DD141155A5 - PROCESS FOR PREPARING N- (TETRAZOL-5-YL) -PROSTAGLANDINCARBOXAMIDE - Google Patents

Abstract

Particularly preferred compounds are as follows: Class 1: N- (Tetrazol-5-yl-9-oxo-11a, 15a-bis-hydroxy-16-phenyl-1 6co-tetranor-5-cis-prostenamide; Class 2: N- (tetrazole 5-yl) 9-oxo-11a, 15a-bis-hydroxy-16-phenoxy-16o-tetranor-13-trans-prostenamide and Class 3: N- (tetrazol-5-yl) 9-oxo-11a, 15a-bis-hydroxy -5 - cis-13-transprostadienamid.

Description

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N- (tetrazol-5-yl) -prostaglandin-carboxamides

Field of application of the invention

The prostaglandins are C ^ _n -unsaturated fatty acids which show various physiological effects. Their structure, nomenclature, biological activities, and medical uses have been described in US Pat. Nos. 3,971,825 and 3,984,400.

Characteristic del known technical solutions A common problem of scientists in the medical field are provided that attempt to biologically active synthetic drugs, is the modification of the biological action of an appropriate lead compound. In a traditional solution for drug synthesis, the researcher is looking for an increase in biological performance. However, the prostaglandin researcher limits his design options to increased oral activity,

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the prolonged duration of action and enhancement of one of the various physiological effects of the prostaglandin class and on the reduction of others. This latter criterion is important because it would show incompatible side effects without a synthetic prostaglandin. For example, it would not be clinically advisable to administer a synthetic anti-ulcer prostaglandin that also causes diarrhea.

Z iel the invention

To achieve increased selectivity, researchers have focused their efforts on the "active" sites of natural prostaglandins. In the first place, these are the Cj-carboxylic acid group, the C 1-4 -ketone or -hydroxyl group, the C ₁ -hydroxyl group and the lipophilic end of the lower side chain. Such work is published in the following publications and patents: U.S. Patents 4,011,262, 4,024,179, 3,971,826, 3,932,389, 3,974,213, 3,054,741, 3,987,087, Netherlands Patent Application 73,006,030, BJ Mayerlein et al., Prostaglandins, 4, (1973) and W. Lipmann, Prostaglandins, Ί, 231 (1974).

It has now surprisingly been found that an increase in the distance between the C _g functionality and the acidic group of the upper side chain by combining an amide group leads to a strong biological activity. Explanation of the essence of the invention

Three classes of Cj-amidotetrazole prostaglandins have been found to have markedly different biological activity profiles. Class 1 includes compounds of Formula 1 which exhibit antiulcer activity.

formula 1

HHHH. , OA-C-C-C CONH HHHH

H H

.B-C-C-Ar: H

HO.

N-

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Class 2 includes compounds of formula 2 which exhibit fertility controlling activity. Formula 2

Y. , J

H HHH, C-A-C-C-C H CON

  HH B-C-C-OAr •: H HO

N-

-N

-N

Class 3 includes compounds of formula 3 which exhibit bronchodilatory or fertility controlling activity, depending on the importance of R and Z.

Formula 3

H H Η "Η ... C-A-C-C-C CONH HHHH

HRHHHH - B-C-C-C-C-CH

: ZHHHH HO

It turns out that the structural differentiation of the classes lies in the identity of the w or lower side chain. However, it is the combination of this functional group with the other important groups, such as the amidotetrazole group, that leads to the different biological activities. Nonetheless, these three classes can be structurally combined into a single parent formula (4).

Parent formula 4

HHHH,,. .CACCC-CONH-, H ₁ HHH

H ~~~ BCG

110

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In each of the above formulas, A is cis-vinylene or ethylene, B is -h-vinylene or ethylene, Y is hydroxy or hydrogen, R is hydrogen or methyl, Z is hydrogen or methyl, Ar is phenyl, fluorophenyl, chlorophenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, Biphenyl or trifluoromethylphenyl and G CH ₂ Ar, CH ₂ OAr or CRZ (CH ₂ J ₃ CH ₃ .

Particularly preferred compounds are the following:

Class 1: N- (tetrazol-5-yl) 9-oxo-11-a, 15a-bis-hydroxy-16-phenyl

16-COE-tetranor-S-cis-prostenamid; Class 2: N- (tetrazol-5-yl) 9-oxo-11a, 15a-bis-hydroxy-16-phenoxy

16-tetranor-13-trans-prostenamide; and Class 3: N- (tetrazol-5-yl) 9-oxo-11a, 15a-bis-hydroxy-5-cis-13-trans-prostadienaraid.

