NO790122L - PROCEDURE FOR PRODUCTION OF PROSTAGLAND INCARBOXAMIDS - Google Patents

Description

The prostaglandins are C-20 chained fatty acids that exhibit various physiological effects. Their structure, nomenclature, biological effects and medical uses are described in US patents 3,971,825 and 3,984,400.

A common problem facing medical researchers attempting to produce biologically effective synthetic drugs is the modulation of the biological action of a suitable lead compound. In a traditional attempt at the synthesis of pharmaceuticals, the researcher will try to find an increase in biological effect. However, the prostaglandin researcher will direct his research towards increased oral activity, increased duration of action and strengthening of one or more physiological effects of compounds in the prostaglandin class and reduction of others. This latter criterion is important, because if this is not taken into account, a synthetic prostaglandin will exhibit incommensurable side effects. E.g. it would be clinically inadvisable to administer an antiulcer synthetic prostaglandin which also caused diarrhoea.

To achieve increased selectivity, researchers have concentrated

its activity against the "active" points of the natural prostaglandins. These mainly comprise the C-1 carboxylic acid group, the C-9 ketone or hydroxyl group, the C-11 hydroxyl group and the lipophilic end of the bottom side chain. Such work is published in the following articles and patents: US Patents 4,011,262,

4,024,179, 3,971,826 , 3,932,38.9, 3,974,213, 3,054,741 and 3,98 7,08 7, Dutch patent application 7,306,030,

B.J. Mayerlein et al., Prostaglandins, A_ (1973) and W. Lipmann, Prostaglandins, 7, 231 (1974).

It has now surprisingly been found that an increase in the distance between the C-9 functionality and the acidic group in the top side chain when an amide group is attached results in a strong biological activity.

According to the invention, three classes C-1 amidotetrazole prostaglandins are produced which have clearly different profiles with regard to biological action. Class 1 comprises compounds of formula 1 which have antiulcer activity.

Formula 1

Class 2 includes compounds with formula 2 that have a fertility-regulating effect.

Formula 2

Class 3 comprises compounds of formula 3 which have broncho-dilatory or fertility-regulating action depending on the meaning of R and Z.

Formula 3

It will be seen that the structural difference between the classes is found in the meaning of the omega or bottom side chain. However, it is the combination of this functional group with the other important groups such as the amidotetrazole group, which causes the different biological effects that have been observed. Nevertheless, these three classes can be structurally combined in the general formula (4).

General formula 4

In each of the above formulas, the symbol A means cis-vinylene or ethylene, the symbol B means trans-vinylene or ethylene, the symbol Y means hydroxy or hydrogen, the symbol R means hydrogen or methyl, the symbol Z means hydrogen or methyl, the symbol Ar means phenyl, fluorophenyl, chlorophenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, biphenyl or trifluoromethylphenyl, and the symbol G means CH2Ar, CH2OAr.or CRZ(CH2)2CH3•

Particularly preferred compounds are the following:

Class 1, N-(tetrazol-5-yl)-9-oxo-11-a,15-a-bishydroxy-16-•phenyl-16-co-tetranor-5-cis-prosthenamide;

class 2, N-(tetrazol-5-yl)-9-oxo-11-a,15-a-bishydroxy-16-phenoxy-16-to-tetranor-13-trahs-prostenamide, and

class 3, N-(tetrazol-5-yl)-9-oxo-11-a,15-a-bishydroxy-5-cis-13-trans-prostadienamide.

In addition, compounds of the PGF type can be prepared corresponding to the three above classes and the pharmacologically acceptable salts, where the tetrazole group is neutralized.

According to the invention, each class of N-(tetrazole)-prostaglandin carboxamides is synthesized from a corresponding

class 11,15-bis-(hydroxyl-protected)- or 11-deoxy-15-(hydroxyl-protected) PGF compounds. This generic starting material has the same basic structure for all classes and includes any arrangement of bond type at the C5-C6 and C13-C14 positions with respect to elements A and B in the formulas

1, 2 and 3. In other words, it is the (11),15-hydroxyl-

protected PGF compound corresponding to the generic formula (4) above. Differentiation of the basic structure according to class is determined by the identity of the end of the base side chain in the respective starting materials. The starting material for class 1

thus has the substitution 16-aryl-16-co-tetranor on the above PGF basic structure; the source material for class 2 has

the substitution 16-aryloxy-16-to-tetranor; and the starting material for Class 3 has 15-n-pentyl, 2-hexyl or 2-methyl-2-hexyl substitution on the bottom side chain of the above PGF backbone. These structures are shown on plan 1 and are respectively Fl, F2 and F3.

