DK143499B - 15-SUBSTITUTED OMEGA-PENTANOR PROSTAGLANDINES OF E2 OR F2 SERIES FOR USE AS FERTILITY CONTROLS - Google Patents

Description

i® (12) PUBLICATION MANUAL od 143499 B

(19) DENMARK

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 6033/73 (51) IntCI.3 Q 07 £ 177/00

(22) Submission day 8 · Nov. 1973 ® 07 ® 267 / 0A

(24) Race day Nov 8 1973 A 61 K 31/867 (41) Aim. available 9 · May 1974 (44) Presented 31 · Aug. 1981 (86) International application # - (86) International filing day (85) Continuation day - (62) Master application no -

(30) Priority Nov. 8 1972, 304750, US

(71) Applicant PFIZER INC., New York, US.

(72) Inventor Hans-Jurgen Ernst Hess, US: Thomas Ken Schaaf, US.

(74) Associate Engineer Hofman-Bang & Bout ard.

(54) 15-substituted omega-pentanor = prostaglandins of the E2 or F2 series for use as a precision control agent.

The invention relates to novel 15-substituted oi-pentanor prostaglandins of or the F2 series for use as fertility control agents.

The prostaglandins are unsaturated fatty acids with 20 carbon atoms exhibiting different physiological effects. Eg. are the prostaglandin dinars of the E and A series potent vasodilators (Bergstrom et al., T> Acta Physiol. Scand. 64: 332-33, 1965; and Bergstrom et al., Life Sci.

^ 6: 449-455, 1967) and lowers systemic arterial blood pressure (vasode- d "depression) by intravenous administration (Weeks and King. Federation

Proc. 23: 327, 1967; Bergstrom et al., 1965; Carlson et al., Acta É Med. Scand. 183: 423-430, 1968; and Carlson et al., Acta Physiol.

3 2 143499

Scand. 75: 161-169, 1969). Another known physiological effect of and PGE1 is as a bronchodilator (Cuthbert, Brit. Med. J. 4: 723- 726, 1969).

Yet another important physiological role is played by the natural prostaglandins associated with reproduction. It is known that PGE2 has the ability to induce labor (Karim et al., J. Obstet Gynaec. Brit. Cwlth. 77i200-210, 1970), to induce therapeutic abortion (Bygdeman et al., Contraception, 4, 293 (1971). )) and to be useful for controlling fertility (Karim, Contraception, 2 * 1973 (1971)). Patents have been issued on several prostaglandins of the E and F series as mammalian web developers (BE patent no. 754 158 and DE patent no. 2 034 641) and on PGF1, -F2 and -F ^ for control of reproduction (ZA patent No. 69/6089). It has been demonstrated that luteolysis can occur as a result of administration of PGF2a (Labhsetwar, Nature 230, 528 (1971)) and that prostaglandins are therefore useful for fertility control in a process where smooth muscle stimulation is not required.

Further known physiological activities of PGE1 include inhibition of gastric acid secretion (Shaw and Ramwell, in: Worcester Symp. On Prostaglandins, New York, Wiley, 1968, pages 55-64) and also of platelet aggregation (Emmons et al. , Brit. Med. J. 2: 468-472, 1967).

It is now known that such physiological effects in vivo will only be produced for a short time after the administration of a prostaglandin. Extensive experience suggests that the cause of this rapid cessation of activity is that the natural prostaglandins are metabolically and rapidly deactivated by β-oxidation of the carboxylic acid side chain and by oxidation of the 15α-hydroxy group (Anggard et al., Acta. Physiol. Scand., 81, 396 (1971) and references cited therein). It has been shown that placing a 15-alkyl group in the prostaglandins has the effect of increasing the duration of action, probably by preventing the oxidation of the C1-hydroxy group (Yankee and Bundy, JACS 3651 (1972), Kirton and Forbes, Prostaglandins 1, 319 (1972)).

, 143499 3

Therefore, it was considered desirable to provide analogous compounds to the prostaglandins, which had physiological activities equivalent to the physiological activities of the natural compounds, but in which the selectivity of action and duration of activity would be increased. An increased selectivity of the effect would be expected to mitigate the serious side effects, especially the gastrointestinal side effects that are frequently observed after systemic administration of the natural prostaglandins (see Lancet, 536, 1971).

