BE898169A - Amide derivatives of 13,14-didehydro-cycloalkyl-prostaglandins. - Google Patents

Abstract

The invention relates to 13, 14-didehydro-cycloalkyl-prostaglandin amides. These new compounds corresponding to formula (I), and the invention relates both to optical isomers and to racemates. These compounds are valuable pharmaceutical substances.

Description

       

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 registered by the so-called company: FARMITALIA CARLO ERBA S. p. AT.
 EMI1.1
 1 having for object: Amidic derivatives of 13, 14-didehydro-cycloalkyl-prostaglandins Qualification proposed: PATENT OF INVENTION

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The present invention relates to amides of 13, 14-didehydrocycloalkyl-prostaglandins, to a process for the preparation of these compounds, to pharmaceutical compositions intended for human and veterinary medicine which contain them, as well as to certain intermediate substances suitable for the preparation of these compounds.



   The present invention relates to optically active isomers or racemates of prostaglandin derivatives which correspond to formula (I)
 EMI2.1
 in which each of the symbols R'and R "represents, independently, a hydrogen atom, an alkyl radical in C1-C6 'aryl or heterocyclic, or else R'and R", considered with the nitrogen atom to which they are linked, form a heterocyclic nucleus; the symbol - represents a single or double bond where: a) when the symbol - represents a double bond,
R1 denotes a hydrogen atom and R2 and Reconsidered

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 together form an oxo group;

   b) when the symbol - represents a single bond,
R1 denotes a hydroxyl radical, R2 denotes a hydrogen atom and R3 denotes a hydroxyl or acyloxy radical, or else R2 and Reconsidered together, form an oxo group; one of the symbols R4 and R5 represents a hydroxyl radical, while the other represents a hydrogen atom; each of the symbols R6 and Ry represents, independently, a hydrogen atom, a C1-C4 alkyl radical or a fluorine atom; n is 0, 1, 2, or 3; Ro represents a cycloalkyl group, unsubstituted or substituted by one or more substituents chosen from a ') halogens; b ') a C1-C6 trihaloalkyl radical; c ') a C1-C4 alkyl radical;

   d ') a C1-C4 alkoxy radical; e ') a phenyl radical and f) a phenoxy radical; as well as the salts of these compounds, acceptable in human or veterinary pharmacy.



   The compounds and the salts in accordance with the present invention have the advantage of having, when administered orally, an activity greater than that of the related compounds described in the prior art, more particularly those defined in the British patent application. NO 2 009 145 A. This higher activity is made possible by their better absorption in the gastrointestinal tract.



   The above-mentioned formula, which defines the compounds to which the scope of the present invention extends, includes all possible isomers, more particularly stereoisomers, as also their mixtures, for example mixtures of epimers. The double bond in positions 5 (6) is a cis double bond. In the formulas of the compounds in accordance with the present invention, the hatched lines

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 (//////////) indicate that the substituents are in the &alpha; configuration, that is to say below the plane of the cycle or of a side chain.
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  The corners (-t) indicate that the substituents are in the P configuration, that is to say above the plane of the cycle or of a side chain. The wavy lines () indicate that the substituents, when the carbon atom to which they are linked is asymmetrical, can be in configuration a or ss or in configuration (a, P), that is to say a mixture of the two epimers . For example, the hydroxyl group linked to the carbon atom in position 15, can be in configurations (a), (ss) and (a, P), that is to say a mixture of the epimers 15 (a ) and 15 (ss).



   Similarly, when the carbon atom in position 16 has two different substituents, these can be in configurations 16 (a), 16 (ss) and 16 (a, ss), that is to say a mixture of the two epimers 16 (a) and 16 (p).



  The symbol S or R of each chiral center is assigned according to the sequential rule arranging the ligands in order of decreasing atomic number.



   The alkyl, alkoxy and trihaloalkyl radicals can be straight or branched chains.



   A halogen atom is preferably a fluorine, chlorine or bromine atom.



   A halogen atom is preferably a fluorine, chlorine or bromine atom. When one of the symbols
 EMI4.2
 or the two symbols R ′ and R ″ represent C 1 -C 6 alkyl radicals and C 1 -C alkyl alkyl, these are preferably methyl, ethyl, propyl or butyl groups.



   When one or both of the symbols RI and R "represent aryl radicals, they are preferably phenyl groups.



   When one or both of the symbols RI and R "represent heterocyclic groups, the radical

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 heterocyclic is preferably chosen from pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pipridyl, piperazinyl, morpholinyl and pyrazolidinyl groups.



   When R ′ and R ″, considered with the nitrogen atom to which they are attached, form a heterocyclic ring, the heterocyclic ring is preferably chosen from the pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyidolinyl, piperidino, piperazinyl radicals , morpholino and pyrazolidinyl. R'and R ", as individual heterocyclic radicals, can also be piperidino or morpholino groups.



   When R3 represents an acyloxy radical, the latter is preferably a benzoyloxy group or a group
 EMI5.1
 C-C alkanoyloxy and Cp-C alkanoyioxy, for example acetoxy or propionyloxy.



  When one or both of the symbols R6 and Ry represent C 1 -C 4 alkyl radicals, they are preferably methyl or ethyl radicals.



   When Rg represents a C3-C7 cycloalkyl group optionally substituted in the manner described above, under paragraphs a ') to f), it is preferably a radical chosen from cyclopentyl, cyclohexyl and cycloheptyl groups.



   The compounds according to the present invention which are preferred are the substances which correspond to formula (I) in which:
 EMI5.2
 R'and R''represent independently of hydrogen atoms or CC alkyl radicals, or else R'and R ", considered with the nitrogen atom to which they are attached, form a pyrrolyl, pyrazolyl, imidazolinyl group , imidazolidinyl, pyrazolinyl, piperidino, piperazinyl or morpholino; the symbol represents a single bond, R1 represents the hydroxyl radical, R2 represents a hydrogen atom

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 and R3 represents the hydroxyl radical or an acyloxy group and R2 and R3, taken together, form an oxo group;

     Rp represents a radical chosen from cyclopentyl, cyclohexyl and cycloheptyl groups, each of these groups not being substituted or being substituted by one or more substituents chosen from a ') halogens, b') trihaloalkyl radicals CC, c ' ) the CC 1 alkyl radicals, d ') the alkoxy radicals, e') the phenyl group, f) the phenoxy radical; R4, R5, R6, R7 and n have the meanings previously assigned to them; as well as the salts of these compounds acceptable in human or veterinary pharmacy.



   Particularly preferred compounds according to the invention are the substances which correspond to formula (I) in which
 EMI6.1
 R * and R''re represent, independently, hydrogen atoms or methyl radicals; or R'and R ", considered with the nitrogen atom to which they are attached, form a piperidino or morpholino nucleus; the symbol - represents a single bond, R1 represents the hydroxyl radical, R2 represents an atom d hydrogen and R3 represents the hydroxyl radical, or else R2 and 43, taken together, form an oxo group;
 EMI6.2
 each of the symbols R6 and Ry represents, independently, each of the symbols R e ep a hydrogen atom, a methyl radical or a fluorine atom;
 EMI6.3
 R e R ,, R and n have the meanings previously assigned to them;

     Rn represents the cyclopentyl or cyclohexyl radical; as well as the salts of these compounds acceptable in human or veterinary pharmacy.



   As mentioned above, the scope of the present invention also extends to the salts of these compounds acceptable in human or veterinary pharmacy.

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   As mentioned above, the scope of the present invention also extends to the salts of these compounds acceptable in human or veterinary pharmacy.



   As examples of the particularly preferred salts of the compounds of formula (I), mention may be made of the acid addition salts obtained with inorganic acids, for example nitric, hydrochloric, hydrobromic, hydroiodic, sulfuric acid, perchloric, and phosphoric, or with organic acids, for example acetic, propionic, glycolic, lactic, roxalic, malonic, malic, maleic, tartaric, citric, benzoic, fumaric, cynnamic, mandelic, salicylic and with organic acids - sulfonic nicks, for example methanesulfonic acid, p-toluenesulfonic and cyclohexyl-sulfonic.



   As examples of preferred compounds in accordance with the invention, there may be mentioned the amides of the following acids: 5c-9 &alpha;, 11 &alpha;, 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5 - -en-13-ynoic;
 EMI7.1
 5c-9 &alpha;, 11 &alpha;, 15 (S) -trihydroxy-20-nor-19-cyclopentyl-prost-5- -en-13-yno: que; 5c-9 < <ll <15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyctohexyl-prost-5-n-13-ynoique; 5c-9ell 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyctohexyl-prost-5-n-13-ynoique; 5c-9o (, 11o (, 15 (S) -trihydroxy-19, 20-dinor-18-cyclohexyl-prost- - 5-n-13-ynoique; 5c-9c <.. 11 b <.. 15 (S) -tri hydroxy-19, 20-di nor-18-cycl opentyl-prost- - 5-en-13-yno! '; 5c-9- .. 15 (R) -tr i hydroxy-16 (S) -f 1 uoro-19, 20-di nor-18- - cyclohexyl-prost-5-n-13-ynorque;

   

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 EMI8.1
 5c-911 ' <, 15 (R, S) -trihydroxy-16 (R) -f 1 uoro-20-nor-19-cyclohexyl-prost-5-en-13-yno! than ; 5c-9c, ll <, l5 (S) -tr; hydroxy-l8l920-tr! nor-17-cyc! ohexy! - - prost-5-en-13-ynoique; 5c-9o (, ll, 15 (S) -trihydroxy-18, 19, 20-trjnor-17-cyclopentylprost-5-en-13-ynoique; 5c-9o <, ll, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor-17- - cyc! ohexy) -prost-5-en-l3-yno! qjte; 5c-9c, lle, 15 (R, S) -tr: hydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cycl ohexyl-prost-5-en-13-ynoique; 5c-9, 11o <, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyc) opentyl-prost-5-en-13-ynoi'que 5c-9 <= <ll. 15 (R, S) -trihydroxy-16 (S) -fluoro-18, 19,10-trinor- - 17-cyclopentyl-prost-5-en-13-ynoique; 5c, 9o (, 11b (, 15 (S) -tihydroxY-17, 18, 19, 20-t: tranor-16-cycl0hexyl-prost-5-en-13-ynoique;

   5c-9., Llo 15 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cyclopenty l-prost-5-en-13-yno ïq ue; 5c-9X. she <l5 (R) -tr: hydroxy-l6 (S) -ftuoro-17l8l9v20-tet. ranor- -16-cyclohexyl-prost-5-en-13-ynoique; 5c-9o <, llc, l5 (R, S) -trihydroxy-l6 (S) -fluoro-17 18rl9, 20-tetra-. nor-16-cyc 1 ohexyl-prost-5-n-13-yno jeque; 5c-9 <', ll <, 15 (R) -tri hydroxy-16 (S) -f! uoro-16-me-thyl-18, 19, 20- - trjnor-17-cyclohexyl-prost-5-n-13-ynoj'que; 5c-9, 11 (, 15 (R, S) -trihydroxy-16 (S) -fluoro-16-methyl-18, 19, 20-trinor-17-cyclohexyl-prost-5-n-13-ynojque; 5c-9c <'. llcl5 (R) -tr: hydroxy-l6 (R) -f! uoro-l6-methyt-l8, l9. 20- - trinor-17-cyclohexyl-prost-5-n-13-ynoic;

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 the
 EMI9.1
 N, N-dimethyl-amides of the following acids: 5c-9c <, 11 <= <, 15 (S) -trihydroxy-20-nor-19-cycl ohexyl-prost-5- / 3 ..



  - en-lj-ynoïque; 5c-9 &alpha;, 11 &alpha;, 15 (S) -trihydroxy-20-nor-19-cyclopentyl-prost-5--en-13-ynoïque;
 EMI9.2
 5c-9 &alpha; <, 11 &alpha;, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cycl ohexyl-prost-S-n-13-ynoique; 5c-9'He, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyc! o- hexyl-prost-5-en-13-ynoïque; 5c-9t 11 #, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexyl-prost- - 5-en-13-yno! eu; 5c-9 @, 11 @, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentyl-prost- -5-en-13-ynoique;
 EMI9.3
 5c-911e <, 15 (R) -trihydroxy-16 (S) -fluoro-19,2C0-dinor-18- - cycl ohexyl-prost-5-en-13-ynoique; 5c-9 <= <, llo <, l5 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-S-en-13-ynoiq'ue.



  5c-9 <11, 15 (S) -trihydroxy-18, 19, 20-trinor-17-cyclohexyl- -prost-5-en-13-ynoi'que; 5c-9, 11 <15 (S) -trihydroxy-18, 19, 20-trinor-17-cyclopentylprost-5-en-13-ynoique; 5c-911 <. 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor-17- - cycl ohexyl-prost-5-en-13-yno'que; 5c-9, lll5 (R, S) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor- 5c-gt., - 17-cycl ohexyl-prost-5-en-13-ynoi'que ; -

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 EMI10.1
 5c-9, 11, 15 (R) -trihydroxY-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyclopentyl-prost-5-en-13-ynoique; 5c-9 110 (, 15 (R, S) -tr {.hydroxy-16 (S) -ftuo.ro-l8.l9. 10-tr. Nor- - 17-cyclop & ntyl-prost-5-en- l3-ynoic; 5c, 911cl5 (S) -trihydroxy-17 <-l8 l920-tetranor-l6-cyc) ohexyl-prost-5-en-13-ynoíque; 5c-9o (, 11o (, 15 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cyc 10pen-tyl-prost-5-en-13-yno'ique;

   5c-90 (, 1115 (R) -trihydroxy-16 (S) -fluoro-17/18, 19, 20-tetranor- -16-cyclohexyl-prost-5-en-13-yno'ique; 5c-91I <. 15 (R, S) -trihydroxy-16 (S) -fluoro-17, 18; 19, 20-tetranor-16-cyclohexyl-prost-5-en-13-yno '! than ; 5c-9 = <, 11 15 (R) -tr 1 hydroxy-16 (S) -f 1 uoro-16-me "thyi-l. &, -19, 20-- - trinor-17-cyclohexyl-prost-S-en- 13-ynoïquej- 5c-911.

   (. 15 (R, S) -trihydroxy-16 (S) -fluoro-16-methyl- - 18, 19, 20-tr i nor-17 -cyc 1 ohexy I-; -prost- 5-e'n- 13-yno'i que; 5c-9 0 (, 110 (, 15 (R) -tr i hydroxy-16 CR) -f 1 uoro-16 -méthy 1-1-8 ,. 19, 20 - tri nor- 17-cycl ohexyl-prost-5-en-13-yno'i que;

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 EMI11.1
 the amides of the following acids: 5c-9-oxo-11, 15 (S) -dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-ll, 15 (S) -dihydroxy-20-nor-19-cyclopentyi-prost- - 5-en-13-yno if que; 5c-9-oxo-llo <, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclo-; ' hexyl-prost-5-en-13-ynoique; 5c-9-oxo-11 (R, S) -dihydroxy-6 (S) -fluoro-20-nor-19- - cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-llo (, 15 (S) -dihydroxy-l9, 20-dinor-18-cyclohexyl- - prost- 5-en-13-yno ïque; 5c-9-oxo-llcl5 (S) -dihydroxy -19, 20-dinor-18-cyclopentyl- - prost-5-n-13-ynoic;

   5c-9-oxo-llc <, 15 (R) -dihydroxy-16 (S) -fluoro-19, 20-dinor-18- -cyclohexyl-prost-5-e 'n-13-ynoi. than ; 5c-9-oxo-ll (, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19- -cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo- ll, 15 (S) -dihydroxy-18, 19, 20-trinor-17-cyclohexyl- -prost-5-en-13-ynoique; 5c-9-oxo-ll c, 15 (S) -dihydroxy-18, 19, 20-trinor-17-cyclopentyl- -prost-5-en-13-ynoi'que; 5c-9-oxo-11, 15 (R) -dihydroxy-16 (S) -fluoro-18, 19, 20 -trin01 "- - 17-cyclohexyl-prost-5-n-13-ynoque; 5c-9-oxo-llc (, 15 (R, S) -dihydroxy-16 (S) -fluoro-18-19-20- tri nor- -17-cyclohexyl-prost-5-en-13-yno ') that ;; 5c-9-oxo-11, 15 (R) -di hydroxy-16 (S) -f 1 uoro-18, 19 , 20-tr i nor- -17-cyclopentyl-prost-5-en-13-yno! 'Qje;

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 EMI12.1
 Sc-9-oxo-llo (, 1S (R, S) -dihydroxy-16 (S) -fluoro-18, 19, 20-tri nor- - 17-cyclopenty! -Prost-5-en-13-ynoique;

   5c-9-oxo-11,15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyctohexyl-prost-5-en-13-ynoi'que; 5c-9-oxo-llo (, lS (S) -di hydroxy-17, 18, 19, 20-tetranor-16-cy clopentyl-prost-S-n-13-yno i'que ;.



