DE3338327A1 - AMIDE DERIVATIVES OF 13,14-DIDEHYDRO-CYCLOALKYL-PROSTA-GLANDINES - Google Patents

Description

FARMITALIA CARLO ERBA S.p.Α., MILAN / ITALY

Amide derivatives of 13, ^ - didehydro-cycloalkyl-prostaglandins

The present invention relates to amides of 13,14-didehydro-cycloalkyl-prostaglandins, a process for their preparation, pharmaceutical and veterinary compositions containing them and certain Intermediate products that can be used for their manufacture.

The invention provides optically active or racemic prostaglandin derivatives of the formula (I) 10

1 ^ CHC-CC- (CH ₂ ) _n -R

characterized in that R 'and

R ″ each, independently of one another _{, denotes hydrogen, C 1} , -alkyl, aryl or a heterocycle or
R 'and R ", taken together with the nitrogen atom,
to which they are bound form a heterocyclic ring;

the symbol represents a single or double bond, where:

(a) in the event that the symbol is a double bond, R _{1 is} a hydrogen atom and R2 and R ^, taken together, form an oxo group;

(b) in the event that the symbol is a single bond, R- are hydroxy, R- are hydrogen and R- are hydroxy or acyloxy or R ₂ and R ₃ , taken together, form an oxo group;

one of the two radicals R. and R _{5 is} hydroxy and the other is hydrogen;

R ₆ and R _{7 are} each, independently of one another, hydrogen, C ₁ , -alkyl or fluorine;

η is 0, 1, 2 or 3;

Rg represents a C, _ ~ -cycloalkyl ring which is unsubstituted or is substituted by one or more substituents selected from

(a ¹ ) Halogen, (b ¹ )
(C) Trihalo-C ₁ , -alkyl, (d ')
(e ¹ ) C _1-4 -AIkOXy,
Phenyl and (f) Phenoxy

are selected;

as well as the pharmaceutically or veterinarily acceptable salts thereof.
30th

The compounds and salts of the present invention have the advantage that they can be administered orally have greater activity than related compounds previously disclosed, in particular those specifically disclosed in British Application No. 2,009,145A. This greater activity is made possible by their better gastrointestinal absorption.

The formula set out above for the compounds which are covered by this invention includes all possible isomers, in particular stereoisomers, as well as mixtures thereof, for example mixtures of epimers. The double bond in 5 (6) is a cis double bond. In the formulas of this invention, dashed lines (mnmm) indicate that the substituents are in the ot configuration, that is, below the plane of the ring or a side chain.

Wedges («*« *) indicate that the substituents in the ß-configuration, i.e. above the level of the ring or a side chain. Wavy lines (i> ) indicate that the substituents, in the event that the carbon atom to which they are attached, are asymmetrical is, either in the c6 or ß configuration, or in the (<? O, ß) configuration, that's a mixture of two epimers, may be present. For example, the hydroxy group attached to the carbon atom bound in position 15 in the configuration fo6), (ß) and (o6, ß), i.e. a mixture of the 15fod.) - and 15 (β) epimers are present. If the carbon atom

has two different substituents in position 16, can these just as 1 6 bO), 16 (ß) and 16 (ok, ß), i.e. a mixture of the two 16 (cM and 16 (β) epimers, be. The symbol S or R of a respective chiral center is assigned according to the sequence rule, which arranges the ligands according to decreasing atomic number.

The alkyl, alkoxy and trihaloalkyl groups can be straight-chain or branched.

A halogen atom is preferably fluorine, chlorine or bromine. When either or both of R ¹ and R "are C 1-4 alkyl, they are preferably methyl, ethyl, propyl, or butyl.

When either or both of R ¹ and R "are aryl, they are preferably phenyl. When either or both of R ¹ and R" are heterocyclic, the heterocyclic group is preferably selected from pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, piperidyl, Piperazinyl, morpholinyl and pyrazolidinyl.

When R ¹ and R ″, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring, the heterocyclic ring is preferably selected from: pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, piperidino, piperazinyl, morpholino and pyrazolidinyl. As individual heterocyclic groups, R ¹ and R ″ can also be piperidino

or be morpholino.

When R_ is acyloxy, it is preferably a benzoyloxy group or a C ~ _ _g alkanoyloxy, for example acetoxy or propionyloxy.

When one or both of R 1 and R are C.. -Alkyl, they are preferably methyl or ethyl.

When R _{g represents} a C 1-4 cycloalkyl group substituted as desired as described in items (a ¹ ) to (f) above, R "is preferably a group selected from cyclopentyl, cyclohexyl and cycloheptyl.

Preferred compounds of the invention are compounds of formula (I), wherein

R ^f and R ", independently of one another, are hydrogen or C. -Alkyl; or R ¹ and R", taken together with the nitrogen atom to which they are attached, represent a pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl , Form piperidine, piperazinyl or morpholine ring;
'

the symbol ------ is a single bond, R. Hydroxy

is, R "is hydrogen and R_ is hydroxy or acyloxy or R ₂ and R ₃ , taken together, form an oxo group; · R _{0 represents} a radical which is derived from cyclopentyl, ο

Cyclohexyl and cycloheptyl is selected, each unsubstituted or by one or more (a ¹ )

Halogen, (b ¹ ) trihalo-C _1-4 ^{alkyl, (c 1} ) C 1-4 (d ') C _1-4 alkOXy, (e ¹ ) phenyl, (f) phenoxy are substituted; R ₄ , R ₅ , R _g , R ₇ and η have the meanings given above;
5

as well as the pharmaceutically or veterinarily acceptable salts thereof.

Particularly preferred compounds of the invention are the compounds of the formula (I), wherein

R ¹ and R "are independently hydrogen or methyl; or R ¹ and R", taken together with the nitrogen atom to which they are attached, form a piperidine or morpholine ring;

the symbol ^^ 2. ^{is a} single bond, R _{1 is} hydroxy, R _{2 is} hydrogen and R_ is hydroxy or R- and R_, taken together, form an oxo group; 20th

R _r and R- ,, independently of one another, each water /

represent substance, methyl or fluorine;

R., R ₅ and η have the meanings given above; R “is cyclopentyl or cyclohexyl;

as well as the pharmaceutically or veterinarily acceptable salts thereof.

As stated above, this invention also covers pharmaceutically or veterinarily acceptable salts

of these connections.

Examples of particularly preferred salts of the compounds of the formula (I) include acid addition salts with inorganic acids, e.g. nitric, hydrogen chloride, hydrogen bromide, hydrogen iodide, Sulfuric, perchloric and phosphoric acid, or with organic acids, e.g. acetic, propionic, glycolic, Milk, oxal, malon, apple, malein, wine, lemon, Benzoic, furaar, cinnamon, almond, salicylic acid, as well as with organic sulfonic acids, e.g. methanesulf on-, p-toluenesulphonic and cyclohexylsulphonic acid, a.

OOOO

Examples of preferred compounds according to the invention are:

5ο-9 <* ν 1 λΦ, 15 (S) -Trihydroxy-20-nor-19-cyclohexylprost-5-en-13-yne acid amide,

5c-9 ^, 1 λ <ρ, 15 (S) -Trihydroxy-20-nor-1 9-cyclopentylprost-5-en-13-yn acid amide,

5c-9 oO, 11oO, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-1 3-yn acid amide,

50-90 ^ / 11 ^ 15 (R, S) -Trihydroxy-1 6 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yne-acid amide,

5c-9ot, 11 ₀ 0.15 (S) -trihydroxy-1 9,20-dinor-1 8-cyclohexyl-prost-5-en-13-yn-acid amide, 20

5c-9ot /, 1 loU 15 (S) -Trihydroxy-1 9, 20-dinor-1 8-cyclopentyl-prost-5-en-13-yne-acid amide,

5c-9oL ·, 11o6-, 15 (R) -Trihydroxy-1 6 (S) -fluor-1 9, 20-dinor-1e-cyclohexyl-prost-S-en-i3-yne-acid amide,

5c-9c £, 11 ₀ C, 1 5 (R, S) -Trihydroxy-1 6 (R) -f luor-20-nor-1g-cyclohexyl-prost-S-en-i3-yne acid amide,

5c-9ot, 1 lot, 15 (S) -Trihydroxy-18,1 9,20-trinor-i 7-cyclohexyl-prost-5-en-i3-yne-acid amide,

5c-9oLr 1 lot, 1 5 (S) -Trihydroxy-1 8, 1 9, 20-trinor-1 7-cyclopentyl-prost-5-en-i3-yne-acid amide,

5c-9d, 11οί ', 1 5 (R) -Trihydroxy-1 6 (S) -fluoro-1 8,19,20-trinor-IT-cyclohexyl-prost-S-en-i3-yne-acid amide,

0 5c-9oL, 1 lot, 15 (R, S) -Trihydroxy-1 6 (S) -fluoro-1 8,19,20-

trinor-17-cyclohexyl-prost-S-en-i3-yne-acid amide,

5c-9oL, 11eL, 15 (R) -Trihydroxy-1 6 (S) -f luor-1 8,19,20-trinor-17-cyclopentyl-prost-S-en-i3-yne-acid amide, 15th

5c-9oL, 11eL, 15 (R, S) -Trihydroxy-16 (S) -f luor-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-yne-acid amide,

5c-9oL, 11cL, 15 (S) -Trihydroxy-17, 18,19, 20-tetranor-16-cyclohexyl-prost-5-en-13-yne acid amide,

5c-9oC, 1 lot, 15 (S) -trihydroxy-1 7,18,19, 20-tetranor-1 6-cyclopentyl-prost-5-en-13-yne acid amide,

5c-9oL, 1 lot, 1 5 (R) -Trihydroxy-1 6 (S) -f luor-1 7, 18,1 9,20-tetranor-1S-cyclohexyl-prost-S-en-i3-in- acid amide,

5c-9oL, 1 U, 15 (R, S) -Trihydroxy-1 6 (S) -f luor-1 7,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-in- acid amide, 30th

5c-9oi., 11 ₀ U 1 5 (R) -Trihydroxy-1 6 (S) -f luoro-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13- insäureamid,

ν ν

₇ 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yne-acid amide,

5c-9oC, 11dL, 15 (R) -trihydroxy-1 6 (R) -f luoro-1 6-methy1 18.1 9.20-trinor-iT-cyclohexyl-prost-S-en-i3-insäureamid,

5c-9eC, 110L, 15 (S) -Trihydroxy-20-nor-1 9-cyclohexylprost-S-en-IS-in-acid-NjN-dimethylairiid,

5c-9oL, 110L, 15 (S) -trihydroxy-20-nor-i 9-cyclopentyl prost-5-en-13-yn-acid-N, N-dimethylamide,

5c-9oL, 11oL, 15 (R) -trihydroxy-16 (S) -f luor-20-norig-cy
amide,

5c-9oC, 1 lol, 15 (R, S) -Trihydroxy-16 (S) -f luor-20-nor-1g-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethyl- amide,

5c-9oL, 110C, 15 (S) -Trihydroxy-1 9, 20-dinor-1 8-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide, 25th

5c-9dL, 110L, 1 5 (S) -Trihydroxy-1 9, 20-dinor-1 8-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide,

5c-9oC, 1 lot, 15 (R) -trihydroxy-1 6 (S) -f luor-1 9, 2 0-dinor-1 8-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,

5c-9oL, 11d, 15 (R, S) -Trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide ,

5c-9oC, 11oC, 15 (S) -Trihydroxy-18, 1 9,20-trinor-i 7-cyclohexyl-prost-5-en-i3-yn-acid-N, N-dimethylamide,

5c-9ci. _f 11eL, 15 (S) -Trihydroxy-1 8, 1 9, 20-trinor-17-0 cyclopentyl-prost-5-en-i3-yn-acid-N, N-dimethyl-

amide,

5c-9oC _f 1 U ,, 15 (R) -Trihydroxy-1 6 (S) -fluoro-1 8,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethylamide,

5c-9oL, 11oU 15 (R, S) -Trihydroxy-1 6 (S) -f luor-1 8,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
20th

5c-9ol, 11oL, 15 (R) -Trihydroxy-1 6 (S) -f luor-18, 19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N- dimethylamide,

5c-9oL, 1U, 15 (R, S) -Trihydroxy-1 6 (S) -f luor-1 8, 1 9, 20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid- N, N-dimethylamide,

5c-9oC 11oL, 15 (S) -Trihydroxy-17, 18,19, 20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethyl- amide,

ν / ν »ν» WW L · I

5c-9o <-, 11cC, 15 (S) -Trihydroxy-17,18,19,20-tetranorlo-cyclopentyl-prost-S-en-IS-yn-acid-N ^ N-dimethylamide,

5c-9oil, 11ol, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-ie-cyclohexyl-prost-S-en-IS-yn-acid-NjN-dimethylamide ,

