LU80789A1 - NOVEL PROSTAGLANDIN N- (TETRAZO-5-YLIC) CARBOXAMIDES AND MEDICAMENTS CONTAINING THEM - Google Patents

Description

1.

Prostaglandins are fatty acids unsaturated at the level of the C-20 atom which exert various physiological effects. Their structures, their nomenclatures, their biological activities and their applications in medicine have been described in US Pat. Nos. 3,971,825 and 3,984,400o.

A common problem faced by researchers in medical science5 who seek biologically effective synthetic drugs. 10 resides in the modulation of the biological action of a main compound capable of performing this action. In a classic way of access to the synthesis of drugs s the researcher endeavors to increase the biological power. However, in the field of prostaglandins, the researcher directs his projects 15 to a gain in oral activity, a prolongation of the duration of action and an improvement of one of the various physiological effects of the class of prostaglandins with reduction of the others. The latter criterion is important because if it were not for a synthetic prostaglandin it would have incompatible side effects. For example, it would be clinically unwise to administer a synthetic anti-ulcer prostaglandin which also causes diarrhea.

To increase selectivity the researchers have concentrated their efforts on the "active" sites of natural prostaglandins. These are mainly the carboxylic acid group in position C-1} the ketone or hydroxyl group in position C-9} the hydroxyl group in position C-11 and the lipophilic end of the lower side chain. The corresponding work has been published in journal articles and in the following patents: United States Patent No. 4,011,262, No. 4,024,179, No. 3,971,826, No. 3,932,389, # 3,974,213, # 3,054,741 and # 3,987,087; Netherlands patent application no. 73/06 030; B.J. Mayerlein 35 and collaborators, "Prostaglandins", _4 (1973) and W. Lipmann, "Prostaglandins", J7, 231 (1974).

We have just discovered the surprising fact that an increase in the distance between the function in position C-9 "2.

and the acid group of the upper side chain by attachment of an amide group results in potent biological activity.

Three classes of 5-amidotetrazo prostaglandins in the C-1 position whose biological activity has markedly different profiles have been discovered. Class 1 includes compounds of formula 1 with antiulcer activity.

Formula 1: / N. H H H H N-

* <N · · - C-A-C-C-C-CONH X

H H H H \

XN-N

H H

Y.. . --B-C-C-Ar

: H

HO

Class 2 comprises compounds of formula 2} which are endowed with anti-conceptual activity.

Formula 2: 0

Χχ. H H H H N-N

X N ... C-A-C-C-C-CONH _X

H H H H

X N-N

H H

Y ... --B-C-C-OAr

: H

HO

Class 3 comprises compounds of formula 3, which are endowed with bronchodilator and anti-conceptual activity according to the identity of R and Z.

Formula 3: q

X H

X \ H H H H --- N

X X ... C-A-C-C-C-CONH I

H H H H [\ N —— ti

H R H H H H

Y.. . --B-C-C-C-C-C-CH

: Z H H H H HO

»3 ο s

It appears that the structural differentiation of classes resides in the identity of the omega or lower side chain. However, it is the combination of this functional group with the other important groups such as the amidotetrazole group which is responsible for the various biological activities observed. However} these three classes can be combined} with regard to their structure} into a single generic formula (4).

Generic formula 4:

H H HH} -N

^ N ··· .C-A-C-C-C-CONH- H H H H _

Y H

• · · - -! - B-C-G

"

HO

In each of the above formulas} the symbol A represents the cis-vinylene or ethylene group "the symbol B represents the trans-vinylene or ethylene group} the symbol Y represents the hydroxy group or a hydrogen atom" the symbol R represents a hydrogen atom or a methyl group "the symbol Z represents a hydrogen atom or a methyl group" the symbol Ar represents a phenyl "fluorophenyl" chlorophenyl "methylphenyl" ethylphenyl "methoxyphenyl" ethoxyphenyl " biphenyl or trifluoromethylphenyl and the symbol G represents a group CF ^ Ar, Ch ^ OAr or CRZCCF ^) ^ CFF ^. The following compounds are particularly appreciated: in class 1 "9-oxo-ll-a" 15-a-bishydroxy-16-phenyl-16-omega-tetranor-5-cis-prostenamide Nd: etrazol-5-yli- than) ; in class 2 "9-oxo-ll-a" 15-a-bishydroxy-16-phenoxy-16-omega-tetranor ~ 13-trans-prostenamide N- (tetrazol-5-ylique); and in class 3 "9-oxo-ll-a" 15-a-bishy-droxy-5-cis-13-trans-prostadienamide.N- (tetras "l-5-ylique) - · The invention covers also the PGF type compounds corresponding to the three classes above and their pharmacologically acceptable salts, the acid tetrazolic portion of which is neutralized.

4.