  5c-9-oxo-11o <, lS (R) -dihydroxy-16 (S) -fluoro-17, 18, 19, 20-tetranor- -16-cyclohexyl-prost-5-en-13-ynoi'que; Sc-9-oxo-110 (, lS (R, S) -dihydroxy-16 (S) -fluoro-17, 18, 19, 20- - tetranor-16-cyclohexyl-prost-5-en-13-ynoique; Sc-9-oxo-11, lS (R) -dihydroxy-16 (S) -fluoro-16-methyl- -18, 19, 20-tr) nor-17-cyctohexyl-pros't: -5-en- 13-yno '! than ; 5c-9-oxo-lle, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl- - 18719, 20-tr i nor-17-cyc! ohexyl-prost-5-en-13-ynoque; 5c-9-oxo-llc, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-m {thyl- -18, 19, 20-trinor-17-cyclohexyl-prost-5-een-13 -ynoi'que

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   5c-9-oxo-110 10 (S) -dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-11 @, 15 (S) -dihydroxy-20-nor-19-cyclopentyl-prost- -5-en-13-ynoic;

   
 EMI13.1
 5c-9-oxo-ilb <, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoipe; 5c-9-oxo-1115 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19- - cycl ohexyl-prost-5-en-13-yno! than ; 5c-9-oxo-11 15 (S) -dihydroxy-19, 20-dinor-18-cyclohexyl- - prost-5-en-13-ynoique; 5c-9-oxo-11 15 (S) -dihydroxy-19, 20-dinor-18-cyclopentyl- -prost-5-en-13-yno! '; 5c-9-oxo-lle,, <, 15 (R) -dihydroxy-16 (S) -fluoro-19, 20-dinor-18- -cyclohexyl-prost-5-en-13-ynoi * que; 5c-9-oxo-l10 (, lS (R, S) -d: hydroxy-l6 (R) -f) uoro-20-nor-l9- -cyclohexyl-prost-5-'én-13-ynoi'que ; 5c-9-oxo-1115 (S) -dihydroxy-18, 19, 20-trinor-17-cyclohexyl- - prost-5-en-13-ynoique; 5c-9-oxo-lll5 (S) -dihydroxy-18, 19, 20-trinor-17-cyc! opentyl- - prost-5-en-13-yr'6! than ; 5c-9-oxo-11, 15 (R) -dihydroxy-16 (S) -fluoro-18, 19, 20-trinor- -17-cyclohexyl-prost-5-en-13-yno! ';

   5c-9-oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18-19-20-trinor- -17-cyclohexyl-pros-5-en-13-ynoique; 5c-9-oxo-ll <, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor- -17-cyclopentyl-prost-5-en-13-ynoïque;

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 EMI14.1
 5c-9-oxo-llo <, 15 (R, S) -dihydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyclopentyl-prost-5-en-13-ynoique; 5c-9-oxo-I1 (, 15 (S) -dihydroxy-17, 18, 19, 20-tetranor-16-cyclohexyl-prost-5-en-13-ynoi que; 5c-9-oxo-l10 (, 15 (S) -dihydroxY-. 17, lg, 19, 20-ttranor-16-cyclopentyl-prost-5-een-13-ynoi'que; 5c-9-oxo-11o (, 15 (R) -di hydroxy -16 (S) -ff uoro-17 ,. 18, 19, 20-tetranor- -16-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-ll, 15 (R, S) - dihydroxY-16 (S) -fluoro-17, 18, 19, 20- - tetranor-16-cyclohexyf-prost-5-n-13-ynoique;

   5c-9-oxo-ll <, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl- - 18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-yno! than ; 5c-9-oxo-110 (, 15 (R, S) -dihydroxy-16 (S) -fluoro-methyl-.



  - 18, 19, 20-tr! nor-17-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-11, 15 (R, S) -d! hydroxy-16 (R) -f! uoro-l6-n! ettiyt- - l8, 19, 20-tr: nor-17-cyc! ohexyt-prost-5-en-l3-yno: que;

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 EMI15.1
 the morpholin-amides of the following acids: 5c-9-oxo-ll. 15 (S) -dihydroxy-20-nor-19-cyclohexyl-prost-5- - en-13-yno! than ; 5c-9-oxo-llc, 15 (S) -d! hydroxy-20-nor-19-cyclopentyl-prost- - 5-en-13-ynoÎq ue; 5c-9-oxo-11, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-n-13-yno¯; - 5c-9-oxo-11,15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19- -cyclohexyl-prost-5-en-13-ynoique; .

   Sc-9-oxo-11, 15 (S) -di hydroxy-19, 20-di nor-18-cycl ohexyl- - prost-5-n-13-ynoique; 5c-9-oxo-llc15 (S) -dihydroxy-19, 20-dinor-18-cyclopentyl- -prost-5-en-13-yno! than ; 5c-9-oxo-11C (, lS (R) -dihydroxy-16 (S) -fluoro-19, 20-dinor-18- - cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo- ll, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19- -cyclohexyl-prost-5-en-13-yno! que; Sc-9-oxo-IIÓ (, lS ( S) -dihydroxy-18, 19, 20-trinor-17-cyclohexyl- -prost-5-étt-13-ynot que; 5c-9-oxo-llo <, l5 (S) -dihydroxy-l8, l9, 20-trinor-l7-cyc! openty! - - prost-5-en-13-yn6! than ; 5c-9-oxo-1 (, lS (R) -dihydroxy-16 (S) -fruoro-18, 19, 20-trinor- - 17-cyclohexyl-prost-5-en-13-ynoique; - '.



  5c-9-oxo-llc, 15 (R, S) -dihydroxy-16 (S) -f! uoro-18-19-20-trinor- -17-cycl ohexyl-prost-5-en-13-ynoi * que;, 5c-9-oxo-11, 15 (R) -dihydroxy-16 (S) -fluoro -18, 19, 20-trinor- - 17-cyclopentyl-prost-5-en-13-ynoique;

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 EMI16.1
 5c-9-oxo-ll, 15 (R, S) -dihydroxY-16 (S) -fluoro-18, 19, 20-tri nor- -17-cyc) openty) -prcst * -5-sn-l3- yno! than ; 5c-9-oxo-11 @, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoïque; 5c-9-oxo-11 @, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic; 5c-9-oxo-11 @, 15 (R) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor- - 16-cyclohexyl-prost-S-en-13-ynoique;

     5c-9-oxo-l10 15 (R, S) -dihydroxy-16 (S) -fluoro-17,18,19,20-
 EMI16.2
 -tetranor-16-cyclohexyl-prost-5-en-13-yno) that; 15 (R) -di hydroxy-16 (S) -f 1 uoro-16-m "thyl- 5c-9-oxo-llze e - 18, 19, 20-tri nor-17-cycl ohexy'l-prost- 5-en-13-ynoi'tque; 5c-9-oxo-110 15 (R, S) -di hydroxy-16 (S) -f 1 uoro-16-me "thyl -18, 19, 20-trinor- 17-cyclohexyl-prost-5-en-13-ynoi'que; 5c-9-oxo-1115 (R, S) -d: hydroxy-16 (R) -fluoro-16-méthyt- - 18, 19, 20-tri nor-li-cycl ohexyl-prost-Sn-13-ynoi 'than.



   When in the above-mentioned list of compounds and below in the examples and claims, reference is made to
 EMI16.3
 Reference is made to the expressions "morpholin-amide": ', "piperidin-amide". "piperazin-amide" and "pyrazolin-amide", these also aim to cover the amide radicals in the case where the atom d amide nitrogen is
 EMI16.4
 a cyclic nitrogen atom in the heterocyclic radical.



  So these groups are respectively
 EMI16.5
 "\ / \.



  - CONjp, -CON, -CONfH and-CON J '

  <Desc / Clms Page number 17>

 
Other names for these groups could be N, N-ethyleneoxyethylene amide, N, N-pentamethylene amide, N, N-ethyleneaminoethylene amide and N, N, -n-propylenaminoamide respectively.



   The compounds of general formula (I) can be prepared by implementing a process characterized in that: a) a reactive derivative of an optical isomer or of a racemic of a compound of the form is reacted (II)
 EMI17.1
 in which when the symbol ---- represents a double bond, R'1 denotes a hydrogen atom and R2 and Reconsidered together, form an oxo group, whereas when the symbol ---- represents a single bond, R ' 1 denotes the hydroxyl radical or a protective group linked to the nucleus via an ethereal oxygen atom, R2 denotes a hydrogen atom, R'3 denotes a hydroxyl, acyloxy radical or a protective group linked to the nucleus by through an ethereal oxygen atom,

   or R2 and R 'taken together, form an oxo group; one of the symbols R'4 and RI-5 represents the hydroxyl radical or a protective group linked to the nucleus via an oxygen atom
 EMI17.2
 ethereal, however that the other of these symbols denotes a hydrogen atom and Rc R s o have the meanings which have been previously assigned to them, on a compound of formula (III)
 EMI17.3
 

  <Desc / Clms Page number 18>

 in which R'and R "have the meanings which have been previously assigned to them, so as to obtain an optically active isomer or a racemic of a compound of formula (IV)
 EMI18.1
 in which
 EMI18.2
 R ', Rit, R', R?, R '., R' ,, R ', Rc, Ry,

   n and Rg have the meanings which have been previously assigned to them and then, when necessary, the radicals protecting the hydroxyl function are removed; or b) reacting an optically active isomer or a racemic of a compound of formula (V)
 EMI18.3
 

  <Desc / Clms Page number 19>

 
 EMI19.1
 in which X M represents a group-C = C-or-CH = C- and X represents
 EMI19.2
 a bromine, chlorine or iodine atom;

   Z represents the hydroxyl radical or a protective group linked to the nucleus via an ethereal oxygen atom; one of the symbols R'4 and R'5 represents the hydroxyl radical or a protective group linked to the nucleus via an ethereal oxygen atom, while the other of these symbols denotes a hydrogen atom ; and R6, R7, n and Ra have the meanings
 EMI19.3
 previously assigned to them, on a Wittig reagent containing a group- (CH,) & -
 EMI19.4
 R '- CON. p ,, where R'and R "have the meanings which their RI have been previously assigned, so as to obtain an optically active isomer or a racemic of a compound of formula (VI)
 EMI19.5
 in which
 EMI19.6
 R ', RH, Z, R' <, R'ct R'c.

   Ry n and Rg have the meanings which have been previously assigned to them, which, when the 11-and 15-hydroxyl radicals are in the protected form, can, if desired, be esterified so as to obtain a derivative of type 9a -acyloxy of a compound of formula (VI) and in that the protective groups are then removed in positions 11 and / or 15, if they are present, both in a compound of formula (VI) and in its acyloxy derivatives, so as to obtain

  <Desc / Clms Page number 20>

 so a compound of formula (I) in which R3 represents the hydroxyl radical or an acyloxy group, R2 denotes a hydrogen atom, R1 denotes the hydroxyl radical, the
 EMI20.1
 symbol ---- represents a single bond and R ', R ", FL,

   Pc * R6-'RR7 'n and Ro have the meanings previously assigned to them; or, c) an optically active isomer or a racemic of a compound of formula (VII) is oxidized
 EMI20.2
 in which
Z 'represents a protective group linked to the nucleus via an ethereal oxygen atom; one of the symbols R'4 and R "represents a protective group linked to the nucleus via an ethereal oxygen atom, while the other of these symbols denotes a hydrogen atom;

   and R ', R ", R Ry, n and Ra have the meanings which have been previously assigned to them, so as to obtain an optically active isomer or a racemic of a compound of formula (VIII)
 EMI20.3
 

  <Desc / Clms Page number 21>

 in which
 EMI21.1
 R ', R ", Z', R" ,, R ", R, Ry, n and Rg have the 41'5 63'7 meanings which have been previously assigned to them, which in turn are submitted to elimination of the groups protecting the ether function, so as to obtain, depending on the reaction conditions employed, either a compound of formula (I) in which ---- denotes a single bond, R1 denotes the hydroxyl radical, Reet
 EMI21.2
 R e Reconsidered together form an oxo radical and R ', R ", L, R ,, R, R,

   n and Ra have the meanings which have been previously assigned to them, or a compound of the formula (I) in which ---- represents a double bond, R1 denotes a hydrogen atom, R2 and R, taken together, form a oxo group and R ', R ", R4, R5, R6, R7, n and Ra have the meanings previously assigned to them; and / or, if desired, a compound of formula (I) is salified or a free compound of formula (I) is obtained from a salt of such a compound; and / or, if desired, a compound of formula (I) or a salt of a such compound, into another compound of formula (I) or into a salt thereof; and / or, if desired, a mixture of isomers is dissolved into the singular isomers.



   A protecting group linked to the nucleus or to the chain via an ethereal oxygen atom, that is to say an ether group, must be easily convertible into a hydroxyl radical under moderate reaction conditions, by example, acid hydrolysis. As examples of such protective groups, there may be mentioned acetal ethers, enolic ethers and silyl ethers.



  The preferred radicals are:

  <Desc / Clms Page number 22>

 
 EMI22.1
 where G represents -0- or -CH2- and Alk represents a lower alkyl radical, for example C1-C4.



   The reaction conditions to be used for carrying out the reaction between a reactive derivative of a compound of formula (II) and an amine of formula (III) depend, more particularly, on the nature of the reagents used.



   A reactive derivative of a compound of formula (II) can be, for example, a reactive ester, more particularly a C1-C6 alkyl ester; an acyl halide, for example a chloride or a bromide; an anhydride; a mixed anhydride; an azide, or a salt, for example a salt generated with alkali or alkaline earth metals.



   When the reactive derivative of a compound of formula (II) is a reactive ester thereof and the compound of formula (III) is ammonia, the reaction can be
 EMI22.2
 carried out using gaseous ammonia at a temperature which fluctuates from about 50C to about 40oC, preferably from 150C to 250C, while if the compound of formula (III) is an amine, the reaction can be carried out, preferably in an inert solvent, for example benzene, toluene, at temperatures which vary from room temperature to reflux temperature.



   When the reactive derivative of a compound of formula (II) is an acyl halide, for example acyl chloride, the reaction on ammonia or on an amine

  <Desc / Clms Page number 23>

 appropriate formula (III) can be carried out in an inert solvent, for example benzene or toluene, or in an aqueous solvent, in the latter case, in the presence of an inorganic base, for example NaHCO3 or Na? CO, serving as an acid acceptor.

   When in the lactol of formula (V) M represents a group - C = C - or CH = CH - where X denotes bromine or iodine, the Wittig reaction can be carried out using approximately 1 to 4 moles, preferably 2 moles of Wittig reagent per mole of lactol and the reaction may take from about 10 to 20 minutes to several hours, depending on the temperature and the concentration of the reaction mixture and the Wittig reagent used.



  When in the lactol of formula (V), M represents a group -CH = CX-in which X denotes chlorine, it is necessary to extend the reaction time up to 10 hours, to use, for example, 1 , 5 to 2.5 moles of Wittig reagent per mole of lactol, or else it is desirable to use shorter reaction periods, it is necessary to use a large excess of Wittig reagent, namely at least 5 moles of Wittig reagent per mole of lactol to obtain reaction times of approximately 30 minutes. Consequently, when in the lactol of formula (V) M represents the group -CH = CX-, X preferably denotes bromine or iodine.



   When in the lactol of formula (V), M represents the group -CH = CX-in which X denotes bromine, chlorine or iodine, the hydrogen atom bonded to the carbon atom in position 13 and the halogen atom linked to the carbon atom in position 14 may be in the trans position, that is to say that they are trans geometric isomers, or in position 6. c ' that is, these are cis geometric isomers. Preferably, these are isomers in the trans position.

   The Wittig reaction is carried out using the conditions usually used for this type of reaction, that is to say in a solvent

  <Desc / Clms Page number 24>

 organic, for example diethyl ether, hexane, dimethyl sulfoxide, tetrahydrofuran, dimethylformamide or hexamethylphosphoramide, in the presence of a base, preferably sodium hydride and potassium tert-butoxide , at temperatures which vary from approximately OOC to the reflux temperature of the reaction mixture, preferably at room temperature or at a temperature below the latter.



     The term "Wittig reagent" includes compounds of the general formula
 EMI24.1
 in which Q represents an aryl group, for example phenyl, or an alkyl radical in C-C, for example ethyl Hal denotes a halogen, for example bromine or chlorine and RI and RI 'have the meanings which have been previously assigned to them.



   The preparation of the Wittig reagent is described in detail by Tripett, Quart. Rev. : (1963) XVII, NO 4. 406.



   When in the lactol of formula (V), M represents the radical -CH = CX-, where X has the meanings which have been previously assigned to it, during the reaction on the Wittig reagent, the dehydrohalogenation takes place as easily when the hydrogen atom linked to the carbon atom in position 13 and the halogen atom linked to the carbon atom in position 14, are in the trans position than when they are in the cis position.

   The optional acylation of the 9a-hydroxyl radical in a compound of formula (VI) to obtain the derivative of the respective 9a-acyloxy type can take place in a conventional manner, for example, by treatment with an anhydride or a halide, for example a chloride of a carboxylic acid, in the presence of a base.

  <Desc / Clms Page number 25>

 Oxidation of the 9a-hydroxyl group to a compound of
 EMI25.1
 the formula (VII) for obtaining the derivative of the type 9-oxo rese e pectif can be carried out via, for example, a Jones reagent (GI Poos et al. Am. Soc. 75, 422, 1953 ) or a Moffatt reagent (Am. Soc. 87, 5661, 1965).



   Removal of known protecting groups linked to the nucleus or respectively to the chain, by an ethereal oxygen atom, for example, in a compound of formula (IV) or in a compound of formula (VI) or in its derivatives of the 9a-acyloxy type is carried out, when necessary, under the conditions of moderate acid hydrolysis, for example by using a mono-or poly-carboxylic acid, for example formic acid, the acid acetic, oxalic acid, citric acid and tartaric acid and in a solvent which may be, for example, water, acetone, tetrahydrofuran, dimethoxyethane and lower aliphatic alcohols and mixtures of these compounds or with a sulfonic acid, for example p-toluenesulfonic acid, in a solvent, such as a lower aliphatic alcohol,

   for example in methanol or in ethanol, or with a sulfonic polystyrene resin.



   For example, a 0.1 to 0.25N aqueous solution of a polycarboxylic acid, for example oxalic or citric acid, is used in the presence of a suitable low boiling cosolvent which is miscible with water and which can be easily removed under vacuum at the end of the reaction.



  As described previously, the elimination of the protective groups in compounds of formula (VIII) can generate, depending on the reaction conditions, either a compound of formula (I) in which the symbol ---- re - has a single bond, R1 represents the hydroxyl radical and R2 and R3 together form an oxo group, ie a compound where ---- represents a double bond, R1 denotes a hydrogen atom and R2 and R3 together form an oxo group . The first of them can be prepared as a single

  <Desc / Clms Page number 26>

 reaction product by carrying out this reaction between 15 and 40oC, while at higher temperatures, for example for several hours at reflux, only the second compound is obtained.



   The separation of a mixture of isomers into the singular isomers can be carried out by the implementation of conventional methods.