5c-9oC, 11oC ·, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20 tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,

5c-9oL 11ol, 1 5 (R) -Trihydroxy-16 (S) -f luoro-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne-acid- N, N-dimethylamide,

5c-9o2-, 11σ0.15 (R, S) -Trihydroxy-1 6 (S) -f luor-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13- in-acid-N, N-dimethylamide,
20th

5c-9 <i, 1 lot, 15 (R) -Trihydroxy-1 6 (R) -f luor-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13- in-acid-N, N-dimethylamide,

5c-9-Oxo-11c6,15 (S) -dihydroxy-20-nor-1 9-cyclohexylprost-5-en-13-yne acid amide,

5c-9-Oxo-11dL, 15 (S) -dihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-yne acid amide,
30th

5c-9-Oxo-11cL, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-1 3-yn acid amide,

BATH

5c-9-Oxo-11cC, 15 (R, S) -dihydroxy-1 6 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yne-acid amide,

5C-9-OXO-110C, 15 (S) -dihydroxy-1 9,20-dinor-1 8-cyclohexyl-prost-S-en-i3-yne-acid amide,

50-9-0x0-11 ^, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-yne-acid amide,

5C-9-OXO-1U, 15 (R) -dihydroxy-16 (S) -fluoro-1 9,20-dinor-1S-cyclohexyl-prost-S-en-i3-yne-acid amide,

5c-9-0XO-1 U ,, 15 (R, S) -dihydroxy-1 6 (R) -f luor-20-nor-1g-cyclohexyl-prost-S-en-i3-yne acid amide, 15th

5c-9-oxo-11ol, 15 (S) -dihydroxy-18, 19, 20-trinor-17 cyclohexyl-prost-5-en-i3-yne-acid amide,

5c-9-Oxo-1 λά ~, 15 (S) -dihydroxy-1 8,19, 20-trinor-17-cyclopentyl-prost-5-en-13-yne acid amide,

, 15 (R) -dihydroxy-1 β (S) -fluoro-1 8,19,20-trinor-17-cyclohexyl-prost-S-en-i3-yne acid amide,

5'c-9-0XO-11oL 1 5 (R, S) -dihydroxy-1 6 (S) -fluoro-1 8,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid amide,

5c-9-oxo-1 Ιοί /, 15 (R) -dihydroxy-16 (S) -f luoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-1 3-yn acid aide, 30

5c-9-Oxo-11oL, 15 (R, S) -dihydroxy-16 (S) -f luoro-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid amide ,

5C-9-OXO-11 <£, 15 (S) -dihydroxy-17, 18,19, 20-tetranor-1S-cyclohexyl-prost-S-en-i3-yne-acid amide,

5C-9-OXO-11 ₀ C, 15 (S) -dihydroxy-17, 18,19, 20-tetranor-1S-cyclopentyl-prost-S-en-i3-yne-acid amide,

5C-9-OXO-1 lot-, 15 (R) -dihydroxy-16 (S) -fluoro-1 7,18,19,20-tetranor-16-cyclohexyl-prost-5-ene-13-yne acid amide,

0 5C-9-OXO-11ol, 15 (R, S) -dihydroxy-1 6 (S) -f luor-1 7, 1 8 _r 1 9, 20-tetranor-16-cyclohexyl-prost-5-en- 13-yn acid amide,

5c-9-Oxo-11oC, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynamide,

5C-9-OXO-11ol, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynamide,
20th

5C-9-OXO-11oC, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynamide,

5c-9-Oxo-11iL, 15 (S) -dihydroxy-20-nor-1 9-cyclohexylprost-5-en-13-yn-acid-N, N-dimethylamide,

5c-9-Oxo-1 IcL, 15 (S) -dihydroxy-20-nor-1 9-cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide, 30

5c-9-Oxo-11C ^, 15 (R) -dihydroxy-1 6 (S) -f luoro-20-nor-i 9-cyclohexyl-prost-S-en-IS-yn-acid-N ^ -dimethylamide ,

3A

5C-9-OXO-11eC, 15 (R, S) -dihydroxy-1 6 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N- dimethylamide,

50-9-0x0-1106.15 (S) -dihydroxy-19,20-dinor-1 8-cyclohexyl-prost-5-en-i3-yn-acid-N, N-dimethylamide,

5C-9-OXO-11oU 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-S-en-i3-yn-acid-N, N-dimethylamide,

5C-9-OXO-11ct, 15 (R) -dihydroxy-1 6 (S) -f luor-19, 20-dinor-1S-cyclohexyl-prost-S-en-i3-yn-acid-N, N- dimethylamide,
15th

50-9-OXO-HoC, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-1 9-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,

5C-9-OXO-11oC, 1 5 (S) -dihydroxy-1 8,19, 20-trinor-17-cyclohexyl-prost-5-en-i3-yn-acid-N, N-dimethylamide,

5C-9-OXO-11oL, 15 (S) -dihydroxy-1 8,19, 20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide,

5C-9-OXO-110U15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
30th

5C-9-OXO-11Λ, 15 (R, S) -dihydroxy-16 (S) -fluoro-18.1 9.20 trinor-17-cyclohexyl-prost-S-en-i 3-yn-acid-N, N-dimethylamide,

5C-9-OXO-1ToC 15 (R), dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-i3-yn-acid-N, N-dimethylamide ,

5C-9-OXO-11oC, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-13-yn-acid-N , N-dimethylamide,

5C-9-OXO-1lot, 15 (S) -dihydroxy-17, 18,19, 20-tetranor-1e-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethyl- amide,

5C-9-OXO-11oC, 15 (S) -dihydroxy-17,18,1 9,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide,

5C-9-OXO-11oC, 15 (R) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
20th

5C-9-OXO-11oil, 15 (R, S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn acid -N, N-dimethylamide,

5c-9-Oxo-1 Ϊ (Κ, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19 ^ O-trinor - ^ - cyclohexyl-prost-S-en-IS-in acid-N, N-dimethylamide,

5C-9-OXO-11öC 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-i7-cyclohexyl-prost-5-en- 13-yn-acid-N, N-dimethylamide,

BATH ORIGINAL

C, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn-acid-N, N- dimethylamide,

Sc-S-Oxo-HoC-, 15 (S) -dihydroxy-20-nor-19-cyclohexyl prost »5 ~ en-13-yn-acid-morpholinamide,

50-9-0x0-1 10C, 15 (S) -dihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-yn-acid morpholinamide, 10

5c-9-Oxo-11cC, 15 (R) -dihydroxy-16 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,

50-9-0x0-1101.15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,

5C-9-OXO-11oL, 15 (S) -dihydroxy-1 9, 20-dinor-1 8-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,

5C-9-OXO-11öU 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-yn-acid-morpholinamide,

5C-9-OXO-11 <jl, 15 (R) -dihydroxy-1 6 (S) -f luor-19, 20-dinor-1S-cyclohexyl-prost-S-en-i3-yn-acid-morpholinamid,

5C-9-OXO-1 lot, 15 (R, S) -dihydroxy-16 (R) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,

5C-9-OXO-11öW 15 (S) -dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-i3-yn-acid-morpholinamide,

VV WV A. t

5c-9-Oxo-11ö £, 15 (S) -dihydroxy-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-morpholinainid,

5c-9-Oxo-1 -id, 15 (R) -dihydroxy-16 (S) -f fluoro-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn-acid-morpho - linamid,

5c-9-Oxo-11ot, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19, 20 trinor-1V-cyclohexyl-prost-S-en-i3-yn-acid-morpholinamide,

5C-9-OXO-11oC, 15 (R) -dihydroxy-16 (S) -f luor-18, 19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid morpholinamide,
15th

5c-9-Oxo-1 IcC, 15 (R, S) -dihydroxy-16 (S) -fluoro-18 , 1 9,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid-morpholinamide,

5C-9-OXO-11cC> 15 (S) -dihydroxy-17,18,1 9,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,

5C-9-OXO-1 IcL ₁ 15 (S) -dihydroxy-17, 18,19, 20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-morpholine amide,

5C-9-OXO-11σΟ * 15 (R) -dihydroxy-16 (S) -f luor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid morpholine amide,

SAD ORIGINAL

5c-9-Oxo-11e6r15 (R _/ S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1e-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,

5C-9-OXO-1 \ fL, 15 (R) -dihydroxy-1 6 (S) -fluoro-1 6-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13- in-acid-morpholinarnide,

5C-9-OXO-11ot, 15 (R, S) -dihydroxy-16 (S) -fluoro-1 6-0 methyl-18,19 _f 20-trinor-1V-cyclohexyl-prost-S-en-13- in-acid-morpholinamid, and

5c-9-Oxo-11ßC, 15 (R, S) -dihydroxy-1 6 (R) -fluoro-1 6-methyl-18,19,20-trinor-iT-cyclohexyl-prost-S-en-13- in-acid-morpholinamide.

Where in the above list of compounds and the claims as well as in the examples below Reference to "Morpholinamid", "Piperidinamid", "Piperazinamid" and "pyrazolidinamide" is taken, these terms are intended to cover amide groups in which the nitrogen atom of the amide group is a ring nitrogen atom is in the heterocyclic group. These groups are accordingly

-CON0, -CON), -CON NH and -CON

Alternative names for these groups could be

- 44 -

N, N-ethyleneoxyethylene amide, N, N-pentamethylene amide, Ν, Ν-Ethylenaminoethylenamid and Ν, Ν-n-Propylenaminoamid be.

The compounds of general formula (I) can be prepared by a process which comprises:

(a) a reactive derivative of an optically active or racemic compound of formula (II)

XOOH

R '

5 | _sC -C_C- (CH ₂ ) _n -R ₈ .. ^R S ^R 7

whereby

in the event that the icon a double bond

means ^ R 'is a hydrogen atom and R ₂ and R', taken together, form an oxo group;

while in the case where the symbol denotes a single bond, R '.. is hydroxy or a protective group bonded to the ring through an ether oxygen atom, R _{2 is} hydrogen, R * is hydroxy, acyloxy or a protective group bonded to the ring through an ether oxygen atom, or R_ and R ', taken together, form an oxo group;

one of the two radicals R 'and R' is hydroxy or one bonded through an ether oxygen atom Protecting group and the other are hydrogen;

and Rg, R ₇ , η and R _{g have} the meanings given in claim 1;

with a compound of the formula (III)

H-N (III)

^ R "

to bring to reaction, where R ¹ and R "have the meanings given in claim 1, 30

so as to give an optically active or racemic compound of formula (IV)

ET /

^R l

¹ C ₅ CCC- (CH ₀ ) -R ₅ *> ^ Δ η ο

^R 5 ^R 7

where R ¹ , R ", R ' ₃ , R ₂ , R ^1. ,, R' ₄ , R ' ₅ , R _g , R ₇ , η and Rg have the meanings given above,

and then, if necessary, the hydroxy protective groups to remove; or

(b) an optically active or racemic compound of the formula (V)

* Ϋ

NC-C- (CH ₂ ) _B -R ₈ ^R i ^R 7

BAD ORlGlMAL.

whereby

M is -C = C- or -CH = C- and X is bromine, chlorine or iodine;

Z is hydroxy or a protecting group attached to the ring through an ether oxygen atom;

one of the two radicals R ". and -R ^{1 is} hydroxy or a protective group bonded to the ring through an oxygen atom and the other is hydrogen;

as well as Rg, Rj, η and R _{ß have} the meanings given in claim 1,

with a Wittig reagent which contains a - (CH ,,).-CON> ^ «ι group to react, where R ¹ and R" have the meanings given in claim 1 to an optically active or racemic compound of the formula (VI)

H OH

.R '

CON ^ (VI)

in the R ^!