This is achieved with respect to fertility control, with the compounds of the invention, which are characterized in that they have the general formula I of the claim or are C er-epimers thereof or are pharmaceutically acceptable salts with bases of the compounds wherein X is -COOH.

The compounds of the invention can be prepared from a corresponding A-substituted alkanoic carboxylic acid ester and a dialkylmethyl phosphonate as illustrated in the following Scheme A and the following Schemes B, C and D, wherein A, n and X are as defined in the claim and THP means 2-tetrahydropyranyl.

The starting material for the preparation of the various compounds of the invention is commercially available or can be prepared by methods well known to those skilled in the art. For example, if will prepare dimethyl 2-oxo-2- (2-indanyl) ethyl phosphonate, the starting material for the synthesis of the 15- (2-indanyl) prostaglandins, cool a solution of dimethyl methyl phosphonate in tetrahydrofuran to -78 ° C. a dry nitrogen atmosphere and then slowly and dropwise add n-butyllithium in hexane. After stirring, ethyl indan-2-carboxylate is added dropwise. After 3-4 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 in chloroform and the combined organic extracts are washed, dried and concentrated to give the desired product.

To prepare the desired 15-substituted 1x-pentanor prostaglandins, as described below for the corresponding A-substituted carboxylic acids, the esters are converted by the usual methods and then to phosphonates as described above for the 15-434349 (2-indanyl) compound. .

To prepare the 15- (2 - (+) - (1,2,3,4-tetrahydronaphthyl)) prostaglandins, the (+) - 2- (1,2,3,4-tetrahydronaphthalene) carboxylic acid is prepared by the method described by Cohen et al., J.

Biol. Chem., 10, 2664 (1969), and the acid is converted to the ester and then to the phosphonate as described for the 15- (2-indanyl) compound.

To prepare the 15- (2 - (-) - (1,2,3,4-tetrahydronaphthyl)) prostaglandins, the (-) - 2- (1,2,3,4-tetrahydronaphthalene) carboxylic acid is prepared. the method described by Cohen et al., J.

Biol. Chem., 10, 2664 (1969), and the acid is converted to the ester and then to the phosphonate as described for the 15- (2-indanyl) compound.

When 15- (2-indanyl) -prostaglandins are desired, indan-2-carboxylic acid, e.g. by the method described by Bergman and Hoffman, J. Org. Chem., 26, 3555 (1961) and the acid is converted to the ester and then to the phosphonate as described above.

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

To prepare the l6- (1-adamantyl) prostaglandins, (1-adamantyl) acetic acid is purchased, e.g. from Aldrich Chem. Co. (No. 12, 727-2), and the acid is converted to the ester and then to the phosphonate as described for the 15- (2-indanyl) compound.

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

For the preparation of the 15- (2- (1) - (1,2,3,4-tetrahydronaphthyl)) prostaglandins, the (I) -2- (1,2,3,4-tetrahydronaphthalene) carboxylic acid is prepared by that method. , described by Cohen et al., J.

Biol. Chem., 10, 2664 (1969), and the acid is converted to the ester and then to the phosphonate as described for the 15- (2-indanyl) compound.

5

U349S

SCHEME A

A - (CH2) n-C00CH3 -> A - (CH2) n-C-CH2-f (OCH,) 20 1 -P 2 (S

_ r- \? .V-ACHO r "A J

<oHsr0 'i +, 0— ^ 5 143499 6

As shown in Scheme A, the first step (1-r * 2) is the concentration of the corresponding ester with a dialkyl methyl phosphonate to form the ketophosphonate 2. Typically, the desired methyl ester is condensed with dimethyl methyl pho sphonate · In 2-> 3, the ketophosphonate 2 react with the known / orey, et al., J. Am. Chem. Soc., 93, 1491 (197-127aldehyde H to form after chromatography or crystallization of the enone 3. The compound in which the p-biphenylcarbonyl group is replaced by a protective p-biphenylcarbamoyl group is also useful in place of H and has the additional advantage that a higher percentage of the desired α-isomer is produced in the reduction step (3-4).