In accordance with the process of the invention, the synthesis of each class of prostaglandin-carboxamides N- (tetrazolics) is carried out from a similar class of PGF 11,15-bis-hydroxylic or ll-deoxy-15- compounds. 5 hydroxyls of which the hydroxyl groups in positions 11? 15 or respectively the hydroxyl group in position 15 are protected. This generic starting component has the same basic structure for all the classes and has any arrangement of the type of bond in the positions C5-C6 and C13-C14 10 relating to the elements A and B of the formulas 1 "2 and 3. In d 'au-v very terms' it is the compound PGF- (ll)' 15-hydroxy-protected which corresponds to the generic formula (4) above. The class differentiation of the basic structure is determined by the identity of the terminal part of the lower side chain of the respective starting components. Thus »the component from which we start for class 1 has» on the basic PGF structure above »the substitution 16-aryl-16-omega-tetranor; the starting component for class 2 has the substitution 16-aryloxy-16-omega-tetranor; and the starting component for class 3 has the substitution 15-n-pentyl "2-hexyl or 2-methyl-2-hexyl on the lower side chain of the above basic PGF structure. These structures are illustrated respectively by diagram 1 and the formulas F1 "F2 and F3.

The starting PGF components for each of the classes are known compounds; the characteristics of the starting 11-hydroxylic components are given in the patents of the United States of America n ° 4,024,179 and n ° 4,011,262 * 'aforementioned' the patents of the United States of America n ° 3,887,589 30 and 4,036,832; British Patent No. 1,324,737; by B.J. Mayerlein et al. "in" Prostaglandins "". 4, 143 (1973) and by E.J. Corey et al. "in nJ. Bitter. Chem. Soc. "" 9_3, 1491 (1971) and the characteristics of the starting 11-deoxy components are given in British Patent No. 1,419,181 "in the patent application of the Federal Republic of Germany DOS No. 2,548,267 "by P. Crabbe et al. In" Tet. Leto "1972, 1123 and by W.

Lipmann in "Prostaglandins", _7, 231 (1974).

5.

The transformation of the starting components into classes of products of the invention is illustrated by scheme A. To transform a starting component into a representative of a class of compounds of the invention, the group is first converted C1 carboxylic acid to an N- (tetrazol-5-yl) carboxamide group at C1 (step 1 of scheme A). Then) This N— (tetrazole) -carboxamide intermediate of PGF is oxidized by the Jones reagent to form the intermediate of PGE which is released by elimination of grou-10 pes (R ′) protecting the 15-monohydroxyl and 11 functions. } 15-- bis-hydroxyl (step 2.1 of scheme A) to form a prostaglandin N- (tetrazolic) carboxamide of formulas 1} 2 or 3. As a variant} a compound of the PGF type corresponding to the compound of the PGE type of Formulas 1} 2 or 3 can be prepared by simple cleavage of the R ′ groups protecting the C-11 and / or C-15 hydroxyl functions of the intermediate N- (tetrazolic) carboxamide.

Diagram 1. - Starting components for the various classes

OH

ê ê

/ \ H H H H

/ v .... C-A-C-C-C-X

H H H H

H H

R'O. ,. __B-C-C-Ar

(THPO): H

(H) R'O

(THPO)

Fl} starting component for class 1; X is a group -C00H

OH

* f (

H H H H

S \ ... C-A-C-C-C-X H H H H

H H

R'O. .. --B-C-C-OAr

(THPO): H

(H) R'O

(THPO)

20 F2} starting component for class 2, X is a group -C00H

6.

OH

"" 4

y \. H H H H

/ \ ... C-A-C-C-C-X

H H H H

H R H H H H

R1O ·· b-c-c-c-c-c-ch

(THPOZ H H H H

(H) R '° (THPO) F3j starting component for class 3} X is a group -COOH. DIAGRAM A. - Step 1: formation of the N- (tetrazol-5-yl) group - „carboxamide

1. CDI reagent

—-> E î where x represents

PI, P2 OR F3 ““ ^ P2 H

2. 5-AT F3 n — N reagent

anhydrous -CONHC ^ f ||

-NOT

Step 2.1: oxidation with Jones 5 reagent and cleavage of the THP group

H 1. co, i r 3 / N-N H9S04

Fl, F2 OR F3, X = -CONHC <C || —-1.2.3

-N 2. CH-CO-H

H2 ° 1. Formula 1, the starting component is Fl 2. Formula 2} the starting component is F2! 3. Formula 3, the starting component is F3.

* Step 2.2: cleavage of the protective THP group 10 for obtaining compounds of the PGF type.

H

N-N CH, COOH

Fl, F2 OUF3, X = CONHOsT I —--> 1,2,3 -N H20

Compound of the PGF type corresponding to formula 1> the starting component is Fl 7.

2. Compound of the PGF type corresponding to the formula 29 the starting component is F2 3. Compound of the PGF type corresponding to the formula 35 the starting component is F3.