R, Z _t R

R ,, R

_, η and R ₀ the / ο

A ' 5 "6 have the meanings given above and

if the 11- and 15-hydroxy groups are protected, esterification can be carried out, if desired, to give a 90 ^ acyloxy derivative of a compound of formula (VI) and then the protecting groups in the 11- and / or 15-positions, if present to remove both in a compound of the formula (VI) and in its acyloxy derivatives, so as to give a compound of the formula (I) in which R_ is hydroxy or acyloxy, R _{2 is} hydrogen and R. is hydroxy

are, the symbol means a single bond

and R ¹ , R ", R ₄ , R ₅ , R ,, R ₇ , η and R _{g have} the meanings given in claim 1; or

(c) to oxidize an optically active or racemic compound of the formula (VII)

H OH

(VII)

R " Rf,

> ⁴ I ⁶ ,

C ₅ CCC- (CH ₂ ) _n -R _g R ₅ R ₇

whereby

Z 'one through an ether oxygen atom to the ring is attached protecting group;

one of the two radicals R ". and R" _{5 is} a protective group bonded through an ether oxygen atom

BM3

and the other are hydrogen;

and R ¹ , R ", R ,, R", η and R _{ß have} the meanings given in claim 1,

to give an optically active or racemic compound of formula (VIII)

j ζ 2 η ο (VIII)

R ₅ R ₇

in which R ', R ", Z', R" R ¹ ', R., R ^, η and R ₀ die

4 O O / O

have previously given meanings, and in turn the removal of the ether protective groups is subjected to, depending on the reaction conditions, either a compound of the formula (I) in which there is a single bond, R

————— I

Hydroxy, R_ and R ,,, taken together, form an oxo group and R ', R ", R ₄ , R ₅ , Rg, R ₇ , η and Rg have the meanings given in claim 1, or a compound of the formula (I ), in

which is a double bond, R, hydrogen

is, R "and R _n " taken together form an oxo group and R ', R ", R., R ₅ , Rg, R ₇ , η and R _{g have} the meanings given in claim 1, to give;

V / V V V

and / or to convert a compound of the formula (I), if desired, into a salt

or to obtain a compound of formula (I) free of a corresponding salt

10

and / or a compound of the formula (I) or a corresponding salt, if desired, into a to convert another compound of the formula (I) or a salt thereof

and / or a mixture of isomers, if desired, to be converted into the individual isomers.

5 One through an ether oxygen atom to the ring or the protective group attached to the side chain, i.e. an ether group, should be used under mild reaction conditions, e.g. acid hydrolysis, easily convertible into a hydroxyl group. Examples are acetal ethers, enol ethers and SiIylether. The preferred ones are

(CH ₃ ) ₃ Si0-

O-Aik

0-

CH, I 3

(CHj, C-Si-O-3 3 ι

CH
3

wherein G ~ -0 or -CH ₂ -, and Alk group, represents a lower, for example, Cj_ ₄ ~ alky!.

The reaction conditions used in the reaction between a reactive derivative of a compound of formula

(II) and an amine of formula (III) are to be used, depend to a particular extent on the type of reagents used.

A reactive derivative of a compound of formula (II) can be a reactive ester, e.g., a C 1-6 alkyl ester; an acyl halide such as chloride or bromide; a Anhydride; a mixed anhydride; an azide; or a Salt, e.g. an alkali or alkaline earth salt. When the reactive derivative of a compound of formula (II) a reactive ester thereof and the compound of formula

(III) are ammonia, the reaction may be performed using gaseous ammonia at a temperature of about 5 to about 4O ⁰ C, preferably from 15 to 25 ° C, are carried out; while the reaction, when a compound of formula (III) is an amine, can preferably be carried out in an inert solvent, for example benzene, toluene, at temperatures from room temperature to reflux temperature.

If a reactive derivative of a compound of formula (II) is an acyl halide, for example acyl chloride, the reaction with ammonia or a suitable amine of formula (III) can be carried out in an inert solvent, for example benzene or toluene, or in an aqueous Solvent, in this case in the presence of an inorganic base, e.g. NaHCO ₃ or Na ₃ CO ₃ , as an acid acceptor,

C I .-

be performed.

When in the lactol of formula (V) M is -C = C- or CH = CX-, wherein X is bromine or iodine, the Wittig reaction can be carried out using about 1 to 4 moles, preferably 2 moles, Wittig reagent per mole of lactol can be carried out and from about 10 to 20 minutes to a few hours last, depending on the temperature and the concentration of the reaction mixture and the one used Wittig reagent. If in the lactol of formula (V) M is -CH = CX-, wherein X is chlorine, it is necessary using, for example, 1.5 to 2.5 moles of Wittig reagent per mole of lactol, the reaction time is up to 10 hours longer, or if shorter If reaction times are required, a large excess of Wittig reagent should be used: for reaction times 30 minutes at least 5 moles of Wittig reagent per mole of lactol. Therefore, X is in the case that in the lactol of formula (V) M is -CH = CX-, preferably bromine or iodine.

If in the lactol of formula (V) M represents -CH = CX-, wherein X is bromine, chlorine or iodine, this can be an the carbon atom in the 13-position bonded hydrogen atom and the halogen atom bonded to the carbon atom in the 14-position is either in the trans position, i.e., geometric trans isomers, or in the cis position, i.e. geometric cis isomers. Preferably they are in the trans position.

The Wittig reaction is carried out using the usual conditions for this type of reaction,

L-Jj ^ _0- / tLJ-i- ¹ * - !? "- ^ - !? Λ t

ie in an organic solvent, for example diethyl ether, hexane, dimethyl sulfoxide, tetrahydrofuran, dimethylformamide or hexamethylphosphoramide, in the presence of a base, preferably sodium hydride and potassium t-butoxide, at temperatures from about ⁰ ° C. to the reflux temperature of the reaction mixture, preferably at room temperature or below . .

The term "Wittig reagent" includes compounds the general formula

(Q) ₃ P- (CH ₂ J ₄ -CON

an, where Q is aryl, ie phenyl, or C1-6 alkyl, ie ethyl; Hal is halogen, for example bromine or chlorine, and R ¹ and R ″ have the meanings given above.

The preparation of the Wittig reagent is described in detail by Trippett, Quart. Rev .: (1963) XVII, No. 4406, discussed.

When in the lactol of formula (V) M is -CH = CX-, wherein X is as defined above, the dehydrohalogenation takes place just as easily during the reaction with the Wittig reagent if that hydrogen atom bonded to the carbon atom in the 13-position and the hydrogen atom bonded to the carbon atom in the 14-position bound halogen atom in the trans position

yj \ J <J C «-» C- I

present / as if they are in the cis position. The process conducted on the desired acylation of 9oL-hydroxy group in a compound of formula (VI) to produce the corresponding 9EC-Acyloxyderivats can be carried out in a customary manner, for example by treatment with an anhydride or a halide such as a chloride of a carboxylic acid ± n the presence of a Base.

The oxidation of the 9 ^ hydroxy group in a compound of the formula (VII) for the preparation of the corresponding 9-oxo derivative can e.g. by means of the Jones reagent, (G.I. Poos et al., Am. Soc. 75. r 422, 1953) or des Moffat reagent (Am. Soc. 8_7, 5661, 1965) will.

The removal of the known, through an ether oxygen atom protecting groups attached to the ring or to the side chain may, if necessary, e.g.

in a compound of the formula (IV) or in a compound of the formula (VI) or in their 9i (.- acyloxy derivatives, be carried out under conditions of mild acid hydrolysis, e.g. with a mono- or polycarboxylic acid, e.g. formic, acetic, oxalic, citric and tartaric acid, as well as in a solvent which e.g. Water, acetone, tetrahydrofuran, dimethoxyethane and lower aliphatic alcohols and a mixture thereof or with a sulfonic acid, e.g., p-toluenesulfonic acid, in a solvent such as a lower aliphatic alcohol, e.g. in methanol or ethanol, or with a polystyrene sulfonic acid resin.

BATHROOM OBlGJMAL

For example, a solution of 0.1 to 0.25N polycarboxylic acid in water, for example oxalic or citric acid, is used in the presence of a suitable low-boiling co-solvent which is miscible with water and which can easily be removed in vacuo at the end of the reaction . As discussed earlier, depending on the reaction conditions, the removal of the protecting groups in compounds of formula (VIII) can either be a compound of formula (I) in which the symbol ------ is a single bond, R _{1 is} hydroxy and R2 and R ₃ together form an oxo group, or

result in a corresponding connection in which

is a double bond, R _{1 is} hydrogen and R2 and Rß together form an oxo group. The first compound can be prepared as the only reaction product by us is held 4O ⁰ C, the reaction between 15 while only the second will be obtained at higher temperatures, for example at reflux for several hours.

Separation of a mixture of isomers into the individual isomers can be carried out by conventional methods be made. For example, the separation of a mixture of epimers, e.g. 15 (S) - and 15 (R) -epimers, by means of fractional crystallization from a suitable solvent or by means of chromatography, either column chromatography or high pressure liquid chromatography, be performed.

The reactive derivative of the acids of formula (II) and the lactols of formula (V) are known compounds,

as described, for example, in the applicant's GB-OS 2 009 145A or in GB-PS 1 483 880 of the applicant, or they can be made by known methods from known Compounds such as those described in the UK patents cited above will.

For example, compounds of formula (V) in which M is -C = C- can be prepared by dehydrohalogenation of the corresponding 14-halogen derivatives. The dehydrohalogenation can be carried out in an aprotic solvent, preferably selected from dimethyl sulfoxide, dimethylformamide and hexamethylphosphoramide, by treatment with a base, preferably selected from potassium t-butoxide, an alkali metal amide and the CH ^ -SO-CH ₉ ~ -anion.

Among the reaction intermediates described above, the compound of formula (IV) is new and represents another object of the present invention.

The compounds of formula (I) are represented by the general formula of British Patent Application No. 2 009 145A of the applicant, but none of them are specifically described therein.

The compounds of formula (I) can be used in mammals under all the conditions at which natural prostaglandins are indicated. They are given in the usual ways, e.g. orally,

3AD GRfGiMAL

parenterally, rectally or by aerosol, with the advantages of superior resistance to the enzyme 15-prostaglandin dihydrogenase, the natural prostaglandin known to be rapidly inactivated. The new connections are also with a long lasting one therapeutic activity endowed as natural prostaglandins when in usual ways and especially administered orally. For example, show the compounds of formula (I), and in particular the 9 ck-hydroxy derivatives, oxytocin effect, i. they can be used in place of oxytocin to induce labor or to treat a dead fetus abort pregnant animals, both humans and animals. In this application, the Compounds either by intravenous infusion at a dose of approximately 0.01 μg / kg / min up to Administered at the end of labor or orally at a single or multiple dose of about 0.1 mg to about 5 mg / dose.

Furthermore, the compounds of formula (I) show especially the 9oC-hydroxy derivatives, also luteolytic ones Activity and can therefore be used in fertility control with the advantage of a considerably reduced capacity for soft muscle stimulation. Therefore the side effects are more natural Prostaglandins such as vomiting and diarrhea not given. The luteolytic activity of the new compounds was found in rats, for example.

In this test, as shown in Table 1, a comparison was made between the activity of a compound of

Invention (R = NH ₂ ) and that of two compounds previously used either after oral (p.os.) or subcutaneous (sc) administration.

Table 1

OH
/ ~ - ~ ^ \ == S ~ ^ S ^ COR
OH R. ^ED 50 T ^{/ kg} s.c. p.os. NH ₂
OCH ₃
OH 2.5
3
4th 40
90
150

^ED c; n represents the minimally effective dose which can induce luteolytic activity in 50% of the rat population under treatment.

Table 1 shows that the amide derivative is the most effective in terms of pharmacological stimulation. Although with sc administration the ED _5Q values are very high

lie close together? it is evident that the amide derivative in particular is the most active when administered orally. The amide therefore shows better gastrointestinal absorption, which corresponds to the different hydrophilic properties which the chemical groups of the prostaglandin derivatives bound _{to the C 1 carbon have.}

Another beneficial pharmacological property of the compounds of formula (I), particularly the 9-oxo derivatives, is their antiulcerogenic activity. Indeed are they applicable to reduce and control excessive gastric secretion in mammals. In this way they reduce or eliminate the formation of gastrointestinal ulcers and at the same time facilitate the healing process of any ulcer already present in the gastrointestinal tract. The connections of formula (I) can therefore also be used to reduce the undesirable gastrointestinal side effects, that of systematic administration of anti-inflammatory prostaglandin synthetase inhibitors originate from, and can therefore be found in association with them for this purpose. The connections of formula (I) can according to these purposes orally, parenterally, i.e. by intravenous injection or infusion, or by intramuscular injection, inhalation or rectally. With oral The compounds of the invention can be administered with a dosage ranging from approx. 1 mg to approx. 10 mg, preferably 5 mg once or three times a day is sufficient. Varies with intravenous infusion

the dosage of approximately 0.01 to 0.05 ug iig per kg body weight per minute. The total daily dose, both for injection and for infusion, is on the order of 0.1 to 20 mg. With the aforementioned treatment conditions, the exact degree of treatment naturally depends on the case history of the patient to be treated. .

The toxicity of the compounds of formula (I) has been found to be quite negligible, so they can be safely used in therapy. The determination of the toxicity (as indicative acute toxicity, ie LD ₅₀ was carried out, for example, as follows. Mice which had been deprived of food for 9 hours were treated orally with a single administration of increasing doses, then housed and fed normally; the LD-Q value was determined on the 7th day after the treatment. For example, the LD _5Q value of the compound 5c-90 £, 1106.15 (R) -Trihydroxy-16 (S) fluoro-18,19,20-trinor-17- cyclohexyl-prost-5-en-13-one-acid amide found with> 3,000 mg / kg body weight The compounds of formula (IV) are endowed with the same pharmacological activities of the compounds of formula (I) and are therapeutic for humans or animals Administered for purposes, at the same dosage levels and by the same routes of administration.