The enone 3 can be reduced with zinc borohydride or with lithium tri-hydroxy borohydrides, such as lithium triethylborohydride, for a mixture of alcohols 4 and 5 which can be separated by chromatography. In this reaction, ethers such as tetrahydrofuran or 1,2-dimethoxyethane are usually used as solvents, although methanol is sometimes preferred to ensure the specificity of the reduction. Further conversions of 4 are shown in Scheme B.

4-Ψ 6 is a base-catalyzed deesterification, thereby removing the protective p-biphenylcarbonyl group. This is most conveniently carried out with potassium carbonate in methanol or methanol / tetrahydrofuran as the solvent. 6-> 7 involves the protection of the two free hydroxy groups with tetrahydropyranyl which can be introduced into the molecule by treatment with dihydropyran and an acidic catalyst in an anhydrous medium. The catalyst is usually β-to-luenesulfonic acid.

7 143499 SCHEME B. a

____ \ 7 ΊΟΚο) A

^ HO '' H ^ * OH

- ^ ·> · 6 H ^ ff

3— (CHgJ-A r W .3— ^ CHp) n “A

2HPO 'ΤΗΡσ. ^ Τ> Γ 2 H · * OTHP · BT OTH? 2 8

HAY

^ - ^^ / 0%) n-A * THPO 'Ιτ ^ ΌΪΚ? JTHPO B * * '01Ή? .2 i £ ·? K 1 o H0-Q ^ CH2) n-A. ΗΟ · θν ^) ^ H0 Ι1 <^ · .0Η · _> '12 .11 8 143499 7 -> 8 is a reduction of lactone 7 to hemiacetal 8 using diisobutyl aluminum hydride in an inert solvent. Low reaction temperatures are preferred and temperatures from -60 ° to -70 ° C are common. However, higher temperatures can be used if there is no over-reduction. 8, if desired, is purified by column chromatography.

8-9 is a Wittig condensation, whereby the hemiacetal 8 is reacted with e.g. (4-carboxy-n-butyl) triphenylphosphonium bromide in dimethylsulfoxide in the presence of sodium ethylsulfinylmethide. 9 is cleaned as mentioned above.

Conversion 9 to 12 is an acidic hydrolyzate of the tetrahydropyranyl groups. Any acid which does not cause degradation of the molecule during removal of the protecting group can be used, but this is most often done using 65% aqueous acetic acid. The product is purified as indicated above.

9-> 10 is an oxidation of the secondary alcohol 9 to the ketone 10.

This can be done using any oxidizing agent which does not attack double bonds, but Jones * reagent is usually preferred. The product is purified as indicated above.

10—> 11 is performed in the same way as 9—> 12. The product is purified as indicated above. Reduction of the compound 11 by sodium borohydride will give the 9B isomer of the prostaglandin analog of the F series, i.e.

PGF2p compounds. This can also be achieved via reduction of 10 with sodium borohydride followed by hydrolysis, as described above for 10-> 11.

As shown in Scheme C, compound 5 can be used instead of 4 in Scheme B to form the C Cim epimeric prostaglandin derivatives 11 'and 12'.

SCHEME C

Oil X—, un '-' HO * HO ^ '. U ^ - 0 a I -'- :-) n-A 11' 9 U3A99

SCHEME D

Island Island

A / ^^^ cooh_ ^ JI; V == ^ v ^ \ qori / —Uxj, · ^ —L ^ xa KO HO H HO HO ·

11 11 E

Δ

ISLAND ISLAND

NVr = yAXv / ^ OOH_ X''X - ^% OOR1

) W

THPO / li rptiTJO '/> H

THPO H THPO THPO

1 °

E

Δ

OH OH

1 A = ^ v / \ A / V ==== / n / \. in

^ 1 'COOH ri COOR

-►

/ \ A <"A / -ΑΓίς-A

[ΓΗΡύ THPO '' 'THPO THPO' H

9 9 E

OH V

ί ^ / λ ^^ qooiJ

/ Ησ HO '«

12 E

10 143499

The biphenylyl esters can be prepared in a variety of ways. These differ in that the esterifying group is attached to the prostaglandin or its precursor at various stages of the synthesis.