The PGF output connections for each of the classes are known.

The characteristic data for the 11-hydroxy starting materials are described in US Patents 4,024,179, 3,887,589, 4,011,262 and 4,036,832, British Patent 1,324,737, B.J. Mayerlein et al, Prostaglandins, 4, 143 (1973) and E.J. Corey et al, J. Amer. Chem. Soc. 9_3'1491 (1971), and the characteristic data for the 11-deoxy starting materials are described in British Patent 1,419,181,

German Publication 2,548,267, P, Crabbe et al,

Tight. Easy. 1972, 1123 and W. Lipmann, Prostaglandins, 7, 231 (1974).

Transformation of starting materials into the new compounds

is illustrated in Scheme A. To convert a starting material into a compound belonging to a class of the new compounds, the C-1 carboxylic acid group is first converted to a C-1 N-(tetrazol-5-yl)-carboxamide group (step 1, scheme A). This N-(tetrazole)-carboxamide-PGF^ intermediate is then oxidized with Jones reagent to produce the corresponding PGE intermediate, which is released by removing the 15-mono- or 11,15-bis-hydroxyl protecting

(R<1>) groups (step 2.1, scheme A) for the preparation of a

N-(tetrazole)-carboxamide-prostaglandin with formula 1, 2 or 3. Alternatively, a compound of the PGF type corresponding to the PGE compound with formula 1, 2 or 3 can be prepared by simple cleavage of the C-II and/or C -15-hydroxyl protecting groups (R<1>) in the N-(tetrazole)-carboxamide intermediate.

Plan 1

Starting materials for the different classes

Fl, -starting material for class 1,. X is -COOH F2, starting material for class 2, X is -COOH

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

Form A

Step 1. Formation of the N-(tetrazol-5-yl)-carboxamide group.

Step 2.1. Oxidation with Jones reagent and THP cleavage.

1. Formula 1, starting material is Fl

2. Formula 2, starting material is F2

3. Formula 3, starting material is F3.

Step 2.2. Removal of the THP protecting group to produce PGF-type compounds.

1. PGF compound corresponding to formula 1, starting material is Fl

2. PGF compound corresponding to formula 2, starting material is F2

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

Reaction steps 2.1 and 2.2 which include removal of the protective groups for hydroxyl in the C-11 and/or C-15 position, and oxidation of the C-9 hydroxyl group to a C-9 oxo (ketone) group are common conversions and are well known in prostaglandin chemistry . Equivalent methods for C-9 hydroxylation and for C-11 and/or C-15 protection are also well known in the art and can be used here. Prostaglandin researchers have found that selective oxidation methods such as the Pfitzner-Moffett oxidation with dimethylsulfoxide and dicyclohexylcarbodiimide, and the Collins oxidation with chromium trioxide-pyridine complex in methylene chloride, can also be used for

to achieve oxidation of hydroxyl to ketone. They have also published the many methods and groups available for protection/liberation of the hydroxyl groups at positions C-11 and/or C-15 of a prostaglandin. Such protecting groups which are labile to mild agents are denoted by R<1>. The tetrahydropyranyl group is also indicated as the preferred group. Some other common protecting groups which are labile to -mild agents and which can be used according to the invention are dimethyl-t-butylsilyl which can be removed with tetra-n-butylammonium fluoride or aqueous acetic acid, and 1-methoxyethylene-1-yl which is analogous to tetrahydropyran-2-yl.

