NO143663B - ANALOGUE PROCEDURE FOR PREPARING A PHYSIOLOGY ACTIVE PROSTAGLAND CONNECTION OF THE E OR F SERIES - Google Patents

Description

The present invention relates to the production of certain

new analogues of naturally occurring prostaglandins of the E or F series.

Prostaglandins are C-20 unsaturated fatty acids that have

various physiological effects. E.g. prostaglandins of the E and A series are powerful vasodilators (BergstrSm et al.,

Acta Physiol. Scand. 64:332-33, 1965 and Bergstrom et al.,

Life Sei. 6:449-455, 1967) and lowers systemic arterial blood pressure (vasodepression) by intravenous administration (Weeks and King,

Federation Pro. 23:327, 1964; Berstrom et al., 1965, op. one.;

Carlson et al., Acta Med. Scand. 183: 423-430, 1968, and Carlson

et al., Acta Physiol. Scand. 75:161-169, 1969).

Another well-known physiological action of PGE 2 and PGE 2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969).

A further important physiological effect of the natural prostaglandins is in connection with the reproductive cycle. PGE.,

is known to have the ability to induce labor (Karim, et al.,

J. Obstet, Gynaec. Brit. Cwlth. 77:200-210, 1970) and induce therapeutic abortion (Bygdema.n et al., Contraception, A, 293 (1971)

and to be useful for regulating fertility (Karim, Contraception,

3<_>, 173 (1971) ) . Patents have been obtained for a number of prosta-

glandins of the E and F series as agents for inducing labor in mammals (Belgian patent 754,158 and West German patent 2,034,641),

and in the case of PGF-^, F2 and F^ for regulation of the reproductive cycle (South African patent 69/6089). It has been shown that luteolysis can occur as a result of the administration of PGF2a [Labhsetwar, Nature 230, 528 (1971)] and that prostaglandins

thus are applicable for fertility regulation in the event of a progress

way where the stimulation of the smooth muscles is not necessary.

Another known physiological effect of PGE^ is the inhibition of gastric acid secretion (Shaw and Ramwell, in:

Worcester Symp. on Prostaglandins, New York, Wiley> 196 8,

pp. 55-64) and of the plate agglomeration (Emmons, et al., Brit. Med.

J. 2:468-472, 1967).

It is known that such physiological effects can

is produced in vivo only for a short time after the administration of a prostaglandin. An extensive material indicates that the reason

to the rapid cessation of action is that the natural prostaglandins are rapidly and efficiently deactivated metabolically by ?-oxidation in the carboxylic acid side chain and by oxidation of the 15a-hydroxyl group (Anggard, et al., Acta Physiol. Scand., 81, 396 (1971) and references indicated therein). It has been shown that the introduction of a 15-alkyl group into prostaglandins has the effect of increasing the duration of action by preventing oxidation at the C15-hydroxyl [Yankee and Bundy, JACS, 94, 3651 (1972)], Kirton

and Forbes, Prostaglandins, 1, 319 (1972).

It was thus desirable to produce analogues of prostaglandins which would have physiological effects which were equivalent to the natural compounds, but where the selective effect and duration effect were increased. Increasing duration of action is expected to mitigate the serious side effects, especially gastrointestinal side effects, which are often followed by systemic administration of natural prostaglandins (Lancet, 536, 1971).

According to the invention, an analogous process for the production of a physiologically active prostaglandin compound of the E or F series is provided with the formula:

or the C^-epimer thereof, where

A is 1-adamantyl, 2-(1,2,3,4-tetrahydronaphthyl) which is racemic or optically active. 2-indanyl or 2-(5,6-dimethoxyindanyl);

n is 0, 1 or 2;

W is a cis double bond,

Z is a trans double bond,

M is oxo or

X is 5-tetrazolyl, a group of the formula -C00R', where R' is hydrogen or alkyl of from 1 to 10 carbon atoms, aralkyl of from 7 to 9 carbon atoms, p-biphenyl or cycloalkyl of from 3 to 8 carbon atoms, or a group of the formula -C0NHR", where R" is alkylsulfohyl with from 1 to 7 carbon atoms,

and the lower alkanoyl, formyl or benzoyl esters of any

free hydroxyl groups in the cg~/ c^\~ 0(? C^^ positions,

or a pharmaceutically acceptable salt of a compound of formula (I) wherein X is -COOH. The procedure is characterized by

(a) a compound of the formula:

wherein A, n, M, R, w, X and Z are as defined above, and THP is 2-tetrahydropyranyl, is reacted with an appropriate acid; (b) a compound of formula (I) above wherein M is oxo is reacted with a suitable reducing agent to form a compound of formula (I) wherein M is and optionally the compound of formula (I) wherein X is -COOH is converted to an ester or a substituted amide, as defined above, by reaction with a suitable esterifying or amidating agent, respectively; and optionally the 9a-, 11a- and 15a-lower alkanoyl-, -formyl- or -benzoyl esters of any free hydroxyl groups are prepared by reacting the compound of formula (I) with a suitable acylating agent;

and optionally a pharmaceutically acceptable salt of a compound of formula (I) where X is -COOH is prepared.

Preferred prostaglandins produced according to the invention are as follows: Compounds of formula I where the prostaglandins are of the E series, compounds of formula I where the prostaglandins are of the Fa~ series, compounds of formula I where the prostaglandins are of the Fp series, compounds of formula I where n is 0, compounds

of formula I where n is 1, compounds of formula I where n is 2, compounds of formula I where n is 0 and the prostaglandin is of the E series, compounds of formula I where n is 0 and the prostaglandin is of the F series, compounds of formula I where n is 1 and the prostaglandin is of the E series, compounds of formula I where

n is 1 and the prostaglandin is of the F series, compounds of formula I where n is 2 and the prostaglandin is of the E series, compounds of formula I where n is 2 and the prostaglandin is of

The F series, compounds of formula I wherein A is 1-adamantyl, compounds of formula I wherein A is 2-indanyl, compounds of formula I wherein A is 2-(5,6-dimethoxy-indanyl), a compound of formula I wherein W is a cis double bond and Z is a trans double bond, a compound of formula I wherein A is 2-indanyl,

n is 0 and the prostaglandin is PGE2, a compound of formula I wherein A is 2-indanyl, n is 0 and the prostaglandin is PGF2a, a compound of formula I wherein A is 2-(5,6-dimethoxy-indanyl), n is 0 and the prostaglandin is PGE2, a compound of formula I wherein A is 2-(5,6-dimethoxy-indanyl), n is 0 and the prostaglandin is PGF2q/ a compound of formula I wherein A is 1-adamantyl, n is 2 and the prostaglandin is PGE2, and a compound of formula I wherein A is 1-adamantyl, n is 2 and the prostaglandin is PGF2a, a compound of formula I wherein A is 2-indanyl, n is 0, the prostaglandin is PGF2q, X is 5-tetrazolyl and R is hydrogen, a compound of formula I where A is 2-indanyl, n is 0, the prostaglandin is PGF2a,

X is -CONHR", R" is methylsulfonyl, and R is hydrogen, a compound of formula I wherein A is 2-indanyl, n is 0, the prostaglandin is PGE2, X is selected from the second subgroup, and R is hydrogen, a compound of formula I wherein A is 2-indanyl, n is 0, the prostaglandin is PGE2, X is -CONHR", R" is methylsulfonyl and R is hydrogen,

a compound of formula I wherein A is 2-(1,2,3,4-tetrahydronaphthy1), X is 5-tetrazolyl, R is hydrogen, the prostaglandin is PGF2q and n is 0, a compound of formula I wherein A is 2- (1,2,3,4-tetrahydronaphthyl), X is -CONHR", R" is methylsulfonyl, n is 0, R is hydrogen and

the prostaglandin is PGF2q, a compound of formula I wherein X is -CO0R', 15-(2-indanyl)-w-pentanor-prostaglandin-E2, 15-(2-indanyl)-w-pentanor-prostaglandin-F2a, 15-[2 -(5,6-dimethoxy-indanyl)]-w-pentanorprostaglandin-E2, 15-[2-(5,6-dimethoxy-indanyl)]-w-pentanorprostaglandin-F2a and 17-(1-adamantyl)-cu- trinorprosta-glandin-F2a.

New intermediate products with the following formulas can be used for the production of the starting materials for the method:

A connection with the formula

where R is hydrogen, and Q is hydrogen or p-phenylbenzoyl, and Ar Z and n are as indicated above;

a connection with the formula

a compound of the formula where THP is tetrahydropyranyl, n is 0, 1 or 2, Z is a trans double bond and X' is =0 or a compound of the form: len: a compound of the formula:

where A has the above meaning.