   For example, a mixture of epimers, for example epimers 15 (S) and 15 (R) can be separated by fractional crystallization from an appropriate solvent or by chromatography, either by chromatography on column or by liquid phase chromatography under high pressure.



   The reactive derivatives of the acids of formula (II) and the lactols of formula (V) are known compounds, for example as described in the published British patent application NO 2 009 145 A or in the British patent NO 1 443 880, or else they can be obtained by using known methods starting from known substances, for example those described in the published British patent application or in the British patent mentioned above.



   For example, compounds corresponding to formula (V) in which M represents the group - C = C- can be prepared by dehydrohalogenation of the corresponding 14-halogenated derivatives. Dehydrohalogenation can be carried out in an aprotic solvent, preferably chosen from dimethyl sulfoxide, dimethylformamide and hexamethylphosphoramide, by treatment with a base chosen, preferably, from potassium tert.-butoxide, an amide.
 EMI26.1
 of alkali metal and the anion CI-LSO-CH '. Among the reaction intermediates described above, the compounds of formula (IV) are new and it is obvious that the scope of the invention also extends to these substances.



   The compounds of formula (I) fall within the definition of the general formula appearing in the application for

  <Desc / Clms Page number 27>

 published British patent NO 2 00 945 A, but none of them is specifically described there.



   The compounds of formula (I) can be applied to all nemmifers in the states where the use of natural prostaglandins is indicated and they can be administered by the usual routes, for example oral, parenteral, rectal, or via aerosols, with the advantages of superior resistance to the enzyme 15-prostaglandin dihydrogenase which, as is well known, rapidly inactivates natural prostaglandins. The new compounds are also provided with a therapeutic activity of longer duration than the natural prostaglandins when they are administered by the usual routes and, more especially, when they are administered by the oral route.

   For example, the compounds of formula (I) and, more particularly the 9a-hydroxylated derivatives, manifest an oxytocic activity, that is to say that they can be used in place of oxytocin to induce labor or to expel a dead fetus in pregnant females, both humans and animals.



  For this application, the compounds are administered
 EMI27.1
 either by intravenous infusion at a dose of approximately 0.01 g / kg / minute until the end of labor, or, orally, in a single dose or in multiple doses of approximately 0.1 mg to about 5 mg per dose.



   In addition, the compounds of formula (I), more particularly the 9-hydroxyl derivatives, also exhibit luteolytic activity and can therefore be used for adjusting or controlling fertility with the advantage of considerably reduced capacity. to stimulate smooth muscles. Therefore, the side effects of natural prostaglandins, such as vomiting and diarrhea, are absent. The luteolytic activity of the new compounds was evaluated, for example in rats.

  <Desc / Clms Page number 28>

 



   During this test, a comparison was established, as Table 1 reveals, between the activity of a compound according to the invention (R = NH2) and that of two compounds of the prior art after their administration orally (p. bone) or subcutaneously (sc).



   TABLE 1
 EMI28.1
 OH COR OH OH 0, m cz-C-il OH 6H '-. 2 / kg OH OH 1 R ----------.-----------! s. vs. p. os 1 1 1 NH2 2.5 5 'i OCH 3 90 1 OH 4 150 l
The ED50 represents the minimum effective dose capable of inducing luteolytic activity in 50% of the rats subjected to the treatment.



   Table 1 shows that the amide derivative constitutes the substance which stimulates the most powerful pharmacological response. More particularly, although the values of Ex 50 are very close by subcutaneous administration, it is obvious that the amide derivative is most active when administered by the oral route.

  <Desc / Clms Page number 29>

 



   Consequently, the amide shows better absorption by the gastrointestinal route, this being due to the different hydrophilic properties which the chemical groups linked to the carbon atom C-1 of the prostaglandin derivatives possess.



   Another interesting pharmacological property of the compounds of formula (1), more particularly the derivatives of the 9-oxo type, lies in their anti-ulcerogenic activity.



  In fact, the compounds in question are useful for reducing and controlling excessive gastric secretion in mammals. Thus, they reduce or eliminate the formation of gastrointestinal ulcers and are simultaneously capable of accelerating the healing process of any ulcers already present in the gastrointestinal tract. Therefore, the compounds of formula (I) are also useful for reducing undesirable gastrointestinal side effects from systemic administration of anti-inflammatory or anti prostaglandin synthetase inhibitors; Logistics and can therefore be used for this purpose in association with them.

   The compounds of formula (I) can, for this purpose, be administered by the oral, parenteral route, that is to say by intravenous infusion or injection, or by intramuscular injection, by inhalation or by the rectal route. When administered orally, the compounds according to the invention can be used in a dose which varies from approximately 1 mg to approximately 10 mg, preferably 5 mg, from 1 to 3 times per day. For intravenous infusion, the dose ranges from approximately 0.01 ug to zig per kilogram of body weight per minute. The total daily dose, both by injection and by infusion, is of the order of 0.1 to 20 mg. Obviously, for the treatment of the aforementioned conditions, the exact treatment dose depends on the anamnesis of the patient to be treated.

  <Desc / Clms Page number 30>

 



   It was found that the toxicity of the compounds of formula (I) was practically negligible and that, therefore, they could be used safely in the therapeutic field. The evaluation of the toxicity (as acute orientation toxicity, i.e. the LD50) was carried out, for example, as follows: mice deprived of food were treated for 9 hours per day. single oral administration of increasing doses, then they were caged and fed normally; the LD50 was checked on the 7th day after treatment. For example, the
Acid amide LD50 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) - fluorine-18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-ynolque was found to be greater than 3,000 mg / kg body weight.



  The compounds of formula (IV) benefit from the same pharmacological activities as the compounds of formula (I) and are administered to humans or animals for the same therapeutic purposes, at the same doses and by the same modes of administration.



   The pharmaceutical compositions in accordance with the present invention are usually prepared by implementing the following conventional methods and are administered in a pharmaceutically suitable form. For example, the forms for oral administration may contain, together with the active compound, diluents, for example lactose, dextrose, sucrose, cellulose, corn starch and potato starch; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols, binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone; disintegrating agents, for example starch, alginic acid, alginates, sodium starch glycolate; effervescent mixtures; colors, sweeteners;

   wetting agents, for example lecithin, polysorbates, laurylsulfates; and, in general, non-toxic substances

  <Desc / Clms Page number 31>

 and pharmacologically inactive used in pharmaceutical compositions. These pharmaceutical preparations can be produced in a known manner, for example by the use of mixing, granulation, tableting, sugar coating or film coating processes. Liquid dispersions suitable for Oral administration can be, for example, in the form of syrups, emulsions and suspensions.

   The syrups can contain, as a vehicle or excipient, for example sucrose or sucrose combined with glycerin and / or mannitol and / or sorbitol; more particularly, a syrup intended for administration to diabetic patients can contain, as a vehicle3 or excipients, only products metabolizable in glucose or which are metabolizable in glucose only in very small quantity, such as sorbitol .



   The suspensions and the emulsions can contain, as a vehicle or an excipient, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The suspensions or solutions intended for intramuscular injections may contain, at the same time as the active compound, a pharmaceutically acceptable vehicle or excipient, for example sterile water, olive oil, ethyl oleate, glycols, for example example propylene glycol and, if desired, an appropriate amount of lidocaine hydrochloride. The solutions intended for intravenous injections or infusions may contain, as a vehicle, for example sterile water or, preferably, they may be in the form of aqueous, saline, isotonic, sterile solutions.



   Suppositories may contain, together with the active compound, a pharmaceutically acceptable vehicle or excipient, for example cocoa butter, polyethylene glycol, a fatty acid ester type surfactant.

  <Desc / Clms Page number 32>

 polyoxyethylene sorbitan or lecithin.



   As mentioned above, another mode of administration may be by inhalation. To this end, the suitable compositions may comprise a suspension or a solution of the active ingredient, preferably in the form of a salt, such as sodium salt, in water, for administration by through a conventional nebulizer or vaporizer. The compositions can also consist of a suspension or a solution of the active ingredient in a conventional liquefied propellant, such as dichlorodifluoromethane or dichlorotetrafluoroethane, which can be administered from a container which contains the compositions in question under pressure, i.e. an aerosol dispenser.



   When the drug is not soluble in the propellant, it may be necessary to add a co-solvent, such as ethanol, dipropylene glycol, isopropyl myristate and / or a surfactant to the composition, in order to suspend the drug in the propellant medium and surfactants of this kind can be any of those commonly used for this purpose, such as nonionic surfactants, for example lecithin.



  Another suitable pharmaceutical form can be, for example, in the form of powders. The powders can be administered via a suitable insufflating device and, in this case, the powders of fine size of the particles of the active ingredient can be mixed with a diluent material such as lactose.



   The present invention will now be illustrated but not limited by the examples which follow.



   The abbreviations THP, DIOX, DMSO, THF, DMF, DIBA, Et20, and EtOH refer respectively to the tetrahydropyranyl, dioxanyl radicals, dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, diisobutylaluminum hydride, diethyl ether and alcohol

  <Desc / Clms Page number 33>

 ethyl. All the temperatures are expressed in degrees centigrade and the measurements of the rotary powers relate to 200C and to a concentration of 1% by weight of the compound in the specific solvent.



  EXAMPLE 1
A solution of methyl 5c-9a, 11a, 15 (S) -trihydroxy-18, 19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoate (0.5 g) was cooled in methyl alcohol (10 ml) with brine and dry NH3 was bubbled through the solution until saturation.



   The reaction vessel was closed and the reaction mixture was kept at room temperature for 24 hours; the NH3 was then removed using N2 and the alcohol was removed.



   The crude product was purified by using a chromatographic preparation technique on silica gel using a mixture of hexane and ethyl acetate (1/1) as eluent: this gave 0, 42 g of pure 5c-9a, 11a, 15 (S) -trihydroxy-18, 19, 20-trinor-17-cyclohexylprost-5-en-13-ynoic acid amide;
 EMI33.1
 zand = + 348; a7365 = + 86.1 (C = 1 EtOH).



   By proceeding in an analogous manner, the amides of the following acids were obtained:

  <Desc / Clms Page number 34>

 
 EMI34.1
 15 (S) -trihydroxy-20-nor-19-cycl oh exyl-pro st- - 5-en-13-ynoïque LD = + 19, 5; 5c-9c <, llo <, 15 (S) -trihydroxy-20-nor-19-cyclopentyl-prost- - 5-en-13-ynoïque - LD = +. 19, 7; 5c-9 '= <llel5 (R) -trihydroxy-16 (S) -f! uoro-20-nor-19-cyc) ohexylo '- - prost-5-en-13-ynoÎque LOSJD = + 8, 8; 5c-9cw ,, 11, 15R S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexy! -Prost-5-n-13-yno! 'Qie Z. / + 7. 2; 5c-9O <, 11o <, 15 (S) -trihydroxy-19, 20-dinor-18-cyclohexyl-prost- - 5-en-13-ynoïque LD = + 13, 9; / -C-VIl / D + 1319; 5c 11c <, 15 (S) -trihydroxy-19, 20-dinor-18-cyclopentyl-prost- -5-en-13-yno: que D "5c-9y l, 15 (R) -trihydroxy-16 (S) - fluoro-19, 20-dinor-18- -cyctohexyl-prost-5-en-13-yno! 'as f 112;

   5c-90 (, 11o (, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexy! -Prost-5-en-13-yno! Que.S / = 38, 7; e / D = + 3817; 5c-9 11c, 15 (S) -trihydroxy-18, 19, 20-trinor-17-cyclopentyl- - prost-5-en-13-yno: 'qne -D 31; 5c-9. 11 <, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor- -17-cyclohexyl-prost-5-en-13-yno! 'As D + 174;

   L, - + 66. 9 (C = 1 EtOH); 365 5c-9oC, llce ,, 15 (R, S) -trihydroxy-16 (S) -fluoro-18, 19, 2 0-tr i nor- -17-cycl ohexyl-pros-t-5-en-13 -ynoi'que + 10, 2;

  <Desc / Clms Page number 35>

 
 EMI35.1
 the N, N-dimethyl-amides of the following acids: 5c-9 <, 11 <= <, 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5l '- en-13-ynolque; 5c-9 ' <lle :, 15 (S) -trihydroxy-20-nor-19-cyclopentyl-prost-5I -en-13-ynoique; - 5c-9o (, llo <, lS (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cycl0hexyl-prost-5-en-13-ynoIque; 5c-911c (, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cycloI hexyl-prost-S-en-13-ynoIque; 15 (S) -tri hydroxy-19, 2C-di nor-18-cyci ohexyl-pros --- - 5-n-13-ynoique; 5c-9 (, Il lS (S) -tri hydroxy-19, 20-di nor-18-cycl opentyl-prost - -S-en-13-ynoique; 5c-9o lû <, 15 (R) -trihydroxy-16 ((S) -fluoro-19, 20-dinor-18- - cyclohexyl-prost-5-en-13-yn <Xque;

   5c-9 ' <1115 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoique; 5c-9 <', llt. 15 (S) -trihydroxy-18, 19, 20-trinor-17-cyclohexyl- - prost-5-en-13-yno! than ; 5c-911c <, 15 (S) -trihydroxy-18, 19, 20-trinor-17-cyclopentyl- - prost-5-en-13-ynoique; Sc-911, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor-17- - cyclohexyl-prost-5-en-13-ynolque; 5c-91115 (R.S) -tr: hydroxy-16 (S) -ftuoro-18, l9. 20-tr: nor-5c-gt> e - 17-cyclohexyl-prost-S-en-13-ynoiqle;

  <Desc / Clms Page number 36>

 
 EMI36.1
 the amides of the following acids: 5c-9c <, llc, l5 (R) -trihydroxy-l6 (S) -fluoro-l8, l9, 20-trinor- - 17-cyclopentyl-prost-5-en-13-yncEque /. / = + 181; 5c-9c <, ll, 15 (R, S) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyclopentyl-prost-5-en-13-ynoique LD = + 12.0;

   5c-9c <, ll <= <. l5 (S) -trihydroxy-17, 18, 19, 20-tetranor-l6-cyc! ohexyl-prost-5-en-13-ynoique L D = + 37 6; 5c-9c <, l1 <, 15 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cyclopentyl-pros-5-en-13-ynolque // = + 37, 2; 5c-90 ll <K., 15 (R) -trihydroxy-16 (S) -fluoro-17, 18, 19, 20-tetranor-16-cyclohexyl-prost-5-en-13-ynolque /.'/ o == + 6 5; 5c-9o (, 11o (, 15 (R, S) -trihydroxy-16 (S) -fluoro-17, 18, 19, 20- - tetranor-16-cyclohexyl-prost-5-en-13-ynolque L? YD = a 11. 2; 5è-9o (, 11, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18, 19, 20- - trinor-17-cyclohexyl-prost-5-en -13-ynolque / r +7, 7; 5c-9 <= <. he <= <. l5 (R.

   S) -tr: hydroxy-l6 (S) -ftuoro-l6-methy! -L8. 19. 20- - trinor-17-cyclohexyl-prost-5-en-13-ynoique LD = + 12, 1; 5c-9c <ll <. 15 (R) -trihydroxy-16 (R) -ftuoro-16-methyl-18, 19, 20- -trinor-17-cyclohexyl-prost-5-en-13-ynoique + 1519;

  <Desc / Clms Page number 37>

 
 EMI37.1
 the N, N-dimethyl-amides of the following acids: 5c-9a, 11a, 15 (S) -trihydroxy-18, 19, 20-trinor-17-cyclohexylprost-5-en-13-ynoic L7D = + 29, 6; 5c-9 ', 11, 13 (R) -tri hydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyclopentyl-prost-5-en-13-ynolque; 5c-9o <llc <.l5 (R.S) -trihydroxy-l6 (S) -F! uoro-l8, l9. 20-tr: nor- -7-cyci opentyl-prost-5-en-13-ynoique; 5c, 911-, 15 (S) -trihydroxY-17, 18, 19, 20-t: tranor-16-cyc10hexyl-prost-S-en-13-ynoïque; 5c-9 (, llo <, 15 (S) -trihydroxY-17, 18, 19, 20-tetranor-l6-cyc! oe pentyl-prost-5-en-13-ynolque; 5c-9c <, l115 (R) -tri hydroxy-16 (S) -ftuoro-17;

   18, 19, 20-tetranor- -16-cyclohexyl-prost-5-en-13-ynolque; Sc-9, 11, 15 (R, S) -trihydroxy-16 (S) -fluoro-17, 18/19, 20 - cetranor-l6-cyc! ohexyl-prost-3-en-13-ynolque; 5c-9c =, 11 15 (R) -tri hydroxy-16 (S) -f) uoro-16-methyt-18, 19, 20- - trinor-17-cyclohexyl-prost-5-en-13-ynolque; 5c-9, 11, 15 (R, S) -trihydroxY-16 (S) -fluoro-16-mthyl- - 18, 19, 20-tri nor-li-cyc 1 ohexyl-: prost-5-en-13 -ynoic; Sc-9 o, ll, 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-1-8, 19, 20- - trinor-17-cyclohexyl-prost-5-en-13-ynoique; the pyrazolidin-amides of the following acids: suc-9 (, ll OC 15 (S) -trihydroxy-18, 19, 20-trinor-17-cyclohexyl- - prost-S-en-13-ynoIque;

  <Desc / Clms Page number 38>

 
 EMI38.1
 5c-9 <= <, lle l5 (S) -trihydroxy-20-nor-l9-cyclohexyl-prost-5- - en-13-ynolque; - 5c-9 o11, 15 (S) -tr) hydroxy-20-nor-l9- cyct openty! -prost-5- - en-13-ynolque;