5 The reaction steps 2.1 and 2.2 which include the cleavage of the groups protecting the hydroxy functions in C-11 and / or C-15 and the oxidation of the hydroxyl group in C-9 to an oxo-ketone group in C- 9 are common transformations and are well known in the field of prostaglandin chemistry. Equivalent methods for the oxidation of the C-9 hydroxyl group and for the protection of C-11 and / or C-15 hydroxyl groups are also well known in the art and are applicable in the present case. Prostaglandin researchers have found selective oxidation processes such as the Pfitzner-Moffett oxidation process to dimethyl sulfoxide and dicyclohexylcar-bodiimide and Collins oxidation with the chromium trioxide complex and pyridine in methylene chloride can also be used to effect oxidation of the hydroxyl group to the ketone group. They also revealed the numerous methods and the numerous groups available for the attachment and the elimination of the groups protecting the hydroxyl functions in the C-11 and / or C-15 positions of a prostaglandin. These labile protecting groups under the action of a mild reagent are designated by the symbol R '. The tetrahydropyranyl group is also shown as a preferred group. Certain other usual protective groups which are labile under the action of a mild reagent which can be used according to the invention are the dimethyltertiobutylsilyl group · 30 which can be eliminated by tetra-n-butylammonium fluoride or an aqueous solution of acetic acid and the group 1-methoxyethylene-1-yl which is analogous to the group tetrahy-dropyran-2-yl.

Step 1 is new in that it makes it possible to prepare a C-1 amide having an acid group as a substituent. The advantage of this structure lies in the fact that the prior art teaches the biologically determining invariance of the distance between the acid group at 8.

C-1 and the function in C-9? while the compounds of the present invention have in fact lengthened the distance in length of two of the amide group atoms. Can the N- (tetrazol-5-yl) -carboxamide group be prepared from the carboxylic acid group by prior formation of a carboxylic acid derivative carrying an easily displaceable leaving group? then conduct the amidation reaction with 5-aminoté-trazole (reagent 5-AT). Any leaving group which can be linked to the carboxyl group of the prostaglandin intermediate derivative 10 (F1, F2} F3} scheme 1) without destroying the rest of the molecule v can be used in the preparation. Certain examples of *. leaving groups and the reagents used for their realization comprise a pivaloyloxy / pivaloyl halide which gives the mixed anhydride derivative and an ethoxyfor-myloxy / ethoxyformyl halide which gives the carbonate derivative.

The preferred leaving group is the imidazol-1-yl group which gives an intermediate acylated imidazole. To prepare the N- (tetrazol-5-yl) -carboxamide group via an acylated imidazole group? first reacting the prostaglandin-derived carboxylic acid used as the starting component (F1? F2 or F3) with the reagent 1? 1-carbonyldiimidazole providing the leaving group in a polar aprotic solvent such as dimethylformamide? diethylformamide? 1 acetonitrile? tetrahydrofuran or dimethyl sulfoxide to form the intermediate acyl imidazole in situ. The imidazol-1-yl group linked to the C-1 carbonyl group is then moved directly with the reagent; 5-AT to form the desired N- (betrazol-5 ~ y]) - carboxamide. The acylated imidazole can be formed and displaced within a range of ‘30 reaction temperatures. This range is from room temperature to about 120 ° C and it is advantageous to conduct the reaction at a temperature of about 90 ° C or at reflux.

When the group N- & etrazol-5-yl) -carboxamide was formed? we proceed to reaction step 2.1 in which a compound of formula 1? 2 or 3 is prepared? or in reaction step 2.2 by which the compound of the PGF type is formed.

As a variant? according to the process of the invention? the N-tetrazolic prostaglandins of each 9.

class can be obtained by direct synthesis from a compound of the corresponding PGE or PGF type of formula:

M

H H H H

^ ··. c-a-c-c-c-cooh

H H K H H

Y * · · --B-C-G

HO

in which A, Y} B and G have the definitions given above and M is an oxo group or a group H 'ΌΗ. In this mode of synthesis5 the PGE or PGF acid is reacted by the process for the formation of the N- (tetrazol-5-yl) -car-boxamide group indicated in step 1 above5 so as to produce directly prostaglandin N- (tetrazolic) carboxamide of formula 1> 2 or 3 above or the corresponding PGF carboxamide. The procedure followed is that of step 1 "provided that * if M must be an oxo9 group no basic reagent is used.

In numerous tests carried out in vivo and in vitro, it has been established that the three classes of prostaglandin compounds of the present invention display extreme selectivity. The result they get biologically is to reduce many of the physiological activities of natural prostaglandins while maintaining activity in one area. The tests which allow to de-terminate this selectivity include} inter alia * a test · "activity on the smooth muscle isolated from the guinea pig's uterus" an activity test on the dog's blood pressure "a test d inhibition of bronchoconstriction under the effect of histamine in lecobay © * a test for inhibition of cold-induced ulceration in leratfA test of anti-secretory activity in dogs and a test of diarrheal activity in mice.