The following new intermediates are used in the process according to the invention:

Connections with the formula:

and CQ and C.c epimers thereof, where R is hydrogen,

THP is 2-tetrahydropyranyl, and

A, W, Z, X and n are as indicated above for formula I.

Those skilled in the art will understand that in the structures indicating hemiacetals, no stereochemistry is indicated for the lactol carbon.

The prostaglandins produced by the method according to the invention, e.g. PGE2 and PGF^^ i are prostaglandins of the "two series". The term prostaglandin shall also be understood to include both epimers at . The term "lower alkyl group" means alkyl groups which

contains 1-4 carbon atoms.

The starting material used in the steps leading to the preparation of the new compounds of formula I are available commercially or can be prepared according to known methods. For the production of dimethyl-2-oxo-2-(2-indanyl)ethylphosphonate, which is the starting material for the synthesis of 15-(2-indanyl)-prostaglandins, a solution of dimethylmethylphosphonate in tetrahydrofuran is cooled to -78°C in dry nitrogen atmosphere and then slowly, dropwise adds n-butyllithium in hexane. After stirring, ethyl indan-2-carboxylate is added dropwise. After 3 to 4 hours at -78°C, the reaction mixture is warmed to ambient temperature, neutralized with acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in water, the aqueous phase is extracted into chloroform and the combined organic extracts are backwashed, dried and concentrated to give the desired product.

For the production of the desired 15-substituted-a)-pentanor-prostaglandins, the suitable acids as described below are transferred to esters according to usual methods and then to phosphonates as stated above for the 15-(2-indanyl) starting material.

For the production of 15-(2-(+)-(1,2,3,4-tetrahydronfatyl))-prostaglandins, (+)-2-(1,2,3,4-naphthalene)carboxylic acid is prepared according to the method of Cohen et al., J. Biol. Chem., 10, 2664 (1969), transfers to the ester and then to the phosphonate as described for the 15-(2-indanyl) compound.

For the preparation of 15-(2-(-)-(1,2,3,4-tetrahydronaphthyl))-prostaglandins, (-)-2-(1,2,3,4-naphthalene)carboxylic acid is prepared according to the method of Cohen et al., J. Biol. Chem., 10, 2664 (1969), is transferred to the ester and then to the phosphonate as described for the 15-(2-indanyl) compound.

If one wishes to produce 15-(2-indanyl)-prostaglandins, indane-2-carboxylic acid is produced, e.g. according to the method of Bergman and Hoffman, J. Org. Chem., 26_, 3555 (1961), transfers it to the ester and then to the phosphonate as described above.

For the preparation of 16-(2-indanyl)-prostaglandins, 2-indanyl-acetic acid is prepared as described by Berman and Hoffman, J. Org. Chem., 26^, 3555 (1961), transfers it to the ester and then to the phosphonate as described for the 15-(2-indanyl) compound.

For the preparation of 15-(2-(5,6-dimethoxyindanyl)-prostaglandins, the necessary 5,6-dimethoxyindan-2-carboxylic acid must be prepared. Condensation of 4,5-bis-chloromethylveratrol

(prepared as described by Wood, Perry and Tung, J. Am. Chem. Soc., 72, 2989 (1950)) with ethyl t-butyl malinate in the presence of sodium hydride gives 2-carboethoxy-2-carbo-t- butoxy-5,6-dimethoxyindane. Treatment of this diester with p-toluenesulfonic acid in benzene

under reflux followed by decarboxylating distillation of the product, gives ethyl 5,6-dimethoxyindan-2-carboxylate, which is transferred to the phosphonate as described for the 15-(2-indanyl) compound.

For the production of 16-(1-adamantyl)-prostaglandins, (1-adamantyl)-acetic acid is produced from Aldrich Chem. Co.

(No. 12, 727-2) is transferred to the ester and then to the phosphonate as for the 15-(2-indanyl) compound.

For the preparation of 17-(1-adamantyl)-prostaglandins, 3-(1-adamantyl)-propionic acid is prepared according to the method of Fieser et al., J. Med. Chem. 10, 517 (1967), is transferred to the ester and then to the phosphonate as described for the 15-(2-indanyl) compound.

For the preparation of 15-(2-(I)-(1,2,3,4-tetrahydronaphthyl))-prostaglandins, (I)-2-(1,2,3,4-naphthalene)carboxylic acid is prepared according to the method of Cohen et al., J. Biol. Chem. 10, 2664 (1969), is transferred to the ester and then to the phosphonate as described for the 15-(2-indanyl) compound.

The following reaction scheme A illustrates the production of intermediate products which are used for the production of the subsequent starting materials for the method according to the invention.

As shown in Scheme A, the first step (1-»2) is the condensation of the appropriate ester with a dialkylmethylphosphonate to give oxophosphonate 2. Typically, the desired methylester is condensed with dimethylmethylphosphonate.

In 2 ■» 3 the oxophosphonate 2 is reacted with the known [Corey, et al., J. Am. Chem. Soc., 93, 1491 (1971)] the aldehyde H and one obtains, after chromatography or crystallization, the enone 3_. The compound in which the p-biphenylcarbonyl group is replaced by a p-biphenyl-carbamoyl protecting group is also usable as a substituent for H and also has the advantage that in the reduction step (3 -» 4) a higher percentage of the desired a- isomer.

The enone _3 can be reduced with zinc borohydride or with a lithium trialkylborohydride, such as lithium triethylborohydride to a mixture of the alcohols 4_ and 5_, which can be separated by column chromatography. In this reaction, ethers such as tetrahydrofuran or 1,2-dimethoxyethane can be used as solvents, although it is sometimes preferred to use methanol to ensure a specific reduction. Additional transfers of 4_ are shown in Scheme B.

4 ■) 6 is a base-catalyzed hydrolysis where the p-biphenyl-carbonyl protecting group is removed. This is conveniently carried out with potassium carbonate in methanol or methanol-tetrahydrofuran solvent. 6_ -> 1_ comprises the protection of the two free hydroxyl groups with an acid-labile protecting group. Any sufficiently acid-labile group is satisfactory, the most common, however, being tetrahydropyranyl, which can be introduced into the molecule by treatment with dihydropyran and an acid catalyst in an anhydrous medium. The catalyst is usually p-toluenesulfonic acid. e

7 -» 8 is a reduction of the lactone 1_ to the hemiacetal 8^ using diisobutylaluminum hydride in an inert solvent. It is preferred to use low reaction temperatures and -60° to -70°C is common. However, higher temperatures can be used if an over-reduction is not obtained. 81 is cleaned, if desired, by using column chromatography. 8 -» 9 is a Wittig condensation where hemiacetal j3 is reacted with, e.g. (4-Carbohydroxy-n-butyl)triphenylphosphonium bromide in dimethylsulfoxide, in the presence of sodium methylsulfinyl methide. 9_ cleaned as above.

The transfer 9_ -* 12_ is an acid hydrolysis of tetrahydro-pyranyl groups. Any acid can be used which does not destroy the molecule during the removal of the protecting group; however, this is often carried out using 65% aqueous acetic acid. The product is cleaned as above. 2. ** A9- is an oxidation of the secondary alcohol 9 to the ketone 10. This can be achieved by using an oxidizing agent that does not attack the double bonds, but Jones's reagent is usually preferred. The product is cleaned as above. 10 -» 11^ are performed in the same way as 9 -» lj2. The product is cleaned as above. The reduction of compound 11 with sodium borohydride gives the 93 isomer of the prostaglandin analogues of the F series, i.e. the PGFOQ compounds. These can also be obtained via sodium borohydride reduction of 10 followed by hydrolysis as described above for 10 -» 11.

As illustrated in Scheme C, compound 5_ can be used in place of compound 4_ in Scheme B to form prostaglandin derivatives 12_' and 11_'.

The new esters of formula I can be prepared in a number of different ways. These differ from each other in that the esterifying group is attached to the prostaglandin or its precursor in different stages of the synthesis.

E.g. Scheme F shows three different routes to the ester "E".

In each case, the esterifying group is introduced by an esterification reaction which can be carried out by bringing the appropriate

prostaglandin analogue or its precursor in contact with the alcohol or phenol in the presence of a catalyst. Alternatively, the prostaglandin or its precursor can be treated with a diazoalkane or cycloalkane in reaction-inert solvents to give the desired ester. A prostaglandin analogue can be used as a substrate for the above esterification reactions and further precursors to such prostaglandins or prostaglandin analogues can also be used as illustrated in Scheme F. For example. 9 can be transferred to 9E by the esterification reaction as indicated above and 9_E can then be transferred to 10E and 12E by the same methods used to transfer £ to 10 and 12 as previously discussed. The compound 10E can be transferred to 11E by reactions described for the transfer of 10 to 11.