   Sc-9 15 (R) -tri hydroxy-16 (S) -f 1 uoro-20-nor-19-cyc 1 ohexyl-prost-5-en-13-yno Ique; 5c-9 ' <, llc <, 15 (R, S) -tr: hydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-n-13-yno lacquer; 5c-9 11, 15 (S) -trihydroxy-19, 20-dinor-18-cyclohexyl-prost- -5-e / n-13-yn oque; 5c-9c <, 11, 15 (S) -trihydroxy-19/20-dinor-18-cyclopentyl-prost- - 5-en-13-ynolque; 5c-9c <ll <15 (R) -trihydroxy-16 (S) -f) uoro-19, 20-dinor-18- - cyclohexyl-prost-5-en-13-ynolque; 5c-9 0 11l5 (R, S) -tr: hydroxy-16 (R) -f! uoro-20-nor-19-cyc! o-. hexyl-prost-5-en-13-yno ic; 5c-911-15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl- - prost-5-en-13-ynoique; 5c-9c <5c-9 <\. ll. l5 (S) -tr: hydroxy-l8, l9, 20-trinor-l7-cyclopenty) - - prost-5-en-13-ynoique; 5c-9c. lll5 (R) -trihydroxy-l6 (S) -f! uoro-l8, l9. 20-trinor-l7- - cyc! ohexy! -prost-5-en-l3-yno Ique;

   5c-9, 11 (-15 (R, S) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyc! Ohexyl-prost-5-en-13-yno Ique;

  <Desc / Clms Page number 39>

 
 EMI39.1
 5c-9 ll 15 (R) -trihydroxy-16 (S) -f! uoro-18, 19, 2Q-tri nor- - 17-cyct openty) -prost-5-en-13-ynoT-que; 5c-91115 (R.S) -tr: hydroxy-16 (S) -ftuoro-18, 1910-tr: nor- - 17-cyclopentyl-prost-5-en-13-ynoique; 5c, 9! ! l <= <, 15 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cyclo- "hexyl-prost-5-en-13-ynolque; 5c-9 <, ll < <. (S) -tr: hydroxy-l7, l8, l9, 20-tetranor-l6-cyc) opentyl-prost-5-n-13-yncique; 5c-9 <. 11 15 (R) -trihydroxy-16 (S) -fluor-o-17, 18, 19, 20-tetranor- -16-cyclohexyl-prost-5-en-13-yno Ique; 5c-9 <, 11.15 (R, S) -trihydroxy-16 (S) -fluoro-17, 18, 19, 20-tetrae nor-16-cyclohexyl-prost-5-en-13-ynoue; 5c-9 llo (, 15 (R) -trihydroxY-16 (S) -fluoro-16-mtbY-18, 19, 20- - trinor-17-cyclohexyl-prost-5-en-13-yno Ique;

   5c-9, 11, 15 (R, S) -trihydroxy-16 (S) -fluoro-16-methyl- - 18, 1920-trinor-17-cyclohexy! -Prost-5-en-13-ynolque; 5c-9 1115 (R) -trihydroxy-16 (R) -fluoro-16-methy-18 19, 20- - trinor-17-cyclohexyl-prost-5-en-13-yno Ique; e the piperidin amides of the following acids: 5c-9a, 11a, 15 (S) -trihydroxy-18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-ynolque;

  <Desc / Clms Page number 40>

 
 EMI40.1
 5c-9llc15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5- / - en-13-ynoï; 5c-9, 11, lS (S) -trihydroxy-20-nor-19-cyclopentyJ-prost-5- - en-13-yno ique; 5c-9rl1, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cycl0hexyl-prost-5-en-13-yn0lque; 5c-9 <11/15 (RS) -tr: hydroxy-16 (S) -f) uoro-20-nor-19-cyc) o- / hexyl-prost-5-en-13-yndlque; 5c-9 / ll <15 (S) -trihydroxy-19, 20-d! nor-18-cyclohexyl-prost- - 5-en-13-ynoïque;

   5c-9 '= / ll 15 (S) -tr! hydroxy-19, 20-dinor-18-cyclopentyl-prost- - 5-en-13-yno Ique; 5c-911 15 (R) -trihydroxy-16 (S) -fluoro-19, 20-dinor-18- - cycJohexyJ-prost-5-n-13-ynoïque; 5c-9 <, ll <., 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyct ohexyl-prost-5-en-13-ynolque; 5c-90 ll <Xl5 (S) -tr: hydroxy-l8 l920-tr! nor-l7-cyc! ohexy! - - prost-5-en-13-ynolque; 5c-9e, 1 <, 15 (S) -trihydroxy-18, 1920-trinor-17-cyct opentyl- - prost-S-en-13-ynoïque; - 5c-9c <11, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor-17- - cycl ohexyl-prost-5-en-13-yno Ique; c-9 <, llc, l5 (RS) -tr: hydroxy-l6 (S) -f 1 uoro-l8, l9, 20-tr i norC-9c., D - 17-cyclohexyl-prost-5-en-13-ynolque ;

  <Desc / Clms Page number 41>

 
 EMI41.1
 5c-911 <. 15 (P) -tr i hydroxy-16 (S) -ftuor o-18, 19. 2j3-tr: nor- - 17-cyclopentyl-prost-5-en-13-ynolque;

   - 5c-9 X 11 <K. 15 (R, S) -tr-hydroxy-16 (S) -fluoro-18, 19, 10-trinor- - 17-cycfopentyl-prost-5-en-13-ynoïque; 5c, 911 15 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cyctohexy! -Prost-5-en-l3-ynolque; .'- 15 (S) -trihydroxy-17, 18, 19 , 20-tetranor-16-cyclopentyl-prost-5-e / n-13-ynoique; 5c-9 11c, 15 (R) -trihydroxy-16 (S) -fluoro-17, 18, 19, 20-tetranor- - 16-cyclohexyl-prost-5-en-13-ynque; 5c-911c <:. l5 (R, S) -trihydroxy-16 (Sj-fluoro-17, 18, 19, 20-tetranor-16-cycl ohexyl-prost-5-en-13-yno lque; 1D (R) -trihydroxy-16 ( S) -f luoro-16-aré-t-hyt-18., 19, 20- -trinor-17-cycl ohexyl-prost-5-en-13-ynoïque; 5c-9o, 11ll, 15 (R, S ) -trihydroxy-16 (S) -fluoro-16-methyl- - 19, 1920-trinor-17-cyclohexyl-prost-5-en-13-ynolque; - 5c-9c (, 11, 15 (R) -trihydroxy -16 (R) -fluoro-16-methyl-18, 19, 20- - trinor-17-cyclohexyl-prost-5-en-13-ynolque; the morpholin-amides of the following acids:

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

  <Desc / Clms Page number 42>

 
 EMI42.1
 5c-9 llo 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5- / - en-13-yndrque; 5-9, 11, 15 (S) -trihydroxy-20-nor-19-cycropentyl-prost-5- - en-13-yndrque; 5c-9cllc, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyc! ohexyl-prost-5-en-13-yncTque; 5c-9 e <11 <, 15 (R <.

   S) -tr: hydroxy-16 (S) -f! uoro-20-nor-l9-cyc! ohexyl-prost-5-en-13-ynolque; 5c-9, 11, 15 (S) -trihydroxY-19/20-dinor-18-cyclohexyl-prost- - -en-13-ynoue; 5c-9 / l10 <, 15 (S) -trihydroxy-19, 20-dinor-18-cyclopentyl-prost- - 5-en-13-ynoIcpe; suc-9-, 11, 15 (R) -trihydroxY-16 (S) -fluoro-19/20-dinor-18- - cycl ohexyl-prost-5-en-13-yno Ique; 5c-9c <', ll 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyc! ohexyl-prost-5-en-13-ynolque; 5c-9. 11l5 (S) -trihydroxy-l8, l9, 20-trinor-l7-cyc! ohexyl- - prost-5-en-13-ynoIque; 5c-9, 1115 (S) -trihydroxY-18, 19/20-trinor-1-cycJopentyl- - prost-5-en-13-ynoique; 5c-911o <(, 15 (R) -trihydroxy-l6 (S) -fluoro-l8, l9, 20-trinor-17- - cyclohexyJ-prost-5-en-13-ynorqle; 5c-9c, ll., L5 (R , S) -trihydroxy-16 (S) -fluoro-18.19, 20-trinor-- e -17-cycl ohexyl-prost-5-en-13-yno lque;

  <Desc / Clms Page number 43>

 
 EMI43.1
 5c-9 1115 (R) -tr:

   hydroxy-16 (S) -ftuoro-18, 19. 2D-tr: nor- - 17-cyclopentyl-prost-5-en-13-ynolque; 5c-9c (, llc. L5 (R, S) -trihydroxy-l6 (S) -fluoro-l8, l9, 10-trinor- - 17-cyclopentyl-prost-5-en-l3-ynolque; 5c, 9 = , lll5 (S) -tr: hydroxy-. 17 iS, 1920-tetranor-lo-cyc) o-. hexyl-prost-5-en-13-ynoique; 5c-911e, 15 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cyc! o- /. pentyl-prost-5-en-13-ynoique; 5c-911. l5 (R) -tr: hydroxy-16 (S) -f! uoro-17, 18, 19.-20-tetranor - 16-cycl ohexyl-prost-5-en-13-yno1que; . 5c-9 <= llcl5 (R.

   S) -tr: hydroxy-16 (S) -ftuoro-17. l3. 19. 20-tetranor-16-cyclohexyl-prost-5-en-13-ynoique; 5c-9. 1115 (R) -trihydroxy-16 (S) -fluoro-16-methyl-l, l9, 20- "- trinor-li-cyclohexyl-prost-5-en-13-ynoique; 5c-9c <. ll., 15 (R, S) -trihydroxy-16 (S) -fluoro-16-mthyt- - 19, 20-trinor-17-cyclohexyl-prost-5-n-13-ynoique; e 5c-9, 1115 (R) -trihydroxy-l6 (R) -fluoro-l6-methyl-l8, l9, 20- - trinor-17-cyclohexyl-prost-5-en-13-ynoique; and 5c-90 (, IKX 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor-17cyclohexyl-prost-5-en-13-ynoique.

  <Desc / Clms Page number 44>

 



  EXAMPLE 2
 EMI44.1
 A solution of potassium tert-butoxide (2,325 g) in dry DMSO (15 ml) was stirred under dry nitrogen; N, N-dimethylamide bromide of triphenylphosphonium pentanoic acid (4.2 g) was added to the solution while cooling with a water bath.



  The temperature of the reaction mixture was maintained below 300C and the addition was completed in about 15 minutes; we then added a solution of 3a,
 EMI44.2
 5a-dihydroxy-2p-Z2-bromo-3 (S) -hydroxy-4 (S) -fluoro-5-cyclohexyl-pent-trans-1-enyl7-la-cyclopentane acetaldehyde-y- lactol-bis-THP-ether (1.7 g) in dry DMSO (15 ml) to the mixture thus obtained.



   The reaction was completed in about 1 hour, then the mixture was cooled with water and extracted with diethyl ether. The solvent was removed and the crude product was purified by preparative chromatography on silica gel using a mixture of ethyl acetate and hexane (1/1) as eluent: 1, 650 was thus obtained g of 11, 15-bis-THP-ether of N, N-dimethylamide of acid 5c- 9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor-17 - cyclohexyl-prost-5-en-13-yno! that: 7D = +42.5 (C = 1 EtOH).



   By repeating the same procedure and using the appropriate triphenylphosphonium derivatives and the suitable bis-THP-ether-lactols, the amides, N, N-dimethylamides, pyrazolidinamides, piperidinamides and morpholinamides of the following acids were obtained. , in the form of the crude 11,15-bis-THP-ethers, which are suitable for carrying out the subsequent reactions and which can optionally be purified by a chromatographic technique:

  <Desc / Clms Page number 45>

 
 EMI45.1
 5c-9O <, 11b (, 15 (S) -trihydroxy-20-nor-19-cyclopentyl-prost- / - 5-en-13-ynoique; 5c-911t <15 (S) -tr: hydroxy-20-nor-19-cyc! ohexyt-prost-5- - en-13-ynolque; 5c-9c (., Llo <.. 15 (R) -trihydroxy-16 (S) -f luoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoique;

   5c-9, 11, lS (R, S) -trihydroxY-16 (S) -fluoro-20-nor-19-cyc10- / hexyl-prost-5-en-13-. ynolque; 5c-9o <., llc <., 15 (S) -trihydroxy-19, 20-dinor-18-cyclohexyl- / - prost-5-en-13-. ynolque; 5c-9th <, llc, l5 (S) -trihydroxy-l9, 20-dinor-18-cyclopenty) - - prost-5-en-13-ynoique; 5c-9 <llo <., 15 (R) -trihydroxy-16 (S) -f) uoro-19, 20-dinor-18- -cyclohexyl-prost-5-en-13-ynolque; 5c-9, 11, l5 (R.

   S) -trihydroxy-16 (R) -fluoro-20-nor-19- / - cycl ohexyl-prost-5-en-13-ynoIque; 5c-9 <, 11eKl5 (S) -trihydroxy-18, 19, 20-trinor-17-cyclohexyl- - prost-5-en-13-ynoique; 5c-911ol5 (S) -trihydroxy-18, 19, 20-trinor-17-cyclopentyl- - prost-5-en-13-ynoique; 5c-9 <, lle, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyclohexyl-prost-5-en-13-ynolque; 5 at llC <, 15 (R, S) -trihydroxy-16 (S) -tluoro-18, 19, 20-trinor- - 17-cyclohexyl-prost-5-en-13-ynolque; 5c-9 11c <, 15 (R, S) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyclopentyl-prost-5-en-13-ynoïque; Sc-9, 11, IS (R) -trihydroxy-16 (S) -fluor8, 19, 20-trinor-17cyclopentyl-prost-S-e3-ynoic;

  <Desc / Clms Page number 46>

 
 EMI46.1
 5c-9. 11 .. 15 (S) -trihydroxy-17, 18, 19, 20-ttranor-16-cyclohexyl-prost-5-en-13-ynolque;

   Sc-9 11, l5 (S) -trihydroxy-17, 18, 19, 20-tetranor-l6-cyc! o-pentyl-prost-5-en-13-ynolque; 5c-90 (, 110 (, lS (R) -trihydroxy-16 (S) -fluoro-17, 18, 19, 20-tetranor-16-cyclohexyl-prost-5-n-13-ynolque; 5c-9c <., 11bE, 15 (R, S) -trihydroxY-16 (S) -fluoro-17, 18, 19, 20- - tetranor-16-cyclohexyl-prost-5-en-13-ynolque; 5c-9 <., llc <, l5 (R) -trihydroxy-l6 (S) -fluoro-l6-methyl-l8, 19, 20- - trinor-17-cyclohexyl-prost-5-en-13-ynolque; 5c-9 < <, lle, l5 (R, S) -trihydroxy-l6 (S) -fluoro-l6-methyl- -18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-ynolque; 5c-9, llo (, l5 (R) -trihydroxy-l6 (R) -fluoro-l6-methyl-18, l9, 20- - trinor-17-cyclohexyl-prost-5-en-13-ynolque;

   and 5c-9a., ll., 15 (R) -trihydroxy-16 (R) -fluoro-18, 19, 20-trinor-17cyclohexyl-prost-S-en-lS-ynoIque EXAMPLE 3
1.5 ml of Jones reagent were added dropwise to a solution, cooled to -250C, of 11, 15-bis-THP-ether of acid amide 5c-9a, 11a, 15 (R ) -trihydroxy- 16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13- yno! as (1.07 g) in acetone (15 ml). After the addition, the temperature was allowed to rise to -80C and the reaction mixture was stirred for 20 minutes. The mixture was then diluted with benzene, washed with a saturated aqueous solution of (NH4) 2SO4 until neutral, it was dried and the solvent was evaporated at 200C under vacuum .

   The residue (0.830 g) was dissolved in 30 ml of acetone and treated with a 1N solution of oxalic acid (5.5 ml)

  <Desc / Clms Page number 47>

 for 8 hours at 40 C.



   After completion of the reaction, the acetone was evaporated in vacuo to give a residue which, by chromatography on Si 2 using a mixture of ethyl acetate and cyclohexane (35 / 65) as eluent, gave 0.325 g of 5c-9-oxo-11a, 15 (R) -dihydroxy-16 (S) - fluoro-18,19,20-trinor-17-cyclohexyl acid amide -prost-5-en-13-ynoic pure: [&alpha;] D = -33,0; [&alpha;] 365 = - 199.2 (C = 1 EtOH).