Step 1 is novel as it allows the preparation of a C-1 amide which has an acidic group as a substituent. The significance of this is the fact that it has previously been stated to be biologically critical that the distance between the C-1 acid group and the C-9 functionality does not vary, while the compounds produced according to the invention have extended this distance by the length of two of the atoms in the amide group. The N-(tetrazol-5-yl)-carboxamide group can be prepared from the carboxylic acid group by first forming a carboxylic acid derivative with an easily replaceable leaving group and then carrying out amidation with 5-amino-tetrazole (5-AT reagent). Any leaving group that can be attached to the prostaglandin intermediate (F1, F2, F3 plate 1) carboxyl group without destroying the rest of the molecule can be used in the preparation. Some typical leaving groups and reagents for the leaving groups used to prepare them include pivaloyloxy/pivaloyl halide which will form the mixed anhydride derivative, and ethoxyformyloxy/ethoxyformyl halide which will form the carbonate derivative. The preferred leaving group is imidazol-1-yl which forms an acyl imidazole intermediate. To prepare the N-(tetrazol-5-yl)-carboxamide group by first passing through an acylimidazole group, one first reacts the prostaglandin carboxylic acid starting material (F1, F2 or F3) with the reagent which forms the leaving group 1,1 -carbonyldiimidazole in a polar, aprotic solvent such as dimethylformamide, diethylformamide, acetonitrile, tetrahydrofuran or dimethylsulfoxide, to form in situ the acyl-imidazole intermediate. The imidazol-1-yl group attached to the C-1 carbonyl is then directly displaced with the 5-AT reagent to form the desired N-(tetrazol-5-yl)-carboxamide. A range of reaction temperatures can be used both to form and to cleave the acyl-imidazole compound. This range goes from ambient temperature to approx. 120°C, and it is appropriate to carry out the turnover at approx. 90°C or return temperature.

After formation of the N-(tetrazol-5-yl)-carboxamide group, reaction step 2.1 is carried out, whereby a compound of formula 1, 2 or 3 is produced, or reaction step 2.2 is carried out, whereby a compound of the PGF type is formed.

According to the invention, the N-(tetrazole)-prostaglandins in each class can alternatively be synthesized directly from a corresponding PGE or PGF compound with the formula

where A, Y, B and G are as indicated above, and M is oxo '.or

In this method, the PGE or PGF acid is reacted to form the N-(tetrazol-5-yl)-carboxamide group indicated in step 1 above, to produce directly an N-(tetrazol)prostaglandin carboxamide of formula 1, 2, 3 above or the corresponding PGF carboxamide. The method used is that stated in step 1, provided that if M is to be oxo, no basic reagent is used.

In numerous in vivo and in vitro investigations, it has been found that the three classes of prostaglandin compounds produced according to the invention exhibit very high selectivity. Their biological advantage is the reduction of many of the physiological activities of the natural prostaglandins, while they retain the activity in one "area. The studies that allow such a determination of selectivity include, among other things, a study for the effect on isolated smooth muscle from guinea pig uterus,

effect on blood pressure in dogs, inhibition of histamine-evoked

bronchial constriction in guinea pigs, inhibition of colds, stress-induced ulceration in rats, antisecretory effect in dogs and diarrhoea-inducing effect in mice.

After comparison with the reactions that are evoked

using natural prostaglandins in the same investigations, the physiological responses elicited by the three classes of experimental prostaglandins in these experiments are useful in determining their applicability in the treatment of natural and pathological adverse conditions. Based on such comparison, the prostaglandins of class 1 are useful as selective antiulcer agents, those of class 2 are useful as fertility regulating agents, those of class 3 where R is methyl or hydrogen and Z is hydrogen are useful as bronchodilators, and those of class 3 where both . R and Z are methyl, are useful as fertility regulating agents. Biological research observations for the class 1 prostaglandins show that they have a strong anti-ulcer effect,■ while they have a reduced hypotensive, uterine smooth muscle, diarrhoea-inducing and bronchodilator effect compared to the investigated natural prostaglandin, PGE2• The same type of observations show that the prostaglandins from class 3 where R is methyl or hydrogen and Z is hydrogen, exhibit strong bronchodilator action and reduced uterine smooth muscle, hypotensive, antiulcer and diarrhoea-inducing action. Likewise, the class 2 prostaglandins exhibit strong uterine smooth muscle activity and a reduction in such investigated activities as hypotensive activity, diarrhoea-inducing activity and bronchodilator activity.