The prostaglandin analogues of formula I and their esters which are acylated at and C15 can be easily prepared from the corresponding starting compounds by acylation, and this is usually carried out by using carboxylic acid anhydride or carboxylic acid chloride as acylating agents. For the preparation of the formyloxy derivatives, the mixed anhydrides are used (e.g. formic acid-acetic anhydride). The Cg, C^ and C^ acyloxy-prostaglandin analogues and their esters are prepared in the same manner as for the desired PGF precursors.

Various modifications are possible on the top side chain of the prostaglandins according to the present invention.

A 5-tetrazolyl group can be placed in the C^ position. E.g. the compound 8 can be reacted with the ylide which is prepared from (4-(tetrazol-5-yl)-n-butyl)-triphenylphosphonium bromide and sodium methylsulfinyl methide to give the C 1 -tetrazole-substituted compound 3_. The transfer of 9_ to the corresponding prostaglandins occurs as indicated above.

Another modification of the top side chain can be made in the prostaglandins of formula I by replacing the carboxylate group at the C₁ position with a carboximide or carboxysulfonamide group. E.g. compound 8 can be reacted with the ylide obtained from (methanesulfonylaminocarbonyl-n-butyl)triphenylphosphonium bromide and sodium methylsulfinyl methide to give C1-N-methanesulfonylcarboxamide-substituted compound £. The transfer of 9_ to the corresponding prostaglandins occurs as indicated above. Alternatively, the new compounds of formula I wherein X is COHNR" and where

R" is, as previously stated, produced, for example, from the compounds

9 and 10 in Scheme B by reaction with suitable acyl or sulfonyl isocyanates, followed by hydrolysis with dilute acid.

In the foregoing methods, where it is desired to purify by means of chromatography, suitable chromatographic supports are neutral alumina, silica gel and .fluoracil. The chromatography is suitably carried out in reaction-inert solvents such as .ether, ., ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane, ....... n-hexane and methanol.

It will be seen that the previously stated formulas produce optically active compounds. It is clear, however, that the corresponding racemates will possess valuable biological action on account of the content of the biologically active optical isomer indicated above, and such racemates are covered by the preceding formulas. The racemic mixtures are easily prepared according to the same methods used to synthesize the optically active precursors by using the corresponding racemic precursors instead of the optically active starting materials.

In numerous in vi<y>o and in vi tro tests we have demonstrated

that the new prostaglandin analogues of formula I have selective physiological effects comparable to those exhibited by the natural prostaglandins. These . tests, include, among other things, a test on the effect on isolated smooth muscle from guinea pig uterus, guinea pig ileum and rat uterus, stimulation of diarrhea in mice, inhibition of histamine-induced bronchospasm in guinea pigs, effect on blood pressure in dogs, inhibition of stress-induced ulceration in rat, inhibition of gastric acid secretion in rats and dogs, inhibition of lipolysis, antiarrhythmic effect, cardiac stimulating effect, inhibition of collagen or ADP-induced platelet agglomeration and aborticidal effect on rats and guinea pigs by luteolytic and non-luteolytic mechanisms.

The physiological responses observed in these tests. are useful in determining the utility of the test substance in the treatment of various natural and pathological conditions. Such proven uses include: antihypertensive action, bronchodilator action, antithrombogenic action. anti-ulcer action, smooth muscle action - (useful as an anti-fertility agent 1, to induce labor and as an aborticide), and anti-fertility action via a mechanism that does not affect smooth muscle, e.g. luteolytic mechanisms, and the synchronization of the estrous cycle in livestock.

The new compounds of formula I have more selective action profiles than the corresponding naturally occurring prostaglandins and are in many cases more powerful and show a longer lasting effect. E.g. shows 15-(2-indanyl)-uj-pentanor-prostaglandin-F2a guinea pig uterine smooth muscle-stimulating activity comparable to PGF2Q, has only 8% guinea pig stimulatory activity, and is at least 30 times more potent than <p>GF2a when applies aborticidal effect in rats.

The various modifications of the upper side-

the chain of the prostaglandins of formula I, as a rule, does not change the essential biological effect, although they may further increase the selectivity and the duration of the effect and reduce the toxicity.

Particularly useful for fertility regulation, abortion and induction of labor are 15-(2-indanyl)-w-pentanorprostaglandins, 15-(1,2,3,4-tetrahydronaphthyl)-w-pentanorprostaglandins, 15-(2-(5,6 -dimethylindanyl))-w-pentanorprostaglandins, 17-(1-adamantyl)-u)-trisnorprostaglandin and 16-(1-adamantyl)-w-tetranor-prostaglandins of the and F2a~series based on strong stimulatory action of smooth muscle, and aborticidal effect on rats and at the same time reduced blood pressure and diarrheal effects. The new prostaglandins with an 0-OH in the 15-position are usually less potent, although they are often more selective than the corresponding α-hydroxyl pimers. Also, prostaglandins having an α-hydroxyl at C-15 are valuable intermediates for prostaglandins having an α-hydroxyl at C-15 via a recycling process involving an oxidation and a reduction at C-15. The new prostaglandin analogs of formula I have useful antifertility properties and are also useful for synchronizing the estrus cycle in animals.

The new compounds of formula I can be used in a variety of pharmaceutical preparations containing the compound and they can be administered in the same way as natural prostaglandins in a variety of ways, such as intravenously, intramuscularly, subcutaneously, orally, intravaginally, intra- and extra-amniotically etc.

For induction of abortion, suitable tablets, an aqueous suspension or alcoholic solution of a 15-substituted-w-pentanorprostaglandin such as 15-(2-indanyl)-co-pentanor-prostaglandin are administered in oral doses of 0.1-20 mg, and 1-7 doses per day.

For intravaginal administration, a suitable formulation would be lactose tablets or an impregnated tampon of the same agent. For such treatments, suitable doses will be from approx. 0.1-20 mg/dose and 1-7 doses are used. For intra-amniotic administration, a suitable formulation is an aqueous solution containing 0.05-10 mg/dose and 1-7 doses are used.

For extra-amniotic administration, a suitable formulation is an aqueous solution containing 0.005-1 mg/dose and 1-5 doses are used. Alternatively, 15-substituted-teu-pentanor-prostaglandins according to the present invention can be administered intravenously for inducing abortion, in doses of 0.05-50 pg/min.

in a period of from approx. 1-24 hours. For synchronizing the estrus cycle in pigs, sheep, cows or horses, a solution or suspension containing 0.03-30 mg/day of 15-substituted-cj-pentanorprostaglandin is administered subcutaneously from 1-4 days.

For the production of the dosage forms indicated above

or other possible forms, various reaction-initiated diluents, excipients and carriers can be used. Such substances include e.g. water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols,

gums, polyalkylene glycols, petroleum jelly, cholesterol and other known carriers for drugs. If desired, these pharmaceutical preparations can contain additional compounds such as preservatives, wetting agents, stabilizing agents and other therapeutic agents such as antibiotics.

The following examples illustrate the preparation of the intermediate products and the actual method according to the invention. In these examples, all temperatures are given in °C, all melting points and boiling points are uncorrected.

Example 1

pimethyl- 2- oxo- 2-( 2- indanyl) ethyl phosphonate:

A solution of 20.4 g (164 mmol) of dimethyl methylphosphonate (Aldrich) in 200 ml of dry tetrahydrofuran was cooled to -78° in

dry nitrogen atmosphere. To the stirred phosphonate solution, 82.6 ml of 2.25 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) was added dropwise over the course of 20 minutes at such a rate that the reaction temperature did not exceed approx. -65°. After a further 5 minutes of stirring at -78°, was added dropwise

14.0 g (73.5 mmol) methylene-2-carboxylate at such a rate that the reaction temperature was kept lower than -70

(20 minutes). After 1.0 hour at -78°, the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 ml of water, the aqueous phase was extracted with 75 ml portions of methylene chloride (4x),

the combined organic extracts were backwashed (75 mL H 2 O), dried (MgSO 4 ) and concentrated (water aspirator) to a crude residue and distilled, b.p. 150-160° (0.1 mm), yielding 17.0 g (86.4%) dimethyl-2-oxo-2-(2-indanyl)ethylphosphonate.

Nuclear magnetic resonance spectrum (CDCl^) of the distilled product showed a singlet at 7.15 6 for aromatic protons,

a doublet at 3.76 6 (J = 11 eps) for OCH^, a singlet at 3.25 6 for benzylic protons, a doublet at 3.18 6 (J = 23 eps) for PCH_2 and a deformed triplet at 3, 13 6 (J = 2 eps) for

CHCO.