   By proceeding in an analogous manner, the amides of the following acids were obtained: 5c-9-oxo-11 @, 15 (S) -dihydroxy-20-nor-19-cyclohexyl-prost-5- -en-13-ynolque / - / D = -6.2;
 EMI47.1
 5c-9-oxo-ll, 15 (S) -dihydroxy-20-nor-19-cyclopenty {-prost- -5-en-13-ynoiqueZC </ -76; 5c-9-oxo-110 (, 15 (R) -dihydroxy-16 (S) -fluoro-2nor-19-cyc10hexyl-prost-5-en-13-ynoique A / D = -9.8; 5-9 -oxo-11/15 (R, S) -djhydroxy-16 (S) -fluoro-20-nor-19- - cyclohexyl-prost-5-en-13-ynolque ZP / -10, 2;

   D 5c-9-oxo-llo (, l5 (S) -dihydroxy-l9, 20-dinor-18-cyclohexyl- - prost-5-en-13-ynolque Z. / * 6, 9; 5c-9-oxo -ll, 15 (S) -dihydroxy-19, 20-dinor-18-cyclopentyl- - prost-5-en-13-ynoique -n '5c-9-oxo-lll3 (R) -dihydroxy-l6 (S) -fluoro-19,20-dinor-18- -cyclohexyl-prost-5-en-13-ynolque /. / * 7, 2; 5c-9-oxo-11,15 (R, S) -djhydroxy-16 ( R) -fluoro-20-nor-19- - cyclohexyl-prost-5-en-13-ynoIque L = - 16, 8; 5c-9-oxo-11, 15 (S) -dihydroxy-18, 19, 20 -trjnor-17-cyclohexyl- - prost-5-en-13-ynoïque LO = - 11, 6;

  <Desc / Clms Page number 48>

 
 EMI48.1
 5c-9-oxo-11, lS (S) -dihydroxy-18, 19, 20-trinor-17-cyclopentyl- - prost-5-en-13-ynolque ZPi / = - 9. 1; -prost-5- / z% 5c-9-oxo-llc, l5 (R) -dihydroxy-16 (R) -fluoro-18, 19, 20-trinor- - l7-cyclohexyl-prost-5-en-13 -ynoic Z / = - 13.5; in 5C-9-oxo-ilo <, 15 (R, S) -dihydroxy-16 (S) -f lu or o-18-19-20-tri nor- - 17-cyclohexyl-prost-5-:

   n-13-ynoIque LD = - 10, 2; 5c-9-oxo-1115 (R) -dihydroxy-16 (S) -fluoro-18, 19, 20-trinor-, Ic 1 - 17-cyclopenyl-prost-5-en-13- ynoique LD = - 38, 2; 5c-9-oxo-lle <, 15 (R, S) -dihydroxy-16 (S) -fluoro-18, 19, 20-tri nor- - 17-cyclopentyl-prost5-n-13-ynoïque LD = - 20, 2; DP 5c-9-oxo-llo (, 1S (S) -dihydroxY-17, 18, 19, 20-ttranor16-cyclo. Hexyl-prost-S-en-13-ynoique L (/ = - 12, 8; 5c-9-oxo-11cl5 (S) -dihydroxy-17, 18, 19, 2 & -tetranor-16-cyclopentyl-prost-S-en-13-ynoIque LD = - 13, 1;

   Sc-9-oxo-l lel5 (R) -dihydroxy-l6 (S) -fluoro-17, l8. 19, 20-tetranor- -16-cyclohexyl-prost-5-en-13-ynoique / .Q '/ - 42, 4; 5c-9-oxo-llc. 15 (R, S) -dihydroxy-16 (S) -fluoro-17, 18, 19, 20- - tetranor-16-cyc 1 ohexy! -Prost-5-en-13- ynoique7D = -37, 7 5c- 9-oxo-ll, 15 (R) -dihydroxY-16 (S) -fluoro-16-methyl- -l8, 19, 20-trinor-17-cyclohexyl-prost-5-en-13- ynoique ZZ-. 5c-9-oxo-llc, 15 (R, S) -dihydroxY-16 (S) -fluoro-16-methyl- - 18719, 20-trinor-17-cyclohexyl-prost-5n-13-ynoique D = -37 , 8; 5c-9-oxo-llc <, 15 (R, S) -dihydroxY16 (R) -fluoro-16-methyl- - 18. 19, 20-trinor-17-cyclohexyl-prost-5-en-13- ynoique lul ¯ 35 li

  <Desc / Clms Page number 49>

 
 EMI49.1
 the N, N-dimethyl-amides of the following acids: Sc-9-oxo-11a, 1S (R) -dihydroxy-16 (R) -fluoro-18, 19, 20-trinor-17-cyclohexyl-prost-5 -en-13-ynoic;

   Sc-9-oxo-110 10 (S) -dihydroxy-20-nor-19-cyclohexyl-prost-5- - en-13- ynoïque; Sc-9-oxo-11 0 (, 15 ($) -di hydroxy-20-nor-19-cycl opentyl-prost - - S-en-13oïque; 5c-9-oxo-ll 15 (R) -d: hydroxy-16 (S) -! uoro-20-nor-l9-cyc! o- / hexyl-prost-5-en-13-ynolque; 5c-9-cxo-ll <15 (R, S) -djhydroxY-16 (S) -fluoro-20-nor-19- -cyclohexyl-prost-5-en-13-ynolque; 5c-9-oxo-1115 (S) -d! hydroxy-19, 20-dinor-18-cyclohexy! - - prost-5-en-13-ynolque; 5c-9-oxo-11 15 (S) -dihydroxy-19, 20-dinor-1S-cyclopenty! - - prost-5-en-13-ynolque; . 5c-9-oxo-11, 15 (R) -d i hydroxy-16 (S) -f 1 uoro-19, 2 O-d i nor-18- - cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-110 (, 1S (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19- - cyclohexyl-prost-5-en-13-ynolque;

   Sc-9-oxo-11, 15 (S) -dihydroxy-18, 19, 20-trinor-17-cyclohexl- - prost-5-en-13-ynoique; 5c-9-oxo-llo = 15 (S) -dihydroxy-18, 19, 20-tr: non-17-cyclopentyl- -prost-5-en-13-ynoique; 5c-9-oxo-lll5 (R) -d! hydroxy-16 (S) -f! uoro-18, 1920-tr: nor- - 17-cyclohexyl-prost-5-en-13-ynoique; ...



  5c-9-oxo-11 (R, S) -dihydroxy-16 (S) -ftuoro-18-19-20-T: rinor- -17-cyciohexyl-prost-5-en-13 - ynolque; 5c-9-oxo-lle, l5 (R) -d: hydroxy-16 (S) -fluoro-18, 19, 20-tr! nor- - 17-cyclopentyl-prost-'5-en-13-ynoique;

  <Desc / Clms Page number 50>

 
 EMI50.1
 5c-9-oxo-11o (, 15 (R, S) -dihydroxY-16 (S) -fluoro-18, 1, 20-tri nor- - 17-cyclopentyl-prost-5-en-13-ynoique; 5c -9-oxo-llc, l5 (S) -dihydroxy-l7, 18, 19, 20-tetranor-16-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-llc, l5 (S) -di hydroxy-17, l8, l9, 20-tetranor-l6-cyctopentyl-prost-5-en-13-ynolque;. 5c-9-oxo-ll e <, 15 (R) -dihydroxy-16 (S) -fluoro-17 ,. 18, 19, 20-tetranor- -16-cyclohexyl-prost-5-en-13-ynoique; . 5c-9-oxo-11,15 (R, S) -dihydroxY-16 (S) -fluoro-17, 18, 19, 20- - tetranor-16-cyclohexyl-prost-5-en-13-ynoique;

   5c-9-oxo-11 <, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl- - l8, l9, 20-trinor-17-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-llcl3 (R, S) -d! hydroxy-16 (S) -fluoro-1-methyt- - 18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-ynolque; 5c-9-oxo-llcl5 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl- -18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-ynoique; the pyrazolidin-amides of the following acids: 5c-9-oxo-110 (, 15 (R) -dihydroxy-16 (R) -fluoro-18, 19, 20-trinor-,.



  - 17-cyct ohexyl-prost-5-en-13-ynoique;

  <Desc / Clms Page number 51>

 
 EMI51.1
 5c-9-oxo-llc 15 (S) -d! hydroxy-20-nor-19-cyclohexyl-prost-5- 11, - en-13- ynoIque-j: 5c-9-oxo-11c <, 15 (S) -dihydroxy-20-nor-19-cyclopentyl-prost-.



  - 5-in-13-ynoique; 5c-9-oxo-lle15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-110 (, 15 (R, S) -dihydroxy-16 (S) -fl uoro-20-nor-19- - cyclohexyl-prost-5-en-13-ynolque; 5c-9-oxo -l1, 15 (S) -dihydroxy-19, 20-dinor-18-cyclohexyf- - prost-S-en-13-ynoIque; 5c-9-oo-ll <, 15 (S) -dihydroxy-19, 20-dinor-18-cyclopentyl- - prost-5-en-13-ynoique; 5c-9-oxo-11, 1S (R) -dihydroxY-16 (S) -fluoro-19, 20-dinor-18- - cyclohexyl-prost-5-en-13-ynolque; 5c-9-oxo-11, 1S (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19- - cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-1115 (S) -dihydroxy-18, 19, 20-trinor-17-cyclohexyl-, - prost-5-en-13-ynoIque; 5c-9-oxo-llo <, 15 (S) -dihydroxy-18, 19, 20-trinor-! 7-cyclopentyl- ./ - prost-5-en-13-ynoIque; 5c-9-oxo-ll l5 (R) -dihydroxy-l6.

   (S) -fluoro-18, 19, 20-trinor- - 17-cyclohexyl-prost-5-en-13-ynoIque; 5c-9-oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-18-19-20-trinor- - 17-cyclohexyl-prost-5-en-13-ynolque; Sc-9-oxo-ll. 15 (R) -dihydroxy-16 (S) -fluoro-18, 19, 20-trinor- / '- 17-cyclopentyl-prost-5-en-13-ynolque;

  <Desc / Clms Page number 52>

 
 EMI52.1
 Sc-9-oxo-ll <IS (R, S) -dihydroxy-16 (S) -fluoro-18, 19, 20-trinor- ,, 15 (- li-cyclopentyl-prost-5-en-13-ynoïque; 5c-9-oxo- he <. 15 (S) -dihydroxy-1718, 19, 20-tetranor-16-cyclohexyl-prost-5-en-13-ynolque; Sc-9-oxo-1115 (S) -dihydroxy-17, 18. 19, 20-tetranor-16-cyct opentyl-prost-5-en-13-ynoique;

   Sc-9-oxo-11, lS (R) -dihydroxY-16 (S) -fluoro-17, 18, 19, 20-ttranor- -16-cyc! ohexyl-prost-5-en-13-ynoique; 5c-9-oxo-lle <, 15 (R, S) -dihydroxy-16 (S) -fluoro-17, 18, 19, 20- -t e + -ranor-16-cycl ohexyl-prost-5-en-13-ynoique; 5c-9-oxo-ll <, 15 (R) -di hydroxy-16 (S) -f) uoro-16-methyl- - 18, 19/20-trinor-17-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-ll, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-mthyl- -18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13- ynoique ;

   Sc-9-oxo-11 ', 15 (RS) -d: hydroxy-16 (R) -f) uoro-16-meihyt- - 18, 19, 20-trinor-17-cyclohexyl-prost-5-n- 13- ynoique; piperidin-amides of the following acids: 5c-9-oxo-11a, 15 (R) -dihydroxy-16 (R) -fluoro-18, 19, 20-trinor- 17-cyclohexyl-prost-5-en-13 -ynoic;

  <Desc / Clms Page number 53>

 
 EMI53.1
 5c-9-oxo-llc 15 (S) -dihydroxy-20-nor-19-cyclohexyL-prost-5- - en-13-ynoique; 5c-9-oxo-llc <,, 15 (S) -di hydroxy-20-nor-19-cycl ope nt y l-pro st-, - - 5-en-13-ynoique; 5c-9-oxo-ll <, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyct ohexyl-prost-5-en-13-ynolque; 5c-9-oxo-llo (, 15 (R, S) -dihydroxY16 (S) -fluoro-20-nor-19- - cyclohexyl-prost-5-en-13- ynoique; '5c-9-oxo-ll , 15 (S) dihydroxy-19, 20-dinor-18-cyclohexyl- -prost-5-en-13-ynoique; 5c-9-oxo-ll, 15 (S) -dihydroxy-19, 20-dinor-18 -cyclopentyl- - prost-5-en-13-ynoique;

   . 5c-9-oxo-l1o <, 15 (R) -dihydoxy-16 (S) -fluoro-19, ZO-dinor-18- /.



  '-cyclohexyl-prost-5-en-13-ynolque; 5c-9-oxo-lle <, 15 (R, S) -dihdroxY-16 (R) -fJuoro-20-nor-19- -cyclohexyl-prost-5-en-13-ynolque ;; 5c-9-oxo-llc <5c-9-oxo-ll <, 15 (S) -dihydroxy-18-19 / 20-trinor-17-cyclohexyt- - prost-5-en-13-ynoique; 5c-9-oxo-11-15 (S) -dihydroxy-18, 19/20-trinor-17-cyclopentyl-, - prost-5-en-13-ynoique; 5c-9-oxo-11, 15 (R) -dihydroxy-16 (S) -fluoro-18, 19/20-trinor-17-cyclohexyl-prost-5-en-13-ynoiqùe; 5c-9-oxo-11,15 (R, S) -dihydroxy-16 (S) -fluoro-18-1920-trinor- -17-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-llo, 15 (R) -dihydroxY-16 (S) -fluoro-18, 19/20-trinor- - 17-cyclopentyl-prost-5-en-13-ynoique;

  <Desc / Clms Page number 54>

 
 EMI54.1
 5c-9-oxo-llb (, lS (R, S) -dihydroxy-16 (S) -fluoro-18, 19, 20-tri nor- -17-cycl ope nt y l-prost-5-en-13 --ynoic;

   5c-9-oxo-11, 15 (S) -dihydroxY-17, 18, 19, 20-tetranor-16-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-llc, 15 (S) -dihydroxy-17, 18, 19, 20-tetranor-16-cyclopentyl-prost-5-en-13-ynoique; 5c-9-oxo-l1l <, 15 (R) -dihydr oxy-16 (S), - fluoro-17, 18, 19, 20-t: tranor- -16-cyclohexyl-prost-5-en-13-. ynoique; 5c-9-oxo-llc, 15 (R, S) -dihydroxy-16 (S) -fluoro-17, 18, 19, 20- - tetranor-1 -cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-llo <(, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl- -18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo- ll, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-m: tyl- - 1, 19, 20-trlnor-17-cyclohexyl-prost-5-en-13- ynoique; 5c-9 -oxo-ll <, 15 (R, S) -dihydroxy-16 (R) -ftuoro-16 - methyl- - 18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-ynoique; the morpholin-amides of the following acids:

   5c-9-oxo-11 (, 15 (R) -dihydroxy-16 (R) -fluoro-18, 19, 20-trinor- - 17-cyclohexyl-prost-5-en-13-ynoIque;

  <Desc / Clms Page number 55>

 
 EMI55.1
 5c-9-oxo-ll <, 15 (S) -dihydroxy-20-nor-19-cyclohexyl-prost-5- / - en-13-ynoique; 5c-9-oxo-11, 15 ($) -dihydroxy-20-nor-19-cyclopentßl-prost- - 5-en-13-ynolque; 5c-9-oxo-11, 15 (R) -dihydroxY-16 (S) -fluoro-20-nor-19-cyc10hexyl-prost-5-en-13-ynoïque; 5c-9-oxo-11/15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19- -cici ohexyl-pros-t-5-en-13-ynoïque; 5c-9-oxo-11-15 (S) -dihydroxy-19, 20-dinor-18-cyclohexyf- - prost-5-en-13-ynoique; 5c-9-oxo-lle l5 (S) -dihydroxy-l9, 20-dinor-l8-cyc! opentyl- - prost-5-en-13-ynoique;

   Sc-9-oxo-l10 (, lS (R) -dihydroxy-16 (S) -fluoro-19, 20-dinor-18- -cyci ohexyl-prost-5-en-13-ynoique; 5c-9-oxo -ll, 15 (R, S) -dihydroxy-16 (R) -f'uoro20-nor-19- - cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-11O (, lS (S ) -dihydroy-18, 19, 20-trinor-17-cyclohexyl-, - prost-S-en-13-ynoïque; 5c-9-oxo-llc, 15 (S) -dihydroxy-18, 19, 20-trinor -17-cyclopentyl- - prost-5-en-13-ynoïque; 5c-9-oxo-llc, 15 (R) -dihydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyclohexyl -prost-5-en-13- ynoique; 5c-9-cxo-11t15 (R, S) -dihydroxy-16 (S) -fluoro-18-19-20-tri nor- - 17-cyclohexyl-prost-5 -en-13- ynoique; 5c-9-oxo-lll5 (R) -dihydroxy-l6 (S) -fluoro-l8, 19, 20-trinor- /.



  - 17-cyct openty! -Prost-5-en-13- ynoique;

  <Desc / Clms Page number 56>

 
 EMI56.1
 5c-9-oxo-11 (R, S) -dihydroxy-16 (S) -flu oro-18, 19, 20-trinor- - 17-cyclopentyl-prost-5-en-13-ynoique; 5c-9-oxO-l1, l5 (S) -dihydroxy-17, l8 / l9, 20-tetranor-l6-cyc! ohexyl-prost-5-en-13-ynolque; 5c-9-oxo-l10 (, 15 (S) -dihydroxy-17, 18, 19, 20-tetranor-16-cyclopentyl-prost-5-en-13-ynolque; 5c-9-oxo-ll, l5 ( R) -d: hydroxy-16 (S) -fluoro-17, 18, 19, 20-tetranor- - 16-cyclohexyl-prost-5-en-13- ynoique; $ c-9-oxo-l10 (, lS (R, S) -dihydroxy-16 (S) -fluoro-17, 18, 19, 20- - tetranor-16-cyclohexyl-prost-5-en-13- ynoique; 5c-9-oxo-llC (, 15 (R) -dihdroxy-16 (S) -fluoro-16-methyl- - 19, 20-trinor-17-cyclohexyl-prost-5-en-13- ynoique; 5c-9-oxo-llc, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl- -18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-ynoique;

   5c-9-oxo-110, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methy \ - - 18, 20-trinor-17-cyclohexyl-prost-5-en-13 - ynoique .

  <Desc / Clms Page number 57>

 



  EXAMPLE 4
We dissolved tert. potassium butylate (3.2 g) in 20 ml of dry DMSO under nitrogen atmosphere and triphenylphosphonium pentanoic acid amide bromide (6.3 g) was added to the solution with stirring using 'a food stirrer.



   The temperature was kept below 300C using a water bath and a solution of 3a, 5a-dihydroxy-2ss-L-bromo-3 (S, R) -hydroxy-4 was added. (S) -fluoro-4-
 EMI57.1
 methyl-5-cyclopentyl-pent-trans-1-enyiy-1 a-cyclopentane acetaldehyde-y-lactol-15-trimethylsilylether (1.9 g) in DMSO (8 ml) to the mixture previously obtained. After the completion of the reaction, the mixture was diluted with cold water and then extracted with diethyl ether. The solvent was removed and the crude product, obtained in 15-deprotected form during the Wittig reaction, was purified by chromatography, so as to collect 1.8 g of 5c-9a, 11a acid amide, 15 (S, R) -trihydroxy-16 (S) -fluoro-16-methyl-18,19, 20-
 EMI57.2
 trinor-17-cyclopentyl-prost-5-en-13-ynoIque: 7p = + 14.95; / o7365 = + 54.2 (C = 1 EtOH).