Eg. Scheme D shows three different pathways to the ester "E", wherein in R means biphenylyl.

In each case, the esterifying group is introduced by an esterification reaction which can be carried out by contacting the corresponding prostaglandin analog or its precursor with the phenol in the presence of a catalyst. Any of the present prostaglandin analogs may be used as a substrate for the aforementioned esterification reactions, and in addition, precursors for such prostaglandin analogs may also be used, as shown in Scheme D. For example. For example, compound 9 can be converted to 9E by the above esterification reaction, and 9E can then be converted to 10E and 12E by the same methods previously described for conversion of 9 to 10 and 12. The compound 10E can be converted to 11 E by the reactions described for the conversion of 10 to 11.

Various modifications are possible in the upper side chain of the prostaglandins. A 5-tetrazolyl moiety may be placed in Conversion, as described in U.S. Application Serial No. 177 102, filed September 1, 1971, and in the following Examples. Eg. For example, compound 8 can be reacted with an ylide formed from (4- (tetrazol-5-yl) -n-butyl) triphenylphosphonium bromide and sodium methylsulfinylmethide to form the Cm-tetrazole-substituted compound 9. Conversion of 9 to the similar prostaglandins occur as described above.

In the above procedures where purification by chromatography is desired, as appropriate chromatographic carriers, neutral alumina, silica gel and fluoracil may be mentioned. The chromatography is conveniently carried out in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane, n-hexane and methanol, as further illustrated in the following examples.

11 143499

It will be seen that the above formulas depict optically active compounds. However, it will be appreciated that the corresponding racemates will exert valuable biological activity because of their content of the above biologically active optical isomer and such racemates should be considered as encompassed by the formulas set forth above and the claims. The racemic mixtures are readily prepared by the same methods used to synthesize the optically active compounds simply by using corresponding racemic precursors instead of the optically active starting materials.

The following intermediates in the above-described processes for preparing the compounds of the invention are also novel:

Compounds of Structural Formula: n ° H HO * '* Compounds of Structural Formula: rf THPO 1 0ΓΗΡ and Compounds of Structural Formula: 12 143499 rf

H0.iX ^ V0%> "A

δΗ in which formulas A and n are as defined in the claim, Q is p-phenylbenzoyl, THP is tetrahydropyranyl, and Y is = 0 or <H ·

^ OH

Compounds of structural formula: A - (CH2) nJ-CH2J <^^ H3 ^^ - och3 and compounds of structural formula: rf wherein A and n are as defined in the claim.

Compounds with the structural formulas:

OH

t i

Y_i ^ Λ, (0H2) nA

13 143499 x

V-i JCH2) nA

THPCV *

OTHP

wherein A, n and X have the meaning set forth in the claim and THP is 2-tetrahydropyranyl, or the C 6 and C 6 epimers thereof.

It will be appreciated by those skilled in the art that in structures depicting hemi-acetals no stereochemistry is applied to lactol carbon atoms.

In numerous tests in vivo and in vitro, it has been demonstrated that the novel prostaglandin analogs of the invention have selective physiological activities compared to those exerted by the natural prostaglandins.

These tests include: a test for effect on isolated smooth muscle of guinea pig uterus, guinea pig ileum and rat uterus, stimulation of diarrhea in mice, inhibition of histamine-induced bronchospasm in guinea pigs, effect on canine blood pressure, inhibition of stress-induced ulceration in the rat, inhibition of gastric acid secretion in the rat and dog, inhibition of lipolysis-antiarrhythmic activity, cardiac stimulant activity, inhibition of collagen- or ADP-induced platelet aggregation, and abortion-inducing activity in 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 treating various natural and pathological conditions. Such established uses include: antihypertensive activity, bronchodilator activity, antithrombogenic activity, anti-ulcer activity, smooth muscle activity / useful as anti-fertility agent, to induce labor and as an abortion inducer7, and anti-fertility activity by a mechanism other than affects smooth muscle, e.g. luteolytic mechanisms, and synchronization of the estrus cycle in farm animals.