Also contemplated are the PGF type compounds corresponding to the above three classes and the pharmacologically acceptable salts wherein the acidic tetrazole residue is neutralized.

In the process of the present invention, each class of N- (tetrazole) prostaglandin carboxamides is synthesized from a similar class of 11,15-bis (hydroxyl-protected) or 11-deoxy-15 (hydroxyl-protected) PGF compounds. This starting template material has the same basic structure for all classes and excludes any arrangement of the bond type at the C ^ -C ₆ and C. .VC., Positions that are related to A and B of the formulas 1, 2 and 3. In other words, the (11), 15-hydroxyl protected PGF compound corresponds to the above Stamra formula (4). A differentiation of the basic structure by class is determined by the identity of the end of the lower side chain of the respective Ausgangsraaterials. Thus, the starting material for class 1 has the substitution 16-aryl-16-f-tetra-nor in the above PGF basic structure; the starting material for class 2 has the substitution 16-aryloxy-16-tetranor and the starting material for class 3 has the substitution 15-n-pentyl,

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2-hexyl or 2-methyl-2-hexyl at the lower side chain of the above PGF basic structure. These structures are shown in the overview 1 and designated F1, F2 or F3.

The PGF output connections for each of the classes are known; the properties and characteristics of the 11-hydroxy starting materials are described in US Pat. Nos. 4,024,179, 3,887,589, 4,011,262, 4,036,832, British Patent 1,324,737, BJ Mayerlein et al., Prostaglandins, 4_ , 143 (1973) and EJ Corey et al., J. Amer. Chem. Soc. 92 '1491 (1971) and that of the 11-deoxy starting materials in British Pat. No. 1,419,181, DE-OS 2,548,267, P. Crabbe et al., Tet. Let. 1972, 1123 and W. Lipmann, Prostaglandins, 1, 231 (1974).

The conversion of the starting materials into the product classes according to the invention is illustrated by Scheme A. In order to convert a starting material into a representative of a class of compounds according to the invention, first the C.-carboxylic acid group is converted to a C.-N- (tetrazol-5-yl) carboxamide group (Step 1, Scheme A). Then, this N- (tetrazole) -carboxamide PGF intermediate is oxidized with Jones reagent to the corresponding PGE intermediate, whose protecting group is removed by removal of the 15-mono- or 11, 15-bishydroxyl-protected (R ¹ ) groups (Step 2.1, Scheme A) to produce an N- (tetrazole) carboxamide prostaglandin of Formula 1, 2 or 3. On the other hand, a compound of the PGF type corresponding to a PGE compound of formula 1, 2 or 3 can be prepared by simply cleaving off the C ₁ - and / or C,--hydroxyl (R ¹ ) protecting groups of the N- (tetrazole) carboxamide Intermediate be made.

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Overview 1

Starting materials for the different classes

OH

R ¹ O. (THPO) (H)

H HHH ... C-A-C-C-C-HHHH

H H

-B-C-C-Ar

: HR ¹ O (THPO)

F1, starting material for class 1, X is -COOH

OH

R ¹ O..

(THPO)

(H)

HHHH

..C-A-C-C-C-X

HHHH

H H -B-C-C-OAr

: HR ¹ O (THPO)

P2 t starting material for class 2, X is -CÖÖH

OH

ii H H. ..OA-C- H H H is H-C-C-HH H H -C-C- H -CH R ¹ O.. H R B-C-C- H -C- u ε H (THPO (H) ϊ ZR ¹ O ff

(THPO)

F3, starting material for class 3, X is -COOH

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Scheme A, step 1. Formation of the N- (tetrazol-5-yl) carboxamide group

1. CDI reagent _{p1 WQrin χ}

F1, F2 or F3 _: - ^ F2 H

2. Anhydrous F3 N-N

"5-AT reagent -CONHC

X.

N is N

Stage 2.1 Oxidation with Jones reagent and THP cleavage

F1, F2 or F3, X = -CONH

H 1. C _r O ₃

NN ^H 2 ^SO 4

1,2,3

N 2.

^H 2 °

1. Formula 1, starting material is Fl

2. Formula 2, starting material is F2

3. Formula 3, starting material is F3

Step 2.2 Cleavage of the THP protecting group to the PGF-type compounds "

vj - N ^; CH, C00H F1, F2 or F3, X = CONHC ^ || -> 1,2,3

1. PGF compound according to formula 1, starting material is F1

2. PGF compound according to formula 2, starting material is F2 ^L

3. PGF compound according to formula 3, starting material is F3

The reaction steps 2.1 and 2.2, which include the removal of the C --- and / or C -, - hydroxy 1-protecting groups and the oxidation of the Cq hydroxyl group in a C ^ -oxo (ketone) group, are conventional transformations and well known in the field of prostaglandin chemistry. Equivalent methods of oxidation

