 and R2 together re-
present oxygen and which are described in Exampl~ 16 b - 16 d,
carboxylic acids of the general formula I, in which R1 and R2
each represent hydrogen or the hydroxyl group:
EXAMPLE 17 b:
7-~2-(3-Hydroxy-3-heptyl-trans-1-propenyl)-5-hydroxy-cyclo-
pentyl~-cis-4-heptenoic acid,
I.R. 3500 cm 1 ~ -
1720 - 1700 cm 1
- 54 -
,. . . . . -:: : ~. :.. ... .: - . : ~

lO~Z003
EXAMPLE 17 c:
7-~2-(3-Hydroxy-3-cyclohexyl-trans-1-propenyl)-5-hydroxy-
cyclopenty ~ -cis-4-heptenoic acld.
I.R. 3500 cm 1
1720 - 1700 cm 1
EXAMPLE 17 d:
7-~2-r3-Hydroxy-3-(1,1-dimethyl-3-oxa-pentyl)-trans-1-pro-
penyl7-5-hydroxy-cyclopenty ~ -cis-4-heptenoic acid.
I.R. 3500 cm 1
1720 - 1700 cm~l :
- - EXAMPLE 17 e:
7-~2-(3-Hydroxy-3-cycloheptyl-trans-1-propenyl)-5-hydroxy-
cyclopentyl7-cis-4~heptenoic acid.
I.R. 3500 cm 1
- 1720 - 1700 cm 1
EXAMPLE 17 ~: -
7-~2-(3-Hydroxy-trans-l-hexenyl)-5-hydroxy-cyclopentyl7-cis-
4-heptenoic acid.
I.R. 3500 cm 1
1720 - 1700 cm~
EXAMPLE 17 g:
7-~2-~3-Hydroxy-3-~1-methyl-~p-(p-chlorophenoxy)-phenoxyJ-
methyl~7-trans-1-propeny~ -5-hydroxy-cyclopenty ~ ~cis-4-heptenoic
acld.
I.R. 3500 cm 1
1720 - 1700 cm 1
EXAMPLE 17 h:
7-~2-~3-Hydroxy-3-~ dimethyl-1-~-(4-chlorophenoxy)-phen-
ox ~ -methyl;7-trans-1-propeny~-5-hydroxy-cyclopentyl-cis-4-
- 55 -
r.
..... . .
t

00~
heptenoic acld.
I.R. 3500 cm 1 -1
1720 - 1700 cm
EXAMPLE 17 i:
7-~2-(3-Hydroxy-3-phenoxymethyl-trans-1-propeny1)-5-hydroxy-
cyclopentyl7-cis-4-heptenoic acid.
I.R. 3500 cm 1
1720 - 1700 cm 1
EXAMPLE 17 j:
7-r2-~3-Hydroxy-3-(4-~luorophenoxy-)-methyl-trans-1-propeny ~-
5-hydroxy-cyclopenty ~ -cis-4-heptenoic acid.
I.R. 3500 cm 1
1720 - 1700 cm 1
EXAMPLE 17 k: ~ -
7-~ -~3-Hydroxy-3-(3-chlorophenoxy)-methyl-trans-1-propenyl7-
5-hydroxy-cyclopenty ~ -cis-4-heptenoic acid.
I.R. 3500 cm 1
1720 - 1700 cm 1
EXAMPLE 17 1:
.
7-~2-~ -Hydroxy-3-(3-tri~luoromethylphenoxy)-methYl-trans~l-
propenyl~-5-hydroxy-cyclopentyl7-cis-4-heptenolc acid.
I.R. 3500 cm 1
1720 - 1700 cm 1
EXAMPLE 17 m:
7-~2-~3-Hydroxy-3-isobutyl-trans-l~propeny y -5-hydroxycyclo-
pentyl~-cis-4-heptenoic acid.
I.R. 3500 cm 1
1720 - 1700 cm 1
- 56 -

1()4;~0Q3
EXAMPLE 17 n:
7-r2-~ -Hydroxy-3-hydroxy-3-(1,1-dimethylpentyl)-trans-1-
propenylJ-5-hydroxycyclopentyl~-cis-4-heptenoic acid.
I.R. 3500 cm 1
1720 - 1700 cm 1
EXAMPLE 18:
The isomer A and the isomer B of 7-~2-(3-hydroxy-3-pentyl-
trans-l-propenyl)-5-oxo-cyclopentyl~-cis-4-heptenoic acid
(Example 16 a) were mixed in a weight proportion of 1:1, dissolved
ln ethyl alcohol, diluted with distilled water and atomized at
a total volume o~ 0.02 ml per minute in an ultrasonic ato~izer. -
For testing the broncho-spasmolytic activity, the measurement
o~ the breath ~olume according to Konzett and Rossler (Arch. exp.
Path. Pharmakol 195, 71 (1940)) was used. As test animals, male
white Guinea pigs having a weight o~ 400 - 500 g were used which
had been anesthetized with 10 mg/kg i.p. of Evipan and 200 mg/kg.
i.p. o~ urethane.
As asthmogenic substance, histamine-dihydrochloride in a dose
o~ 1 - 5 ug/kg was administered. The experimental data were sub-
jected to a regression analysis and the equation of the
regression line Y = A + B 5 1 g ~X) was calculated. Therewith,
also the average inhibition dos~ (ED50) as the dose which
inhibits the asthmogenic action by 50% of it~ initial value,
could be determined.
Results
-
,
7-~2-(3-Hydroxy-3-pentyl-trans-1-propellyl)-5-oxo-cyclopen-
tyl/-cis-4-heptenoic acid
- 57 ~
:.
. .

~04Z~3 -:
Average inhibition dose - .
i.v. Aerosol
~,/kg) ~g/animal)
Isomer A ` 0 . o8 o . o
Isomer B - 0.1 0.1
Mixture A + B (1:1) 0.1 0.002
_
- -- 58 --
. ~ : - -: - - -
- , . ................... . .
... . . . .
, ~ . . :