U3499 14

The compounds of the invention have more selective activity profiles than the corresponding naturally occurring prostaglandins and are in many cases more potent and have a longer duration of action. Eg. has 15- (2-indanyl) -u-pentanorprostaglandin F2A, which exhibits a guinea pig uterus and smooth muscle stimulating activity of the same size as PGF only 8% of guinea pig ileum stimulating activity and is at least 30 times more potent than PGF in terms of abortion-inducing activity in rats.

Particularly useful for fertility control, abortion induction and labor induction are the 15- (2-indanyl) -u) -pentanorprostaglandins, the 15- (1,2,3,4-tetrahydronaphthyl) -β-pentanorprostaglandins, 17-C1-adamantyl ) -u) -trisnorprostaglandins and the 16- (1-adamantyl) -uJ-tetra-norprostaglandins of the E2 and F2q series, based on vigorous smooth muscle stimulating and abortion-induced activity in rats and at the same time reduced blood pressure and diarrhea. - inducing effects.

The novel prostaglandins with a β-hydroxy group at the 15-position are generally less potent but often more selective than the corresponding oc-hydroxy epimers. In addition, the prostaglandins having a β-hydroxy group of C- are valuable intermediates for prostaglandins with an α-hydroxy group at C · via a recycling process involving an oxidation and reduction at C15 *. The novel prostaglandin analogs of E₂ or The F2 series has useful anti-fertility properties and is further useful for synchronizing the oestrus cycle in animals.

TEST REPORT

A number of compounds of the invention were subjected to the following tests for comparison with natural PGE2 and PGF2a, for which a large number of pharmacological and clinical studies have been published: A. Spasmogenic effect on isolated guinea pig uterus, relative potency (PGEg / PGF ^^ s 100 ): a test for fertility control activity by a uterus-stimulating mechanism.

B. Protection of guinea pigs from a toxic aerosol dose of histamine by aerosol administration of the compound, approximately% protection by equimolar aerosol dose to 100 µg / ml PGE2 (ie PGE2 = 100): a test for bronchodilator activity.

C. Hypotensive effect on anesthetized dogs, threshold value in µg / kg i.v. (PGE2 = 0.16 depressor; PGF110 pressor): a test for antihypertensive activity.

D. Induction of diarrhea in mice, relative potency (PGE2 = 100): a test for a common gastrointestinal side effect of prostaglandins.

E. Inhibition of pentagastrin-induced gastric acid secretion in rats, relative potency (strength x variance, PGE2 = 100): a test for antisectoral (anti-ulcer) activity. : F. Abortion-Inducing Activity in Rats, Relative Strength (PGEp / PGFp1-100): a test for fertility control in a non-uterus stimulant ie. luteolytic mechanism.

The results are summarized in the following table.

U3499 16 ----- I o o o

Cl, 'O O O

™ η a a i m ® i i 5 1 I 1

M O S ^ β H O, Μ ri H

m · Η (1) Η H 3 H

ι ~ ΙΑ o

Q ΙΑ LA ΙΓ \ ΙΑ AI A

V V V__V___ I +

O'- 'O H

O O O · + _? ~

o Al A1 A! -ri "'-' Η O

__ / \ __ ✓S ^ ____ Φ φ φ d · 3 d β S3 Φ Φ Φ Φ Φ Φ

m A Α Αί> WJ .¾> bO Ai> bO

** 3 η ° • Η cd Η Η cd Η · Η cd Η Ο

ο Ο Ο A HA

ο ο ο ι ι

A Η Η Η A A

C 1 1

^ Ο A

A A

OO <1 * AI A

VO A HH

Η H HH

. Φ Φ 1 I II

ft Η · Η C'- A Ο SO Η Η CO Α Η Η røo Ο Ο Η Η Η Η I I I. I I rCM I & 3 ι cd 3 «3 ο ^ 1¾ ''" 'ft