Example 2

2-[ 3a- p- phenylbenzoyloxy- 5a- hydroxy- 2p-( 3- oxo- 3-( 2- indanyl)- trans- 1- propen- l- yl)- cyclopent- la- yl] acetic acid, y- lactone :

To a solution, cooled in ice under nitrogen, of 17.2 ml

(32.6 mmol) of a 1.90 M solution of n-butyllithium in hexane in 150 ml of dry 1,2-dimethoxyethylene was added dropwise 9.2 g (34.5 mmol) of dimethyl-2-oxo-2-( 2-indanyl)ethylphosphonate. The solution was stirred cold for 10 minutes and then 11.9 g (33.5 mmol) of the known 2-[3α-phenylbenzoyloxy-5α-hydroxy-23-formyl-cyclopent-la-yl]acetic acid, γ-lactone was added . The ice bath was removed; the mixture was stirred for 1.0 h and then quenched by the addition of glacial acetic acid (pH ~ 5). The mixture was concentrated and the resulting mixture was dissolved in methylene chloride (300 mL).

The organic layer was washed with water (100 mL), saturated sodium bicarbonate (50 mL), saturated brine (50 mL), was dried (anhydrous magnesium sulfate) and was concentrated to a half-

solid. Recrystallization of the crude product from isopropyl alcohol:methylene chloride gave the desired 2-[3α-p-phenylbenzoyloxy-5α-hydroxy-20-(3-oxo-3-(2-indanyl)-trans-1-propen-1-yl) -cyclopent-la-yl]acetic acid, 6-lactone as white feathers melting at 170-172°, weight 6.85 g (42.8%).

Infrared spectrum (CHC1,) of the product showed absorptions

-1 -1

at 1775 cm for lactone carbonyl, at 1710 cm for ester-

carbonyl, 1670 and 1625 cm^ for ketone carbonyl and at 975 cm^

for trans double bond.

Example 3

2-( 3a- p- phenylbenzoyloxy- 5a- hydroxy- 2g-( 3a- hydroxy- 3-( 2- indanyl)- trans- l- propen- l- yl) cyclopent- la- yl) acetic acid, y~ lactone and 2-(3a-p-phenylbenzoyloxy-5a-hydroxy-3-(2-indanyl)-)-trans-1-propen-l- yl)cyclopent- layl)acetic acid, ylactone

To a solution of 6.73 g (14.0 mmol) of 2-(3α-p-phenylbenzoyloxy-5α-hydroxy-2 3-(3-oxo-3-(2-indanyl)-trans-1-propene-1 -yl) cyclopent-la-yl) acetic acid, γ-lactone in 67 ml of dry tetrahydrofuran in a dry nitrogen atmosphere at ambient temperature was added dropwise to 14.0 ml of a 0.5 M zinc borohydride solution.

After stirring at room temperature for 1.5 hours, a saturated sodium bitartrate solution was added dropwise to 14.0 ml of a 0.5M zinc borohydride solution. After stirring at room temperature for 1.5 hours, a saturated sodium bitartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 minutes and 150 ml of dry methylene chloride was added. After drying (MgSO 4 ) and concentration (water aspirator), the resulting semi-solid material was purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh) using ethyl acetate:ether mixtures as eluents. After elution of less polar impurities, a fraction containing 2.21 g (32.8% yield) of 2-(3a-phenylbenzoyloxy-5a-hydroxy-2(3-(3a-hydroxy-3-(2-indanyl) -trans-l-propen-l-yl) cyclopent-la-yl) acetic acid, γ-lactone and a fraction containing 1.79 g (26.6% yield) 2-(3a-p-phenylbenzoyloxy-5a-hydroxy -23-(33-hydroxy-3-(2-indanyl)-trans-1-propen-yl)-cyclopent-la-yl)acetic acid, lactone.

Infrared spectrum (CHC1,) of both products had

-1 -1

strong adsorption at 1770 cm (lactone carbonyl) and 1705 cm (ester carbonyl) and a medium adsorption at 970 cm 1 (trans-olefin).

Example 4 2-[3a,5a-dihydroxy-2g-(3a-hydroxy-3-(2-indanyl)-trans-l-propen-l-yl)cyclopent-la-yl]acetic acid, γ-lactone: A heterogeneous mixture of 2.21 g (4.46 mmol) of 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-23-(3a-hydroxy-3-(2-indanyl)-trans-l-propen-l-yl) cyclopent-la-yl]acetic acid, Y-lactone, 40 ml of dry tetrahydrofuran, 40 ml of absolute methanol and 0.61 g of finely powdered anhydrous potassium carbonate were stirred at room temperature for 1 hour and then cooled to 0°. To the cooled solution was added 4.46 ml of a 1.0N aqueous hydrochloric acid. After stirring at 0° for a further 10 minutes, 75 ml of water were added with simultaneous formation of methyl-p-phenylbenzoate which was collected by filtration. The filtrate was concentrated by rotary evaporation and then extracted with ethyl acetate (3x), the combined organic extracts were dried (MgSO 4 ) and concentrated to give 924 mg (66%) of a viscous oily 2-t3a,5a-dihydroxy-2B-( 3α-hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-la-yl]-acetic acid, γ-lactone. Infrared spectrum (CHC10) showed a strong adsorption at -1 -1 1770 cm for lactone carbonyl and a medium adsorption at 970.cm for trans double bond.

Example 5

2-[5o-hydroxy-3a-(tetrahydropyran-2-yloxy)-23-(3g-tetrahydropyran-2-yloxy]-3-(2-indanyl)-trans-1-propen-1-yl) cyclopent- la - yl]-acetic acid, y- lactone

To a solution of 0.924 g (2.94 mmol) of 2-[3α,5α-dihydroxy-23-(3α-hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-la- yl]-acetic acid, γ-lactone in 49 ml of anhydrous methylene chloride and 0.86 ml of 2,3-dihydropyran at 0° in a dry nitrogen atmosphere were added a few crystals of p-toluenesulfonic acid, monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 mL of ether, the ether solution was washed with saturated sodium bicarbonate (1 x 15 mL), then brine (1 x 15 mL), dried (MgSO 4 ) and concentrated to give 1.38 g (97.8%) crude 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-23-(3a-[tetrahydropyran-2-yloxy]-3-(2-indanyl)-trans-1-propene -1-yl)cyclopent-la-yl]acetic acid,

γ-lactone which was used without purification.

Infrared spectrum (CHCl,) of the product showed a strong

-1

adsorption at 1755 cm for the lactone carbonyl and a medium absorption at 965 cm 1 for the trans double bond.

Example 6 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-23-(3α-[tetrahydropyran-2-yloxy]-3-(2-indanyl)-trans-1-propen-1-yl) cyclopent-la-yl3-acetaldehyde, Y~ hemiacetal: A solution of 1.39 g (2.9 mmol) of 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-23-(3a-[tetrahydropyran- 2-yloxy]-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-la-yl]acetic acid, Y-lactone in 20 ml of dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution was added dropwise 4.2 ml of 20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics) at such a rate that the internal temperature did not exceed -65° (15 minutes). After a further 30 minutes of stirring at -78°, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature and was concentrated by rotary evaporation. The resulting oil was suspended in methanol and then filtered to remove aluminum salts. Concentration of the filtrate gives the crude product which was purified by silica gel (Baker "Analyzed" 60-200 mesh) column chromatography using mixtures of benzene:ethyl acetate as eluents. After the removal of less polar impurities, the desired 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-23-(3α-[tetrahydropyran-2-yloxy]-3-(2-indanyl)-trans- l-propen-l-yl)-cyclopent-la-yl acetaldehyde, Y-hemiacetal as a viscous oil, weight 1.17 g (84.3%). Infrared spectrum (CHC1,) of the purified product showed ^1 a medium absorption at 975 cm for the trans double bond and no carbonyl absorption. Example 7 9ahydroxy-lla, 15a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-(j- pentanorprostadic acid: To a solution of 3.21 g (7, 24 mmol) of (4-carbohydroxy-n-butyl)triphenylphosphonium bromide under a dry nitrogen atmosphere in 6.0 mL of dry dimethyl sulfoxide was added 6.96 mL (14.0 mmol) of a 2.01 M solution of sodium methylsulfinyl methide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 1.16 g (2.41 mmol) 2-[5a-hydroxy-3ct-(tetrahydropyran-2-yloxy)-26-(3a-[tetrahydropyran-2-yloxy]-3-(- 2-indanyl)-trans-l-propen-l-yl)-cyclopent-la-yl]acetaldehyde, γ-hemiacetal in 2.0 mL of dry dimethylsulfoxide over 20 min. After further stirring for 2 h at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was acidified to pH ~ 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3x) and the combined organic extracts washed with water (2x), dried (MgSO 4 ) and because then mpet to a fixed residue. This solid residue was triturated with ether and filtered. The filtrate was concentrated, yielding 1.99 g (>100%) of 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-u -pentanor-prostadienic acid which was used without purification.