The new prostaglandins from the three classes can be used

in a number of different pharmaceutical preparations containing the prostaglandin or its pharmaceutically acceptable salts. They can be administered, similarly to natural prostaglandins, by a number of different routes, such as intravenous, oral or topical including aerosol, intravaginal, intra- and extra-amniotic and intranasal. The selective effect of the special class of prostaglandins produced according to the invention and the desired application will of course determine the route of administration used. The appropriate routes before class 2 prostaglandins are e.g. intravenous, oral, intravaginal and intra- and extra-amniotic, while the appropriate routes for class 3 bronchodilator prostaglandins are aerosol, intranasal, oral and intravenous.

For pharmaceutical preparations containing the three

classes of prostaglandins are the useful pharmacologically acceptable salts of the acidic tetrazole moiety with pharmacologically acceptable metal cations, amine cations or quaternary ammonium cations.

Particularly preferred metal cations are alkali metal,

e.g. lithium, sodium and potassium, and alkaline earth metal, e.g. magnesium and calcium, although cationic forms of other metals, e.g. aluminium, zinc and iron can also be used.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, triethylamine, ethylamine, benzylamine, α-phenylethylamine, 3-phenylethylamine, as well as. heterocyclic amines, e.g. piperidine, morpholine, pyrrolidine and piperazine, as well as amines containing water-solubilizing or hydrophilic groups, e.g. mono-, di- and triethanolamine, ethyldiethanolamine, galactamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, etc.

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

The three classes of prostaglandins produced according to the invention can be used in a number of different pharmaceutical preparations containing the compound or a pharmacologically acceptable salt thereof, and they can be administered by several routes of administration as described above. Although the particular dose, preparation form and route of administration depend on the individual condition of each patient and the knowledge of the attending physician, the guidelines set out below for the three classes of prostaglandins produced according to the invention describe the usefulness of class 1 as anti-ulcer agents, class 2 as fertility regulating agents , class 3 where R is hydrogen or methyl and Z is hydrogen as bronchodilator agents, and class 3 where both R and Z are methyl as fertility regulating agents.

Class 1 prostaglandins are useful as anti-ulcer agents. For the treatment of peptic ulcers, these agents are suitably administered orally in the form of a-v aqueous suspensions, ethanol solutions or preferably in the form of capsules or tablets containing 0.001 to 0.10 mg/kg of prostaglandin per dose with up to 12 doses per day.

To induce abortion, the prostaglandins from class 2 and those from class 3 where both R and Z are methyl can be administered orally in suitably compounded tablets, aqueous suspensions or alcoholic solutions containing approx. 0.05-5 mg prostaglandin per dose, with 1-7 doses used per day. For intravaginal administration, a suitable preparation would be lactose tablets or an impregnated tampon containing approx. 0.1-10 mg prostaglandin per dose, using 1-7 doses. For intra-amniotic administration, a suitable preparation form will be an aqueous solution containing the prostaglandin in an amount of 0.05 to 5 mg per dose, with 1-7 doses being used. For extra-amniotic administration, a suitable preparation form would be an aqueous solution containing the prostaglandin in an amount of 0.01-1 mg/dose,

with 1-5 doses being used. Alternatively, the prostaglandins from class 2 and those from class 3 where both R and Z are methyl can be infused intravenously to induce abortion in doses of 0.05-50 ug prostaglandin per minute for a period of approx. 1-24 hours.

Another use for the class 2 prostaglandins

and from class 3 where both R and Z are methyl, are for inducing labour. For this purpose, an ethanol-saline solution of the prostaglandins is used for an intravenous infusion in an amount of from approx. 0.1-10 yg/kg/min of prostaglandin for approx. 1-24 hours.

Another use for the class 2 prostaglandins

and those from class 3, where both R and Z are methyl, are fertility regulation. For this purpose, a tablet is used for intravaginal or oral administration containing 0.1-10 mg of prostaglandin per dose, with 1-7 doses being used on or after the expected day of menstruation. For synchronization of the estrous cycle in pigs, sheep, cows or horses, a solution or suspension containing 0.3-30 mg/dose of the prostaglandin is administered subcutaneously or intramuscularly for 1-4 days.