1 cm cc5 ft 1 * 1 * HO HO

Η Η TJ-P Η ft Η AI £> ft bft >> 0 cd Φ i >> O! >> ft β J gl 40 cl ι-p -Pft -p O cd ri cd ri d gi vo 1 rii rift ^ ° 5 rori H 3 AI ed ri Cd I riri riri cti ao iiw ao ag down down d rori HHO ro ri ro o ι-P 1 h * · ϋ cd ft Sft ti cd ti ri Alri <m ri cd ri Φ-Ρ 1 ed ri eden ^ φ ι-Ρ 1 fl ri lP ih 1 ft i ft vo Φ Aed O VO Φ C'- ri Al Al HP H 3 ri H -P HP H 3 H 3 35 --- m

H

Φ ri ·

• HriHAJ A <f AVO

ri

ISLAND

ft 17 143499 o o o o o o o o o o o o

ft O O O ΙΛ O KN

Η Η Η H

--- 1-

V

iii * 3

AM Pi «Λ PI hi PI

© © * H 0 0 -Η 0 © · Η © ©

> H rid> H X> H ^> M

o 3g® 3q® SC-h

Η ia rifflti h 3 d h 3 Π H 3 H

0 o o o o o

O -4 -4 H HH H

v v v "+" + o "" o

UH H

--- j j- 'i i ® © o © D · ϋ d τί ri p | p | Pi gj {j øø øø ø rid> high rid> high rid> ho

Sdrl ridC-H 3ΰΗ Sgrl

ffl O ri fflrl ri fflH r | fflrl Ή fflH

ICE

ΙΛ: - CO S · Η H f ** <ΙΑ Η (M -4

LA VO

-4 fA CM

O H CTi H

H I <3 \ I

• I IS -4 I Ά

ft IA LA CM IA 00 CM

SO O O H H Ch H

CO O H__H___ i · *

--j - I »II I

*> a ia a γα, d ø i 3

»I IA n. R i CM - ft I ril 1 ^ I

cm o: ·> d a cm a --4¼ cm cd cd ft cmh ^ a

- Pi J CM CM not CM -I I CM HCUPi Ȍ-Prl I >> H CM

H d 3 H * 5 (¼ Hoife i >> ft 0 H oifl ί >> I

- IOH £ IUI ϋ Pil-P '- "Pi © I HLA Pip 1, ώ' - 'Ρΰ' -'d 3 ft i -dr — ø Pi κι i H ft oi 3ft pi cm co ^ iit >> ii cm > »^ I 'do ø cm! >> ii riiH · α i> I PH P CM jd · -' Pi I flH PS PH I, 3 3 CMPi Pi O Pi Pi

+ 3 t> i o I CD ^ -N o So ri III s / -silptjø CdNHO

ri pcjø ^ ifl '' PHd coPiÆri i -p ri coPi — op o © i ri ΰ · ρ · ρ® ft-p >> 3 ^ -pP 3 cm ri ø '-' • p- ^ cu ra m Pi cm 3 - I Λ-P ^ fflfl-p ^ fflil '- ØH I 0 Φ-Ρ' —- p ι-io, ri ip-ppi i -p pi, pi in Pift ι · ρ ^ ρη -d ø i ri m * s® in i ri o ia i cd © in ι η in iioi> i i-pmo ΗIA Pl ft H -4 ft ft H -4 Pi ft H 3 ril Η4? Ρβ CCN-Ή ft rø

H

0

D · O H CM

Pi ri IS CD cn Η Η H

u o (X4 I I ..... ~ .1 ------- 1--1 1 U3499 18

From the table can be deduced:

Compound 1,6-adamantyl-w-tetranor-PGE2 is a more selective agent for fertility control than PGE2 because of its potent uterus-stimulating activity and reduced bronchodilator, hypotensive, diarrhea and antisecretory effects.

Compound 2, 15-epi-16 ~ adamantyl-u-tetranor-PGE2, is a more selective agent for fertility control than PGE2 because of its potent uterus-stimulating activity and reduced bronchodilator, hypotensive and diarrhea-inducing effects.

Compound 3, 16-adamantyl-w-tetranor-PGE2a, is a more selective agent for fertility control than PGF2q; because of its potent uterus-stimulating activity and reduced hypertensive and diarrhea-inducing effects.