After comparison with the responses elicited by natural prostaglandin in the same tests * the physiological responses elicited by the three classes of experimental pros-30 taglandins in these assays help to determine it.

undermining their usefulness for the treatment of natural and pathological disorders. On the basis of this comparison "the prostaglandins of class 1 of the invention are of interest as selective antiulcer agents" those of class 2 have interest as contraceptive agents "of those of class 3, in which R is a methyl group or a hydrogen atom and Z is a hydrogen atom are of interest as bronchodilators ^ and those of class 3 in which R and Z each represent a methyl-10 group are of interest as contraceptives. The observation of biological tests "for class 1 prostaglandins" show that these prostaglandins have a great anti-ulcer activity "however that their hypotensive activity" their activity on the smooth muscle of the uterus "their acti-15 fast diarrhea and their bronchodilator activity are reduced compared to the natural prostaglandin PGE £ used as reference in this test. The same type of observations show that the prostaglandins of class 3 in which R is a methyl group or a hydrogen atom and Z is a hydrogen atom exhibit potent bronchodilator activity and exert reduced effects with respect to activity on the smooth muscle of the uterus »hypotensive activity» anti-ulcer activity and diarrheal activity. Likewise "prostaglandins of class 2 de-25 exert a great activity on the smooth muscle of the uterus" while we note a decrease in the activities which have been the subject of determinations such as hypotensive activity " activity and bronchodilator activity.

The three classes of prostaglandins from the pre-. The present invention can be used in various pharmaceutical formulations which contain this prostaglandin or its pharmaceutically acceptable salts. They can be administered in the same manner as natural prostaglandins by various suitable routes of administration "eg intravenously" orally and topically "eg aerosol" intravaginally "intra- and extra-amniotic and intranasal. Obviously "the selective activity of the particular class of prostaglandins 11.

the invention and the purpose for which they are intended determine the path which should be used. For example "the routes which are suitable for prostaglandins of class 2 are the intravenous" oral "intravaginal routes. , intra- and extra-5 amniotics "while the routes suitable for prostaglandins with bronchodilator action of class 3 include administration in the form of aerosol and the intranasal routes" oral and intravenous.

For pharmaceutical formulation and preparation. From solid compositions of the three prostaglandin classes "pharmacologically acceptable salts of the acid tetrazole group are those formed with metal cations" amine cations or quaternary ammonium cations acceptable from the point of view of pharmacological view.

Particularly preferred are the metal cations derived from an alkali metal such as lithium "sodium and potassium, and from an alkaline earth metal such as magnesium and calcium" although the cationic forms of other metals such as aluminum " zinc and iron are within the scope of the invention.

The pharmacologically acceptable amine cations are the cations which are derived from primary, secondary or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, triethylamine, ethylamine, benzylamine, α-phenylethylamine, β-phenylethylamine, as well as heterocyclic amines such as piperidine, morpholine. »Pyrrolidine and piperazine and amines containing water solubilization groups or hydrophilic groups» eg '30 monoethanolamine »diethanolamine» triethanolamine »ethyldiethanolamine» galactamine »N-methylglucosamine , ephedrine "phenylephrine" epinephrine "procaine" etc.

Preferred examples of pharmacologically acceptable qua-ternary ammonium cations are the tetramethylammonium, tetraethylammonium, benzyltrime-thylammonium "phenyltriethylammonium" cations, etc.

The three classes of prostaglandins of the invention can be used in various pharmaceutical preparations.

ceutiques which contain the compound or a pharmacologically acceptable salt of this compound} and can be administered by different routes as described above;

Although the dose, the particular formulation and the route of administration depend on the individual condition of each patient and on the advice of the attending physician the guidelines given below with regard to the suitability of the prostaglandin classes of The present invention defines compounds of class 1 as anti-ulcer agents; those of class 2 as contraceptives; those of class 35 when R is a hydrogen atom or a methyl group and Z is an atom. hydrogen} as bronchodilators and those of class 3} when R and Z each represent a methyl group} as anticonception agents.

Class 1 prostaglandins are useful to use as anti-ulcer agents. For the treatment of peptic ulcers, these drugs are advantageously administered orally in the form of aqueous suspensions> of ethanolic solutions or, preferably, in the form of capsules or tablets containing per dose 0} 001 to 0} 10 mg / kg prostaglandin} with a maximum of 12 doses per day.

To initiate abortion} prostaglandi-25 born of classes 2 and 3 in which R and Z are methyl groups can be administered orally in tablets} aqueous suspensions or suitably formulated alcoholic solutions "containing per dose about 0.05 to 5 mg * of prostaglandin ”using 1 to 7 doses per day. For intravaginal administration "a suitable formulation would consist of lactose tablets or an impregnated tampon containing per dose about 051-10 mg of prostaglandin" using 1-7 doses.

For intra-amniotic administration, a suitable formulation would consist of an aqueous solution containing prostaglandin in the amount of 0.05 to 5 mg per dose using 1 to 7 doses. For extra-amniotic administration, a suitable formulation would consist of a solution.

tion containing 0.01 to 1 mg prostaglandin per dose, using 1 to 5 doses. Alternatively, class 2 and class 3 prostaglandins, when R and Z each represent a methyl group "may be administered by intravenous infusion to initiate abortion at doses of 0.05 to 50 micrograms of prostaglandin per minute, for a period of approximately 1 to 24 hours.

Class 2 prostaglandins and class 3 pros-10 taglandins in which R and Z are methyl groups can also be used to induce labor. To this end, an ethanolic prostaglandin saline solution is used for an intravenous infusion in an amount of about 0.1 to 10 micrograms of prostaglandin 15 per kg per minute for about 1 to 24 hours.