The class 3 prostaglandins where R is hydrogen or methyl and Z is hydrogen are useful as bronchodilators and to increase nasal patency or clarity. A suitable dosage form for this treatment is a solution of the prostaglandin in aqueous ethanol or t-butanol --.or a suspension thereof used as an aerosol, using an inert gas as a propellant, using an amount of prostaglandin of approx. 5-500 yg/dose.

For the preparation of any of the above dosage forms or any of all the others

■possible forms, different reaction-inert diluents, auxiliaries or carriers can be used. Such substances include e.g. water, ethanol, gelatin>lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol and other known carriers for pharmaceuticals. Optionally, these pharmaceutical preparations may contain additional substances such as preservatives, wetting agents, stabilizing agents or other therapeutic agents such as antibiotics.

The following examples shall serve to further illustrate the invention, but shall not be construed as limiting. The infrared spectral data were obtained on a Perkin-Elmer Grating Infrared Spectrometer and are given in microns. The nuclear magnetic resonance spectral data was obtained on a Varian HA-60 spectrometer and is 6 ppm. Melting points are uncorrected and are in °C. Thin-layer chromatographic measurements were obtained on silica gel and are given as R^ values.

When the reaction temperatures in the examples are not further specified, this generally means ambient or room temperature, which varies from 15 to 30°C.

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

A.E. Schwarting, R.J. Gritter, Van Nostrand-Renhold, N.Y. 1968]. In general, the reaction was considered nearly complete when the TLC spot representing the critical starting material disappeared or ceased to change appearance.

Example 1

N-(tetrazol-5-yl)-9-g-hydroxy-lI-q,15-a-bis-(tetrahydropyran-■ 2-yloxy)-5-cis-l3-trans-prostadienamide ( 1)

To a solution of 415 mg (0.795 mmol) of 9-α-hydroxy-11-α,15-α-bis-(tetrahydropyran-2-yloxy)-5-cis-13-trans-prostadioic acid (SM) in 10 ml of dry dimethylformamide was added 134 mg (0.825 mmol) of 1,1-carbonyldiimidazole. The solution was heated under nitrogen at 95° for 4 hours, and then 70 mg (0.825 mol) of anhydrous 5-amino-tetrazole was added. The solution was heated under nitrogen for 1.5 hours at 95° and then concentrated by rotary evaporation to give the crude title compound (1) as a viscous oil weighing 823 mg. Its NMR spectrum (CDCl 3 ) showed the following characteristic absorptions (at 6 ppm):

5.65-5.24 (multiplet) - olefinic

4.81-4.62 (multiplet

1.92 (triplet, j = 4 eps) - CH3

Example 2

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

A solution of 200 mg of crude N-(tetrazol-5-yl)-9-α-hydroxy-11-α,15-α-bis-(tetrahydropyran-2-yloxy)-5-cis-13-trans-prostadienamide ( 1) in 10 ml of a 65-35 mixture of acetic acid-water was stirred at room temperature for 18 hours under nitrogen and then concentrated by rotary evaporation. Benzene was added and removed by rotary evaporation (3x). Purification of the crude residue by silica gel column chromatography during use

of a mixture of chloroform and ethyl acetate as eluent gave the title compound (2) which weighed 6 mg and melted at 16 8-172°

(after recrystallization from ethanol-ether) .

TLC Rff was 0.26 (3:2, chloroform:methanol).

Example 3

N-(tetrazol-5-yl)-9-oxo-ll-a,15-a-bis-(tetrahydropyran-2-yloxy)-5-cis-13-trans-prostadienamide ( 3)

To a solution, cooled to -20°, of 623 mg (1.06 mmol) of N-(tetrazol-5-yl)-9-α-hydroxy-11-α,15-α-bis-(tetrahydropyran-2- yloxy)-5-cis-13-trans-prostadienamide (1) in 15 ml of acetone was added 0.38 ml of Jones reagent. The mixture was stirred for 20 minutes and then cooled by the addition of 0.38 ml of isopropyl alcohol. The mixture was stirred for 5 minutes and then diluted with ethyl acetate (25 mL), washed with water (3x5 mL) and brine (5 mL), dried (magnesium sulfate) and concentrated to give the title compound (3) as a viscous oil with a weight of 295 mg. TLC Rff was 0.48 (9:1, methylene chloride:methanol).