Compound 4, 17-adamantyl - "- trisnor-PGF2a, is a more selective agent for fertility control than PGF2a because of its potent abortion-inducing activity and reduced uterine-stimulating, hypertensive and diarrhea-inducing effects.

Compound 5, 15- (2-indanyl) -w-pentanor-PGE2, is a more potent and more selective agent for fertility control than PGE2 because of its more potent abortion-inducing activity and reduced uterus-stimulating, hypotensive, bronchodilator and diarrhea-inducing effects. .

Compound 6, 15- (2-indanyl) γ-pentanor-PGF2Q, is a more potent and more selective agent for fertility control than PGF2a because of its more potent abortion-inducing activity and reduced uterine-stimulating and diarrhea-inducing effects.

Compound 7, 15 - ((R) -2- (1,2,3,4-tetrahydronaphthyl)) - γ-penta-nor-PGE 2, is a more potent and more selective agent for fertility control than PGE 2 due to of its more potent abortion-inducing activity and reduced bronchodilator, diarrhea-inducing, and antisecretory effects.

Compound 8, 15 - ((R) -2- (1,2,3,4-tetrahydronaphthyl)) - w-pentanor-PGF2a, is a more potent and more selective agent for fertility control than PGF2a due to its stronger uterus -stimulatory and abortion-inducing activity and reduced hypertensive and diarrhea-inducing effects.

Compound 9, 15 - ((S) -2- (1,2,3,4-tetrahydronaphthyl)) - pentanor-PGF2a, is a more potent and more selective agent for fertility control than PGF2a because of its more potent abortifacient activity and reduced diarrhea-inducing effect.

Compound 10, 15- (2-indanyl) -u-pentanor-PGF2α-β-biphenyl ester, is a more potent and more selective agent for fertility control than PGF2α because of its more potent abortion-inducing activity and reduced uterine-stimulating, hypertensive and diarrhea-inducing effects. .

Compound 11, 15- ((S) - 2- (1,2,3,4-tetrahydronaphthyl)) -vi-penta-nor-PGEg-p-biphenyl ester, is a more potent and more selective agent for fertility control than PGE2 due to of its more potent abortion-inducing activity and reduced uterine stimulating and diarrhea-inducing effects.

Compound 12, 2-descarboxy-2- (tetrazol-5-yl) -15- (2-indanyl) -u-pentanor-PGF2a, is a more potent and more selective agent for fertility control than PGF2a because of its more potent abortifacient activity. and reduced uterine stimulating and diarrhea-inducing effects.

20 143499

The compounds of the invention can be used in a wide variety of pharmaceutical compositions containing the compound and can be administered in the same way as natural prostaglandins by a variety of routes, such as intravenous, intramuscular, subcutaneous, oral, intravaginal, intra- and extra amniotic.

In order to induce abortion, tablets or an aqueous suspension or alcoholic solution containing a 15-substituted-C1-pentanorprostaglandin of the invention, such as 15- (2-indanyl) -ω-pentanorprostaglandin, may conveniently be administered in oral doses of about 0.1 -20 mg using 1-7 doses per day. day. For intravaginal administration, a suitable composition would be lactose tablets or fine impregnated tampon of the same agent. For such treatments, suitable doses will be about 0.1 to about 20 mg / dose, using 1-7 doses. For intramuscular administration, a suitable composition will be an aqueous solution containing 0.05-10 mg / dose, using 1-7 doses.

For extra-amniotic administration, a suitable composition will be an aqueous solution containing 0.005-1 mg / dose, using 1-5 doses. Alternatively, the subject 15-substituted W-penta-norprostaglandins may be infused intravenously to induce miscarriage at doses of 0.05-50 µg / minute over a period of from about 1 to about 24 hours. To synchronize the oestrus cycle in pigs, sheep, cows or horses, a solution or suspension containing 0.05-30 mg / day of the 15-substituted Ui-pentanorprostaglan-din is administered subcutaneously for 1-4 days.