   By proceeding in a similar manner, we obtained. the amides of the following acids:

  <Desc / Clms Page number 58>

 
 EMI58.1
 5c-9-cw, ', It c <.. 15 (S) -trihydroxy-20-n or-19-cycl oh exyl-p rost- '- en-13-ynoique; - 5c-9 =, 11o <, 15 (S) -trihydroxy-20-nor-19-cyclopentyl-pros-5- - en-13-ynoïque; 5c-9 <-ll: 15 (R) -tr! hydroxy-16 (S) -f) uoro-20-nor-19-cyc) ohexyl-prost-5-en-13-ynolque; 5c-9 =. 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyc10hexyl-prost-5-en-13-ynoique; Sc-9o (, 11o (, 15 (S) -trihydroxy-19, 20-dinor-18-cyclohexyl-prost- -5-en-13-ynoi-que; 5c-9c </ llel5 (S) -tr! hydroxy-l920-d! nor-18-cyc) openty) -prost- - 5-en-13-ynolque; 5c-9 lc <, 15 (R) -tr i hydroxy-16 (S) -f 1 uoro-19, 20-d i nor-18- - cyclohexyl-prost-5-en-13-ynolque; 5c-9 11l5 (R.

   S) -trihydroxy-l6 (R) - F! uoro-20-nor-19-cyctohexyl-prost-5-en-13-ynoique; 5c-9o <ll <15 (S) -tr i hydroxy-18, 19, 20-tr i nor-17-cyc 1 ohexyl- -prost-5-en-13-ynoique; 5c-9c <, 11o <, 15 (S) -trihydroxy-18, 19, 20-trinor-11-cyclopentylprost-5-en-13-ynoic; 5c-9c 1115 (R) -trihydroxy-16 (S) -f tuor o-18, 19, 20-trinor-17- -cycl ohexyl-prost-5-en-13-ynoique; 5c-9o <, ll 15 (R, S) -tr: hydroxy-l6 (S) -f! uoro-18, 19, 20-tr i nor- -17-cyci ohexyl-prost-5-en-13-ynoïque;

  <Desc / Clms Page number 59>

 
 EMI59.1
 5c-911 <, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor- -17-C c e - 17-cyclopentyl-prost-5-en-13-ynoïque; 5c-9, 11/15 (R, S) -trihydroxy-16 (S) -fluoro-18/19/10-trinor- - 17-cyclopentyl-prost-5-en-13-ynolque; 5c, 9o (, 11o <, lS (S) -trihydroxy-17, 18, 19, 20-ttranor-16-cyclohexyl-prost-5-en-13-ynoique;

   5c-9 o <llol5 (S) -trihydroxy-l7 l8, 19, 20-tetranor-l6-cyc! opentyl-prost-5-en-13-ynoIque; 5c-9 ' <, ll <715 (R) -trihydroxy-16 (S) -fluoro-17, 18, 19, 20-tetranor- - 16-cyclohexyl-prost-5-en-13-ynoique; 5c-9. 11 <, 15 (R, S) -tr: hydroxy-16 (S) -fluoro-17, 18, 19, 20-tetranor-16-cyclohexyJ-prost-5-en-13-ynoique; 5c-9 <. llX, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18, 19, 20- - trinor-17-cyclohexyl-prost-5-en-13-ynoique; 5c-9o </ lle. 15 (R, S) -tr i hydroxy-îó (S) -f! uoro-16-methyl- -18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-ynoique; 5c-9 (, 11D (, 15 (R) -trihydroxY-16 (R) -fluoro-16-methyl-8, 19, 20- - trinor-17-cyclohexyl-prost-5-en-13-ynoique;

  <Desc / Clms Page number 60>

 
 EMI60.1
 the N, N-dimethyl-amides of the following acids: 5c-9 <, 11 <= <, 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5- - en-lj-ynoique;

   5c-9 '= <1115 (S) -trihydroxy-20-nor-l9-cyclopentyl-prost-5- '"- en-13-ynoique; 5c-9c <, llo <, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cycl0hexyl-prost-5-n-13-ynoique; 5c-9111c (, lS (R, S) -trihydroxY-16 (S) -fluoro-20-nor-19-cyc10hexyl-prost-5-en-13-ynolque; 5c-9, 110 (, 15 (S) -trihydroxy-19, 20-dinor-18-cyclohexyl-prost- -5-en-13- ynoique; 5c-9o <, 11.15 (S) -trihydroxy-19, 20-dinor-18-cyclopentyl-prost- - 5-en-13-ynoique; 5c-9c <, 11, 15 (R) -trihydroxy-16 (S) -fluoro-19, 20-dinor-18- -cyc! Ohexyt-prost-5-en-13-ynoique; 5c-9 <, l115 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cycloheyl-prost-5-n-13-ynoique; 5c-9 '= <1115 (S) -trihydroxy-18, 19, 20-trinor-17-cyclohexyl- - prost-5-en-13- ynoique, 5c-9 (, 11c <, lS (S) -trihydroxy-18, 19, 20-trinor-1-cyclopentyl- - prost-5-en-13-ynoique;

   (R) -trihydroxy-16 (S) -f 1 uoro-18, 19, 20-tri nor-17- -cyclohexyl-prost-5-en-13-ynoïque; Sc-911-15 (R, S) -trihydroxy-16 (S) -fluoro-18,19, 20-trinor- - 17-cyclohexyl-prost-5-en-13-ynoïque;

  <Desc / Clms Page number 61>

 
 EMI61.1
 5c-911cl3 (R) -tri hydroxy-16 (S) -ftuoro-18, 19, 20-tri nor- -17-cyclopentyl-prost-5-en-13-ynolque; 5c-9 <= <lll5 (RS) -tr {-hydroxy-l6 (S) -f! uo.ro-l8, l9. 10-tr! nor- - 17-cyclopentyl-prost-5-en-13-ynoIque; 5c, 91115 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cyc) ohexyl-prost-S-en-13-ynoIque; 5c-911o (, l5 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cyc) opentyl-prost-5-en-13-ynoique; 5c-9th. 11-15 (R) -trihydroxy-16 (S) -fluoro-17; 18, 19, 20-tetranor- - le-cyclohexyl-prost-5-en-13-ynoIque; 5c-9, 11, 15 (R, S) -trihydroxY-1é (S) -fluoro-17, 18; 19, 20-ttranor-le-cyclohexyl-prost-S-en-13-ynoIque;

   5c-91115 (R) -trihydroxy-16 (S) -fluoro-16-methyt-18. 19, 2C- - trinor-17-cyclohexyl-prost-5-en-13-ynoique; -911. (.15 (R. S) -tr: hydroxy-l6 (S) -ft uoro-l6-me-t: hyt-. D 0 and - 18, 19, 20-trinor-17-cyclohexyl-prost-5- en-13-ynolque; 5c-9o (, (R) -trihydroxy-16 (R) -fluoro-16-methyl-1S. 19, 20- - trinor-17-cyclohexyl-prost-5-en-l3- ynoique ; e

  <Desc / Clms Page number 62>

 
 EMI62.1
 the pyrazolidin-amides of the following acids: Sc-9c 11, lS (S) -trihydroxy-20-nor-19-cyclohexyJ-prost-S- - en-13-ynoique;

   Sc-9 01., il (S) -trihydroxy-20-nor-19-cyclopentyl-prost-5-. 1 - en-13-ynoique; 5c-9C (, 11o <, lS (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cycl0e hexyl-prost-5-en-l3-ynoique; 5c-9 <, 11 <, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyc10hexyl-prost-5-en-13-ynoique; 5c-9, ll <=, 15 (S) -trihydroxy-19, 20-dinor-18-cyclohexyl-prost- - S-en-13-ynoique; 5c-90 (, 11, 15 (S) -trihydroxY-19, 20-dinor-18-cyclopenyl-prost- - 5-en-13-ynoique; - 5c-9, 116 (, 15 (R) -trihydroxy -16 (S) -fluoro-19, 20-dinor-18- -cycl ohexyl-pros-t-5-en-13-ynoique; 5c-911l5 (RS) -tr! Hydroxy-l6 (R) -ft uoro -20-nor-l9- <= yc! ohexyl-prost-5-en-13-ynoique; 5c-9, 11, 15 (S) -trihydroxY-18, 19, 20-trinor-li-cyclohexy1- - prost-5-en-13-ynoique; suc-90 11015 (S) -tr: hydroxy-18 19. 20-trinor-17-cyc topentyt- - prost-S-en-13-ynoique;

   5c-9 <, ll. 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor-17- - cyclohexyl-prost-5-en-13-ynoique; 5c-9, 11o (, 15 (R, S) -trihydroxY-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyclohexyl-prost-5-en-13-ynoique;

  <Desc / Clms Page number 63>

 
 EMI63.1
 5c-9 ll5 (R) -trihydroxy-l6 (S) -f! uoro-18, 19, 2Q-trinor- - 17-cyctopentyl-prost-5-en-13-yiOique; 5c-9 1Ic15 (PS) - crt-hydroxy-16 (S) -f! Uoro-18,19. 10-tr! nor- - 17-cyc t opentyl-prost-5-en-13-, ynoique; 5c, 11 <, 1 (S) -trihydroxy-17, 18, 99, 20-tetranor-16-cycl ohexyl-prost-5-en'n-13-ynoique; 15 (S) -tr i hydroxy-17, 18, 19, 20-t'étranor-16-cycl opentyl-prost-S-n-13-ynoique; 1-ce e 5c-911. 15 (R) -tri hydroxy-16 (S) -ftuoro-17, 18, 19, 20-tetranor- - 16-cyclohexyl-prost-5-n-13-ynoique; 5c-9o <. ll, 15 (R, S) -trIhydroxy-l6 (S) - Ft uoro-17, l8, l9. 20-tetranor-16-cyclohexyl-prost-5-en-13-ynoique;

   5c-9, 11o (, 15 {R) -trihydroxy-16 (S) -fluoro-16-methyl-18, 19, 20- - tr i nor-17-cyc! oxy I-pros't: -5-en-13-ynoTque; t 5c-911 <15 (R, S) -trihydroxy-16 (S) -fluoro-lô-me-chy! - -18, 19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoique; 5c-9, 110 (., 15 (R) -tri hydroxy-16 (R) -fl uoro-16-m6thy.

   J-18, 19/20-Sc-9 W ,, 11 ç>, - tri nor-17-cycl ohexyl-prost-5-en-13 ynoique;

  <Desc / Clms Page number 64>

 
 EMI64.1
 piperidin amides of the following acids: 5c-9 <= <llc 15 (S) -trihydroxy-20-nor-l9-cycl ohexyl-prost-5- - en-13-ynoique; - 5c-9, 11, 15 (S) -trjhydroxy-20-nor-19-cycropentyr -prost-5- - en-13-. ynoique; ; 5c-9'K / -l1 <15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoique; 5c-9 11 15 (R, S) -tr! hydroxy-16 (S) -f! uoro-20-nor-19-cyc i ohexyl-prost-5-en-13-ynolque;

   Sc-911 < <15 (S) -tr: hydroxy-l9 / 20-d: nor-l8-cyc! ohexyt-prost- - 5-en-13-ynoique; 5c-911l5 (S) -tr: hydroxy-l920-d! nor-lo-cyct opentyt-prost- - 5-n-13-ynoïque; 3c-9 ', 11. 15 (R) -tr: hydroxy-l6 (S) -f! uoro-l9, 20-d! nor-18- -cyclohexyl-prost-5-en-13-ynoique; 5c-9 <, 11, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyc) ohexyl-prost-5-en-13-ynoique; 5c-90 11 <15 (S) -tr: hydroxy-l8, l9. 20-tr: nor-17-cyc! ohe <y! - -prost-5-'én-13- ynoique; Sc-9, 110 (, 15 (S) -trihydroxy-18, 19, 20-trinor-17-cyc! Opentyl- - prost-5-n-13-ynoique;.



  , D e 5c-9cll, 15 (R) -tr: hydroxy-l6 (S) -ftuoro-l8, l9720-tr '! nor-17- -cyclohexyl-prost-5-en-13-ynolque; 5c-9o <., lle 15 (R, S) -tr: hydroxy-16 (S) -fluoro-18, l920-trinorSc-gc> .- - 17-cyclohexyl-prost-5-en-13-ynolque;

  <Desc / Clms Page number 65>

 
 EMI65.1
 z II, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 2e-trinor- - l7-cyc! opentyl-prost-5-en-13-ynoique; = -911 <K. 15 (R.S) -tr: hydroxy-16 (S) -f! uoro-l8, l9, 10-tr! nor- - 17-cyc! opentyl-prost-5-en-13-ynolque; 5c 9. 11 ', 15 (S) -trihydroxy-17, 18, 19, 20-tetrenor-16-cycl ohexyl-prost-5-en-13-ynolque; 5c-91% <, 1 1,. e etranor-1 5c-9, 11, 15 (S) -trihydroxY-17, 18, 19, 20-tranor-16-cycl0pentyt-prost-5-en-13-ynolque; 5c-9, 11, 15 (R) -tri hydroxy-16 (S) -f! uoro-1718, 19, 20-tetranor- -16-cyclohexyl-prost-5-e / n-13-ynoique;

   5c-9, 11, 15 (R, S) -trihydroxY-16 (S) -fluoro-17, 18i19, 20-tetranor-16-cyc, l ohexyl-prost-5-en-13-ynolque; 5-c-11 t .. e e-L-h bic-9 11 </ l5 (R) -tr; hydroxy-16 (S) -f! uoro-16methyL-18, 19, 20--tri nor-17-cyci ohexyl-prost-5-en-13-ynoique; 5 c-9 <> ,,, 11 4 x ,, 15 (R, S) - rihydro '>' y-16 (S) -fluoro-16-m'éthyl- -18, 19, 20-trinor-17-cyclohexyl- prost-5-en-13-ynolque; 5c-9o (, lll5 (R) -trihydroxy-l6 (R) -fluoro-l6-methyl-18, l9, 20- -trinor-17-cyclohexyl-prost-5-e / n-13-ynoïque;

  <Desc / Clms Page number 66>

 
 EMI66.1
 morpholin-amides. of the following acids: 5c-911 <X., 15 (S) -tri hydroxy-2. 0-nor-19-cyclohexyl-prost-5- - en-13-ynoique;

   SC-9 w ', 15 (S) -trihydroxy-20-nor-19-cyclopentyl-prost-' - en-13-ynoique; 5c-9cv ,, rllw ,, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyt-prost-5-en-13-ynoique; - 5c-9e <ll <l5 (RS) -tr) hydroxy-l6 (S) -f! uoro-20-nor-l9-cyct o <hexyl-prost-5-en-13-ynoique; Sc-9 re 5c-9, 11, 15 (S) -trjhydroxy-19, 20-dinor-18-cyclohexyl-prost- - 5-en-13-ynoique; 5c-9 </ ll, 15 (S) -trihydroxy-19, 20-dinor-18-cyclopenty) -prost- - 5-n-13-ynolque; 5c-9, 11C (, 15 () -trihydroxy-16 (S) -fluoro-19, 20-dinor-18- - cyclohexyl-prost-5-en-13-ynoique; 5c-90 (, 11, 15 ( R, S) -trihydroxY-16 (R) -fluoro-20-nor-19-cyc10hexyl-prost-5-en-13-ynolque; 5c-9c, 11, 15 (S) -tr! Hydroxy-1819. 20 -tr: nor-17-cyct ohexyt- - prost-5-en-13-ynoique; 3c-911ol5 (S) -trihydrpxy-18, 19, 20-trinor-17-cyclopentyt-.



  -.



  -prost-5-en-13-, ynoique; 5c-9, 110 (, 15 (R) -trihydroxY-16 (S) -fluoro-18, 19, 2Q-trinor-17- - cyc! Ohexyl-prost-5-en-13-ynoique; 5c-9o llc ., 15 (RS) -tr: hydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyclohexyl-prost-5-en-13-ynoique;

  <Desc / Clms Page number 67>

 
 EMI67.1
 15 (R) -trihydroxy-16 (S) -f lu or o-18, 19, 20-trinor- - 17-cyc! openty! -pros'i: -5-en-l3- ynoique; 5c-9 o:, llc, 15 (R, S) -tr i hydroxy-16 (S) -f 1 uoro-18, 19, '10 -tr i nor- -17-cycl opentyl-prost-5-en -13-ynolque; 5c, ze Il ilbe ,, 15 (S) -trihydroxy-17, 18, 19, 20-tétr an or-16-cycl ohexyl-prost-5-en-13-ynolque; . 5c-9cll & <, 15 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cycl opentyl-prost-5-en-13-ynoique; 15 (R) -trihydroxy-16 (S) -f lu or o-17, 18, 19, 20-tetranor- '-16-cyc! ohexyl-prost-5-en-13-ynolque;

   5c-9 <= K. 11, 15 (R, S) -tr i hydroxy-16 (S) -uoro-17, 18, 19, 20-tetranor-16-cycl ohexyl-prost-5-é n-13-ynoique; 5c-9.-11-. 15 (R) -tr i hydroxy-16 (S) -f) uoro-16-methyl-18, 19, 20- - tr! nor-17-cycl ohexyl-prost-5-en-13-ynoique; e 3c-9c <, 11.15 (R, S) -tr i hydroxy-16 (S) - F! uoro-l6-m & thyl- - 18, 19, 20-tri nor-17-cycl oh ex yi -prost-5-n-13- ynoique; ' 5c-9bç, 11o (/ lS (R) -trihydroxy-16 (R) -fJuoro-16-méthyJ-18, 19 / 20- -trinor-17-cyci ohexyl-prost-5-en-13-ynoique; and 5c-9 (, ll (X, 15 (R) -trihydroxy-16 (S) -f! uoro-18, 19, 20-tri nor-17- -cyci ohexyl- prost-5-en-13-ynoique.