Infrared spectrum (CHCl^) of the purified product showed a

-1 J

strong absorption at 1710 cm for acid carbonyl and a medium absorption at 970 cm ^ for trans double bond.

Example 8

9a, lia, 15a- trihydroxy- 15-( 2- indanyl)- cis- 5- trans- 13- co-pentanor-prostadioic acid

A solution of 602 mg of 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-Gis-5-trans-13-β-pentanor-prostadioic acid in 10 ml of a 65 :35 mixture of glacial acetic acid:water was stirred under nitrogen at room temperature for 18 hours and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7 100-22 mesh) using chloroform:ethyl acetate mixtures as eluents. After elution of less polar impurities, 9a,11a,15a-trihydroxy-15-(2-indanyl)-cis-5-trans-13-o-trinorprostadic acid was collected as a white solid, weight 156 mg (39%) and which melts at 114-115° (from ethyl acetate).

Infrared spectrum (KBr) of the product showed a strong absorption at 5.77 µ for the acid carbonyl and a medium absorption at 10.25 µ for the trans double bond.

Example 9

9- oxo-llp, 15a~ bis-( tetrahydropyran-2- yloxy)- 15-( 2- indanyl)-cis-5- trans- 1 3-( o- pentanorprostadic acid

To a solution cooled to -10° under nitrogen of 1.32 g (2.34 mmol) of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis -5-trans-13-a)-pentanorprostadioic acid in 15 ml of analytical grade acetone was added dropwise to 1.17 ml of Jones reagent. After 15 min at -10°, 1.17 mL of 2-propanol was added and the reaction mixture was stirred for a further 5 min and then combined with ethyl acetate, washed with water (2x), dried (MgSO 4 ) and concentrated to give 1.11 g (84.2%) of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-u-pentanorprostadioic acid which was used without purification.

Example 10

9-oxc-lia, 15a-dihydroxy-15-(2-indanyl)-cis-5-trans-13-co-pentanoprostadic acid;

A solution of 1.11 g of 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-u-pentanorprostadioic acid

in 15 ml of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at room temperature for 18 hours and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) using chloroform:ethyl acetate mixtures as eluents. After elution of less polar impurities, 9-oxo-11a,15a-dihydroxy-15-(2-indanyl)-cis-5-trans-13-u-pentanorprostadic acid was collected as a white solid, weight 288 mg (37% ) and which melts at 110-112° (from ethyl acetate:hexane).

Infrared spectrum (KBr) of the product showed strong absorptions at 5.68 u for the ketone carbonyl and at 5.84 u for the acid carbonyl and a medium absorption at 10.25 u for the trans double bond.

Example 11 p-biphenyl-9-oxolla, 15a-dihydroxy-15-(2-indanyl)-cis-5-trans-13-co-pentanor-prostadienoate: To a mixture of 60 mg (0.15 mmol) 9-oxo-lla,15a-dihydroxy-15-(2-indanyl)-cis-5-trans-13-u-pentanorprostadic acid and 255 mg (1.5 mmol) of p-phenylphenol in 6 ml of dry methylene chloride were added 1, 65 ml of a 0.1M solution of dicyclohexylcarbodiimide in methylene chloride. The mixture was stirred at room temperature for 16 hours under nitrogen and then concentrated. The solid residue was purified by silica gel (Baker "Analyzed" 60-200 mesh) chromatography using chloroform:ethyl acetate mixtures as eluents. After the removal of less polar impurities, p-biphenyl-9-oxo-lla,15a-dihydroxy-15-(2-indanyl)-cis-5-trans-13-w-pentanorprostadienoate was obtained, weight 43 mg

and sm.p. 103-104.5° (from methylene chloride:hexane).

Infrared spectrum (KBr) of the product showed strong adsorptions at 5.65 y for ketone carbonyl and 5.70 y for ester carbonyl and a medium absorption at 10.35 y for trans double bond.

Example 12

p- biphenyl- 9- oxola, 15B- dihydroxy- 15-( 2- indanyl)- cis- 5- trans-13-( j- pentanor- prostadienoate

To a mixture of 60 mg (0.15 mmol) of 9-oxo-lla,153-dihydroxy-15-(2-indanyl)-cis-5-trans-13-u-pentanorprostadienoate and 255 mg (1.5 mmol) p-phenylphenol in 6 ml of dry methylene chloride was added to 1.65 ml of a 0.1 M solution of dicyclohexylcarbodiimide in methylene chloride. The mixture was stirred for 16 hours at room temperature under nitrogen and then concentrated. The purification of the solid residue using silica gel (Baker "Analyzed"

60-200 mesh) chromatography using mixtures of chloroform: ethyl acetate as eluent. After the removal of less polar impurities, the solid p-biphenyl-9-oxo-lla,153-dihydroxy-15-(2-indanyl)-cis-5-trans-13-co-pentanoirprostadienoate was obtained, weight 34 mg and sm. p. 98-100° (from methylene chloride:hexane).

Infrared spectrum (KBr) of the product showed strong absorptions at 5.66 y for the ketone carbonyl and 5.77 y for the ester carbonyl and a medium absorption at 10.35 y for the trans double bond.

Example 13

p- biphenyl- 9a, lia, 15a- trihydroxy- 15-( 2- indanyl)- cis- 5- trans- 13-co- pentanorprostadienoate: To a mixture of 60 mg (0.15 mmol) 9a, lia, 15a- trihydroxy-15-(2-indanyl)-cis-5-trans-13-co-pentanorprostadienoate and 255 mg (1.5 mmol) of p-phenylphenol in 6 ml of dry methylene chloride were added to 1.65 ml of a 0.1 M solution of dicyclohexylcarbodiimide in methylene chloride. The mixture was stirred for 16 hours at room temperature under nitrogen and then concentrated. The solid residue was purified by silica gel (Baker "Analyzed" 60-200 mesh) chromatography using chloroform:ethyl acetate mixtures as eluents. After the removal of less polar impurities, the solid p-biphenyl-9a,11a,15a-trihydroxy-15-(2-indanyl)-cis-5-trans-13-u-pentanorprostadienoate was obtained, weight 41 mg and melting at 134- 135° (from methylene chloride:hexane).

Infrared spectrum (KBr) of the product showed a strong absorption at 5.6 8 y for the ester carbonyl and a medium absorption at 10.35 y for the trans double bond.

Example 14

p- biphenyl- 9a, lla, 153- trihydroxy- 15-( 2- indanyl)- cis- 5- trans- 13-( j- pentanorprostadienoate: To a mixture of 60 mg (0.15 mmol) 9a, lia, 15a -trihydroxy-15-(2-indanyl)-cis-5-trans-13-co-pentanorprostadienoate and 255 mg (1.5 mmol) of p-phenylphenol in 6 ml of dry methylene chloride were added

1.65 ml of 0.1M solution of dicyclohexylcarbodiimide in methylene chloride. The mixture was stirred for 16 hours at room temperature under nitrogen and then concentrated. The solid residue was purified by silica gel (Baker "Analyzed" 60-200 mesh) chromatography using chloroform:ethyl acetate mixtures as eluents. After the removal of less polar impurities, the solid p-biphenyl-9a,11a,15a-trihydroxy-15-(2-indanyl)-cis-5-trans-13-co-pentanorprostadienoate was obtained, weight 40 mg and melting at 98- 100° (from methylene chloride:hexane).

Infrared spectrum (KBr) of the product showed a strong absorption at 5.65 y for the ester carbonyl and a medium absorption at 10.20 y for the trans double bond.

Example 15

2- carbethoxy- 2- carbo- t- butoxy- 5, 6- dimethoxyindan

To a suspension, stirred under nitrogen, of 12.9 g

(306 mmol) of a 57% sodium hydride suspension in 280 ml of dry tetrahydrofuran was added dropwise to 28.8 g (153 mmol) of ethyl t-butyl malonate. After the addition was complete, the solution was stirred for another 20 minutes and then 2.49 g was added

(15 mmol) of potassium iodide followed by a solution of 36.0 g

(153 mmol) of 1,2-dimethoxy-4,5-bis-chloromethylbenzene in 180 mL of dry tetrahydrofuran. The mixture was heated under reflux for 2.5 hours, then cooled, and concentrated by rotary evaporation. The resulting suspension was dissolved in methylene chloride (300 mL), washed with water (2 x 100 mL), dried (anhydrous magnesium sulfate), and concentrated to give the desired crystalline 2-carboethoxy-2-carbo-t-butoxy -5,6-dimethoxyindane,

weight 46.2 g (86.2%) and melts at 70-73° (from ether).

Infrared spectrum (KBr) of the recrystallized product

showed a strong absorption at 5.77 y for carbonyl groups.