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Cg hydroxyl and protect the C ₁₁ - and / or Cj _5-hydroxyl group are also well known in the art and applicable here. Prostaglandin researchers have found that selective oxidations, such as Pfitzner-Moffett oxidation with dimethylsulfoxide and dicyclohexylcarbodiimide, as well as Collins oxidation with chromium trioxide-pyridine complex in methylene chloride can also be used to perform hydroxylin-ketone oxidation. Also numerous methods and available groups for the protection and deprotection of the hydroxyl groups in C --.-.- and / or O published ₁ c-positions of a prostaglandin. Such mild labile protecting groups are designated R ¹ . The tetrahydropyranyl group also proves to be the preferred group. Some other common mildly labile protecting groups useful in the present invention are dimethyl-t-butylsilyl, removable with tetra-butylammonium fluoride or aqueous acetic acid, and 1-methoxyethylen-1-yl, an analog to tetrahydropyran-2-yl.

Step 1 is novel, by allowing the preparation of a C. amide having an acidic group as a substituent. The significance of this design resides in the fact that the prior art teaches the biologically critical invariance of the distance of the acidic C ₁ -GrUpPe to the C-9 functionality, while in the compounds of the invention, in fact, the distance has been extended by two of the atoms of the amide group is. The N ~ (tetrazol-5-yl) carboxamide group can be prepared from the carboxylic acid group by first preparing a carboxylic acid derivative having an easily displaceable leaving group and then amidating with 5-aminotetrazole (5-AT reagent). Any leaving group which can be attached to the carboxyl group of the prostaglandin intermediate (F1, F2, F3, Table 1) without destroying the remainder of the molecule can be used in the preparation. Some typical leaving groups and the reagents used for their preparation are, for example, pivaloyloxy / pivaloyl-halide, which is the mixed anhydride

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Derivative forms, and ethoxyformyloxy / Xthoxyformyl halide, which forms the carbonate Deriyat. The preferred leaving group is imidazol-1-yl which results in an acylimidazole intermediate. To prepare the N- (tetrazol-5-yl) carboxyamide group via an acylimidazole intermediate, first the prostaglandin carboxylic acid starting material (F1, F2 or F3) with the leaving group reagent, 1,1-carbonyldiimidazole, in a polar aprotic solvents, such as dimethylformamide, diethylformamide, acetonitrile, tetrahydrofuran or dimethylsulfoxide, to form in situ the acylimidazole intermediate. The imidazol-1-yl group linked to the C ₁ -carbonyl is then directly displaced with the 5-AT reagent to give the desired N- (tetrazol-5-yl) carboxamide. For both the formation and the displacement of the acylimidazole, reaction temperatures in a range between room temperature and about 12O ⁰ C may be used; Conveniently, the reaction is carried out at about 9O ⁰ C and reflux.

After formation of the N- (tetrazol-5-yl) carboxamide group, reaction step 2.1 is carried out, after which a compound of formula 1, 2 or 3 is prepared, or the reaction step 2.2 is carried out, whereupon a compound of the PGF type is prepared becomes.

On the other hand, according to the process of the invention, the N- (tetrazole) prostaglandins of each class may be directly derived from a corresponding PGE or PGF compound of the formula

HHHH. ..C-A-C-C-C-OH HHHH

H B-C-G.

HO

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in which A, Y, B and G are as defined above and M is oxo or H * ^ "" OH. In this way, the PGE or PGF acid is synthesized using the method of directly producing an N- (tetrazole) prostaglandin-carboxamide of the above formula to form the N- (tetrazo3.-5-yl) carboxamide group indicated above in Step 1 1, 2 or 3 or the corresponding PGF carboxamide reacted. It works on step 1, provided that if M is to be oxo, no basic reagent is used.

Numerous in vivo and in vitro tests have found that the three classes of prostaglandin compounds according to the invention show extreme selectivity. Their biological performance lies in the reduction of many physiological activities of natural prostaglandins while maintaining activity in one area. The attempts to allow such a determination of selectivity are i.a. e.g. a test for the influence on isolated smooth muscle of the guinea pig, the influence on the blood pressure of the dog, the inhibition of histamine-induced bronchoconstriction in the pig, the inhibition of cold, stress-induced ulceration in the rat, the antisecretory activity in the dog and the diarrhea Effect on the mouse.