The pharmaceutical compositions of the invention are usually made by conventional methods and in a pharmaceutically acceptable form

administered. For example, the solid oral forms, together with the active compound, diluents t e.g. lactose, dextrose, sucrose, cellulose, corn. · And potato starch? Lubricant, ZoB. Silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; Binders, ζ.Bο starches, gum arabic, gelatine, methyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate; Foaming mixtures; Dyes; Sweeteners; Wetting agents, for example lecithin, polysorbates, lauryl sulfates; as well as generally non-toxic and pharmacologically inactive, included in pharmaceutical formulations

«
put substances contained. The pharmaceutical preparations mentioned can be manufactured in a known manner, for example by means of mixing, granulating, tabletting, sugar-coating or film-coating processes. The liquid dispersions for oral administration can be, for example, a syrup, emulsions and suspensions. The syrup forms can contain, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol as a carrier; In particular, a syrup to be administered to diabetics can only contain products as carrier substances which cannot metabolize to glucose or which can only be metabolized to glucose in very small amounts, such as sorbitol.

The suspensions and emulsions can be used as a carrier, for example a natural gum, agar, sodium alginate, Pectin, methyl cellulose, carboxymethyl cellulose

or polyvinyl alcohol. The suspensions or solutions for intramuscular injections can be together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, Ethyl oleate, glycols such as propylene glycol and, if desired, an appropriate amount of lidocaine hydrochloride contain. The solutions for intravenous injections or infusions can be used as carriers for example contain sterile water or are preferably in the form of sterile aqueous isotonic Saline solutions.

The suppositories can, together with the active compound, be a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitol carboxylic acid ester surfactant or lecithin.

As noted above, another route of administration may be by inhalation. For such a Suitable compositions can use a suspension or solution of the active ingredient, preferably in the form of a salt, such as the sodium salt, in water for administration by means of a conventional one Include fogger. Alternatively, the compositions can be a suspension or solution of the active Component in a conventional liquefied propellant such as dichlorodifluoromethane or dichlorotetr-afluoroethane, to be administered from a pressurized container, i.e. an aerosol dispenser.

If the drug is not soluble in the propellant

it may be necessary to use a co-solvent, such as ethanol, dipropylene glycol, isopropyl myristate and / or adding a surfactant to the composition to keep the medicament in the propellant medium to distribute. Such surfactants can be any generally used for this purpose Be means, such as non-ionic surface agents, ZoB. Lecithin. Other suitable pharmaceutical forms can for example be powder. Powder can means a suitable injection device, in which case the fine particle powder of the active ingredient are mixed with a diluent material such as lactose.

The present invention will now be explained with reference to the following examples, but is not intended to be restricted thereto be.

The abbreviations THP, DIOX, DMSO, THF, DMF, DIBA, DIBA, ^E ^ o0 and EtOH refer to tetrahydropyranyl, dioxanyl, dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, diisobutylaluminum hydride, diethyl ether or ethyl alcohol. All temperatures are ^{expressed in °} C., the measurements of the optical rotation relate to 20 ^° C. and a concentration of 1% by weight of the compound in the specific solvent.

example 1

A solution of 5c-9cL, 11ol, 15 (S) -trihydroxy-18,19,20-trinor-1V-cyclohexyl-prost-S-en-i3-yn-acid methyl ester (0.5 g) in methyl alcohol (10 ml ) was cooled with cold brine and dry NH ₃ was bubbled into this solution until saturation.

The reaction vessel was closed and the reaction mixture was kept at room temperature for 24 hours; then the NH _{3 was} stripped off by means of N ₂ and the alcohol removed.

The crude product was purified by preparative chromatography on silica gel using hexane / ethyl acetate = 1: 1 as the eluent. 0.42 g of pure 5c-9oC, 1 ieM 5 (S) -trihydroxy-18,19,20-trinor-17-cyclohexy _v 1-prost-5-en-13-yn acid amide were obtained.

/ oC / _ = +34.8; / oi / ^ cc = +86.1 (C = 1 EtOH)

- - yy - -

The following connections were obtained by an analogous procedure:

5c-9c6,11eC, 15 (S) -trihydroxy-20-nor-i 9-cyclohexylprost-5-en-13-yn-acid amide /^.7 _D = +19.5;

5c-9 /, 11 * C, 15 (S) -Trihydroxy-20-nor-19-cyclopentylpros.t-5-en-13-yn-acid amide / ^ _{17 n} = +19.7; 30th

5c-9ct, 11 <£, 15 (R) -Trihydroxy-16 (S) -f luor-20-nor-1 9-cyclohexyl-prost-S-en-IS-yn-acid amide Zc6? _D = +8.8;

5c-9a, 11a, µ5 (R, S) -Trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yne acid amide [a] _ = +7.2;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexyl-prost-S-en-IS-yne-acid amide [a3 _D = + 13.9;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn acid amide [α] _β = +24.7;

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-19,20-dinor-IS-cyclohexyl-prost-S-en-IS-yn-acid amide [α] _ = +11.2;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro - 20-nor-19-15

cyclohexyl-prost-S-en-IS-yne-acid amide [α] - = +38.7;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid amide [a.] _D = +31.0;

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro -18,19,20-0 trinor-17-cyclohexyl-prost-5-en-13-yn-acid amide [a] _D = + 17.4? [Ct] ₃₆₅ = +66.9 (C = 1 EtOH);

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-S-en-13-yne-acid amide Ia] ₀ '= +10.2;

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclohexylprost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (S) -Trihydroxy ^ O-nor - ^ - cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide;

5C-9CX, 11α, 15 (R) -Trihydroxy-16 (S) -fluoro-20-nor · -! ^ cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-1 iJ-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (S) -Trihydroxy - ^^ O-dinor-iS-cyclohexylpros t-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a _/ 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide; 15th

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;

5c-9.a, 11a, 15 (R, S) -Trihydroxy-16 (S) -f luoro-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn-acid-N , N- dimethylamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn acid amide [a] _D = +18 ,1;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-S-en-13-yn-acid amide [a] _D = +12.9;

5c-9a, 11a, 15 (S) -Tr! Hydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yne acid amide [α] = +37.6;

5c-9α, 11α, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid amide [a] _D = +37.2;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid amide [a] _D = +6.5;

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-i3-yne-acid amide [a] _D = +11.2;

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne-acid amide [a] _D = +7.7;

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne acid amide [ a] _D = +12.1;
30th

5c-9a, 11a, 15 (R) -Trihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne-acid amide [a] _D = 415.9;

5c-9α, 11α, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide [cx] _D = +29 , 6;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-i3-yn-acid-N, N- dimethylamide;

5c-9a, 11a, 15 (S) -trihydroxy-17, iS ^^ O cyclohexyl-prost-S-en-IS-yn-acid-NjN-dimethylamide; 15th

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19, 20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-0 tetranor-10-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
30th

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-16-methy1-18,19.2 0-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-N, M-dimethylamide?

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclohexylprost-5-en-13-yn-acid pyrazolidinamide; 10

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid pyrazolidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-in-acid-pyrazolidinamide?

5c-9a, 11a, 15 (S) -Trihydroxy-19,20-dinor-iS-cyclohexylprost-S-en-IS-in-acid-pyrazolidinamide?

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid pyrazolidinamide; 25th

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinorle-cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;

5c-9α, 11α, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9a, 11α, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-IT-cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;
10

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-IS-in-säure-pyrazoli- dinamid;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-yn-acid-pyrazoli- dinamid;

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-rprost-S-en-IS-yn-acid-pyrazolidinamide; 25th

5c-9α, 11α, 15 (S) -trihydroxy-17,18,19,2 0-tetranor-16-cyclopentyl-prost-S-en-IS-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-IS-in-acid-pyrazzo- lidinamide;

5c-9α, 11α, 15 (R, S) -Tr! Hydroxy-1β (S) -fluoro-17,18,19,20-tetranor-IS-cyclohexyl-prost-S-en-IS-yn acid -pyrazo-1idinamide?

5c-9a, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid pyrazolidinamide;

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid- pyraz olidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide ;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide ;

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid-piperidinamide; 25th

5c-9a, 11a, 15 (R) »trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-piperidinamide;

5c-9a, i1a, 15 (R, S) = trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-piperidinamide;

5c-9a, 11α, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -f luoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid <-piperidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide; 15th

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18 , 19,20- trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
25th

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;

0 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9α, 11α, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9α, 11α, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
10

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-16-methy1-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide ;

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl »prost-5-en-13-yn-acid- piperidinamide;

5c-9a, 11a, 15 (R) -Trihydroxy-16 (R) -fluoro-16-methy1-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne-acid-piperidinamide?

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;

5C-9CX / 11α, 15 (S) -Trihydroxy ^ O-nor - ^ - cyclopentylprost-5-en-13-yn-acid morpholinamide;

5c-9a, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (R / S) -trihydroxy-16 (S) - ± luoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-morpholinamide;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a / 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid-morpholinamide; 15th

5c-9a, 11a / 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-S-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;

5c-9a / 11a, 15 (S) -trihydroxy-18,19 / 20-trinor-17-cyclohexylprost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19 / 20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide; 30th

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;

5c «9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-yn-acid-morpho-1inamid?

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-in-acid-morpho- 1inamidι

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16 ™ cyclohexylT-prost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-13-yn-acid-morpholinamide;

5σ-9α, 11α, 15 (R, S) -trihydroxy-1β (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-morpho linamid;

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluqr-16-methyl-18 ^ 19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-säuremorpholinamidι

5c-9a, 11α, 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-

18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid morpholinamide?
30th

5c-9a, 11a / 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-18,19 / 20-trinor-1V-cyclohexyl-prost-S-en-13-yne-acid morpholine amide; and

5C-9CX / 11α, 15 (R) -Trihydroxy-16 (S) -f luoro-18 / 19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid-piperazinamide.

Example 2

A solution of potassium t-butoxide (2.325 g) in dry DMSO (15 ml) was stirred under dry nitrogen; triphenylphosphonium pentanoic acid-N, N-dimethylamide bromide (4.2 g) was added to the solution while cooling with a water bath. The temperature of the reaction mixture was kept below 3O ⁰ C, and terminates the addition in about minutes; then a solution of 3d, 5oC- dihydroxy-2ß- / 2-bromo-3 (S) -hydroxy-4 (S) -fluoro-5-cyclohexyl-pent-trans-i-enylj-iel-cyclopentane acetaldehyde- ^ -lactol-bis-THP-ether (1.7 g) in dry DMSO (15 ml) was added to the mixture obtained.

The reaction was complete in about 1 hour, then the mixture was quenched with water and extracted with diethyl ether. The solvent was removed and the crude product was purified by preparative chromatography on silica gel using ethyl acetate / hexane = 1: 1 as the eluent. 1.650 g 5c-9 <^, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, M- dimethylamide-11,15-bis-THP-ethex were obtained as the pure product: / öt7 _D = +42.5 (C = 1 EtOH).

Using the same procedure and using it the corresponding triphenylphosphonium derivatives and the appropriate bis-THP ether lactols were the amides, Ν, Ν-pimethylamide, pyrazolidinamides, piperidinamides and morpholinamides ^ as 11, IS-bis-THP-ether crude products of the following acids obtained for the following

Reactions are applicable and optionally purified by chromatography:

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn acid;

5c-9a / 11a, 15 (S) -trihydroxy-20-nor-.i 9-cyclohexyl-prost-5-en-13-yn acid;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn acid;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro ^ O-nor-i 9-cyclohexyl-prost-5-en-13-yn acid; 15th

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn acid;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn acid;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn acid;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl: -prost-5-en-13-yn acid;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn acid; 30th

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn acid;

5c-9a, 11α, 15 (R) -trihydroxy-16 (S) -luoro-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn acid;

5c-9a, 1 1a, 15 (R, S) -trihydroxy-16 (S) -fluoro-1 8,19,20-trinor ™ 1y-cyclohexyl-prost-S-en-IB-yn acid;

5c-9a, 11α, 15 (R, S) -trihydroxy-16 (S), -fluoro-18,19,20-trinor-IT-cyclopentyl-prost-S-en-IS-yn acid;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-IV-cyclopentyl-prost-S-en-IS-yn acid;

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn acid; 15th

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn acid;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-IS-yn acid;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-IG-cyclohexyl-prost-S-en-IS-yn acid;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn acid;

5c-9a, 11a, 15 (R, S) -trihydroxy-1β (S) -fluoro-16-methyl-18,1.9,20-trinor-17-cyclohexyl-prost-5-en-13-yoic acid;

5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methy1-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yne acid; and

5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-18,19,20-trinor-n-cyclohexyl-prost-S-en-IS-yn acid.