Example 16

2- carboxy- 5, 6- dimethoxyindan- 2- carboxylic acid:

A solution of 46.2 g (132 mmol) of 2-carboethoxy-2-carbo-t-butoxy-5,6-dimethoxyindane and 2.25 g (13.2 mmol) of p-toluenesulfonic acid monohydrate in 460 ml of benzene was heated under reflux using a Deans-Stark trap for 4 hours. The solution was cooled, washed with water (3 x 50 mL), dried (anhydrous magnesium sulfate)

and was concentrated, giving the desired crystalline 2-carboethoxy-5,6-dimethoxyindan-2-carboxylic acid, weight 38.9 g (100%) and melting at 146-148° (from ethyl acetate-cyclohexane).

Infrared spectrum (KBr) of the recrystallized product

showed strong absorptions at 5.77 y for ester carbonyl and 5.67 y for acid carbonyl.

Example 17

Ethyl-5,6-dimethoxyindan-2-carboxylate:

A 46.8 g (159 mmol) portion of 2-carboethoxy-5,6-dimethoxy-indan-2-carboxylic acid was heated (oil bath 200-210°)

under reduced pressure (oil pump). The desired ethyl 5,6-dimethoxyindan-2-carboxylate was collected by distillation,

weight 29.6 g (74.6%); k.p. 170-176° at 1.0 mm, m.p. 46-48°.

Infrared spectrum (KBr) of the product showed a strong absorption at 5.75 y for ester carbonyl.

Example 13

N-methanesulfonyl-9α-hydroxyl-lla, 15α-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-d)- pentanorprostadienamide: To a solution of 2.37 g (4.56 mmol) of (methanesulfonylamino-carbonyl-n-butyl)-triphenylphosphonium bromide in a dry nitrogen atmosphere in 5.0 ml of dry dimethylsulfoxide was added to 4.50 ml (8.62 mmol)

of a 1.90M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of

735 mg (1.52 mmol) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2B-(3a-1 tetrahydropyran-2-yloxy]-3-(2-indanyl)-trans-1- propen-l-yl) cyclopent-la-yl] acetaldehyde, Y-hemiacetal in 6.0 ml of dry dimethylsulfoxide. After a further 1 hour of stirring at room temperature, the reaction mixture was poured onto ice water.

The basic aqueous solution was acidified to pH ~ 3 with

10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3x) and the combined organic extracts were washed once with water (10 mL), dried (MgSO 4 ) and evaporated to a solid residue. The crude product was purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh) using mixtures

of chloroform:ethyl acetate as eluents. After the removal of high R^ impurities, 899 mg (81.5%) of N-methanesulfonyl-9a-hydroxy-lla,15a-bis-(tetrahydropyran-2-yloxy)-15-( 2-indanyl)-cis-5-trans-13-co-pentanorprostadienamide.

Infrared spectrum (CHC1,) of the product showed medium absorptions at 1710 cm for carbonyl group and at 970 cm for trans double bond.

The treatment of the above hemiacetal with the ylide from (4-(tetrazol-5-yl)-n-butyl)-triphenylphosphonium bromide gives a product which can be converted to 2-decarboxy-2-(tetrazol-5-yl)-prostaglandins as described in the examples 19-21.

Example 19

N- methanesulfonyl- 9a, 11a, 15a— trihydroxy- 15-( 2- indanyl)- cis- 5-trans- 13- o- pentanorprostadienamide: A solution of 500 mg of N-methanesulfonyl-9a-hydroxy-lla, 15a-bis -(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-u-pentanorprostadienamide in 10 ml of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at room temperature for 18 hours and was then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC7 100-200 mesh) using chloroform:ethyl acetate mixtures as eluents. After elution of less polar impurities, N-methanesulfonyl-9a,11a,15a-trihydroxy-15-(2-indanyl)-cis-5-trans-13-u-pentanorprostadienamide was collected as a viscous oil, weight 257 mg (69, 6%).

Infrared spectrum (CHC1,) of the product showed a strong absorption at 1705 cm -1 for the carbonyl group and a medium absorption at 965 cm for the trans double bond.

Example 20

H- methanesulfonyl- 9- oxola, 15a- bis-( tetrahydropyran-2- yloxy)- 15-( 2- indanyl)- cis- 5- trans- 13- oj- pentanorprostadienamide:

To a solution, cooled to -10° under nitrogen, av

399 mg (0.62 mmol) N-methanesulfonyl-9a-hydroxy-11a,15a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-cj-pentanorprostadienamide in 15 ml of analytical grade acetone was added dropwise to 0.31 ml of Jones reagent. After 15 minutes at

-10° was added 0.31 mL of 2-propanol and the reaction mixture was stirred for an additional 5 minutes and was then combined with ethyl acetate, washed with water (2x), dried (MgSO4 ) and concentrated to give 371 n<j (93 %). N-methanesulfonyl-9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-6)-pentanorprostadienamide which was used without purification.

Example 21

N-methanesulfonyl-9-oxola, 15α-dihydroxy-15-(2-ind;yl)-cis-5-trans-13-cj- pentanorprostadienamide: A solution of 371 mg of N-methanesulfonyl-9-oxola . room temperature for 16 hours and was then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7 100-200 mesh) using chloroform:ethyl acetate mixtures as eluents. After elution of less polar impurities, N-methanesulfonyl-9-oxo-11a,15adihydroxy-15-(2-indanyl)-cis-5-trans-13-w-pentanorprostadienamide was collected as a viscous oil, weight 65 mg (23, 8%).

Infrared spectrum (CHC1_) of the product showed strong

-1 -1 absorptions at 1740 cm for ketone carbonyl, 1720 cm for sulfonimide carbonyl, and at 970 cm 1 for trans double bond.

Example 22.

Dimethyl- 2- oxc— 3-( 2- indanyl) propylphosphonate:

A solution of 20.4 g (164 mmol) of dimethyl methylphosphonate (Aldrich) in 200 ml of dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution, 82.6 ml of 2.25 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) was added dropwise over 20 minutes at such a rate that the reaction temperature did not exceed -65°. After a further 5 minutes of stirring at -78°, 14.0 g (73.5 mmol) of methyl-(2-indanyl)acetate were added dropwise at such a rate that the reaction temperature is kept lower than -70° (20 minutes). After 1.0 hour at -78°, the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 ml water, the aqueous phase was extracted with 75 ml portions of methylene chloride (4x), the combined organic extracts were backwashed (75 ml H 2 O), dried (MgSO 4 ) and concentrated (water aspirator) to a impure residue and distilled, dimethyl 2-oxo-3-(2-indanyl)propylphosphonate.

The product from this reaction is the starting material for the synthesis of 16-(2-indanyl)-o>-tetranorprostaglandins of the E or F series via the methods in examples 2-10, 18-21, 26

and 35.

Example 2 3

Dimethyl- 2- oxo- 2-( 2-( 1, 2, 3, 4- tetrahydronaphthyl) ethylphosphonate:

A solution of 20.4 g (164 mmol) of dimethyl methylphosphonate (Aldrich) in 200 ml of dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution, 82.6 ml of 2.25 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) was added dropwise over 20 minutes at such a rate that the reaction temperature did not rise above -65°. After a further 5 minutes of stirring at -78°, 14.0 g were added dropwise

(73.5 mmol) methyl 2-(1,2,3,4-tetrahydronaphthylcarboxylate) at such a rate that the reaction temperature was less than -70°

(20 minutes). After 1.0 hour at -78°, the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml of acetic acid and rotary evaporated to a white gel. The

gelatinase material was taken up in 50 mL water, the aqueous phase was extracted with 75 mL portions of methylene chloride (4x), the combined organic extracts were backwashed (75 mL H 2 O), dried (MgSO 4 ), and concentrated (water aspirator) to an impure residue and distilled to give dimethyl 2-oxo-2-(2-(1,2,3,4-tetrahydronaphthyl))ethylphosphonate.

The reaction product is the starting material for the synthesis of 15-(2-(1,2,3,4-tetrahydronaphthyl))-to-tetranorprostaglandins of the E or F series via the methods in examples 2-10, 18-21, 26 and 35.

Example 24

Dimethyl- 2- oxo- 2-( 2-( R- 1, 2, 3, 4- tetrahydronaphthyl)) ethylphosphonate:

A solution of 20.4 g (164 mmol) of dimethyl methylphosphonate (Aldrich) in 200 ml of dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution, 82.6 ml of 2.25 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) is added dropwise over 20 minutes at such a rate

that the reaction temperature does not rise above -65°. After a further 5 minutes of stirring at -78°, 14.0 g were added dropwise

(73.5 mmol) methyl 2-(R-1,2,3,4-tetrahydronaphthylcarboxylate)

at such a rate that the reaction temperature was kept below -70°

(20 minutes). After 1.0 hour at -78°, the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml of acetic acid and rotary evaporated to a white gel. The

gelatinous material was taken up in 50 mL water, the aqueous phase was extracted with 75 mL portions of methylene chloride (4x), the combined organic extracts were backwashed (75 mL H 2 O), dried (MgSO 4 ) and concentrated (water aspirator) to a crude residue which was purified by column chromatography to give dimethyl-2-oxo-2-(2-(R-1,2,3,4-tetrahydronaphthyl))ethylphosphonate.