When compared to the reactions elicited by natural prostaglandin in the same assays, the physiological responses elicited by the three classes of experimental prostaglandins in these assays are helpful in determining their usefulness for treating natural and pathological failures. On the basis of such comparison, the Class I prostaglandins according to the invention have utility as selective antiulcer agents, class 2 such fertility control agents, those of class 3 in which R is methyl or hydrogen and Z is hydrogen bronchodilators and those of class 3, in which both R and

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Z are methyl, usability as fertility controlling agents. Observations in biological tests of the Class 1 prostaglandins show that they have strong antiulcer activity, while having reduced hypotensive activities, those on the uterine smooth muscle, diarrhea and bronchodilating activities compared to the natural prostaglandin PGE ₂ as a test standard , The same type of observations shows that class 3 prostaglandins, where R is methyl or hydrogen and Z is hydrogen, have strong bronchodilatory activity and reduced activity on uterine smooth muscle, hypotensive, anti-ulcer and diarrhea activity. Similarly, class 2 prostaglandins show strong activity on the smooth uterine musculature and a reduction in such particular activities as hypotensive, diarrhea and bronchodilating activity.

The three classes of prostaglandins of the invention can be used in a variety of pharmaceutical compositions containing the prostaglandin or its pharmaceutically acceptable salts. They may be administered as well as natural prostaglandins in a number of suitable ways, e.g. intravenously, orally and locally, e.g. as aerosol, intravaginal, intra- and extra-amniotic and intranasal, i.a. Of course, the selective activity of the particular class of prostaglandins of the invention and their intended use will determine the route used. For example, the appropriate routes for Class 2 prostaglandins are intravenous, oral, intravaginal, and intra- and extra-amniotic, while the appropriate routes for Class 3 bronchodilating prostaglandins are aerosol, intranasal, oral, and intravenous.

For pharmaceutical composition and for the solid composition of the three classes of prostaglandins are the

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useful pharmacologically acceptable salts of the acidic tetrazole moiety, such as those with pharmacologically acceptable metal cations, amine cations or quaternary ammonium cations. ".

Particularly preferred metal cations are those derived from alkali metal, e.g. Lithium, sodium and potassium, as well as alkaline earth metal, e.g. Magnesium and calcium, although cationic forms of other metals, e.g. Aluminum, zinc and iron are within the scope of the invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, triethylamine, Ä'thylamin, benzylamine, ct-phenylethylamine, ß-phenylethylamine, and heterocyclic amines, e.g. Piperidine, morpholine, pyrrolidine and piperazine and amines having water-solubilizing or hydrophilic groups, e.g. Mono-, di- and triethanolamine, ethyldiethanolamine, galactamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetraethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

The three classes of prostaglandins of the present invention can be used in numerous pharmaceutical preparations containing the compound or a pharmacologically acceptable salt thereof, and can be administered in various ways as described above. Although the particular dose, composition and mode of administration of the particular condition of each patient and the knowledge

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of the prostaglandin classes of the invention describe the utility of class 1 compounds as antiulcer agents, class 2 as fertility controlling agents, class 3 in which R is hydrogen or methyl and Z is Hydrogen, as bronchodilators and Class 3, in which both R and Z are methyl, are fertility-controlling agents.

Class 1 prostaglandins are useful as antiulcer agents. For the treatment of gastric ulcers, these medicaments are conveniently administered orally in the form of aqueous suspensions, ethanolic solutions, or preferably in the form of capsules or tablets containing 0.001 to 0.10 mg / kg of prostaglandin per dose at up to 12 doses per day.

To induce abortion, Class 2 and Class 3 prostaglandins in which both R and Z are methyl can be orally administered in suitably-composed tablets, aqueous suspensions or alcoholic solutions containing approximately 0.05 to 5 mg of prostaglandin per dose at 1 be administered up to 7 doses per day. For intravaginal administration, a suitable composition is in the form of lactose tablets or an impregnated tampon containing about 0.1 to 10 mg of prostaglandin per dose at 1 to 7 doses administered. For intra-amniotic administration, a suitable composition is an aqueous solution with prostaglandin at 0.05 to 5 mg per dose at 1 to 7 doses used. For extra-amniotic administration, a suitable composition is an aqueous solution containing 0.01 to 1 mg of prostaglandin per dose at 1 to administered doses. On the other hand, class 2 and class 3 prostaglandins in which both R and Z are methyl can be infused intravenously to induce abortion at doses of 0.05 to 50 % prostaglandin per min for about 1 to 24 hours.

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More likely, class 2 and class 3 prostaglandins, in which both R and Z are methyl, can be used to induce labor. For this purpose, an ethanolic saline solution of the prostaglandin for intravenous infusion is used in an amount of about 0.1 to 10 kg / min of prostaglandin for about 1 to 24 hours.