Example 4

N-(tetrazol-5-yl)-9-oxo-ll-a,15-a-dihydroxy-5-cis-l3-trans-prostadienamide (4)

A solution of 295 mg of crude N-(tetrazol-5-yl)-9-oxo-11-α,15-α-bis-(tetrahydropyran-2-yloxy)-5-cis-13-trans-prostadienamide (3 ) in 30 ml of a 65:35 mixture of acetic acid-water was stirred at room temperature under nitrogen for 18 hours. The solution was concentrated by rotary evaporation, and benzene was added, and the solution was concentrated (3x). Purification of the residue by silica gel column chromatography using mixtures of chloroform and ethyl acetate as eluents gave the title compound (4) with a weight of 22 mg and a melting point of 16 2 °.

Its IR spectrum (KBr) showed the following characteristic absorptions (in microns):

5.71 (ketone)

5.87

(amide)

6.12

10.33 (trans olefin)

Example 5

The following additional compounds were prepared using the procedures described in Examples 1 to 4

and using the appropriate starting PGF carboxylic acid in place of the compound (SM) of Example 1.

5A. N-(tetrazol-5-yl)-9-oxo-11-α,15-α-dihydroxy-13-trans-prostenamide, m.p. - fixed. NMR (CD₂OD) (in 6 ppm): 5.76, 5.44 (multiplet) trans-ole fin, 1.88 (triplet, j= 4cps) CH3-5B. N-(tetrazol-5-yl)-9-oxo-11-α,15-α-dihydroxy-5-cis-16-phenyl-16-to-tetranorprostenamide. Sm.p. 75-78°

NMR (CD 3 OD) (in 6 ppm): 7.08 (singlet) 5.43-5.17 (multiplet) cis-olefin.

5C. N-(tetrazol-5-yl)-9-oxo-11-α,15-α-dihydroxy-13-trans-16-phenyl-16-α)-tetranorprostenamide. Sm.p. 149-150°.

IR (KBr) (in microns): 5.67 (ketone), 5.83 and 6.10 (amide), 10.28 (trans-olefin).

5D. N-(tetrazol-5-yl)-9-a,ll-a,15-a-trihydroxy-5-cis-13-trans-16-phenoxy-16-o>-tetranorprostadienamide, Sm.p . 87-90°

IR (KBr) (in microns): 5.97 and 6.25 (amide), 10.35 (trans-olefin).

5E. N-(tetrazol-5-yl)-9-oxo-11-α,15-α-dihydroxy-5-cis-• 13-trans-16-phenoxy-16-co-tetranor-prostadienamide. Sm.p. 105-107° IR (KBr) (in microns): 5.68 (ketone, 5.85 and 6.10 (amide), 10.28 (trans-olefin).

The synthesis of the compounds in Examples 1 to 5 shows that the 11-hydroxyprostaglandins of classes 1, 2 and 3 and the corresponding PGF-type compounds can be synthesized using the chemical methods described in Examples 1 to 4 by using the appropriate 11 ,15-bis-(tetrahydropyran-2-yl)-PGF2, 13,14-dihydro-PGF2, PGF-j^or PGFQwhere the substituent

at the C-16 position is phenyl or substituted phenyl for the preparation of class 1, phenoxy or substituted phenoxy for the preparation of class 2, and n-butyl or both methyl and n-butyl for the preparation of class 3, instead of the PGF intermediate designated (SM ) in example 1, the substituents on said phenyl and phenoxy groups being fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, phenyl and trifluoromethyl.

Example 6

N-(tetrazol-5-yl)-9-g-hydroxyl-15-g-(tetrahydropyran-2-yloxy)-16-phenoxy-16-co-tetranor-13-trans-prostenamide ( 6 )

To a solution of 0.795 mmol of 9-α-hydroxy-15-α-(tetrahydropyran-2-yloxy)-16-phenoxy-16-co-tetranor-13-trans-prostenic acid (DSM) in 10 ml of dry dimethylformamide is added 134 mg (0.825 mmol). 1,1-Carbonyldiimidazole. The solution is heated under nitrogen at 95° for 4 hours, and then 70 mg (0.825 mmol) of anhydrous 5-amino-tetrazole is added. The solution is heated under nitrogen for 1.5 hours at 95° and can then be concentrated by rotary evaporation to give the crude title compound (6).