Another application of class 2 and class 3 prostaglandins when R and Z each represents a methyl group is the limitation of fertilization. For this purpose, a tablet is used, by intra-vaginal or oral administration, containing 0.1 to 10 mg of prostaglandin per dose, using 1 to 7 doses at the time of menstruation or after the expected day of menstruation. For synchronization of the estrus cycle in sows, ewes, cows and mares, a solution or suspension is administered containing 0.3 to 30 mg of prostaglandin per dose, subcutaneously or intramuscularly for 1 to 4 days.

Prostaglandins of class 3, in which R is a hydrogen atom or a methyl group and Z is a hydrogen atom, are useful as bronchodilators and for increasing or obstructing the nasal passages facilitate access. A preferred dosage form for this mode of treatment is a solution of prostaglandin in ethanol or aqueous tert-butanol or a suspension used as an aerosol in an inert gas (propellant) / the amount of prostaglandin then being approximately 5 to 500 micrograms per dose.

To prepare any of the above dosage forms or any of the many others 14.

possible forms: various inert diluents, excipients or vehicles can be used. These substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene. glycols, petroleum jelly, cholesterol and other known drug carriers. Where appropriate, these pharmaceutical compositions may contain auxiliary substances such as preservatives, wetting agents, stabilizers and other therapeutic agents such as antibiotics.

- The invention is illustrated by the following examples, given without limitation. The results of the infrared spectral analysis were obtained on an infrared spectrometer with a "Perkin-Elmer" grating and were expressed in micrometers. The results of the nuclear magnetic resonance spectrum were obtained on a "Varian" model HA-60 spectrometer and the delta values are expressed in ppm. The melting points, which have not been corrected, are expressed in 20 degrees Celsins. The thin layer chromatography measurements were carried out on silica gel and are expressed by the values of Rf.

In general, the reaction temperatures described in the examples, unless otherwise specified, correspond to room temperature or to the room temperature, which varies from 15 to 30 ° C.

The reaction times described in the examples, unless otherwise specified, were determined by * checking by thin layer chromatography. The usual thin layer chromatography system was used, involving silica gel applied to glass ("E. Merck", E. Merck, Dormstadt, Federal Republic of Germany silica gel plates) using as diluents a benzene / ether or methanol / chloroform mixture and as developers a vanillin / ethanol or iodine mixture [see "Introduction to Chromatography", JM Bobbitt, AE Schwarting, RJ

Gritter, Van Nostrand-Reinhold, fUY. 1968]. In general, the reaction in question was considered to be essentially 15.

* completed when the thin layer chromatography spot representing the determining starting component disappears or stops changing its appearance.

EXAMPLE 1 - 9-g-hydroxy-ll-oi? 15-a-bis- (tetrahydropyran-2-5 yloxy) -5-cis- 13-trans-prostadienamide N- (tetrazol-5-ylique) (1)

134 mg (0? 825 mmol) of 1? 1-carbonyl-diimidazole is added to a solution of 415 mg (0.795 mmol) of 9-a-hydroxy-11-α? 15-a-bis- (tetrahydropyran-2-yloxy) -5-cis-13- * 10 trans-prostadienoic (SM) in 10 ml of anhydrous dimethylformamide. Is the solution heated under a nitrogen atmosphere at 95 ° C for 4 hours? then 70 mg (0.825 mmol) of anhydrous 5-aminotetrazole are added. Is the solution heated under a nitrogen atmosphere for an hour and a half at 95 ° C? then it is concentrated on a rotary evaporator to obtain the compound (1) indicated in the title? in the form of a viscous oil weighing 823 mg. Its nuclear magnetic resonance spectrum (CDC13) has the following characteristic absorptions (in S ppm): 20 5? 65 - 5.24 (multiplet) - olefinic 0 4.81 - 4.62 (multiplet) - CH-0 1, 92 (triplet, j = 4 Hz) - CH ^.

EXAMPLE 2 - 9-a, 11-a, 15-a-trihydroxy-5-cis-13-trans-prosta-25 dienamide N- (tetrazol-5-ylique) (2)

A solution of 200 mg of 9-a-hydroxy-11-α? 15-a-bis- (tetrahydropyran-2-yloxy) -4-cis-13 is stirred at room temperature for 18 * hours under a nitrogen atmosphere. -trans-prostadienamide N- (tetrazol-5-ylique) (1) crude in 10 ml of a 65:35 mixture of acetic acid and water; the mixture is then concentrated by evaporation on a rotary evaporator. Benzene is added which is then removed on a rotary evaporator (three evaporations). By purification of the crude residue by chromatography on a column of silica gel? 35, using a mixture of chloroform and ethyl acetate as eluent, the compound (2) indicated in the title is obtained weighing 6 mg and melting at 168-172 ° C. (after recrystallization 16.

in a mixture of ethanol and ether).

Thin layer chromatography: R ^ f = 0.26 (chloroform: methanol 3: 2).