The reaction product is the starting material for the synthesis

of 15-(2-(R-1,2,3,4-tetrahydronaphthyl))--tetranorprostaglandins of the É or F series via the procedures in Examples 2-10, 18-21, 26 and 35.

Example 25

Dimethyl-2-oxo-2-(2-(S-1,2,3,4-tetrahydronaphthyl))ethylphosphonate:

A solution of 20.4 g (164 mmol) of dimethyl methylphosphonate (Aldrich) in 200 ml of dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution, 82.6 ml of 2.25 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) is added dropwise over 20 minutes at such a rate

that the reaction temperature does not exceed -65°. After further stirring for 5 minutes at -78°, 14.0 g (73.5 mmol) methyl-2-(S-1,2,3,4-tetrahydronaphthyl) is added dropwise at such a rate that the reaction temperature is kept lower than -70° ( 20 minutes).

After 1.0 hour at -78°, the reaction mixture is allowed to warm to ambient temperature, neutralized with 20 ml of acetic acid and rotary evaporator to a white gel. The gelatinous material is taken up in 50 ml water, the aqueous phase is extracted with 75 ml portions of methylene chloride (4x), the combined organic extracts are backwashed (75 ml H 2 O), dried (MgSO 4 ) and concentrated (water aspirator) to an impure residue which is purified by column chromatography,

and dimethyl-2-oxo-2-(2-(S-1,2,3,4-tetrahydro-naphthyl))ethylphosphonate is obtained.

The reaction product is the starting material for the synthesis of 15-(2-(S-1,2,3,4-tetrahydronaphthyl))-w-tetranorprostaglandins of the E or F series via the methods in examples 2-10, 18-21. 26 and 35.

Example 2 6

16- ( 1- adamantyl)- u>tetranorprostaqlandin- F2ø

To a solution, under ice-cooled nitrogen, of 100 mg (0.233 mmol) of 16-(1-adamantyl)-ui-tetranorprostaglandin-E2 in 10 ml of absolute methanol was added an ice-cooled solution of 300 mg of sodium borohydride in methanol. The solution was cooled at 0°C

20 minutes and then at room temperature for 1.0 hour.

The solution was added to 2.0 ml of water and the methanol was removed by rotary evaporation. The resulting aqueous solution was layered with ethyl acetate (10 mL), acidified by addition of 10% hydrochloric acid and extracted with ethyl acetate (4x5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (anhydrous magnesium sulfate)

and was concentrated. Purification of the crude residue by silica gel chromatography using mixtures of methylene chloride:methanol as eluent gave 16-(1-adamantyl)-^tetranorprostaglandin-F2Q (49 mg) and 16-(1-adamantyl)-CA>-tetranorprostaglandin- F2i3 (39 mg).

The other prostaglandin F^ analogs

of formula I are prepared in a similar manner from the suitable E precursors.

Example 27

17- ( 1- adamantyl) - u>- trisnorprostaglandin- F2p:

To a solution, under nitrogen cooled in ice, of 100 mg

(0.225 mmol) of 17-(1-adamantyl)-u>-trisnorprostaglandin-E2 in 10 ml of absolute methanol was added to an ice-cooled solution of 300 mg

sodium borohydride in methanol. The solution was stirred at 0° i

20 minutes and then at room temperature for 1.0 hour.

The solution was added to 2.0 ml of water and the methanol was removed by rotary evaporation. The resulting aqueous solution was triturated with ethyl acetate (10 mL), acidified by the addition of 10% hydrochloric acid and extracted with ethyl acetate (4x5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (anhydrous magnesium sulfate)

and was concentrated. The purification of the crude residue by means of silica gel chromatography using mixtures of methylene chloride:

methanol as eluent gave 17-(1-adamantyl)-u-»-trisnorprostaglandin-

F2a (28 mg) and 17-(1-adamantyl)-^'-trisnorprostaglandin-F,^ (28 mg).

The other prostaglandin F^ analogs

of formula I are prepared in a similar manner from the corresponding ones

The e-precursors.

Example 28

Cvklooktyl- 9Q!, 11 a . 15a- trihydroxy- 17-( 1- adamantyl) - 5- cis- 13-trans- o^- trisnorprostadienoate: To a solution of 130 mg (0.30 mmol) 9a, Ila, 15a- trihydroxy-17-(1-adamantyl)-5-cis-13-trans-o^-trisnorprostadic acid

in 7 ml of dry methylene chloride was added 33 mg (0.33 mmol) of triethyl

amine. The mixture is stirred for 5 minutes and then 36 mg (0.33 mmol) of pivaloyl chloride is added. The solution is stirred for 45 minutes at room temperature under nitrogen and then 192 mg (1.5 mmol) of cyclooctyl alcohol and 225 µl of pyridine are added. The mixture re-

stirred at room temperature for a further 2 hours and then diluted with ethyl acetate. The diluted solution is washed with water (2x) and saturated salt solution (lx), dried (anhydrous magnesium sulfate)

and concentrate. The purification of the crude residue by means of silica gel chromatograph gives cyclooctyl-9c,11a!,15G!-trihydroxy-17-(1-adamantyl)-5-cis-13-trans-o^>-trisnorprostadienoate.

The other prostaglandin cyclooctyl esters

with formula I is prepared in a similar way from the

corresponding to the E or F precursors.

Example 29

15- epi- 16-( 1- adamantyl)- out- tetranorprostaglandin- E^- ethyl ester:

To a solution of 15-epi-15-(1-adamantyl)-w-tetranorprostaglandin-E2 (25 mg) in 5 mL of ether was added a solution of diazoethane in ether until the reaction mixture remained yellow for 5

minutes. Concentration of the reaction mixture followed by silica gel column chromatography of the residue using chloroform as eluent gave the desired 15-epi-15-(1-adamantyl)-β-tetranorprostaglandin-E2-ethyl ester, weight 22 mg.

The other prostaglandin ethyl esters

of formula I are prepared in a similar manner from the corresponding E or F precursors.

Example 30

Methyl-9a,11a,15a-trihydroxy-16-(2-indanyl)-5-cis-13-trans-u>-tetranorprostadienoate;

A yellow solution of diazomethane in ether (prepared from N -methyl-N'nitro-N-nitrosoguanidine) until the yellow color persists for 5 minutes. Concentration of the solution and purification by silica gel chromatography of the crude residue gives methyl 9a,11a,15a-trihydroxy-16-(2-indanyl)-5-cis-13-trans-w-tetranorprostadienoate.

The other prostaglandin methyl esters

of formula I are prepared in a similar manner from the corresponding ones

The E or F precursors.

Example 31

Cyclopropyl- 9a, 11a, 15a- trihydroxy- 15-( 2-( 1, 2, 3, 4- tetrahydronaphthyl))-5 - cis- 13- trans- to- pentanorprostadienoate: To a solution of 82 mg (0.20 mmol) 9a,lla,15a-trihydroxy-15-(2-(1,2,3,4-tetrahydronaphthyl))-5-cis-13-trans--pentanorprostadic acid ( 12a) in 5 ml of dry methylene chloride is added to 22 mg ( 0.22 mmol) triethylamine. The mixture is stirred for 5 minutes and then 24 mg (0.22 mmol) of pivaloyl chloride is added. The solution is stirred for 45 minutes at room temperature under nitrogen and then 58 mg (1.0 mmol) of cyclopropyl alcohol and 150 µl of pyridine are added. The mixture is stirred at room temperature for a further 2.0 hours and then diluted with ethyl acetate. The diluted solution is washed with water (2x) and saturated saline (lx), dried (anhydrous magnesium sulfate) and concentrated. The purification of the impure residue by by silica gel chromatograph in gives cyclopropyl-9a, 11a, 15a-trihydroxy-15-(2-(1,2,3,4-tetrahydronaphthyl))-5-cis-13-trans pentanorprostadienoate.

The other prostaglandin cyclopropyl esters of formula I are prepared in a similar manner from the corresponding E or F precursors.