Another use for Class 2 and Class 3 prostaglandins, where both R and Z are methyl, is fertility control. For this purpose, a tablet for intravaginal or oral administration is administered with 0.1 to 10 mg of prostaglandin per dose at 1 to 7 doses on or after the expected menstruation day. For synchronization of the oestrus cycle in pigs, sheep, cows or horses, a solution or suspension of 0.3 to 30 mg / dose of prostaglandin is administered subcutaneously or intramuscularly for 1 to 4 days.

Class 3 prostaglandins, wherein R is hydrogen or methyl and Z is hydrogen, are useful as bronchodilators and to enhance nasal patency or accessibility. A suitable dosage form for this treatment is a solution of the prostaglandin in aqueous ethanol or t-butanol or its suspension used as an aerosol using an inert gas as the propellant, the amount of prostaglandin contained therein being about 5 to 500 ng per dose.

Various inert diluents, excipients or carriers can be used to prepare any of the above dosage forms or any of the numerous other possible forms. Such substances are e.g. Water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohol, resins, polyalkylene glycols, refined natural petrolatum, cholesterol and others known in the art

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Carrier for medicines. If desired, these pharmaceutical agents may contain auxiliary substances such as preservatives / wetting agents, stabilizers or other therapeutic agents such as antibiotics.

The following examples are for illustration only and are not intended to limit the scope of the invention. The IR spectral data were obtained with a Perkin-Elmer grating IR spectrometer and reported in μm. The NMR spectral data were obtained with a Varian HA-60 spectrometer and are reported in 6ppm. Melting points are uncorrected and given in ⁰ C. Thin-layer chromatographic measurements were obtained on silica gel and recorded as R _f values.

In general, temperatures of the reactions described in the Examples, mean indicated if not closer to about room temperature, ie a range of 15 to 3O ⁰ C.

The time required for the reactions described in the examples was determined by thin-layer chromatography, unless stated otherwise. The usual thin-layer chromatography system was silica gel on glass (E. Merck silica gel plates, E. Merck) with benzene / ether or methanol / chloroform as diluent and vanillin / ethanol or iodine as developer ("Introduction to Chromatography" J.M.

 Bobbitt, A.E. Schwarting, R.J. Gritter, Van Nostrand-Renhold, N.Y. 1968). As a general rule, the reaction in question was considered to be substantially complete when the thin layer chromatography stain representing the critical starting material disappeared or ceased to change appearance.

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Ausfühiungsbeispiele example 1

N- (tetrazol-5-yl) 9a-hydroxy-11a, 15a-bis- (tetrahydropyran-2-yloxy) -S-cis-IS-trans-prostadienamide (1)

To a solution of 415 mg (0.795 mmol) of 9a-hydroxy-11a, 15a-bis- (tetrahydropyran-2-yloxy) -5-cis-13-trans-prostadienoic acid (SM) in 10 ml of dry dimethylformamide was added 134 mg (0.825 mmol) of 1,1-carbonyldiimidazole. The solution was heated to 95 ° under nitrogen for 4 hours, then 70 mg (0.825 mole) of anhydrous 5-aminotetrazole was added. The solution was heated to 95 ° under nitrogen for 1.5 h, then concentrated on a rotary evaporator to give the crude title compound (1) as a viscous oil weighing 823 mg. Their NMR spectrum (CDCl-.) Showed the following characteristic absorptions (in 5 ppm):

5.65 - 5.24 (multiplet) - olefinic

O 4.81-4.62 (multiplet) - CH-O

1.92 (triplet, j = 4 Hz) - CH ₃

Example 2

N- (tetrazol-5-yl) 9a, 11a, 15a-trihydroxy-5-cis-13-trans-prostadienamide (2)

A solution of 200 mg of crude N- (tetrazol-5-yl) 9a-hydroxy-11a, 15a-bis (tetrahydropyran-2-yloxy) -5-cis-i3-trans-prostadienamide (1) in 10 ml of a 6 5/35 acetic acid / VJasser mixture was stirred at room temperature under nitrogen for 18 h; then was concentrated on a rotary evaporator. Benzene was added and removed on a rotary evaporator (three times). Purification of the crude residue by column chromatography on silica gel using a mixture of chloroform and ethyl acetate as eluant afforded the title compound (2) of 6 mg, mp 168-172 ° (after recrystallization from ethanol / ether).

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

Example 3

N- (tetrazol-5-yl) 9-oxo-11a, 15a-bis- (tetrahydropyran-2-ylpxy) -S-cis-IS-trans-prostadienamide (3)

To a -20 ° cooled solution of 623 mg (1.06 mol) of N- (tetrazol-5-yl) 9a-hydroxy-11a, 15a-bis- (tetrahydropyrane-2-yloxy) -5-cis-13 trans Prostate amide (1) in 15 ml of acetone was added 0.38 ml of Jones reagent. The mixture was stirred for 20 minutes, then rapidly added 0.38 ml of isopropyl alcohol in the cold. The mixture was stirred for 5 min, then diluted with ethyl acetate (25 mL), washed with water (3x5 mL) and brine (5 mL), dried (over magnesium sulfate), and concentrated to afford the title compound (3) as a viscous oil Weight of 295 mg. Thin layer chromatography: R _f f 0.4 8 (9: 1 methylene chloride /

Methanol).