EXAMPLE 3 - 9-oxo-ll-o !, 15-ot-bis- (tetrahydropyran-2-yloxy) -5 5-cis-13-trans-prostadienamide N- (tetrazol-5-yligue) (3)

0.38 ml of Jones' reagent is added to a solution, cooled to -20 ° C, of 623 mg (1.06 mmol) of 9-a-hydroxy-. 11-a j 15-a-bis- (tetrahydropyran-2-yloxy) -5-cis-13-trans-prosta-

Iq dienamide N- (tetrazol-5-ylique) (1) in 15 ml of acetone. The mixture is stirred for 20 minutes, then deactivated in the cold by adding 0.38 ml of isopropyl alcohol. Stirred for 5 minutes, then diluted with 25 ml of ethyl acetate, washed with three times 5 ml of water and 5 ml of saturated brine, dried over magnesium sulfate and it is concentrated to obtain the compound (3) indicated in the title, in the form of a viscous oil weighing 295 mg.

Thin layer chromatography: R ^ f = 0.48 (methylene chloride: methanol 9: 1).

EXAMPLE 4 - 9-oxo-11-a, 15-a-dihydroxy-5-cis-13-trans-prostadienamide N- (tetrazol-5-ylique) (4)

A solution of 295 mg of 9-oxo-11-a, 15-a-bis (tetrahydropyran-2-yloxy) -5-cis-13-trans-prosta is stirred at room temperature under a nitrogen atmosphere for 18 hours. -25 dienamide N- (tetrazol-5-ylique) (3) crude in 30 ml of 65:35 mixture of acetic acid and water. The solution is concentrated on a rotary evaporator and benzene is added, then concentrated three times. By purification of the residue by chromatography on a silica gel column, using mixtures of chloroform and ethyl acetate as eluents, the compound (4) indicated in the title is obtained, weighing 22 mg and melting at 162 °. vs. Its infrared spectrum (KBr) has the following characteristic absorptions (in micrometers): 5.71 ketone 35 5.87) 6.12 ((amlde) 10.33 (trans-olefin) "EXAMPLE 5 - 17.

The other compounds below were prepared using the procedures described in Examples 1 to 4 and replacing the compound (SM) in Example 1 with the corresponding PGF type carboxylic acid.

5A. 9-oxo-ll-a, 15-a-dihydroxy-13-trans-prosté-namide N- (tetrazol-5-ylique), solid. Nuclear magnetic resonance (CD ^ OD) (in S ppm): 5> 76? 5> 44 (multiplet) trans-olefin; 1> 88 (triplet> j = 4 Hz) CH ^.

10 5B. 9-oxo-ll-a> 15-a-dihydroxy-5-cis-16-phenyl- * 16-omega-tetranor-prostenamide N- (tetrazol-5-ylique)> melting point 75-78 ° C. Nuclear magnetic resonance (CDgOD) (in S ppm): 7> 08 (singlet) CgH ^; 5> 43-0> 17 (multiplet) cis-olefin.

15 5C. 9-oxo-11-a, 15-a-dihydroxy-13-trans-16-phenyl-16-omega-tetranor-prostenamide N- (tetrazol-5-ylique)> melting point 149-150 °. Infrared spectrum (KBr) (in micrometers) 5> 67 (ketone)> 5> 83 and 6> 10 (amide)> 10> 28 (trans-olefin).

5D. 9-a> ll-a-15-a-trihydroxy-5-cis-13-trans-16-20 phenoxy-16 ~ omega-tetranor-prostadienamide N- (tetrazol-5-yli-que)> melting point 87 -90 °. Infrared spectrum (KBr) (in micrometers): 5> 97 and 6 * 25 (amide)> 10> 35 (trans-olefin).

5E. 9-oxo-ll-a> 15-a-dihydroxy-5-cis-13-trans-15-phenoxy-16-omega-tetranor-prostadienamide N- (tetrazol-5-yli-25 que)> melting point 105 -107 ° C. Infrared spectrum (KBr) (in micrometers): 5> 68 (ketone)> 5> 85 and 6> 10 (amide)> 10.28 (trans-olefin) o

The synthesis of the compounds of Examples 1 to 5 demonstrates that classes 1> 2 and 3 of 11-hydroxyprostaglandins of the invention and the corresponding PGF-type compounds can be obtained by the chemical methods described in Examples 1 to 4 by replacing the intermediate compound of the PGF type called SM in Example 1 by the compound ll, 15-bis- (t-trahydropyran-2-yl) -PGF2j 13,14-dihydro-PGF2> PGF ^ or 35 corresponding, whose substituent in position C-16 is a phenyl or substituted phenyl group for the preparation of compounds of class 1> phenoxy or substituted phenoxy for the preparation of compounds of class 2 and n-butyl or both methyl and n- butyl for the preparation of the compounds of: 18.

class 3} the substituents of the phenyl and substituted phenoxy groups being fluoroj chloro, methyl, ethyl ethoxys, methoxys, phenyl and trifluoromethyl radicals.