Example 3

1.5 ml of Jones reagent was added to a solution of 5c-9oC, 1I ₀ L, 15 (R) -trihydroxy-16 (S) -f luor-18,1 9,20-trinor-1V-cyclohexyl-prost -S-en-i3-in-amide 11,15-bis-THP-ether (1.07 g), which was cooled to -25 ⁰ C in acetone (15 ml), dropwise. After the addition, a temperature rise to -8 ⁰ C was admitted and the reaction mixture stirred for 20 minutes. The mixture was then diluted with benzene, washed with saturated aqueous (NH ₄₎ "Sun solution to neutrality, dried and the solvent evaporated at 20 ⁰ C under vacuum. The residue (0.830 g) was dissolved in 30 ml of acetone and treated with 1N oxalic acid solution (5.5 ml) ^{at 40 ° C. for 8 hours.}

After the reaction was complete, the acetone was evaporated in vacuo to give a residue which could be obtained by chromatography on SiO ₂ using ethyl acetate / cyclohexane = 35:65 as the eluent 0.325 g of pure 5c-9-oxo-11 «£, 15 ( R) -dihydroxy-16 (S) -f luor-

amide provided: /5.7 _Λ = -33.0; / * C7, <- * = -199.2 (C =

- - D - - IOD

EtOH).
25th

The following compounds were obtained by an analogous procedure:

5c-9-Oxo-11 ₀ L ₄ , 15 (S) -dihydroxy-20-nor-i 9-cyclohexylprost-5-en-13-yn acid amide / ^ - 7 _n = -6.2?

"■ ■" "IJ

- 82 5c-9-0ΧΟ-11α, 15 (S) -dihydroxy-20-nor-19-cyclopentyl-

prost-5-en-13-yn acid amide [ct] _ = -7.6;

5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid amide [a] _D = -9.8 ;

5C-9-OXO-11a-15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor- "ig-cyclohexyl-prost-S-en-IS-yn-acid amide [a] _D = - 10.2;

5c-9-Oxo-11a, 15 (S) -dihydroxy-19,20-dinor-18-eyelohexyl-prost-5-en-13-yn-acid amide tcx] _ = -6.9;

5C-9-OXO-11a, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl prost-5-en-13-yn acid amide [a] _D = -7.7;
15th

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinorle-cyclohexylr-prost-S-en-IS-yn-acid amide tec] - = -7.2;

5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid amide [ot] _D = -16 ,8th;

5C-9-OXO-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-S-en-IS-yn-acid amide [a] _D = -11.6;

5C-9-OXO-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-

cyclopentyl-prost-S-en-IS-yn-acid amide [α] _β = -9.1;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (R) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-IS-yne-acid amide
ta] _D = -13.5;

50-9-0x0-1 1α, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-13-yne-acid amide [a ] _D = -10.2;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-1.8,19,20-trinor - ^ - cyclopentyl-prost-S-en-13-yne-acid amide [a] _D = -38.2;

5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-0 trinor-17-cyclopentyl-prost-5-en-13-yne acid amide [aJ _D = -20.2;

5C-9-OXO-11a, 15 (S) -dihydroxy-17,18,19,20-tetranor-15

Lö-cyclohexyl-prost-S-en-13-yne-acid amide [cx] _D = -12.8;

5C-9-OXO-11a, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn acid amide [α] _ = -13.1;

5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yne-acid amide [a] _D = -42.4;

5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yne acid amide [ a] _D = -37.7;

5c-9-Oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne acid amide [ a] _D. = -56.6;

5c-9-Oxo-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18 / 19,20-trinor-1V-cyclohexyl-prost-S-en-i3-ynamide [ a] _D = -37.8;

5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid amide lo.] - = -35.1;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (R) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-
dimethylamide;

5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclohexylprost-5-en-13-yn-acid-N, N-dimethylamide;
15th

5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclopentyl prost-5-en-13-yn acid-N, N-dimethylamide;

5c-9-Oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-1g-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethyl- amide;

5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5C-9-OXO-11α, 15 (S) -dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9-Oxo-11α, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

- 85 -

5c-9-Oxo-11α, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinor-1e-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;

5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor- ^ -cyclohexyl-prost-S-en-IS-yn-acid-N ^ -dimethylamide;

5C-9-OXO-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-S-en-IS-yn-acid-N1-dimethylamide;

5C-9-OXO-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-S-en-IS-yn-acid-N1-dimethylamide;
15th

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N- dimethylamide;

5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-IS-in-acid-N,! * ! - dimethylamide?

5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5C-9-OXO-11a, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopenty1-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9-Oxo-11a, 15 (R) -dihydroy-16 (S) -fluor-17, 18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide; . ν

5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-17, 18,19,20-tetranor-Lö-cyclohexyl-prost-S-en-i3-yn-acid- N, N-dimethylamide;

5c-9-Oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid- N, N-dimethylamide;

5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-ISi ^^ O-trinor - ^ - cyclohexyl-prost-S-en-IS-yn-acid - N, N-dimethylamide;

5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid-N, N-dimethylamide;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (R) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;
30th

5c-9-OXO-11a, 15 (S) -dihydroxy ^ O-nor - ^ - cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

IIa, 15 (S) -dihydroxy-20-nor-19-eyelopentylprost-5-en-13-yn-acid-pyrazolidinamide;

5c-9-Oxo-11a, 15 (R) -dihydroxy-16 (S) cyclohexyl-prost-S-en-13-yn-acid-pyrazolidinamide;

5c-9-0XO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-13-yn-acid-pyrazolidinamide;

50-9-OxO-Ha, 15 (S) -dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9-Oxo-11a, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-yn-acid-pyrazolidinamide; 15th

5c-9-oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

50-9-OxO-Ha, 15 (R, S) -dihydroxy-16 (R) -f luoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5C-9-OXO-11α, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9-Oxo-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclopentyl-prost- * 5-en-13-yn-acid-pyrazolidinamide;

5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;

5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-IS-in-säure-pyrazoli- dinamid;

5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-IS-in-säure-pyrazoli- dinamid;

5C-9-OXO-11a, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide; 15th

5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-10-cyclohexyl-prost-S-en-13-yn-acid-pyrazoli dinamid;

5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-S-en-13-yn-acid- pyrazolidinamide;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid pyrazolidinamide;
30th

5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid pyrazolidinamide;

5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in- acid pyrazolidinamide;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (R) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-yn-s-acid-piperidinamide;

5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid-piperidinamide;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-piperidinamide;

5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-piperidinamide; 20th

5c-9-Oxo-11a, 15 (S) -dihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn-acid-piperidinamide;

5c-9-Oxo-11a, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid-piperidinamide;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinorle-cyclohexyl-prost-S-en-iS-yn-acid-piperidinamide;

5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;

Ha, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclo hexyl-prost-5-en-13-yn-acid-piperidinamide;

5C-9-OXO-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;

IIa, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-IV-cyclohexyl-prost-S-en-i3-yn-acid-piperidinamide; 10

5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-18, 1,9,20-trinor-17-cyclohexy1-prost-5-en-13-yn-acid-piperidinamide ;

50-9-Οχο-ΙΙα, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;

5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperi dinamid;

5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide; 25th

5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;

5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-17, 18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-piperidine amide;

5C-9-OXO-11α, 15 (R / S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-yne-acid- piperidinamide;

5c-9-Oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-16-methy1-

18,19,2 0-trinor-17-cyclohexyl-prost-S-en-13-yn-acid-piperidinamide;

5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid- piperidinamide;

5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid piperidinamide;

5C-9-OXO-11α, 15 (R) -dihydroxy-16 (R) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
20th

5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclohexylprost-5-en-13-yn-acid-morpholinamide;

5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid-morpholinamide;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexylprost-5-en-13-yn-acid-morpholinamide;

5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;

5c ~ 9-Oxo ~ 11α, 15 (S) -dihydroxy = 19, 2Q = dinor-18-cyclohexyl-prost-5-en ~ 13-yn ~ acid ~ sii © rpholinamide?

5c-9 ~ Qxo = 11a ,, 15 (S) -dihydroxy-19.20 ~ dinor-18 ~ cyclo ~ pentyl ~ prost ~ 5-en ~ 13 ~ in-s

5c-9-Oxo-1 Ία, 15 (R) -dihydroxy-Ί β (S) .- fluoro-19, 20-dinor-

5 ~ en = 13 = in ~ acid ~ morpholinamidj

5c-9-Oxo = 11a _f 15 (R, S) -dihydroxy-Ίβ (R) = fluoro-20-nor »19-cyclohexyl-prost-5 = en-13-yn-acid = morpholinamide?

5c-9 »Oxo-11a, 15 (S) -dihydroxy =! 8,19,20-trinor ~ 17 * = cyclohessyl-prost-S-en-IS-iR-säure-morpholinamiäi 15th

5C-9-OXO-11a, 15 (S) -dihydroxy-13,19,20 = trinor = 17-cyclopentyl ~ prost-5 = en ~ 13-yne = acid-morpholine amidef

5c-9-Osso-11a, 15 (R) -dihydroxy-1β (S) -f fluoro-18,19,20-trinor = 17 = cyclohexyl = prost = 5 = en = 13-yn-s-mure-morpholine amide ϊ

5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor = 17-cyclohexyl-prost = 5-ene = 13-yn-s-morpholinamide?

5C-9-OXQ-11a, 15 (R) -dihydroxy = 16 (S) -fluoro-1δ, 19.20 = trinor = 17 = cyclopentyl ^e prost = 5- = en = 13 = in = acid-morpholine amide?
30th

5c-9-OXO-11a, 15 CR, S) -dihydroxy-1 β (S) -fluoro-18,19,20 = trinor = 17 = cyclopantyl- = prost = 5 = en = 13 = in = acid = morpholine = amide?

5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-10-cyclohexyl-prost-S-en-13-yn-acid-morpholinamide;

5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-S-en-13-yn-acid-morpholinamide;

5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) ~ fluoro-17,18,19,20-tetranor-ie-cyclohexyl-prost-S-en-i3-yn-acid-morpholinamide;
10

5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid- morpholinamide;

5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-

18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid morpholine amide;

5c-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid- morpholinamide; and

5c-9-Oxo-11α, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid morpholinamide.

Example 4

Potassium t-butoxide (3.2 gl was dissolved in 20 ml of dry DMSO Dissolved under dry nitrogen and triphenylphospho = nium-pentansäurearnid-bromiä C6.3 g) of the solution under Magnetic stirring added =

Di © temperature was maintained by a water bath below 30 ⁰ C and a solution of 3d, 5 ^ -D! ™ 2ß hydroxy ~ ^ 2 ~ bromo-3 = (S ₁₁ R) -hydroxy-4 (S) -f = luor 4 = methyl = 5-cyclopentyl-pent-trans-1-enyiy-itft-cyclopentanacetaldehydylactol-15-trimethylsilyl ether (1.9 g) in DMSO (3 ml) added to the previously obtained mixture Diluted water and then extracted with diethyl ether, the solvent was removed and the crude product, which was obtained without a protective group in the 15-position, which was split off during the Wittig reaction, was purified by chromatography to give 1.8 g of 5c- = 9 ^, 11 ^ C, 15 (S, R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-i7-cyclopent'yl-prost = 5 "-en = ' i3 ~ yn acid amide to give • PJ _O = +14.95? L \ 7 _2S5 = +54.2 (C = 1 StOH) ₀

The following compounds were obtained by an analogous procedure?

5c = 9.oC, 1 1 ₀ L, 15 (S) -trihydroxy-20-nor-i 9-eyclohexyl prost-5-en-13 = yn-acid amide;

5c-9a, 1 "Ια, 15 (S) -trihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-yn acid amide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -luoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn acid amide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) .- fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn acid amide;

0 5c-9a, 11 a, 15 (S) -Trihydroxy-19.20 ^ InOr-IS-CyClOhSXyI-prost-5-en-13-yn-acid amide;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn acid amide; 15th

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-S-en-IS-yn-acid amide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn acid amide;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid amide;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn acid amide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,1 9,20-trinor-IT-cyclohexyl-prost-S-en-IS-yn-acid amide; 30th

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-IV-cyclohexyl-prost-S-en-IS-yn-acid amide;

5c-9a, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-18,1 9,20-trinor-17 »cyclopentyl = prost-5 ~ en ~ 13-yn acid amide?

5c-9a, 11a, 15 (R, S) -Trihyäroxy-1β (S) ~ fluoro-18,19,20-trinor-17 = cyclopentyl = prost-5 = -en = 13 ~ in = acid amiä?

Sc-Ba ₁₁ 11a, 15 (S) -Trihyäroxy-1 7,18,1-9,20-tetranor-16-cyclohexyl-prost-5-en = 13 = ia- = acid © amiä?

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost = -5- = en = 13 ~ in = acid amide?