Example 4

N- (tetrazol-5-yl) 9-oxo-11a, 1 5a-dihydroxy-5-cis-T3 transprostate amide (4)

A solution of 295 mg of crude N- (tetrazol-5-yl) 9-oxo-11a, 15-bis- (tetrahydropyran-2-yloxy) -5-cis-13-trans-prostadienamide (3) in 30 ml of a 65: SS -Acetic acid / water-Gernischs was stirred for 18 h under nitrogen at room temperature. The solution was concentrated on a rotary evaporator and benzene was added and concentrated (three times). Purification of the residue by column chromatography on silica gel using chloroform / ethyl acetate mixtures as eluant afforded the title compound (4), weighing 22 mg, mp 162 °. Their IR spectra (KBr) showed the following characteristic absorptions (in μm):

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5.71 (ketone) 5.87

(Amide) 6,12 10,33 (trans-olefin)

Example 5

The following further compounds were prepared using the procedures described in Examples 1 to 4 and replacing the compound (SM) in Example 1 with the appropriate starting PGP carboxylic acid: 5A. N- (tetrazol-5-yl) 9-oxo-11a, 15a-dihydro-13-trans-prostenamide, m.p., solid, NMR (CD ₃ OD) (in ppm): 5.76, 5.44 (multiplet ), trans-olefin; 1.88 (triplet, j = 4 Hz) CH ₃

5B. N- (tetrazol-5-yl) 9-oxo-11a, 1 5a-dihydroxy-5-cis-16-phenyl-ΐώ-tetranorprostenamide, mp 75-78 °, NMR (CD ₃ OD) (in ppm): 7, 'O8 (singlet) C ₅ H ₅ ; 5.43 - 0.17 (multiplet), cis-olefin.

5C. N- (tetrazol-5-yl) 9-oxo-11a, 15a-dihydroxy-13-trans-16-phenyl-j, 6'-tetranorprostenamide, mp 149-150 °, IR (KBr) (in μΐη): 5.67 x (ketone), 5.83 and 6.10 (amide), 10.28 (trans-olefin).

5D. N- (tetrazol-5-yl) 9a, 11a, 15a-trihydroxy-5-cis-13-trans-16-phenoxy-vHf 1 -tetranorprostate amide, m.p. 87-90, IR (KBr) (in μΐη): 5 , 97 and 6.25 (amide), 10/35 (trans-olefin).

5E. N- (tetrazol-5-yl) 9-oxo-11a, 15a-dihydroxy-5-cis-13-trans-16-phenoxy-1,6t> -te * tranorpro stage amide, m.p. 105-107, IR (KBr) ( in μΐη): 5.68 (ketone), 5.85 and 6.10 (amide), 10.28 (trans-olefin).

The synthesis of the compounds of Examples 1 to 5 shows that the 11-hydroxyprostaglandins of classes 1, 2 and 3

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according to the invention and the corresponding compounds of the PGF type can be synthesized according to the chemical processes described in Examples 1 to 4 by using the appropriate 11,15-bis (tetrahydropyran-2-yl) PGF ₂ , the 13,14- Dihydro PGF, the PGF. or PGF _Q , wherein the substituent in C, - position is phenyl or substituted phenyl for the preparation of class 1, phenoxy or substituted phenoxy for the preparation of class 2 and η-butyl or both methyl and η-butyl for the Preparation of Class 3 is substituted for the PGF intermediate stage designated (SM) in Example 1, the substituents for the substituted phenyl and phenoxy classes being fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, phenyl and trifluoromethyl.

Example 6

N- (tetrazol-5-yl) 9a-hydroxy-15a (tetrahydropyran-2-yloxy) -16-phenoxy-l6ü-tetranor-13-trans-prostenamide (6)

To a solution of 0.795 mmol of 9a-hydroxy-15α- (tetrahydropyran-2-yloxy) -16-phenoxy-16α-tetranor-13-trans-prostenoic acid (DSM) in 10 ml of dry dimethylformamide is added 134 mg (0.825 mmol) 1 , 1 ~ carbonyldimidazole given. The solution is heated to 95 ° under nitrogen for 4 h, then 70 mg (0.825 mol) of anhydrous 5-amino-tetrazole are added. The solution is heated at 95 ° for 1.5 h under nitrogen and can then be concentrated on a rotary evaporator to the crude title compound (6) ζυ. deliver.