EXAMPLE 6 - 9-a-hydroxy-15-a- (tetrahydrooyran-2-yloxy) -16-5 phenoxy-16-omeqa-tetranor-13-trans-prostenamide N- (tetrazol-5-ylique) (6)

134 mg (0} 825 mmol) of 1,1-carbonyl-diimidazole is added to a solution of 0} 795 mmol of 9-a-hydroxy-15-a- (tetrahydropyran-2-yloxy) -16-phenoxy acid -16-omega-tetranor-, 10 13-trans-prostenoic (DSM) in 10 ml of anhydrous dimethylformamide. The solution is heated under a nitrogen atmosphere at 95 ° C for 4 hours, then 70 mg (0.825 mole) of anhydrous 5-aminotetrazole is added thereto. The solution is then heated for one and a half hours at 95 ° C under a nitrogen atmosphere, then it can be concentrated in a rotary evaporator to obtain the title compound (6), in crude form.

EXAMPLE 7 - 9-a? 15-a-dihydroxy-16-phenoxy-16-omeqa-tetranor-13-trans-prostenamide N- (tetrazol-5-yligue) (7) The mixture is stirred at room temperature under atmos nitrogen sphere for 18 hours, then a 200 mg solution of 9-a-hydroxy-15-a- (tetrahydropyran-2-yloxy) -16-phenoxy-16-omega-tetranor is concentrated on a rotary evaporator Crude 13-trans-prostenamide N- (tetrazol-5-ylique) (6) in 10 ml 26 of a 65:35 mixture of acetic acid and water. Benzene is added which is then removed on a rotary evaporator (three evaporations). By purification of the crude residue by chromatography. written on a column of silica gel, using mixtures of chloroform and ethyl acetate as eluents, the compound (7) indicated in the title can be obtained in the pure state.

EXAMPLE 8 9-oxo-15-a- (tetrahydropyran-2-yloxy) -16-phenoxy-16-omeqa-tetranor-13-trans-prostenamide W - (- tetra-zol-5-ylique) (8) 35 0.38 ml of Jones reagent is added to a 19.

t solution} cooled to -20 ° C5 of ls06 mmol of 9-a-hydroxy-15-a- (tetrahydropyran-2-yloxy) -16-phenoxy-16-omega-tetranor- 13-trans-prostenamide N- (tetrazol -5-ylique) (6) in 15 ml of acetone. The mixture is stirred for about 20 minutes and then quenched in the cold by the addition of 0.38 ml of isopropyl alcohol. The mixture is stirred for 5 minutes} then it is diluted with 25 ml of ethyl acetate} it is washed with water (3 x 5 ml) and saturated brine (5 ml)} it is dried over magnesium sulfate and concentrated to obtain the compound No. 8 indicated in the title.

V EXAMPLE 9 - 9-oxo-15-a-hydroxy-16-phenoxy-16-omeqa-tetranor- 13-trans-prostenamide N- (tetrazol-5-ylique) (9)

A solution of 295 mg of 9-15 'a-hydroxy-15-α- (tetrahydropyran-2-yloxy) -16-phenoxy-16-omega-tetranor- is stirred at room temperature for 18 hours under a nitrogen atmosphere. Crude 13-trans-prostenamide N- (tetrazol-5-ylique) (3) in 30 ml of 65:35 mixture of acetic acid and water. The solution is concentrated on a rotary evaporator, then benzene is added, which is removed in the same way (three times). By purification of the residue by chromatography on a silica gel column using mixtures of chloroform and ethyl acetate as eluents, the compound (9) indicated in the title is obtained.

The synthesis of the compounds of Examples 6 to 9 of 25 shows that the 11-deoxyprostaglandins of classes 1, 2 and 3 of the invention and the corresponding PGP type compounds can be obtained using the chemical methods. written in Examples 6 to 9 by replacing the PGP type intermediate compound designated by the abbreviation DSM in Example 6 by the compound 11-deoxy-15-tetrahydropyran-2-yl-PGF2} 13 s 14 -dihydro-PGF2} PGF ^ or pgfq corresPondan't: s whose substituent in position C-16 is a phenyl or phenyl group substituted for the preparation of compounds of class 1} phenoxy or phenoxy substituted for the preparation of com -35 layers of class 2 and n-butyl or methyl and n-butyl for the preparation of compounds of class 3} the substituents of the phenyl and substituted phenoxy groups being radicals: 20.

* fluoro, chloroj methylj ethyl, methoxy, ethoxy5 phenyl and trifluoromethyl.

EXAMPLE 10 9-a-hydroxy-11-a, 15-a-bis-Ctetrahydropyran-2-yloxy) -16,16-dimethyl-5-cis-13-trans-prosta-5 dienamide N- (tetrazol- 5-league) (10)

134 mg (0.825 mmol) of 1,1-carbonyl-diimidazole are added to a solution of 0.795 mmol of 9-a-hydroxy-ll-a j15-a-bis- (tetrahydropyran-2-yloxy) -16 acid, 16-dimethyl-5-cis-13-trans-prostadienoic (RSM) in 10 ml of anhydrous dimethylfor- * 10 mamide. The solution is heated under a nitrogen atmosphere at 95 ° C for 4 hours "and then 70 mg (0i2 & Jumole.} Of anhydrous 5-aminotetrazole is added. The solution is heated under a nitrogen atmosphere for an hour and a half at 95 ° C, then it is concentrated on a rotary evaporator to obtain the compound (10) 15 indicated in the title "in the form of a viscous oil.