5c-9a, 11a, 15 (R) -Trihydroxy-1β (S) -fluoro-17,18,19,20-tetranor-16 ~ cyclohexyl = prost- = 5 = en = -13-in = acid amide? 15th

5c-9a _f 1 la, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1S-cyclohexyl-prost-S-en-IS-yne acid amide;

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5 = en-13-yn-acid- amide;

5c-9a, 11a, 15 (R, S) -Trihydroxy-1β (S) -fluoro-16-methyl-18,19,20-trinor = 17-cyclohexyl-prost-5-en-13 = yn-acid amide?

5c-9a, 11a, 15 (R) -trihydroxy-1β (R) -f luoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn acid amide;
30th

5c-9a, 11a, 15 (S) -Trihydroxy-20-nor-19 = cyclohexylprost-5-en-13-yn-acid-N, N-dimi

5c-9a, 11α, 15 (S) -trihydroxy ^ O-nor-ig-cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-N ^ -dimethylamide;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-S-en-IS-yn-acid-N / N-dimethylamide;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide; 15th

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinorle-cyclohexyl-prost-S-en-IS-yn-acid-N / N-dimethylamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-1β (S) -f luoro-18,19,20-trinor-17-eyclohexyl-prost-5-eii-13-yn-acid-N , N-dimethy1 amide?

5e ~ 9a, 11a, 15 (R) ~ trihydroxy ~ 1 β (S) -f luor-1 8,19,20 » trinor ~ 17-eyelopentyl ~ prost-5-en = 13-yn-acid-N, Να imethy! amid?

5c-9a, 11a, 15 (R, S) -Trihydroxy-1β (S) -fluoro-18,19,20-trinor-IT-cyclopentyl-prost-S-en-IS-in-säure-NjN- dimethylamide?

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en = 13-yn-acid-N, H-dimethylamide? 15th

5c ~ 9a, 11α, 15 (S) -trihydroxy ~ 17,18,19,20-tetranor-16-cyclopentyl-prost-5-ene = 13-yn-acid-N, N-dimethylamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-0 tetranor-1β-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethy! amide ?

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor = 16 = cyclohe2cyl-prost = 5-en-13-yn-acid-N, N-dimethylamide?

5c-9a "11α, 15 (R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20 = trinor-17-cyclohesyl-prost-5-en-13-yn-acid-N, N ^ dimethylamide?
30th

5c-9a, 11a, 15 (R, S) -Trihydroxy = 16 (S) -fluoro-16-methyl-18,19,20 = trinor-17-cyclohessyl-prost-5-en-13-yn-acid- N, H-dimethylamide ?

5c-9a, 11a, 15 (R) -Trihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid-Ν, Ν-dimethylamide;

5c-9a, 11a, 15 (S) -trihydroxy ^ O-nor - ^ - cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-yn-acid pyrazolidinamide; 10

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn-acid pyrazolidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentyl prost-5-en-13-yn-acid pyrazolidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18 cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide; 25th

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9α, 11α, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-ene = 13 = in-acid-pyrasolidinamide;

5c-9a _f 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5 ~ en-13-yn-acid-pyrazalidin-amide?

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;

5c-9a, 11a, 15 (R) -Trihydroxy »16 (S) -fluoro-18,19,20-trinor-IT-cyclopentyl-prost-S-en-IS-in-acid-pyrazolidinamide?
15th

5c-9a _i , 11a _i 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-yn-acid-pyrazolidinamidy

5c-9a, 11a, 15 (S) = trihydro3sy-17,18,19, 20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid pyrazolidinamide;

5c-9a, 1Ia ₄ -IS (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-S-en-IS-yn-acid-pyrazolidinamide; 25th

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-IS-cyclohexyl-prost-S-en-IS-in-acid-pyrazolidinamide?

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1S-cyclohexyl-prost-ö-en-i3-yn-acid-pyrazolidinamide?

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yne-acid pyrazolidinamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn-acid pyrazolidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-18,19,2 0-trinor-17-cyclohexyl-prost-5-en-13-yn-acid pyrazolidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
15th

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -luoro-20-nor-19-cyclohexyl-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-in-acid-piperidiftamide;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentyl prost-5-en-13-yn-acid-piperidinamide; 30th

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (S) -Trihydroxy-18,19,20-trinor ~ 17-eyclohexyl-prost-5 = en-13-yne = acid ~ piperidinamide?

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyi-prost-5-en-13-yn-acid-piperidinamide;

5c = 9a, 11a, 15 (R) -trihydroxy-1 δ (S) -fluoro-18.1 9.20-trinor-17-cyclohesyl-prost-5-en = 13-yn-acid-piperidinamide?

5c-9a, 11a, 15 (R, S) -Trihydroxy-1 β (S) -fluoro-18,19,20-trinor-iy-cyelohexyl-prost-S-en-IS-in-säure-piperidine- amid y

5c-9a _f 11 a, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en = 13-yn-acid-piperidinamide?

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-IS-in-säure-piperidinamid?
25th

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-S-en-IS-yn-acid-piperidinamide;

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5 = en-13-yn-acid-piperidinamidj

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-IS-in-säure-piperi- dinamid;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-10-cyclohexyl-prost-S-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid- piperidinamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-16-methy1-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methy1-18,19,2 0-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
20th

5c-9a, 11a, 15 (S) -trihydroxy ^ O-nor-ig-cyclohexylprost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid morpholinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11α, 15 (S) -trihydroxy-19,20-dihor-18-cyclohexylprost-5-en-13-yn-acid-morpholinamide;

5c-9α, 11α, 15 (S) -Trihydroxy-19,20 ~ dinor-18-cyclopentylprost-5-en-13-yn-acid-morpholinamide?

5c ~ 9a, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18- = cyclohe3syl-prost-5-en-13-yn-acid-morpholinamide;

5c-9ai: 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohesyl-prost-S-en-IS-yn-acid-morpholinamide;

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5 = en-13-yn-acid-morpholinamide; 15th

5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1V-cyclohexyl-prost-S-en-IS-in-acid-morpholine-

5c-9a, 11a, 15 (R, S) -Trihydroxy-1β (S) -fluoro-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid-morpholinamidi

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-1V-cyclopentyl-prost-S-en-i3-yn-acid-morpho-1inamidj
30th

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-yn-acid-morpholinamide?

5C-9CX / 11α, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-S-en-IS-yn-acid-morpholinamide;

5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-S-en-IS-yn-acid-morpholinamide;

5c-Sa, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-10-cyclohexyl-prost-S-en-13-yn-acid-morpholinamide;
10

5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid morpholine amide;

5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid- morpholinamide;

5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid morpholine amide; and

5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperazinamide.
30th

Example 5

A solution of 5c-9-Oxo-11 ^, 15 (S) -dihydroxy-16 (R) fluoro-18,19,20-trinor-17-cycloheptyl-prost-5-en-13-yn-acid-piperidinamide -11.15-bis-THP ether (0.57 g) in acetone (10 ml) became more aqueous upon treatment with 1N aqueous Oxalic acid (10 ml) refluxed for 7 hours <, The excess acetone was removed under vacuum and the solution extracted with diethyl ether.

The organic extract was concentrated and absorbed onto acid washed silica gel. Elution with benzene / diethyl ether gave 0.21 g of 5c-9-oxo-15 (S) hydroxy-16 (R) -fluoro-18,19,20-trinor-17-cycloheptylprosta-5,10-diene-13-yne Acid-piperidinamide: /^.7 _n = +2.5 (C = 1 EtOH).

Using the same procedure, starting from 9-oxo-11,15-bis-THP-ether intermediate derivatives obtained according to Example 3, the following connections were made:

5c »9-Oxo-15 (S) -hydroxy ^ O-nor - ^ - cyclohexyl-prosta-5,10-diene-13-yne acid amide;

5c-9-Oxo-15 (S) -hydroxy- ^ O-nor-liJ-cyclopentyl-prosta-5,10-diene-13-yne acid amide;

5C-9-OXO-15 (R) -hydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prosta-5,10-diene-13-yne acid amide;

5C-9-OXO-15 (R, S) -hydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prosta-5,10-diene-13-yne acid amide;

5C-9-OXO-15 (S) -hydroxy-19/20-dinor-18-cyclohexylprosta-5,10-diene-13-yn acid amide;

5c-9-Oxo-15 (S) -hydroxy-19,20-dinor-18-cyclopentylprosta-5,10-diene-13-yn acid amide;

5C-9-OXO-15 (R) -hydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prosta-5,10-diene-13-yn acid amide;

5C-9-OXO-15 (R / S) -hydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prosta-5,10-diene-13-yne acid amide; 15th

5C-9-OXO-15 (S) -hydroxy-18,19,20-trinor-17-cyclohexylprosta-5/10-diene-13-yn acid amide;

5C-9-OXO-15 (S) -hydroxy-18 / 19,20-trinor-17-cyclopentylprosta-5/10-diene-13-yn acid amide;

5C-9-OXO-15 (R) -hydroxy-16 (S) -fluoro-18/19/20-trinor-17-cyclohexyl-prosta-5,10-diene-13-yne acid amide;

5C-9-OXO-15 (R / S) -hydroxy-16 (S) -fluoro-18 / 19,20-trinor-17-cyclohexyl-prosta-5,10-diene-13-yne acid amide;

5c-9-Oxo-15 (R) -hydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prosta-5,10-diene-13-yn acid amide; 30th

5C-9-OXO-15 (R / S) -hydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prosta-5,10-diene-13-yne acid amide;

5C-9-OXO-15 (S) -hydroxy-17,18,19,20-tetranor-16-cyclohexyl-prosta-5,1O-diene-13-yne acid amide;

5C-9-OXO-15 (S) -hydroxy-17 / 18,19,20-tetranor-16-cyclopentyl-prosta-5,10r-diene-13-yne acid amide;

5c-9 ~ Oxo-15 (R) -hydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1S-cyclohexyl-prosta-5,1O-diene-13-yne acid amide;

5C-9-02CO-15 (R, S) -hydroxy-16 (S) -f fluoro-17,18,19,20-tetranor-16-cyclohexyl-prosta-5,1O-diene-13-yne acid amide ϊ

5C-9-OXO-15 (R) -hydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prosta-5,1O-diene-13-yn acid amide?

5C-9-OXO-15 (R, S) -hydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prosta-5,1O-diene-13-in acid amide; as

18,19,20-trinor-17-cyclohexyl-prosta-5,1O-diene-13-yoic acid amide.
25th

Example 6

To a solution of 5c-9 <* ·, 11dC, 15 (R) -Trihydroxy-16 (S) fluor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yne-acid- piperazinamide (0.2 g) in 95% ethyl alcohol (5 ml) became a stoichiometric amount Given 1N HCl. The solvent turned to dryness evaporated, in this way 5c-9ct-, 11 <? C, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-i7-cyclohexylprost-S-en-IS-in- acid piperazinamide hydrochloride as white crystals.

Example 7

5c, 9oC, 11oC, 15 (R) -Trihydroxy-1 6 (S) -fluoro-18,19,20-trinor-IT-cyclohexyl-prost-S-en-IS-in-acid-N ^ - dimethylamide- 11.15-bis-THP ether (0.65 g) was dissolved in 10 ml of dry CCl ₄ and 0.5 ml of pyridine and then 0.1 ml of acetyl chloride was added dropwise to the solution.

The solution was stirred for about 2 hours at room temperature, _{neutralized with 10% NaH 3} PO ₄ solution and extracted with diethyl ether.

The solvent was removed and the crude product chromatographed on silica gel using Purified ethyl acetate / cyclohexane = 80:20 as eluent.

The pure 5c-9c * -, 11 ₀ C, 15 (R) -Trihydroxy-1 6 (S) -f luor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn acid- N, N-dimethylamide-11,15-bis-THP-ether-9-acetate was obtained, dissolved in a mixture of acetone (10 ml) and 1N oxalic acid (10 ml) and ^{stirred at 40 °} C. for 6 hours. The reaction solution was diluted with 10 ml of water, the acetone was distilled off and the mixture was extracted with ethyl ether.

The crude product was purified on silica gel using ethyl acetate / cyclohexane = 50:50 as the eluant to give 0.320 mg of pure 5c-9eC, 11oC, 15 (R) -trihydroxy-16 (S) -fluoro-18.19 To give 20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethylamide-9-acetate: / ^ J _D = +76.2 (C = 1 EtOH).

The 9-acetate derivatives were obtained by an analogous procedure all compounds listed in Example 1 obtained.