Example 7

N-(tetrazol-5-yl')-9-g-15-a'-dihydroxy-16-phenoxy-16-io-tetranor-13-trans-prosteriamide (7)

A solution of 200 mg of crude N-(tetrazol-5-yl)-9-a-hydroxy-15-a-(tetrahydropyr.ran-2-yloxy)-16-phenoxy-16-w-tetranor-13-trans- prostenamide (6) in 10 ml of a 65-35 mixture of acetic acid:water is stirred at room temperature for 18 hours under nitrogen and then concentrated by rotary evaporation.

Benzene is added and removed by rotary evaporation (3x). Purification of the crude residue by silica gel column chromatography using a mixture of chloroform and ethyl acetate as eluents can be carried out to purify the title compound (7).

Example 8

N-(tetrazol-5-yl)-9-oxo-15-a-(tetrahydropyran-2-yloxy)-16-phenoxy-16-(io-t.etranor-13-trans-prosthenamide ( 8)

To a solution, cooled to -20°, of 1.06 mmol of N-(tetrazol-5-yl)-9-α-hydroxy-15-α-(tetrahydropyral-2-yloxy)-16-phenoxy-16- oj-tetranor-13-trans-prostenamide (6) in 15 ml of acetone add 0.38 ml of Jones reagent. The mixture is stirred for approx. 20 minutes and then cooled by adding 0.38 ml of isopropyl alcohol. The mixture is stirred for 5 minutes and then diluted with ethyl acetate (25 mL), washed with water (3x5 mL) and brine (5 mL), dried (magnesium sulfate) and concentrated to give the title compound

Example 9

N-(tetrazol-5-yl)-9-oxo-15-α-hydroxy-16-phehoxy-16-to-tetranor-13-trans-prostenamide (9)

A solution of 295 mg of crude N-(tetrazol-5-yl)-9-α-hydroxy-15-α-(tetrahydropyran-2-yloxy)-16-phenoxy-16-co-tetranor-13-trans-prostenamide ( 3) in 30 ml of a 65:35 mixture of acetic acid-water is stirred at room temperature under nitrogen for 18 hours. The solution is concentrated by rotary evaporation, and benzene is then added and removed in the same manner (3x). Purification of the residue by silica gel column chromatography using chloroform-ethyl acetate mixtures. as eluents, gives the title compound (9).

Synthesis of the compounds of Examples 6 to 9 shows that the 11-deoxy-prostaglandins of classes 1, 2 and 3 and the corresponding PGF-type compounds can be synthesized using the chemical methods described in Examples' 6 to 9 using the appropriate 11-desoxy-15-tetrahydropyran-2-yl-PGF2, 13,14-dihydro-PGF2,' PGF1 or PGF the starting material where the substituent in the C-16 position is phenyl or substituted phenyl for the preparation of class 1, phenoxy or substituted phenoxy for the preparation of class 2 and n-butyl or both methyl and n-butyl to produce class 3, instead of the PGF intermediate designated (DSM) in example 6, the substituents in the substituted phenyl and phenoxy groups being fluorine, chlorine, methyl, ethyl , methoxy, ethoxy, phenyl and trifluoromethyl.

Example- 10

N-(tetrazol-5-yl)-9-a-hydroxy-lla-a,15-a-bis-(tetrahydropyran-2-yloxy)-16,16-dimethyl-5-cis-13-trans-prostadienamide ( 10)

To a solution of 0.795 mmol of 9-α-hydroxy-11-α,15-α-bis-(tetrahydropyran-2-yloxy)-16,16-drmethyl-5-cis-13-trans-prostadioic acid (RSM) in 10 ml of dry dimethylformamide is added 134 mg (0.825 mmol) 1,1-carbonyldiimidazole. The solution is heated under nitrogen at 95° for 4 hours, and then 70 mg (0.825 mmol) of anhydrous 5-aminotetrazole is added. The solution is heated under nitrogen for 1.5 hours at 95° and then concentrated by rotary evaporation to give the crude title compound (10) as a viscous oil.