Example 7

N- (tetrazol-5-yl) 9a, 15a-dihydroxy-16-phenoxy-16u-tetranor-13-trans-prostenamide (7)

A solution of 200 mg of crude N- (tetrazol-5-yl) 9a-hydroxy-15a (tetrahydropyran-2-yloxy) -16-phenoxy-; i'6ü-tGtranor-13 trans-prostenamide (6) in 10 ml of a 65/35 acetic acid / water

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Mixture is stirred for 18 h under nitrogen at room temperature and then concentrated on a rotary evaporator. Benzene is added and removed on a rotary evaporator (three times). Purification of the crude residue by column chromatography on silica gel using chloroform / ethyl acetate mixture as eluent may be used to purify the title compound (7). be applied. ..

Example 8

N- (tetrazol-5-yl) 9-oxo-15a (tetrahydropyran-2-yloxy) -16-phenoxy-i-y-tetranor-13-trans-prostenamide (8)

To a -20 ° cooled solution of 1.06 mmol of N- (tetrazol-5-yl) 9a-hydroxy-15α- (tetrahydropyran-2-yloxy) -16-phenoxy-reo-tetranor-13-trans-prostenamide ( 6) in 15 ml of acetone are added 0.38 ml of Jones reagent. The mixture is stirred for about 20 minutes, then quenched with 0.38 ml of isopropyl alcohol in the cold. The mixture is stirred for 5 minutes, then it is diluted with ethyl acetate (25 ml), washed with water (3 times 5 ml) and saturated brine (5 ml), dried (over magnesium sulfate) and concentrated to afford the title compound (8) ,

Example 9

N- (tetrazol-5-yl) 9-oxo-15a-hydroxy-1 6-phenoxy-1-ecobutane

13-trans-prostenamide (9) '

A solution of 295 mg of crude N- (tetrazol-5-yl) 9a-hydroxy-15α-tetrahydropyran-2-yloxy-16-phenoxy-1,6-tetranor-13-trans-prostenamide (3) in 30 ml of a 65: 35 acetic acid / water mixture is stirred for 18 h under nitrogen at room temperature. The solution is concentrated on a rotary evaporator and benzene is added and also removed (three times). Purification of the residue by column chromatography on silica gel using chloroform / ethyl acetate mixtures as eluant affords the title compound (9).

21 01 98

The synthesis of the compounds of Examples 6 to 9 shows that the 11-deoxy prostaglandins of classes 1,2 and 3 according to the invention and the corresponding compounds of the PGF type are synthesized using the chemical processes described in Examples 6 to 9 can, by the appropriate 11-deoxy-15-tetrahydropyran-2-yl-PGF ₂ , the 13,14-dihydro-PGF ₂ , PGF. or PGFQ starting material, wherein the Cg-substituted substituent is phenyl or substituted phenyl for the preparation of Class 1, phenoxy or substituted phenoxy for the preparation of Class 2 and η-butyl or both methyl and η-butyl for the preparation of the class 3 is substituted for the PGF intermediate designated (DSM) in Example 6, wherein the substituents for the substituted phenyl and phenoxy classes are fluoro, chloro, methyl, ethyl, methoxy, ethoxy, phenyl and trifluoromethyl.

Example 10

N- (tetrazol-5-yl) 9cc-hydroxy-11a, 1α-bis (tetrahydropyran-2-yloxy) -16, IG-dimethyl-S-cis-IS-trans-prostadienamide (10)

To a solution of 0.795 mmol of 9a-hydroxy-11a, 15a-bis- (tetrahydropyran-2-yloxy) -16,16-dimethyl-5-cis-13-transprosthenoic acid (RSM) in 10 ml of dry dimethylformamide is added 134 mg (0.825 mmol) of 1,1-carbonyldimidazole. The solution is heated to 95 ° under nitrogen for 4 h, then 70 mg (0.825 mol) of anhydrous 5-aminotetrazole are added. The solution is heated to 95 ° under nitrogen for 1.5 h, then concentrated on a rotary evaporator to give the crude title compound (10) as a viscous oil.

Example 11

N- (tetrazol-5-yl-9a, 11a, 15a-trihydroxy-16,16-dimethyl-5-cis-13-trans-prostadienamide (11)

A solution of 200 mg of crude N- (tetrazol-5-yl) 9a-hydroxy

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11α, 15a-bis- (tetrahydropyran-2-yloxy) -16,16-dimethyl-5-cis-13-trans-prostadienamide (10) in 10 ml of a (S: 35-acetic acid / water mixture is heated for 18 h Nitrogen at room

temperature stirred; then it is concentrated on a rotary evaporator. Benzene is added and stripped on a rotary evaporator (three times). Purification of the crude residue by column chromatography on silica gel using a chloroform / ethyl acetate mixture as eluent may be carried out to afford the title compound (11).