FORMULATION EXAMPLES

Formulation 1 ; Tablet (1 mg)

Tablets, each weighing 80 mg and containing 1 mg of the active substance, are prepared as follows;

Composition (for 100,000 tablets)

5c-9 $ C, 11 <^, 15 (R) -Trihydroxy-15 (S) -fluoro-18 / 19,20-trinor-i7-cyclohexyl-

Prost-5-en-13-yn acid amide 100 g

Lactose 5000 g

Cornstarch. 2720 g

Talc powder 150 g

Magnesium stearate 30 g

5c-9s <, 1 U, 15 (R) -Trihydroxy-16 (S) -f luor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-IS-in-acid amide / the lactose and half the corn starch are mixed; the mixture is then passed through a 0.5 mm mesh screen. The corn starch (18 g) is suspended in warm water (180 ml). The resulting paste is used to granulate the powder. The granules are dried, fine over a 1.4 mm mesh sieve crushed, then the remaining amount of starch, talc and magnesium stearate is added, carefully mixed and the mixture formed into tablets using dies of 5 mm diameter.

Formulation 2; Capsule (1 mg)

Composition ^

5c-9oC, 11oC, 15 (R) -trihydroxy-16 (S) fluoro-18,19,20-trinor-17-cyclohexylprost-5-en-13-yn acid amide 1.0 mg

Lactose 89.8 mg

Corn starch 9.0 mg

Magnesium stearate ο , 2 mg

total 100.0 mg

This formulation was encapsulated in two-piece hard gelatin capsules.

Claims (9)