Example 11

N-( tetrazole- 5- y1- 9- a, 11- g, 15- a- trihydroxy- 16, 16- dimethyl- 5- cis-13- trans- prostatienamide ( 11)

A solution of 200 mg of crude N-(tetrazol-5-yl)-9-α-hydroxy-11-α, 15-α-bis-(tetrahydropyran-2-yloxy)-16,16-dimethyl-5-cis- 13-trans-prostadienamide (10) in 10 ml of a 65-35 mixture of acetic acid:water is stirred at room temperature for 18 hours under nitrogen and then concentrated by rotary evaporation. Benzene is added and removed by rotary evaporation (3x). Purification of the crude residue by silica gel column chromatography using a mixture of chloroform and ethyl acetate as eluent can be carried out to obtain the title compound (11).

Example 12

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

To a solution, cooled to -20°, of 623 mg

(1.06 mmol) N-(tetrazol-5-yl)-9-α-hydroxy-11-α,15-α-bis-(tetrahydropyran-2-yloxy)-16,16-dimethyl-5-cis -13-trans-prostadienamide (10) in 15 ml of acetone is added 0.38 ml of Jones reagent. The mixture is stirred for approx. 20 minutes and then cooled by adding 0.38 ml of isopropyl alcohol. The mixture is stirred for 5 minutes and then diluted with ethyl acetate (25 mL), washed with water (3 x 5 mL) and brine (5 mL), dried (magnesium sulfate) and concentrated to give the title compound (12).

Example 13

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

A solution of 295 mg of crude N-(tetrazol-5-yl)-9-oxo-11-α,15-α-bis-(tetrahydropyran-2-yloxy)-16,16-dimethyl-5-cis-13- trans-prostadienamide (12) in 30 ml of a 65:35 mixture of acetic acid-vahn is stirred at room temperature under nitrogen for 18 hours. The solution is concentrated by rotary evaporation, and benzene is added and concentrated (3x). Purification of the residue by silica gel column chromatography using mixtures of chloroform and ethyl acetate as eluents can be carried out to obtain the title compound (13).

The synthesis of the compounds according to examples 10 to 13 shows that the new 11-hydroxy- or 11-deoxy-16,16-dimethyl-prostaglandins and the corresponding compounds of the PGF type can be synthesized using the chemical methods described in examples 10 to 13 by using the appropriate 11,15-bis-(tetrahydropyran-2-yl)- or 11-deoxy-15-(tetrahydro-pyran-2-yl)-16,16-dimethyl-PGF2, 13,14-dihydro- PGF2, PGF1 or PGFQ instead of the PGF intermediate designated (RSM) in Example 10.

Claims (4)

1. Process for preparing a compound of formula I: and pharmacologically acceptable salts thereof, where A is ethylene or cis-vinylene, B is ethylene or trans-vinylene, Y is hydrogen or hydroxy, G is CH2 Ar, CH~2OAr or CRZ(CH2 )3 CH3 , Ar is phenyl, fluorophenyl, chlorophenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, biphenyl or trifluoromethylphenyl, R is hydrogen or methyl, and Z is hydrogen or methyl, characterized in that (a) an intermediate of formula (II) where A, B and G are as above, L is H or OR', and R<1> is a protecting group which is labile to a mild agent, reacts with a mild agent, or (b) an intermediate of formula ( III) where A, B and G are as above, reacted with a reagent containing a leaving group to form a carboxylic acid group derivative with an easily replaceable leaving group, followed by replacement of the leaving group with 5-amino-tetrazole, and optionally the compound prepared according to (a) or (b) is reacted with a pharmacologically acceptable metal base, amine, ammonia or quaternary amine base to form a pharmacologically acceptable salt of a compound of formula I. 2. Method as stated in claim la, characterized in that R' is tetrahydropyran-2-yl, dimethyl-t-butylsilyl or 1-methoxyethylene-1-yl, and the mild agent is aqueous acetic acid. 3. Method as stated in claim 1b, characterized in that the reagent containing the leaving group is pivaloyl halide, ethoxyformyl halide or 1,1-carbonyldiimidazole. 4. Method as stated in claim 1b, characterized in that the reagent containing the leaving group is 1,1-carbonyl-diimidazole, and the reaction is carried out in a polar, aprotic solvent at a temperature from ambient temperature to 120°C.