EXAMPLE 11 - 9-a »11-a» 15-a - trihydroxy-16 »16-dimethyl-5-cis - 13-trans-prostadienamide N- (tetrazol-5-ylique) (11)

A solution of 200 mg of 9-hydroxy-ll-a »15-a-bis- (tetrahydropyran-2-yloxy) -16> 16-dimethyl- 5 is stirred at room temperature for 18 hours under a nitrogen atmosphere. -cis-13-trans-prostadienamide N- (tetrazol-5-ylique) (10) crude in 10 ml of a 65:35 mixture of acetic acid and water "then the solution is concentrated on an evaporator rotary. Benzene was added and then removed on a rotary evaporator (three evaporations). The crude residue can be purified by chromatography on silica gel using a mixture of chloroform and ethyl acetate as eluent to obtain the compound (11) indicated in the title.

Example 12 - 9-oxo-ll-a »15-a-bis- (tetrahydropyran-2-yloxy) - 16» 16-dimethyl-5-cis-13-trans-prostadienamide N- (tetrazol-5-ylique) (12)

0.38 ml of Jones' reagent is added to a cooled solution at -5 ° of 623 mg (1.06 mmol) of 9-a-hydroxy-35 11-a, 15-a-bis- (tetrahydropyran-2- yloxy) -16,16-dimethyl-5-cis-13-trans-prostadienamide N- (tetrazol-5-ylique) (10) in 15 ml of acetone. The mixture is stirred for approximately 20 minutes, - 21.

* then it is deactivated in the cold by adding 0} 38 ml of isopropanol. It is stirred for 5 minutes "then diluted with 25 ml of ethyl acetate" it is washed with water (three times 5 ml) and with saturated brine (5 ml) "it is dried 5 on magnesium sulfate and concentrated to obtain the compound 12 indicated in the title.

EXAMPLE 13 - 9-oxo-11-a »15-a-dihydroxy-16» 16-dimethyl-5-cis-13-trans-prostadienamide N- (tetrazol-5-ylique) (13). A solution of 295 mg of 9-oxo-ll-a »15-a-bis- (tetrahydropyran-2-yloxy) -15» 16- is stirred at room temperature under a nitrogen atmosphere for 18 hours. crude dimethyl-5-cis-13-trans-prostadienamide N- (tetrazol-5-ylique) (12) in 30 ml of a 65:35 mixture of acetic acid and water. The solution is concentrated on a rotary evaporator and benzene is added and then concentrated (three times). The residue can be purified by column chromatography on silica gel using mixtures of chloroform and ethyl acetate as eluents to obtain the title compound 13.

The synthesis of the compounds of Examples 10 to 13 demonstrates that the 11-hydroxy or 11-deoxy-16 "-16-dimethyl-prosta-glandins of the invention and the corresponding PGF-type compounds can be obtained using the chemical methods. as described in examples 10 to 13 ”by replacing the intermediate PGF compound called RSM in example 10 by the compound ll” 15-bis- (tetrahydropyran-2-yl) - or ll-deoxy-15- (tetrahydropyran- 2-yl) -16 "16-dimethyl-PGF2> 13" ll-dihydro-PGFg "" PGF ^ or corresponding PGFq.

♦

Claims (5)

22. * ” 1. A compound of formula: X s_ „H H H H / S N, .... C-A-C-C-C-CONH- X 'H H H H -K H H Y ... __B-C-C-G J: H HO (or a pharmacologically acceptable salt of this compound) formula wherein: 5. is an ethylene or cis-vinylene group; B is an ethylene or trans-vinylene group; Y is a hydrogen atom or a hydro-xy group; G is a group Ct ^ Ar »CHgOAr or CRZ (CH2) 3CH3; Ar is phenyl fluorophenyl chlorophenyl methylphenyl ethylphenyl methoxy phenyl ethphenphenyl biphenyl or trifluoromethylphenyl; R is a hydrogen atom or a methyl group; And Z is a hydrogen atom or a methyl group. 2. The 9-oxo-ll-aj15-a-bis-hydroxy-16-phenyl-16-omega ^ tefcr®nor-5-cis-prostenamide N- (tefrazol ^ S-ylique) according to claim 1. 3. The 9-oxo-ll-a, 15-a-bis-hydroxy-16-phenoxy-16- omega-fetranor-5-cis-13-fcrans ~ prostadienantide N- (tetracol-5-ylique) according to claim 1. 4. 9-oxo-11-a, 15-a-bis-hydroxy-5-cis-13-trans-prostadienamide N- (tetrazol-5-ylique) according to claim 1. *: 23. h 5. Medicament "characterized in that it consists of or in that it contains a compound according to any one of claims 1 to 4. 9 -ï