Example 32

9/3, Ila. 15a-trihydroxyv- 17-( 1- adamantyl)-5-cis-13-trans transnorprostadic acid- tris- hydroxymethylaminomethane salt: To a solution of 319 mg (0.70 mmol) 9/3,lia, 15a-trihydroxy-17-( 1-adamantyl)-5-cis-13-trans-<^-trisnorprostadien-

acid (12b) in 35 ml of dry acetonitrile, heated to 80 °C, a solution of 86 mg (0.68 mmol) of tris-hydroxymethylaminomethane in 0.15 ml of water is added with vigorous stirring. The mixture is allowed to cool to room temperature and 9/3,11a,15a-trihydroxy-17-(1-adamantyl)-5-cis-13-trans-u>-trisnorprostadic acid-tris-hydroxymethylamino-methane salt is obtained.

Example 33

9a, lia, 15a- trispivaloyloxy- 15-( 2- indanyl)- 5- cis- 13- trans- - pentanorprostadic acid: To a solution of 80 mg (0.2 mmol) 9a, lia, 15a-trihydroxy-15-( 2-indanyl)-5-cis-13-trans-pentanorprostadic acid in 1 ml of pyridine was added 120 mg (1.0 mmol) of pivaloyl chloride.

The solution is stirred for 4 hours at 45° under nitrogen and then cooled to room temperature. 36 mg (2.0 mol) of water are then added to the solution. The solution is stirred at room temperature for 2.0 hours, and then diluted with ethyl acetate. The diluted solution is washed with 0.ln hydrochloric acid (2x), with water (lx) and saturated salt solution (lx), dried (anhydrous magnesium sulfate) and concentrated. The purification of the crude residue by means of silica gel chromatography gives 9a,11a,15a-tris-pivaloyloxy-15-(2-indanyl)-5-cis-13-trans-pentanorprostadic acid.

Example 34

9- oxo- lla. 15a- bisformyloxy- 15-( 2-( 5, 6- dimethoxyindanyl))-5-cis-13- trans- cJ- pentanorprostadic acid: To a solution of 46 mg (0.1 mmol) of 9-oxo-lla,15a- dihydroxy-15-(2-(5,6-.dimethoxyindanyl))-5-cis-13-trans-w-pentanorprostadic acid in 0.5 ml of dry tetrahydrofuran was added to 29 mg

(0.33 mmol) formic-acetic anhydride and 35 mg (0.33 mmol) 2,6-lutidine. The solution is stirred for 1 hour under nitrogen

room temperature and then add 36 mg (2.0 mmol) of water. The mixture is stirred at room temperature for a further 1.0 hour

and then diluted with ethyl acetate. The diluted solution is washed with 0.1N hydrochloric acid (lx), with water (lx) and with saturated salt solution (lx), dried (anhydrous magnesium sulfate) and concentrated. The purification of the crude residue by means of silica gel chromatography gives 9-oxo-11a,15a-bisformyloxy-15-(2-(5,6-dimethoxyindanyl))-5-cis-13-trans-β0-pentanorprostadic acid.

Example 35

17-(l-adamantvl)-t**- trisnorprostaglandin- F2a;

A heterogeneous mixture of 447 mg (1.0 mmol) of 15-epi-17-(1-adamantyl)-c*>-trisnorprostaglandin-F2a and 4.5 g of activated manganese dioxide in 45 ml of dry methylene chloride is stirred overnight at room temperature, filtered and concentrate and you get 15-keto-17-(1-adamantyl)-w-trisnorprostaglandin-F2Q! which is used without purification.

To a solution, cooled in ice, of 223 mg (0.50 mmol) of 15-keto-17-(1-adamantyl)-tJ-trisnorprostaglandin-F2a in 22 ml of absolute methanol is added an ice-cooled solution of 669 mg of sodium borohydride in 85 ml absolute methanol. After stirring for 20 minutes at 0° and 1.0. hour at room temperature, the reaction is stopped by adding 6.6 ml of water. The methanol is removed by rotary evaporation and the resulting aqueous solution is layered with ethyl acetate, acidified with 10% hydrochloric acid and further extracted with ethyl acetate. The combined organic extracts are washed with water and saturated saline, dried (anhydrous magnesium sulfate) and concentrated. The purification of the crude residue by means of silica gel chromatography gives 17-(1-adamantyl)-uJ-trisnor-prostaglandin-F2a and 15-epi-17-(1-adamantyl)-oJ-trisnorprostaglandin-F„ .

2a

The other 15-epi-prostaglandins of formula I can be similarly converted to their C 1 -epimers by the above procedure.

Example 36

N- benzoyl- 9- ox- olla, 15a- bis-( tetrahydropyran-2- yloxy)- 15-( 2-( 5, 6-dimethoxyindanyl))- 5- cis- 13- trans- oJ- pentanorprostadienamide: To a solution, under nitrogen, of 594 mg (1.0 mmol) of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-15-(5,6-dimethoxy-indanyl))-5-cis-13 -trans-u>-pentanorprostadioic acid in 6 ml of dry tetrahydrofuran was added 102 mg (1.0 mmol) of triethylamine. The solution is stirred for 1 minute and then 1.2 ml of a 1.0M solution of benzoisocyanate in tetrahydrofuran is added. The solution is stirred for a further 10 minutes and the reaction is stopped by adding glacial acetic acid. The solution is concentrated and the residue is dissolved in ethyl acetate (20 mL), washed with water (1x), dried (anhydrous magnesium sulfate) and concentrated to give the desired N-benzoyl-9-oxo-lla,15a-bis-(tetrahydropyran) -2-yloxy)-15-(2-(5,6-dimethoxyindanyl))-5-cis-13-trans-i>>-pentanorprostadienamide which is used without purification.

The above product can be converted to N-benzoyl-9-oxo-11a,15a-dihydroxy-15-(2-(5,6-dimethoxyindanyl))-5-cis-13-trans-uj-pentanorprostadienamide by the method of Example 10. Using the above method, the other prostaglandin acid analogues can be transferred to the

corresponding N-substituted prostaglandin carboxamides.

Example 37

2 - 1 3a, 5a- dihydroxy- 2/ 3- ( 3a- hydroxy- 3- ( 2- indanyl) - trans- l- propen- l-yl) cyclopent- la- yl] acetaldehyde, /- hemiacetal: To a solution, cooled to -78°, of 750 mg (1.5 mmol) of 2-[ 3a-p-phenylbenzoyloxy-5a-hydroxy-2( 3-(3a-hydroxy-3-(2-indanyl)-trans-l- propen-l-yl)cyclopent-la-yl]acetic acid, /-lactone in 15 ml of toluene was added 7.5 ml of a 20% solution of diisobutylaluminum hydride in hexane (Alfa).The reaction mixture was stirred cold for 1.0 hour and the reaction is stopped by the addition of methanol until gas evolution ceases. The mixture is warmed to room temperature and then concentrated. The residue is stirred with methanol (3x) and concentrated. The purification of the crude product by means of silica gel chromatography gives the desired 2-[ 3a,5a-dihydroxy-2 /3-(3α-Hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-la-yl]-acetaldehyde, β-hemiacetal.

The above product can be transferred to the 15-(2-indanyl)-oo-pentanor-PGF20;-analogs of formula I. Using the above method, the other F-type prostaglandin analogs of formula I can be prepared.

Claims (1)

Analogous process for the preparation of a physiologically active prostaglandin compound of the E or F series with the formula: or the C^,.-epimer thereof, where A is 1-adamantyl, 2-(1,2,3,4-tetrahydronaphthyl) which is racemic or optically active, 2-indanyl or 2-(5,6-dimethoxy-indanyl); n is 0, 1 or 2; W is a cis double bond; Z is a trans double bond; M is oxo or r X is 5-tetrazolyl, a group of the formula -COOR', where R' is hydrogen or alkyl of from 1 to 10 carbon atoms, aralkyl of from 7 to 9 carbon atoms, p-biphenyl or cycloalkyl of from 3 to 8 carbon atoms, or a group with the formula -CONHR", where R" is alkylsulfonyl with from 1 to 7 carbon atoms, and the lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups in the Cg-, C^- and C-^ positions, or a pharmaceutically acceptable salt of a compound of formula (I) wherein X is -COOH, characterized in that: (a) a compound of the formula: wherein A, n, M, R, W, X and Z are as defined above, and THP is 2-tetrahydropyranyl, is reacted with an appropriate acid; (b) a compound of formula (I) above wherein M is oxo is reacted with a suitable reducing agent to form a compound of formula (I) wherein M is , and A, n, R, W, X and Z are as indicated above; and optionally the compound of formula (I) where X is -COOH is converted into an ester or a substituted amide, as defined above, by reaction with a suitable esterifying or amidating agent, respectively; and optionally the 9a-, 11a- and 15a-lower alkanoyl-, -formyl- or -benzoyl esters of any free hydroxyl groups are prepared by reacting the compound of formula (I) with a suitable acylating agent; and optionally a pharmaceutically acceptable salt of a compound of formula (I) where X is -COOH is prepared.