Example 12

N- (tetrazol-5-yl) 9-oxo-11a, 15a-bis- (tetrahydropyran-2-yloxy) -16, lo-dimethyl-S-cis-IS-trans-prostadienamide (12)

To a cooled to -20 ° C solution of 623 mg (1.06 mmol) of N- (tetrazol-5-yl) 9a-hydroxy-11a, 15a-bis (tetrahydro-pyran-2-yloxy) -16,1 Dimethyl-S-cis-IS-trans-prostadienamide (10) in 15 ml of acetone is added to 0.38 ml of Jones reagent. The mixture is stirred for about 20 minutes, then quenched with 0.38 ml of isopropyl alcohol in the cold. The mixture is stirred for 5 min, then diluted with ethyl acetate (25 mL), washed with water (3x5 mL) and brine (5 mL), dried (over magnesium sulfate), and concentrated to afford the title compound (12).

Example 1 3

N- (tetrazol-5-yl) 9-oxo-11a, 1 5a-dihydroxy-16,16-dimethyl-5-cis-13-trans-prostadienamide (13)

A solution of 295 mg of crude N- (tetrazol-5-yl) -9-oxo-11a, -15a-bis (tetrahydropyran-2-yloxy) -16,16-dimethyl-5-cis-13-trans-prostadienamide (12) in 30 ml of a 65:35 acetic acid / water mixture is stirred for 18 hours under nitrogen at room temperature. The solution is concentrated on a rotary evaporator and benzene is added and concentrated (three times). Cleaning the return

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Stages by column chromatography on silica gel using chloroform / ethyl acetate mixtures as eluant can be carried out to give the title compound (13).

The synthesis of the compounds of Examples 10 to 13 shows that the 11-hydroxy or 11-deoxy-16,16-dimethyl-prostaglandins according to the invention and the corresponding compounds of the PGF type using the chemical described in Examples 10 to 13 Can be synthesized by using the appropriate 11,15-bis (tetrahydropyran-2-yl) or 11-deoxy-15- (tetrahydropyran-2-yl) -16,16-dimethyl PGF ₂ ', 13,14- Dihydro PGF ₂ , PGF ₁ or PGF ₀ is substituted for the PGF intermediate designated (RSM) in Example 10.

Claims (2)

-M- 2.1 01 98 invention claim 1. A process for the preparation of a novel prostaglandin of the formula γ ' HHM · - "C-A-C-C-C-CONH H H HHH -B-C-G Oh or a pharmaceutically acceptable salt thereof, wherein: A is ethylene or cis-vinylene, B is ethylene or trans -vinylene, Y is hydrogen or hydroxy, G is CH ₂ Ar ,. CH ₂ OAr or CRZ (CH 1 CH-j Ar is phenyl, fluorophenyl, chlorophenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, biphenyl or tri fluoromethyl! phenyl ,.
R is hydrogen or methyl and
Z is hydrogen or methyl.,
characterized in that
a) an intermediate compound of the formula: M WHH --C- AC- CC-CONH H μ Η β-C-G HHH -i H N- -N N-N R ¹ O wherein A, B and G are as defined above, L is hydrogen or OR ¹ and R ^{f is} a labile hydroxyl-protected group, is reacted with a mildly hydrolyzed means to convert the protecting group R ¹ to hydrogen; or b) an intermediate compound of the formula: γ J ... "-C-A-C-C-C-COOH fi") υ Η HMH CG OH v / orin A, B, Y and G are as defined above, reacted with an acidic reagent to form a carbocyclic acid derivative having an easily cleavable acidic group and then replacing the acidic group with 5-aminotetrazole and, if desired, the compound of formula (II) I) is still step (a) or (b) with a pharmaceutically acceptable base, an amine, ammonia or a quaternary amine to form a .Pharmaceutically acceptable salt of a compound of formula (I). 2. The method according to item 1, characterized in that R ^{f is} Te- 'trahydropyran-2-yl, dimethyl-t-butyl ~ silyl or 1-methoxyethylene-1-yl and as a mild hydrolyzing agent in step (a) aqueous acetic acid is used ₀ Method according to item 1, characterized in that the protecting group reagent in step (b) is pivaloylohalide, ethoxyformyl halide or 1,1-carbonyldiimidazole ₀ A method according to item 1, characterized in that the protecting agent used in step (b) is 1,1-carbonyl diimidazole and the reaction in a polar, aprotic solvent at a temperature from room temperature to 12O ⁰ C is performed.