  <Desc / Clms Page number 68>

 



   EXAMPLE 5
We carried a solution of 5c-9-oxo-11a, 15 (S) -dihydroxy-
16 (R) -fluoro-18, 19, 20-trinor-17-cycloheptyl-prost-5-en-13-ynoyl-piperidin-amide 11, 15-bis THP-ether (0.57 g) in acetone (10 ml), treated with a 1N aqueous solution of oxalic acid (10 ml), at reflux for 7 hours. The excess acetone was removed in vacuo and the solution was extracted with diethyl ether. The organic extract was concentrated and absorbed on acid-washed silica gel.

   Elution with a mixture of benzene and diethyl ether gave 0.21 g of 5c-9-oxo-15 (S) -hydroxy-16 (R) -fluoro-18, 19, 20 acid piperidinamide -trinor-17-cyclo-heptyl-prosta-5, 10-dien-13-ynoic: a7 = + 2.5, (C = 1 EtOH).



   By repeating the same procedure, but starting from the intermediate 9-oxo-11,15-bis-THP-ethers obtained by implementing the process described in Example 3, the amides of the following acids were obtained: tc-9-oxo-15 (S) -hydroxy-20-nor-19-cyclohexyl-prosta-5, 10- - dien-13-ynolque; 5c-9-oxo-15 (S) -hydroxy-20-nor-19-cyclopentyl-prosta-5,10- -dién-13-ynoique; 5c-9-oxo-15 (R) -hydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-
 EMI68.1
 -prosta-5, 10-di'én-13-ynoique; 5c-9-oxo-15 (R, S) -hydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl- - prosta-510-d! en-13-ynolque; 5c-9-oxo-15 (S) -hydroxy-19, 20-dinor-18-cyclohexyl-prosta- - 510-dien-13-ynolque;

  <Desc / Clms Page number 69>

 
 EMI69.1
 5c-9-oxo-1S (S) -hydroxy-19, 20-di nor-18-cycl op entyl-prosta- - 5, 10-di en-13-ynolque;

   Sc-9-oxo-1S (R) -hydroxy-16 (S) -fluoro-19, 20-dinor-18-cycl0hexyl-prosta-5, 10-di en-13-ynolque; 5c-9-oxo-l5 (R, S) -hydroxy-l6 (R) -ftuoro-20-por-l9-cyc! ohexy! - - prosta-S, 10-dien-13-ynoique; 5c-9-oxo-15 (S) -nydroxy-18, 19, 20-trinor-17-cyclohexyl-prosta-.



  - 510-d! en-13-ynolque; 5c-9-oxo-15 (S) -hydroxy-18r19, 20-trinor-17-cyclopentyl-prosta- - 10-di en-13-ynolque; 5c-9-oxo-15 (R) -hydroxy-16 (S) -ftuoro-18, 19, 20-trinor-17-cyc! ohexyl-prosta-510-di en-13-ynolque; 5c-9-oxo-15 (S, ¯g) -hydroxy-16 (S) -f luoro-18, 19, 20-trinor-17- -cycl oh exyl-prosta-5, 10-di'én-13 -ynoic; Sc-9-oxo-is (R) -hydroxy-16 (S) -fluoro-18, 19, 20-trinor-17-cyclopentyl-prosta-S, 10 en-13-ynolque; Sc-9-oxo-lS (R, S) -hydroxy-l6 (S) -f! uoro-18l9, 20-trtnor-17- - cycl opentyl-prosta-510-dien-13-ynolque; 5c-9-oxo-15 (S) -hydroxy-1718, 19, 20-tetranor-16-cyclohexyl- - prosta-5fl0-d! en-13- ynoique; 5c-9-oxo-15 (S) -hydroxy-17, 18, 19, 20-ttranor-16-cyclopentyl- - prosta-5, 10-di en-13-ynoique; - 5c-9-oxo-15 (R) -hydroxy-16 (S) -f 1 uoro-17, 18, 19, 20-ttranor-16-.



  - cyctohexyl-prosta-5, 10-d! en-13-ynolque; Sc-9-oxo-15 (R, S) -hydroxY-16 (S) -fluoro-17, 18, 19, 20-ttranor- -16-cyclohexyl-prosta-5, 10-dien-13-ynoïque;

  <Desc / Clms Page number 70>

 
 EMI70.1
 5c-9-oxo-15 (R) -hydroxy-16 (S) -fluoro-16-methyl-18, 9, 20- - tri nor-17-cycl ohexyl-prosta-5, 10-d: en-13 -ynolque; 5c-9-oxo-15 (R, S) -hydroxy-16 (S) -fluoro-16-methyl-18, 19, 20- ./ - tr! nor-17-cyctohexyl-prosta-5, 10-d) en-13-ynolque; 5c-9-oxo-15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18, 19, 20- -trinor-17-cyclohexyl-prosta-5, 10-die / n-13 - ynoique EXAMPLE 6
To a solution of piperazinamide of acid 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13- flood (0.2 g) in 95% ethyl alcohol (5 ml), a stoichiometric amount of 1N HCl was added.

   The solvent was evaporated to dryness so as to obtain the piperazinamide hydrochloride of acid 5c-9 &alpha;, 11 &alpha;, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor -17-cyclohexyl-prost-5-en-13-ynoique, in the form of white crystals.



  EXAMPLE 7
5c-9 &alpha;, 11 &alpha;, 15 (R) -trihydroxy-16 (S) - fluoro-18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-ynoyl- N were dissolved N-dimethylamide 11,15-bis-THP-ether (0.65 g) in 10 ml of dry CC14 and 0.5 ml of pyridine, then 0.1 ml of acetyl chloride was added dropwise to the solution.



   The solution was stirred for about 2 hours at room temperature and was neutralized with 10% NaH2PO4 solution and extracted with diethyl ether.



   The solvent was removed and the crude product was purified by chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (80/20) as eluent.

  <Desc / Clms Page number 71>

 



   5c-9a, 11a, 15 (R) -trihydroxy-16 (S) - fluorine-18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13-nonylN, N-dimethylamide 11 were collected , 15-bis pure THP-ether-9-acetate and dissolved in a mixture of acetone (10 ml) and 1N oxalic acid (10 ml) and stirred for 6 hours
 EMI71.1
 at 40oC. The solution was diluted with 10 ml of H 2 O, the acetone was distilled and the mixture was extracted with diethyl ether.



   The crude product was purified on silica gel using a mixture of ethyl acetate and cyclohexane (50/50) as eluent, so as to obtain 0.320 mg of 5c-
 EMI71.2
 9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor-17cyclohexyl-prost-5-en-13-ynoyl-N, N-dimethylamide-9-acetate pure ad = + 76.2 (c = 1 EtOH).



   By proceeding in an analogous manner, derivatives of the 9-acetate type of all the compounds indicated in example 1 were obtained.



  COMPOSITION EXAMPLES Composition 1: tablet (1 mg).



   Tablets are produced, each weighing 80 mg and containing 1 mg of active substance, as follows: Composition (per 100,000 tablets)
 EMI71.3
 
 <tb>
 <tb> Amide <SEP> from <SEP> acid <SEP> 5c-9a, <SEP> 11a, <SEP> 15 <SEP> (R) -trihydroxy-16 <SEP> (S) <SEP> (fluoro-
 <tb> 18, <SEP> 19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoïque <SEP> 100 <SEP> g
 <tb> Lactose <SEP> 5000 <SEP> g
 <tb> Starch <SEP> from <SEP> but <SEP> 2720 <SEP> g
 <tb> Talc <SEP> in <SEP> powder <SEP> 150 <SEP> g
 <tb> Stearate <SEP> from <SEP> magnesium <SEP> 30 <SEP> g
 <tb>
 
The 5c-9a, 11a, 15 (R) -trihydroxy- 16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide is mixed. lactose and half the corn starch;

   the mixture is then forced through a sieve to

  <Desc / Clms Page number 72>

 mesh size of 0.5 mm. Corn starch (18 g) is suspended in hot water (180 ml). The paste thus obtained is used to granulate the powder. The granules are dried, ground on a sieve with a mesh size of 1.4 mm, then the residual amount of starch, talc, magnesium stearate is added, the whole is mixed thoroughly and the mixture is transformed into tablets using punches with a diameter of 5 mm.



  Composition II: capsule (1 mg)
 EMI72.1
 
 <tb>
 <tb> Amide <SEP> from <SEP> acid <SEP> 5c-9a, <SEP> 11a, <SEP> 15 <SEP> (R) <SEP> -trihydroxy-16 <SEP> (S) <SEP> -fluoro-
 <tb> 18, <SEP> 19, <SEP> 20-trinor-17-cyclohexyl-prost-5-en-13-ynoïque <SEP> 1, <SEP> 0 <SEP> mg
 <tb> Lactose <SEP> 89, <SEP> 8 <SEP> mg
 <tb> Starch <SEP> from <SEP> but <SEP> 9, <SEP> 0 <SEP> mg
 <tb> Stearate <SEP> from <SEP> magnesium <SEP> 0, <SEP> 2 <SEP> mg
 <tb> Total <SEP> 100, <SEP> 0 <SEP> mg
 <tb>
 
This composition is introduced into hard gelatin capsules in two pieces.


    

Claims (9)