HOFFMANN · BITLEI & PARTNER " PATENT LAWYERS DR. ING. E. HOFFMANN (1930-1976) DIPL.-ING. W. EITLE · D R. R E R. NAT. K. HOFFMANN · Dl PL.-ING. W. LEH N DIPL.-ING. K.FDCHSLE DR. RER. NAT. B. HANSEN ARABELLA STREET 4. D-8000 MUNICH 81. TELEPHONE (089) 911087. TELEX 05-29619 (PATHE) 39 FARMITALIA CARLO ERBA S.p.Α., MILAN / ITALY Amide derivatives of 13,14-didehydro-cycloalkyl-prostaglandins PATENT CLAIMS \1. J Optically active or racemic prostaglandin derivatives of the formula (D • R ' coN-r (D C- (CH.) -R _Q 2.. Zn ο ^R 7 " characterized in that R ¹ and
R ″ each, independently of one another, denotes hydrogen, C., g-alkyl, aryl or a heterocycle or
R ¹ and R ", taken together with the nitrogen atom,
to which they are bound form a heterocyclic ring; the symbol represents a single or double bond, where: (a) in the event that the symbol is a double bond, R _{1 is} a hydrogen atom and R ₂ and R-., taken together, form an oxo group; (b) in the case that the symbol is a single bond, R .. Hydroxy, R ₂ water substance and R _{3 are} hydroxy or acyloxy or R ₂ and R_, taken together, form an oxo group; one of the two radicals R ₄ and R _{5 is} hydroxy and the other is hydrogen; Rg and R ^ each, independently of one another, hydrogen, C 1-4 alkyl or fluorine; η is 0, 1, 2 or 3; Ro represents a C_., - cycloalkyl ring which is unsubstituted or is substituted by one or more substituents selected from (a ¹ ) Halogen, (b ¹ ) Trihalo-C._ ₆ ~ alkyl, (C) C _1-4 alkyl, (d) C _1-4 -AIkOXy, (e ¹ ) Phenyl and (f ') Phenoxy are selected; as well as the pharmaceutically or veterinarily acceptable salts thereof.
15th 2. A compound according to claim 1, characterized in that R 'and R "are, independently of one another, hydrogen or a C -.- alkyl or R ¹ and R", taken together with the nitrogen atom to which they are bonded, is a pyrole, pyrazole, imidazoline, imidazolidine, pyrazoline -, piperidine, piperazine or morpholine ring;
25th the symbol is a single bond, R. Hydroxy R _{2 is} hydrogen and R _{3 is} hydroxy or acyloxy or R- and R ₇ , taken together, form an oxo group;
30th R _{0 represents} a radical selected from cyclopentyl, Cyclohexyl and cycloheptyl is selected, each unsubstituted or ^{substituted by one or more (a 1} ) halogen, (b ¹ ) trihalo-C,, -alkyl, (c ¹ ) C _1-4 -AlCyI, (d ¹ ) C _{1- 4-} alkoxy, (e ¹ ) phenyl, (f) phenoxy are substituted; R., R ₅ , Rg, R ₇ and η have the meanings given in claim 1; as well as the pharmaceutically or veterinarily acceptable salts thereof. 3. A compound according to claim 1, characterized in that R ¹ and R ", independently of one another, are hydrogen or methyl, or R ¹ and R", taken together with the nitrogen atom to which they are attached, form a piperidine or morpholine ring; the symbol is a single bond, R _{1 is} hydroxy R _{2 is} hydrogen and R _{3 is} hydroxy or R2 and R-3, taken together, form an oxo group; 25th R 1 and R ₇ each, independently of one another, represent hydrogen, methyl or fluorine; R ₄ , R ₅ and η have the meanings given in claim 1; Rg is cyclopentyl or cyclohexyl; as well as the pharmaceutically or veterinarily acceptable salts thereof.
5 4. Compound selected from the group consisting of the end: 5c-9e6,1 10 (/, 15 (S) -Trihydroxy-20-nor-i 9-cyclohexylprost-5-en-13-yn acid amide (ynoic acid), 5C-S ^, 1 Λ &, 15 (S) -Trihydroxy-20-nor-i9-cyclopentylprost-5-en-13-yne acid amide, 5c-90O, 11ck, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-1 9-cyclohexyl-prost-5-en-13-yne acid amide, 5c-9c36.11 <λ /, 15 (R, S) -Trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-1 3-yn acid amide, 20 5C-90L- / 11 ₀ U15 (S) -Trihydroxy-1 9, 20-dinor-1 8-cyclohexyl-prost-5-en-13-yn-acid amide, 5c-9d, _r 11 ₀ U15 (S) -Trihydroxy-1 9, 20-dinor-i 8-cyclopentyl-prost-5-en-13-yn-acid amide, 5c-9o! /, 1 1d /, 15 (R) -Trihydroxy-1 6 (S) -f luor-1 9, 20-dinorle-cyclohexyl-prost-S-en-i3-yne-acid amide, Sc-Βφ, 11öC, 15 (R, S) -Trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yne-acid amide, 5c-9st, 11dL, 15 (S) -trihydroxy-1 8, 1 9, 20-trinor-i 7-cyclohexyl-prost-5-en-i 3-yne acid aide, 5c-9oL, 1 lot, 15 (S) -trihydroxy-1 8, 1 9, 20-trinor-i 7-cyclopentyl-prost.-5-en-i3-yne acid amide, 5c-9oL, 11oL, 1 5 (R) -Trihydroxy-1 6 (S) -fluoro-1 8, 1 9,20-trinor-17-cyclohexyl-prost-5-en-13-yne acid amide, 0 5c-9ol, 11ol, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,1 9,20-trinor-17-cyclohexyl-prost-5-en-13-yne-acid amide, 5c-9oL, 1 lot, 15 (R) -Trihydroxy-16 (S) -fluoro-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-yne-acid amide, 15th 5c-9oL, 11cC, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,1 9,20-trinor - ^ - cyclopentyl-prost-S-en-i3-yne-acid amide, 5c-9oL, 11oL, 15 (S) -trihydroxy-1 7, 18,19, 20-tetranor-16-cyclohexyl-prost-5-en-13-yne acid amide, 5c-9ol, 1 lot, 15 (S) -trihydroxy-1 7, 18,19, 20-tetranor-16-cyclopentyl-prost-5-en-13-yne acid amide, 5c-9oL, 1 lot, 1 5 (R) -Trihydroxy-1 6 (S) -fluoro-1 7,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yne acid amide, 5c-9oL, 11oC, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20 _tetranor-16-cyclohexyl-prost-5-en-13-yne-acid amide, 30th 5c-9oC, 11dL / 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18.19 ^ O-trinor - ^ - cyclohexyl-prost-S-en-i 3-insäureamid, 5c-9oL, 11 ₀ L, 15 (R, S) -Trihydroxy-1 6 (S) -fluoro-1 6-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13- in-acid amide, 5c-9dl, 11d ₇ 15 (R) -Trihydroxy-1 6 (R) -fluoro- 1 6-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-amide, 5c-9oC, 11oL, 15 (S) -Trihydroxy-20-nor-i 9-cyclohexylprost-5-en-13-yn-acid-N, N-dimethylamide, 5c-9oC, 11oC, 15 (S) -Trihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide, 5c-9oC, 11oL, 15 (R) -Trihydroxy-1 6 (S) -fluor-20-nor-1g-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethylamide, 5c-9o (., 11oU15 (R, S) -Trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethyl amide, 5c-9cL _e 11oC, 15 (S) -trihydroxy-1 9,20-dinor-18-cyclohexyl-prost = 5-en-13-yn-acid-N, N-dimethylamide, 25 5c-9dU 11dL / 15 (S) -Trihydroxy-1 9, 20-dinor-1 8-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide, 5c-9oU 11oL _f 15 (R) -Trihydroxy-16 (S) -fluoro-1 9,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethyl amide, 5c-9oL, 11οί, 15 (R, S) -Trihydroxy-16 (R) -f luor-20-nor-1g-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethylamide, 5c-9oL, 11oC, 15 (S) -Trihydroxy-18, 19, 20-trinor-i 7-cyclohexyl-prost-S-en-lS-yn-acid-N ^ N-dimethylamide, 5c-9o (., 11cL, 15 (S) -trihydroxy-18,19, 20-trinor-17-0 cyclopentyl-prost-S-en-i3-yn-acid-N, N-dimethyl- amide, 5c-9oL, 11ol, 15 (R) -Trihydroxy-16 (S) -f fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide , 5c-9oC, 11oC, 15 (R, S) -trihydroxy-1 6 (S) -fluoro-1 8,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N , N-dimethylamide,
20th 5C-90CII0L, 15 (R) -trihydroxy-1 6 (S) -f luor-18, 19, 20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide , 5c-9oC, 1 U, 15 (R, S) -Trihydroxy-1 6 (S) -f luor-1 8,19,20-trinor-1V-cyclopentyl-prost-S-en-i3-yn-acid- N, N-dimethylamide, 5c-9oC 1 lot, 1 5 (S) -Trihydroxy-1 7,18,1 9, 20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethyl- amide, _ Q - 5c-9cL, 11cL, 15 (S) -Trihydroxy-1 7, 18,19, 20-tetranor-10-cyclopentyl-prost-S-en-i3-yn-acid-N, N-dimethylamide, 5c-9cL, 11oC, 15 (R) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N- dimethylamide, 5c-9oC, 1 lot-, 15 (R, S) -trihydroxy-16 (S) -fluoro-1 7,18,19,20 0 tetranor-1ö-cyclohexyl-prost-S-en-i3-yn-acid-N, Να imethylamide, 5c-9ol, 11o6,1 5 (R) -Trihydroxy-1 6 (S) -f luoro-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid-N, N-dimethylamide, 5c-9oL, 11oU 15 (R, S) -Trihydroxy-1 6 (S) -f luoro-1 6-methyl-18,19 ^ O-trinor - ^ - cyclohexyl-prost-S-en-i 3-yn acid-N, N-dimethylamide,
20th 5c-9oC, 1 lot, 15 (R) -trihydroxy-1 6 (R) -f luoro-1 6-methyl-18.19 ^ O-trinor - ^ - cyclohexyl-prost-S-en-IS-in-säure-N, N-dimethylamid, 5c-9-Oxo-1 lot, 1 5 (S) -dihydroxy-20-nor-1 9-cyclohexylprost-5-en-13-yne acid amide, 5c-9-Oxo-11oL, 15 (S) -dihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-yne acid amide,
30th 5C-9-OXO-1 ld-, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-1 3-yn acid amide, 5C-9-OXO-1let, 1 5 (R, S) -dihydroxy-1 6 (S) -f luor-20-nor-1S-cyclohexyl-prost-S-en-i3-yne acid amide, 5c-9-Oxo-11oU 15 (S) -dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-i3-yne acid amide, 5c-9-Oxo-11oL, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-yne acid amide, 0 5C-9-OXO-1 ld, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yne acid amide, 5C-9-OXO-1 1öC, 1 5 (R, S) -dihydroxy-1 6 (R) -f luor-20-nor-ig-cyclohexyl-prost-S-en-i3-yne-acid amide, 15th 5C-9-OXO-1 1cjC, 15 (S) -dihydroxy-1 8, 1 9, 20-trinor-1 7-cyclohexyl-prost-5-en-13-yne acid amide, 5C-9-OXO-11σΙ, 15 (S) -dihydroxy-18, 1 9,20-trinor-i 7-cyclopentyl-prost-ö-en-i3-yne-acid amide, 5C-9-OXO-11oL, 15 (R) -dihydroxy-1 6 (S) -f luor-18,19, 20-trinor-17-cyclohexyl-prost-S-en-13-yne-acid amide, 5C-9-OXO-11oL, 15 (R, S) -dihydroxy-16 (S) -f fluoro-1 8,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid amide , 5C-9-OXO-11o6,15 (R) -dihydroxy-1 6 (S) -f luor-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-yne-acid amide, 30th 5C-9-OXO-1 lit, 15 (R, S) -dihydroxy-1 6 (S) -f luor-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-in acid amide, 50-9-0x0-11 ^, 15 (S) -dihydroxy-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-yne-acid amide, 5C-9-OXO-1I ₀ C, 15 (S) -dihydroxy-17,18,1 9,20-tetranor-16-cyclopentyl-prost-5-en-13-yne acid amide, 5C-9-OXO-11oU 15 (R) -dihydroxy-16 (S) -f fluoro-1 7,18,1 9,20-tetranor-1S-cyclohexyl-prost-S-en-13-yne-acid amide , 0 5C-9-OXO-1 10L, 15 (R, S) -dihydroxy-16 (S) -f luoro-1 7,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13 -in-acid amide, 5C-9-OXO-1 "loL, 15 (R) -dihydroxy-16 (S) -f fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13 -ic acid amide, 5c-9-Oxo-11o6,15 (R, S) -dihydroxy-1 6 (S) -f luoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13- insäureamid /
20th 5C-9-OXO-11oC, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynamide, 5c-9-Oxo-11oL, 15 (S) -dihydroxy-20-nor-19-cyclohexylprost-5-en-13-yn-acid-N, N-dimethylamide _f 5c-9-Oxo-11öL, 15 (S) -dihydroxy-20-nor-1 9-cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide, 30th 5C-9-OXO-1 λό ^, 15 (R) -dihydroxy-1 6 (S) -f luoro-20-nor-1 9-cyclohexyl-prost-S-en-IS-yn-acid-NjN-dimethylamide , 5C-9-OXO-11oC, 15 (R, S) -dihydroxy-1 6 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N- dimethylamide, 50-9-0x0-110 ^, 15 (S) -dihydroxy-19, 20-dinor-1 8-cyclohexyl-prost-5-en-i3-yn-acid-N, N-dimethylamide, 5c-9-Oxo-11oL, 1 5 (S) -dihydroxy-1 9, 20-dinor-i 8-eyelopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide, 5c-9-Oxo-11oL, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide ,
15th 5c-9-Oxo-11ol, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide , 5C-9-OXO-11oL, 1 5 (S) -dihydroxy-18, 19, 20-trinor-i 7-cyclohexyl-prost-5-en-i3-yn-acid-N, N-dimethylamide, 5C-9-OXO-1 IcL, 1 5 (S) -dihydroxy-18, 1 9, 20-trinor-i 7-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide, 5C-9-OXO-11ct, 15 (R) -dihydroxy-16 (S) -f luoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-i3-yn-acid-N, N -dimethylamide,
30th 5C-9-OXO-11Λ, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexy1-prost-5-en-13-yn-acid-N, N-dimethylamide, 15 (R), dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide, 5C-9-OXO-1I ₀ C, 15 (R, S) -dihydroxy-1 6 (S) -f luor-1 8,19,20 trinor - ^ - cyclopentyl-prost-S-en-i3-in- acid-N, N-dimethylamide, 5c-9-Oxo-1 lot, 15 (S) -dihydroxy-17,18,1 9,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethyl- amide, 5c-9-0XO-11oC, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide , 5C-9-OXO-11oC, 15 (R) -dihydroxy-16 (S) -fluoro-1 7,18,19,20-tetranor-io-cyclohexyl-prost-5-en-13-yn acid -N, N-dimethylamide,
20th 5c-9-Oxo-11 <JL, 15 (R, S) -dihydroxy-1 6 (S) -fluoro-1 7, 1 8, 1 9, 20 · tetranor-1ö-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethylamide, 5C-9-OXO-11 ^ w 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn acid N, N-dimethylamide, 5c-9-Oxo-11öU 15 (R, S) -dihydroxy-16 (S) -fluoro-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-S-en- 13-yn-acid-N, N-dimethylamide, 50-9-0x0-1100.15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-1V-cyclohexyl-prost-S-en-13-in- acid-N, N-dimethylamide, 5c-9-Oxo-1id, 15 (S) -dihydroxy-20-nor-i 9-cyclohexyl prost-5-en-13-yn-acid-morpholinamide, 5c-9-Oxo-11d, 15 (S) -dihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid-morpholinamide, 10 5C-9-OXO-11oC, 15 (R) -dihydroxy-1 6 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide, 5c-9-Oxo-1 lot, 15 (R, S) -dihydroxy-1 6 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamid, 5c-9-Oxo-11oC, 1 5 (S) -dihydroxy-1 9, 20-dinor-i 8-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide, 5c-9-0XO-11 oil, 15 (S) -dihydroxy-19, 20-dinor-1 8-cyclopentyl-prost-5-en-i3-yn-acid-morpholinamide, 5C-9-OXO-11 * U 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinor-1e-cyclohexyl-prost-S-en-i3-yn-acid-morpholinamide, 5C-9-OXO-1 lot, 1 5 (R, S) -dihydroxy-1 6 (R) -f luoro-20-nor-1g-cyclohexyl-prost-ö-en-13-yn-acid-morpholine amide 5C-9-OXO-1 1öL, 1 5 (S) -dihydroxy-1 8, 1 9, 20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide, 5c-9-Oxo-116, 15 (S) -dihydroxy-1 8, 1 9, 20-trinor-1 7-cyclopentyl-prost-5-en-i 3-yn-acid morpholinaitiid, 5C-9-OXO-11oC, 15 (R) -dihydroxy-1 6 (S) -f luor-1 8,1 9,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid- morpho 5C-9-OXO-1 * [(L ·, 15 (R, S) -dihydroxy-16 (S) -f luoro-1 8,19,20 trinor-17-cyclohexyl-prost-5-en-13 -in-acid-morpholinamide, 5C-9-OXO-11c6,15 (R) -dihydroxy-1 6 (S) -f luor-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid morpholine amide,
15th 50-9-0x0-1100.15 (R, S) -dihydroxy-1 6 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid-morpholinamide, 5C-9-OXO-11ot> 1 5 (S) -dihydroxy-1 7, 18,1 9, 20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide, 5C-9-OXO-1 lot, 1 5 (S) -dihydroxy-17,18,19, 20-tetranor-Ί ö-cyclopentyl-prost-S-en-i3-yn-acid-morpholinamide, 5C-9-OXO-11i? U 1 5 (R) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1e-cyclohexyl-prost-S-en-i3-yn acid -0 morpholinamide, 50-9-0x0-11 ^, 15 (R, S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-10-cyclohexyl-prost-S-en-13-yn acid -morpholinamide, 5C-9-OXO- 1λϋί, 15 (R) -dihydroxy-1 6 (S) -fluoro-1 6-methyl-18,19,20-trinor-1V-cyclohexyl-prost-S-ene-13-yne acid morpholinamide, 5C-9-OXO-1 lot, 1 5 (R, S) -dihydroxy-1 6 (S) -fluoro-1 6-0 methyl-18,19,20-trinor-iT-cyclohexyl-prost-S-en-13-yn-acid-morpholinamide, and 5C-9-OXO-1 1uC, 15 (R, S) -dihydroxy-1 6 (R) -f luoro-1 6-methyl-18,19,20-trinor-1V-cyclohexyl-prost-5-5 en-13-yn-acid morpholinamide. 5. Process for the preparation of compounds of the formula (I) listed according to Claim 1, characterized in that characterized in that the method comprises: (a) a reactive derivative of an optically active or racemic compound of formula (II) COOH whereby in case the symbol has a double bond means, R 'is a hydrogen atom and R "and R 'taken together form an oxo group; while in the case where the symbol denotes a single bond, R 'is hydroxy or a protecting group attached to the ring through an ether oxygen atom, R _? Is hydrogen, R '., Hydroxy, acyloxy or a protecting group attached to the ring through an ether oxygen atom, or R ^ and R ^1. ,, taken together, form an oxo group; one of the two radicals R ¹ . and R 'is hydroxy or a protecting group attached through an ether oxygen atom and the other is hydrogen; as well as R, -, R. ,, η and R ₀ the given in claim 1 O / O have benign meanings; with a compound of the formula (III) H-N (III) to bring to reaction, where R ¹ and R "have the meanings given in claim 1, 30 so as to give in this way an optically active or racemic compound of formula (IV) CON ¹ C ₅ CCC- (CH ₀ ) -R Ij f ώ η CF / ^R i -R ₀ η ο (IV) where R ¹ , R ", R ' ₃ , R ₂ , R ^, R' ₄ , R ' ₅ , R _g , R ₇ , η and R _{0 have} the meanings given above and then, if necessary, to remove the hydroxyl protective groups; or (b) an optically active or racemic compound of the formula (V) (V) MC C- (CH _-) -R whereby M is -ChC- or -CH = C- and X is bromine, chlorine or iodine; Z is hydroxy or a protecting group attached to the ring through an ether oxygen atom; one of the two radicals R ¹ . and RV is hydroxy or a protecting group attached to the ring through an ether oxygen atom and the other is hydrogen; and R _fi , R ₇ / η and R "have the meanings given in claim 1, to react with a Wittig reagent which contains a - (CH ₂ K-CON ^ "group, where R 'and R" have the meanings given in claim 1, to give an optically active or racemic compound of the formula ( VI) H OH CONC (VI) in which R ¹ , R ", Z, R ' ₄ , R' ₅ , R _g , R ₇ , η and R _{g have} the meanings given above and 10 when the 11- and 15-hydroxy groups are protected, can be esterified, if desired, to give a 90 ^ acyloxy derivative of a compound of the formula (VI) and then the protecting groups in the 11 and / or 15 positions, if any, both in a compound of the formula (VI) as well as in their acyloxy derivatives to remove such a To give compound of formula (I) in which R-, hydroxy or acyloxy, R- is hydrogen and R. Hydroxy are, the symbol means a single bond and R ¹ , R ", R", R _c , R ,, R- ,, η and R ₀ are 4 D D / O Claim 1 have given meanings; or 15 20 (c) to oxidize an optically active or racemic compound of the formula (VII) H OH (VII) 25th whereby Z 'one through an ether oxygen atom to the ring is attached protecting group; 30th one of the two radicals R ″, and R ¹ V is a protective group bonded through an ether oxygen atom - 21 - and the other are hydrogen; and R ¹ , R ", R _fi , R ₇ , η and R_ have the meanings given in claim 1, to give an optically active or racemic compound of formula (VIII) in which R ¹ , R ", Z ¹ , R" R "R ,, R- ,, η and R _Q die 4 D D / O have previously given meanings, and in turn the removal of the ether protective groups is subjected to, depending on the reaction conditions, either a compound of the formula (I), in which there is a single bond, R. Hydroxy, R "and R_, taken together, form an oxo group and R ¹ , R", R ₄ , Rj-, Rg / R ₇ / η and Ro have the meanings given in claim 1, or a compound of the formula (I) , in which is a double bond, R. hydrogen is, R "and R ^, taken together, form an oxo group and R ', R", R ₄ , R ₅ , R _g , R ₇ , η and R _{g have} the meanings given in claim 1 to give; and / or to convert a compound of the formula (I), if desired, into a salt or to obtain a compound of formula (I) free of a corresponding salt and / or a compound of the formula (I) or a corresponding salt, if desired, into a to convert another compound of the formula (I) or a salt thereof and / or a mixture of isomers, if desired, to be converted into the individual isomers. 6. Optically active or racemic compound of the formula (IV) ^T C = CC- G- (CH ₀ ) -R ₅ , R [ί ' ₅ R ₇ wherein R ¹ , R ", R ', R ₂ , R' -, / ^R> 4 ' ^{R <} 5' ^R 6 ' ^R 7' ⁿ and R _{0 has} the meanings given in claim 5 ο as well as the pharmaceutically or veterinarily acceptable salts thereof. 7. Pharmaceutical composition, characterized in that it is a suitable Carriers and / or diluents as well as, contains as an active principle a compound of formula (I) according to any one of claims 1 to 4 and 6, or a pharmaceutically acceptable salt thereof.
5 8. A compound or pharmaceutically acceptable salt thereof according to any one of the claims. 1 to 4 and 6, for use in a surgical treatment of the human or animal body, a therapy or a diagnosis made on the human or animal body. 9. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and 6 or A pharmaceutical composition according to claim 7 for use in administration to humans or Animal used to induce labor or to abort a dead fetus in pregnant females, to control fertility in female animals, the formation of gastrointestinal ulcers Reduce, or turn off, the healing process of gastrointestinal ulcers to speed up, as well as to lessen the undesirable gastrointestinal side effects caused by systematic Administration of anti-inflammatory prostaglandin synthetase inhibitors originate.