CLAIMS 1. Optically active or racemic isomers of prostaglandin derivatives which correspond to formula (I)  EMI73.1  in which each of the symbols R 'and R "independently represents a hydrogen atom, a C1-C6 alkyl, aryl or heterocyclic radical, or else R'and R", considered with the nitrogen atom to which they are linked, form a heterocyclic nucleus; the symbol ---- represents a single or double bond where: a) when the symbol - represents a double bond, R1 denotes a hydrogen atom and R2 and Reconsidered together, form an oxo group;  b) when the symbol ---- represents a single bond, R1 denotes a hydroxyl radical, R2 denotes a hydrogen atom and R3 denotes a hydroxyl or acyloxy radical, or else R2 and Reconsidered together, form an oxo group; one of the symbols R4 and R5 represents a hydroxyl radical, while the other represents a hydrogen atom;  <Desc / Clms Page number 74>  each of the symbols R6 and Ry represents, independently, a hydrogen atom, a C1-C4 alkyl radical or a fluorine atom; n is 0, 1, 2, or 3; Rp represents a cycloalkyl group, unsubstituted or substituted by one or more substituents chosen from a ') halogens; b ') a C1-C6 trihaloalkyl radical;    c ') a C1-C4 alkyl radical; d ') a C1-C4 alkoxy radical; el) a phenyl radical and f) a phenoxy radical; as well as the salts of these compounds, acceptable in human or veterinary pharmacy.  2. Compounds according to Claim 1, characterized in that: R'and R''represent independently of hydrogen atoms or C1-C4 alkyl radicals, or else R 'and R ", considered with the nitrogen atom to which they are attached, form a pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, piperidino, piperazinyl or morpholino group; the symbol ---- represents a single bond, R1 represents the hydroxyl radical, R2 represents a hydrogen atom and R3 represents the hydroxyl radical or an acyloxy group and R2 and Rus, taken together, form an oxo group;    Rg represents a radical chosen from cyclopentyl, cyclohexyl and cycloheptyl groups, each of these groups not being substituted or being substituted by one or more substituents chosen from a ') halogens, b') C1-C6 trihaloalkyl radicals, cl) C1-C4 alkyl radicals, d ') alkoxy radicals, e') phenyl group, f) phenoxy radical; R4, R5, R6, R7 and n have the meanings  <Desc / Clms Page number 75>  which have been assigned to them in claim 1, as well as the salts of these compounds acceptable in human or veterinary pharmacy.  3. Compounds according to claim 1, characterized in that:  EMI75.1  R'and R '* independently represent hydrogen atoms or methyl radicals; or else RI and RI '. taken together with the nitrogen atom to which they are attached, form a piperidino or morpholino nucleus; the symbol ---- represents a single bond, R1 represents the hydroxyl radical, R2 represents a atom of hy-  EMI75.2  drogen and R3 represents the hydroxyl radical, or else R2 and Reconsidered together form an oxo group; each of the symbols R6 and Ry represents, independently, a hydrogen atom, a methyl radical or a fluorine atom;  EMI75.3  R ,, Rc and n have the meanings assigned to them in claim 1;  Ra represents the cyclopentyl or cyclohexyl radical; as well as the salts of these compounds acceptable in human or veterinary pharmacy.  4. Compounds chosen from the group formed by: the amides of the following acids:  EMI75.4  5c-9-oxo-Ilte ,, 15 (R, S) -dihydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cyclopentyl-prost-5-en-13-ynolque; Sc-9-oxo-11 <15 (S) -dihydroxy-17, 18, 1920-tetranor-16-cyclohexyl-prost-5-en-13-ynolque; 5c-9-oxo-11115 (S) -dihydroxy-17, 18, 19, 20-tetranor-16-cyclopentyl-prost-5-en-13-ynolque; 5c-9-oxo-11,15 (R) -di -dihydroxY-16 (S) -fluoro-17, 18, 19, 20-ttranor- -16-cyclohexyl-prost-5-en-13-ynolque;  <Desc / Clms Page number 76>    EMI76.1  5c-9-oxo-11,15 (R, S) -dihydroxy-16 (S) -fluoro-17, 18, 19, 20- - tetranor-16-cycl ohexyl-prost-5-en-13-ynolque; 5c-9-oxo-11, 15 (R) -di hydroxy-16 (S) -ft uoro-16-methyl- - 18, 19, 20-tri nor-17-cyci ohexyl-prost-5-en-1 "-ynoic;  5c-9-oxo-11O (, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-mthyl- -18, 19, 20-trinor-17-cyclohexyl-prost-5-en-13- ynoique; 5c-9-oxo-11O 15 (R, S) -dihydroxy-16 (R) -fluoro-16-mthyl-. -18, 19, ZO-trinor-17-cyclohexyl-prost-5-en-13 - ynoic; the morpholin-amides of the following acids: 5c-9-oxo-1115 (S) -dihydroxy-20-nor-19-cyclohexyl-prost-5- -é1n-13-ynoique; 5c-9-oxo- ll15 (S) -di hydroxy-20-nor-l9-cycl opentyl-prost- - 5-en-13-ynolque; 5c-9-oxo-ll &, l5 (R) -d! hydroxy-16 (S) -f! uoro-20-nor-19-cyc 1 ohexyl-prost-5-en-13-ynolque; 5c-9-oxo-11 / lS (R, S) -dihydroxy-16 (S) -fluoro-20 -nor-19- -cyc! ohexyl-prost-5-en-13-ynoique ;; 5c-9-oxo-ll <15 (S) -di hydroxy-19, 20-di nor-18-cycl ohexyl- - prost-5-en-13-ynoique; 5c-9-oxo-llc, 15 (S) -d! hydroxy-19, 20-di nor-18-cycl opentyl- -prost-5-en-13-ynoique; 5C-9-oxo-11 z <, 15 (R) -di hydroxy-16 (S) -f 1 uoro-19, 20-di nor-18-,. - cycl ohexyl-prost-5-en-13-ynoique; 5c-9-oxo-11-15 (R, S) -d; hydroxy-16 (R) -fluoro-20-nor-19- - cycl ohexyl-prost-5-en-13-ynoique;  <Desc / Clms Page number 77>    EMI77.1  5c-9-oxo-116 (, 15 (S) -dihydroxy-18, 19, 20-trinor-17-cyclohexyl- - prost-5-en-13-ynolque; 5c-9-oxo-ll <<, 15 lS (S) -dihydroxy-18, 19, 20-trinor-17-cyclopent yl- - prost-5-en-13-ynolque; 5c-9-oxo-11, 15 (R) -dihydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cycl ohexyl-prost-5-en-13-ynoique; 5c-9-oxo-llt- (15 (R, S) -di hydroxy-16 (S) -f 1 uoro-18-19-20-tri nor- - 17-cyclohexyl-prost-5-en-13-ynoique; 5c-9-oxo-ll, 15 (R) -dihydroxy-16 (S) -fluoro -18, 19, 20-trinor- 5c-9-oxo-11 te - 17-cyc! Openty! -Prost-5-en-l3-ynolque; 5c-9-oxo-llc, 15 (R, S) - dihydroxy-16 (S) -f! uoro-18, 19, 20-tri nor- -17-cyclopentyl-prost-5-e "n-13-ynoique;  Sc-9-oxo-llo <, 15 (S) -d: hydroxy-17l8, 19/20-tetranor-16-cyct ohexyl-prost-5-en-13-ynoique; 5c-9-oxo-11 <, 15 (S) -di hydroxy-17, 18, 19, 20-tetranor-16-cyctopentyl-prost-5-en-13-ynolque; 5c-9-oxo-ll, 15 (R) -di hydroxy-16 (S) -f 1 uoro-17, 18, 19, 20-te / tranor- -16-cyclohexyl-prost-5-en-13- ynoique; 5c-9-oxo-11,15 (R, S) -dihydroxY-16 (S) -fluoro-17, 18, 19, 20- - tetranor-16-cycl ohexyl-prost-5-en-13-ynoique;  Sc-9-oxo-11, lS (R) -dihydroxy-16 (S) -fluoro-16-methyl- - ,, 19, 20-tr i nor-17-cyc! ohexyt-prost-5-en-13-ynolque; 5c-9-oxo-ll <(, 15 (R, S) -di hydroxy-16 (S) -f! Uoro-16-methyl- - l8, 19, 20-tr i nor-17-cyc! Ohexyt- prost-5-en-13-ynolque; 5c-9-oxo-ll, 15 (R, S) -dihßdroxY-16 (R) -fluoro-16-mthyl- -18, 19, 20-trinor-17-cyclohexyl -prost-5-en-13-ynoique;  <Desc / Clms Page number 78>  the N, N-dimethyl-amides of the following acids: 5c-9-oxo-11C 15 (S) -dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic; 5c-9-oxo-11 @, 15 (S) -dihydroxy-20-nor-19-cyclopentyl-prost- -5-en-13-ynoic;  EMI78.1  5c-9-oxo-11 0 (, 15 (R) -di hydroxy-16 (S) -f lu or o-20-nor-19-cycl ohexyl-prost-5-en-13-ynoique; 5c-9 -oxo-11, lS (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19- - cyclohexyl-prost-5-en-13-ynoique;  Sc-9-oxo-11, 1S (S) -dihydroxy-19, 20-djnor-18-cyclohexyl- - prost-5-en-13-ynolque; c-9-oxo-11 15 (S) -dihydroxy-19, 20-dinor-18-cyclopentyl- - prost-5-en-13-ynoique; 5c-9-oxo-1115 (R) -d! hydroxy-16 (S) -f! uoro-19, 20-dinor-18- -cycle cyctohexyl-prost-3-en-13-ynolque; 5c-9-oxo-l10 (, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19- -cycle ohexyl-prost-5-en-13-ynoique; 5c-9-oxo -ll <15 (S) -dihydroxy-18, 19, 20-trinor-17-cyclohexyl- - prost-S-en-13-ynoique; 5c-9-oxo-11OC, lS (S) -dihydroxy-18, 19, 20-trinor-17-cyclopentyJ- - prost-5-en-13-ynoique;. 5c-9-oxo-ll 15 (R) -dihydroxy-16 (S) -fluoro-18, 19, 20-trinor - -17-cycl ohexyl-prost-5-en-13-ynoique; 5c-9-oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18-19-20-trinor- - 17-cyc! Ohexy! -Pros: -5-en-13-ynolque;    5c-9-oxo-11 @, 1S (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor- -17-cyclopentyl-prost-5-en-13-ynoïque;  <Desc / Clms Page number 79>    EMI79.1  5c-9-oxo-11O <, lS (R, S) -dihydroxy-16 (S) -fluoro-18, 19J20-tri nor- -17-cycl opentyl-prost-5-en-13-ynoique; 5c-9-oxo-11b (, 15 (S) -dihydroxY-17, 18, 19, 20-ttranor16-cyclo-. Hexy1-prost-5-en-13-ynoïque; 5c-9-oxo-110 (, 15 (S) -dihydroxY-17, 18, 19, 20-ttranor-16-cyclopentyl-prost-5-en-13-ynolque; 5c-9-oxo-lle <, 15 (R) -di hydroxy-16 ( S) -ftuoro-17, 18, 19, 20-tetranor- -16-cycl ohexyl-prost-5-en-13-ynoique; 5c-9-oxo-llo (, lS (R, S) -d! Hydroxy -16 (S) -f! uoro-17. 18, 19. 20- -tetranor-16-cyc! ohexyl-prost-5-en-13-ynolque; 5c-9-oxo-11, 15 (R) - dihydroxY-16 (S) -fluoro-16-methyl- - lS, 19, 20-trinor-17-cyclohexyl-prost-Sn-13-ynoique;  5c-9-oxo-11,15 (R, S) -dihydroxy-16 (S) -fluoro-16-me-ehyl- - 181920-trinor-17-cyclohexyl-prost-S-en-13-ynoIque; 5c-9-oxo-11c <, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl- -18, 19, 20-trinor-17-cyclohexyl-prost-5-é'n- 13-ynoïque;  <Desc / Clms Page number 80>    EMI80.1  . 5c-9-oxo-11,15 (S) -dihydroxy-20-nor-19-cyc / ohexyl-pros-5- - en-13-ynoïque; 5c-9-oxo-ll, 15 (S) -dihydroxy-20-nor-19-cyclopentyl-prost- "- 5-en-13- ynoïque; 5c-9-oxo-llO (, 15 (R) -dihydroxy -16 (S) -fluoro-20-nor-19-cyc / ohexyl-prost-5-en-13-ynolque; 5c-9-oxo-ll, 15 (R, S) -dihydroxY-16 (S) - fluoro-20-nor-19- - cyct ohexyl-prost-5-en-13-ynolque; 5c-9-oxo-llo =, 15 (S) -di hydroxy-19, 20-dinor-18-cyc! ohexyl - - prost-5-n-13-ynoïque; - 5c-9-oxo-11, 15 (S) -dihydroxy-19, 20-dinor-18-cyclopentyl- - prost-5-en-13-ynoïque;  5c-9-oxo-11, 15 (R) -dihydroxY-16 (S) -fluoro-19, 20-dinor-18- - cycl ohexyl-prost-5-en-13-ynoïque; 5c-9-oxo-11 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19- -cycle ohexyl-prost-5-en-13-ynoique; 5c-9-oxo-11 15 (S) -di hydroxy-18, 19, 20-tri nor-17-cyct ohexyl- - prost-3-ert-13-ynolque; 5c-9-oxo-11,15 (S) -dihydroxy-18,19,20-trinor-17-cyclopentyl- - prost-5-en-13-ynoïque; 5c-9-oxo-11, 15 (R) -dihydroxy-16 (S) -fluoro-18, 19/20-trinor- - 17-cycl ohexyl-prost-5-en-13-ynolque; 5c-9-oxo-llo (, 15 (R, S) -dihydroxy-16 (S) -fluoro-18-19-20-tri nor- - 17-cyclohexyl-prost-5-en-13-ynoïque; 5c -9-oxo-11,15 (R) -di hydroxy-16 (S) -f! Uoro-18,19,20-tr: nor- - 17-cyclopentyl-prost-5-en-13-ynolque;  <Desc / Clms Page number 81>    EMI81.1  5c-9, 11, 15 (R) -trihydroxy-16 (S) -fluoro-18, 19, 20-trinor- - 17-cycl opentyl-prost-5-en-13-ynolque;  5c-9 <llc <, 15 (RrS) -trihydroxy-16 (S) -f lu or o-18, 19, 10-trinor- -. 7-cyc! opentyl-prost-5-en-13-ynolque; - 5c, 911c, 15 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cycl o-. hexyl-prost-5-en-13-ynolque; Sc-9c, 11, 15 (S) -tr: hydroxy-17, 18, 19, 20-tetranor-16-cyc! opentyl-prost-5-en-13-ynoique; 5c-97llT </ 15 (R) -tr) hydroxy-l6 (S) -f! uoro-17/18, l9, 20-tetranor- -16-cycl ohexyl-prost-5-en-13-ynoïque; 5c-9c <, 15 (R, S) -tr i hydroxy-16 (S) -f 1 uoro-17.-18, 19, 20-te / tranor-16-cyc 1 ohexyl-prost-5-en- 13- ynoique; 5c-9o (, 11, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyf-18, 1, 20-- - tr i nor-17-cyct ohexyt-prost-5-en-13- ynolque; 5c-911 (, l5 (R, S) -tr i hydroxy-16 (S) -ftuoro-16-méthy! - - 18, 19, 20-tr i nor-17-cyc 1 ohexyl-prost-5 -en-13-ynolque; 5c-9 11.15 (R) -tr i hydroxy-16 (R) -f! uoro-l6-methyl-18, 19, 20- - tr i nor-17-cyc 1 ohexyl -prost-5-en-13-ynolque;  .  <Desc / Clms Page number 82>    EMI82.1  the N, N-dimethyl-amides of the following acids: 5c-9c <, 11 <= <, 15 (S) -trihydroxy-20-nor-19-cycl ohexyl-prost-5- - en-13-ynoique; 5c-9 <<, lle <15 (S) -tr: hydroxy-20-nor-19-cycl opentyl-prost-5- - en-13- ynoïque; - 5c-9o (lle <. 15 (R) -trihydroxy-16 (S) -f) uoro-20-nor-l9-cyc! ohexy! -prost-5-en-13-ynolque; 5c-9 11 15 (R, S) -trihydroxy-l6 (S) -f! uoro-20-nor-l9-cyc! ohexyl-prost-5-en-13-ynolque; 5c-911 l5 (S) -tr i hydroxy-19, 20-di nor-18-cyc 1 ohexyl-prost- - 5-en-13-ynolque; - 5c-9cll l5 (S) -tr i hydroxy-19 , 20-di nor-18-cyc! opentyl-prost- - 5-en-13-ynoique; 5c-9, ll <15 (R) -tr! hydroxy-16 (S) -f! uoro-19, 20-dtnor-18- -cycle ohexyl-prost-S-e-13-ynolque; . 5c-9o (, 11o (, 1S (R, S) -rihydroxY-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynolqùe;  5c-9a (, 11, lS (S) -trihydroxy-18, 19, 20-trinor-li-cycJohexyl- - prost-5-en-13-ynolque; 5c-9o (, 11; 15 (S) -trihydroxy -18, 19, 20-trinor-1i-cyclopentyl- - prost-5-en-13- ynoique; 5c-911 <. 15 (R) -trLhydroxy-16 (S) -f! Uoro-18, 19, 20 -tri nor-17- - cycl ohexyl-prost-5-en-13-ynoique; * '* 5c-9, 11, 15 (R, S) -trihydroxY-16 (S) -fJuoro-18, 19, 20 -trinor- -17-cycl ohexyl-prost-5-en-13-ynoique;  <Desc / Clms Page number 83>    EMI83.1  5c-911 <, 15 (R) -trihydroxy-16 (S) -f! uoro-18, 19, 20-trinor- -17-cycl opentyl-prost-5-en-13-ynolque; 5c-9, 11, 15 (R, S) -trihydroxy-16 (S) -fluoro-18, 19, 10-trinor- -17-cyclopentyl-prost-5-en-13-ynolque; 5c, 9 '<, ll, 15 (S) -trihydroxy-17, 18, 19, 20-tetranor-16-cycl ohexyl-prost-5-en-13-. ynolque; 5c-9., 11o <15 (S) -tr: hydroxy-17, 18, 19, 20-tetranor-16-cycl opentyl-prost-5-en-13-ynoique;  5c-9 11-- <, 15 (R) -tri hydroxy-16 (S) -f 1 uoro-17, 18 ,, 19, 20-tetranor- -16-cyclohexyl-prost-5-en-13-ynolque ; 5c-9 = 11. 15 (R, S) -tr i hydroxy-16 (S) - t uoro-17, 18, 19, 2 0-tetranor-16-cycl-ohexyl-prost-5-en-13 -ynoic; 5c-9 <. llX. 15 (R) -tri hydroxy-16 (S) -f) uoro-16-methyl-18, 19, 20- - tinor-1-cycJohexyl-prost-5-n-13-ynoique; 5c-9o <, 11, 15 (R, S) -trihydroxy-16 (S) -fluoro-16-methyl- -18, 19, 20-trinor-17-cyclohexyl-prost-5-é'n-13- yno3: that; 5c-9 11 e. 15 (R) -tr! hydroxy-16 (R) -f) uoro-16-methy! -l8, 19. 20- - tri nor-17-cyc! ohexyl-prost-5-en-13-ynolque;  <Desc / Clms Page number 84>  Sc-9o 11 @, 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5- - en-13-ynoic;    5c-9 @, 11 @, 15 (S) -trihydroxy-20-nor-19-cyclopentyl-prost-5- - en-13-ynoïque;  EMI84.1  5c-9 <<11.15 (R) -tri hydroxy-16 (S) -f! uoro-20-nor-19-cycl ohexyl-prost-5-en-13-ynolque; Sc- (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynolque; 5c-9c - ,,,,, 11 c. ,, 15 (S) -tri hydroxy-19, 20-di nor-18-cycl ohexyl-prost- - 5-en-13-ynolque; 5c-9o <l 15 (S) -tr: hydroxy-19,20-d! nor-l8-cyc! opentyl-pros- '-5-en-13-ynoique; 5c-9a <(ll <= <, 13 (R) -tr i hydroxy-16 (S) -f 1 uoro-19, 20-di nor-18- - cyclohexyl-prost-5-en-13-ynoIque. ; 15c-9 '<, l <15 (R, S) -tri hydroxy-16 (R) -f! Uoro-20-nor-19-cycl o-hexyl-prost-5-en-13-ynoïque; 5c-9o 11 @, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl- - prost-S-en-13-ynoIque;  5c-9 @, 11 @, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoIque;  EMI84.2  5c-9o <, ll <<, 15 (R) -trihydroxy-16 (S) -f) uoro-18, 19, 20-trinor-17- -cyc! Ohexyl-prost-5-en-13-ynolque; 5c-9 <, ll 13 (R, S) -tr i hydroxy-16 (S) -ftuoro-18, 19, 20-tr: nor- -17-cyctohexyl-prost-5-en-13-ynolque.  <Desc / Clms Page number 85>    5. Process for preparing the compounds of formula (I) according to claim 1, characterized in that: a) reacting a reactive derivative of an optical isomer or of a racemic of a compound of the formula (II )  EMI85.1  in which when the symbol ---- represents a double bond, R'1 denotes a hydrogen atom and R2 and R ', taken together, form an oxo group, whereas when the symbol ---- represents a single bond , R'1 denotes the hydroxyl radical or a protecting group linked to the nucleus via an ethereal oxygen atom, R2 denotes a hydrogen atom, R'3 denotes a hydroxyl, acyloxy radical or a protecting group bound to the nucleus via  EMI85.2  of an ethereal oxygen atom,  or R2 and Reconsidered together, form an oxo group; one of the symbols R'4 and RI5 represents the hydroxyl radical or a protective group linked to the nucleus via an ethereal oxygen atom, while the other of these symbols denotes a hydrogen atom and Rr , Ry, n and Ru have the meanings assigned to them in claim 1, on a compound of formula (III)  EMI85.3    <Desc / Clms Page number 86>  in which R'and R "have the meanings which have been assigned to them in claim 1, so as to obtain an optically active isomer or a racemic of a compound of formula (IV)  EMI86.1  in which  EMI86.2  Rsp Rttg R13y R 9 Rilt Rt 1 e R ', R ", R', R, R ', R', R'Rg, Ry,  n and Ra have the meanings which have been previously assigned to them and then, when necessary, the radicals protecting the hydroxyl function are removed; or b) reacting an optically active isomer or a racemic of a compound of formula (V)  EMI86.3    <Desc / Clms Page number 87>    EMI87.1  in which X 1 M represents a group-C- = C-or-CH = C- and X represents  EMI87.2  a bromine, chlorine or iodine atom;  Z represents the hydroxyl radical or a protective group linked to the nucleus via an ethereal oxygen atom; one of the symbols R'4 and R'5 represents the hydroxyl radical or a protective group linked to the nucleus via an ethereal oxygen atom, while the other of these symbols denotes  EMI87.3  a hydrogen atom;  and R, R, n and Ra have the meanings assigned to them in claim 1, on a Wittig reagent containing a group- (CH) .-  EMI87.4  RI u e - CONRn where R'and R "have the meanings which  EMI87.5  have been previously assigned, so as to obtain an optically active isomer or a racemic of a compound of formula (VI)  EMI87.6  in which  EMI87.7  R ', R ", Z, R' <, R'e, R ', Ry, n and Rg have the meanings which have been previously assigned to them, which, when the 11-and 15-hydroxyl radicals are in the form protected, can, if desired, be esterified so as to obtain a 9a-acyloxy type derivative of a compound of formula (VI) and in that the protective groups are then removed in positions 11 and / or 15,    if they are present, both in a compound of formula (VI) and in its derivatives of the acyloxy type, so as to obtain  <Desc / Clms Page number 88>  so a compound of formula (I) in which R3 represents the hydroxyl radical or an acyloxy group, R2 denotes a hydrogen atom, R1 denotes the hydroxyl radical, the symbol ---- represents a single bond and R ' , R ", R4, R5, R6, R7, n and Ra have the meanings which have been assigned to them in claim 1, c) an optically active isomer or a racemic of a compound of formula (VII) is oxidized  EMI88.1  wherein Z're represents a protective group linked to the nucleus via an ethereal oxygen atom;  one of the symbols R'4 and R "represents a protective group linked to the nucleus via an ethereal oxygen atom, while the other of these symbols denotes a hydrogen atom; and R ', R ", R Ry, n and Rg have the meanings which have been assigned to them in claim 1, so as to obtain an optically active isomer or a racemic of a compound of formula (VIII)  EMI88.2    <Desc / Clms Page number 89>  in which R ', R ", Z', R" 4, R "5, R6, R7, n and R8 have the meanings assigned to them above, which are then submitted for elimination groups protecting the ether function, so as to obtain, depending on the reaction conditions used,  or a compound of formula (I) in which - denotes a single bond, R1 denotes the hydroxyl radical, R2 and R3, considered together form an oxo radical and RI, R ", R ,, Rc, R, R, n and Ra have the meanings assigned to them in claim 1, or a compound that formula (I) in which ---- represents a double bond, R1 denotes a hydrogen atom, R2 and R, taken together, form an oxo group and R ', R ", R4, R5, R6, R7, n and Rn have the meanings which have been previously assigned to them;  and / or, if desired, a compound of formula (I) is salified or a free compound of formula (I) is obtained from a salt of such a compound; and / or, if desired, converting a compound of formula (I) or a salt of such a compound, into another compound of formula (I) or into a salt thereof; and / or, if desired, a mixture of isomers is resolved into the singular isomers.  6. Optically active or racemic isomers of the compounds of formula (IV)  EMI89.1    <Desc / Clms Page number 90>  in which  EMI90.1  R ', R ", R', Rp, R ', R'., R'c, R, Ry, n and Rg have the meanings assigned to them in claim 5, e as well as the salts of these compounds acceptable in human and veterinary pharmacy.  7. Pharmaceutical compositions containing an excipient  EMI90.2  ea or suitable vehicle and / or diluent and, as active principle, at least one compound of formula (I) according to any one of claims 1 to 4 and 6, or a salt of such a pharmaceutically acceptable compound .  8. Compounds and their pharmaceutically acceptable salts, according to any one of claims 1 to 4 and 6, to be used for the treatment of the body of a human or animal by surgery, therapy or diagnosis performed on the body of the human or animal concerned.  9. Compounds or salts of these pharmaceutically acceptable compounds according to any one of claims 1 to 4 and 6, or pharmaceutical compositions according to claim 7, to be used for administration to humans or animals, in order to induce labor or expel a dead fetus in pregnant females, to regulate fertility in females, to reduce or eliminate the formation of gastrointestinal ulcers, to accelerate the healing process of ulcers present in the gastrointestinal tract -intestinal and to reduce unwanted gastrointestinal side effects resulting from systemic administration of anti-inflammatory prostaglandinsynthetase inhibitors.