Various reaction-inert diluents, excipients or carriers can be used to prepare any of the above dosage forms or any of the numerous other possible forms. Such substances include e.g. water, ethanol, gelatins, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, rubbers, polyalkylene glycols, petroleum vaseline, cholesterol and other known carriers for drugs. If desired, these pharmaceutical compositions may contain adjuvants such as preservatives, wetting agents, stabilizers or other therapeutic agents such as antibiotics.

21 143Λ99

The following examples serve to illustrate the preparation of the compounds of the invention. In these examples, all melting and boiling points are uncorrected.

EXAMPLE 1

Dimethyl-2-oxQ-2- (2-lndanyl | ethylEhosBhonat

A solution of 20.4 g (164 millimoles) of dimethyl methyl phosphonate in 200 ml of dry tetrahydrofuran was cooled to -78 ° C in a dry nitrogen atmosphere. To the stirred phosphonate solution, 82.6 ml of 2.25M n-butyllithium in hexane solution was added dropwise over 20 minutes at such a rate that the reaction temperature never rose above -65 ° C. After a further 5 minutes of stirring at -78 ° C, 14 , 0 g (73.5 millimoles) of methylindan-2-carboxylate dropwise at a rate that kept the reaction temperature below -70 ° C (20 minutes). After 1.0 hour at -78 ° C, the reaction mixture was allowed to warm to ambient temperature, then 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 extracted with 75 ml portions of methylene chloride (4 times), the combined organic extracts washed back with 75 ml of water, dried over magnesium sulfate and concentrated using suction pump for a crude residue and distilled. to give 17.0 g (86.4%) of dimethyl 2-oxo-2- (2-indanyl) ethyl phosphonate; kp. 150-160 ° C (0.1 mmHg).

The NMR spectrum of the distilled product showed a singlet at 7.15S for the aromatic protons, a doublet at 3.76S (J = 11 Hz) for OCH +, a singlet at 3.25S for the benzyl protons, a doubled at 3.188 (J = 23 Hz) for PCH2 and a deformed triplet at 3.13 £ (J = 2 Hz) for COCO.

22 143499

> N

ω S

_ ro κλ ^ c \] in ro «» v ^ -j 00 ^ *

Cq yv y-s T) Ό B ^ v_x 0 ro co> 5 cn o w ro ro ϋ

to / -N / <- N

'tf »d * d

Nw «'W

S O ITV

e c * · ts ^ »· * ro rov

y — N y — V

ti bo bO

h S3 a Is S CM O,

* H O O

ti £ O O

Q) X w

S <d_ S

S3 U O

in ^ P

© w © o o

tQ W «C \ J O

Η O O H O

© _ X * CM CM

d O = 0 II

S CM ά m K o σ \

£> y CM H

u 0 = 0,

O CM

«Η ^

ISLAND

<D tO

U W

0) Oh

M

• pH

H U

S ω ω to

d S

tH CO

p

(D

bO

Ή

H

<0

Ti >>

-P

EXAMPLE 2 2- [5a-p-Phenylbenzoyloxy-5a-hydroxy-2β- (3-oxo-3- (2-indanyl) -trans-1-progen-1-yl] -cyclopolyte-1α yl / acetic acid fy ^ lactQn: ___________________

To a solution of 17.2 ml (32.6 millimoles) of a 1.90M solution of n-butyllithium in hexane in 150 ml of dry 1,2-dimethoxyethane, cooled in ice under nitrogen, was added dropwise 9.2 g (34 (5 millimoles) of dimethyl 2-oxo-2- (2-indanyl) ethyl phosphonate. The solution was stirred in the cold for 10 minutes, to which was added 11.9 g (33.5 millimoles) of the known 2- / 3 <x-p-phenylbenzoyloxy-5? -Hydroxy-2? The ice bath was removed and the mixture was stirred for 1.0 hour and the reaction then quenched by the addition of glacial acetic acid (pH about 5). The mixture was concentrated and the resulting mixture dissolved in methylene chloride (300 ml). The organic layer was washed with water (100 ml), saturated sodium hydrogen carbonate (50 ml) and saturated brine (50 ml), dried over anhydrous magnesium sulfate and concentrated to a semi-solid residue. Recrystallization of the crude product from isopropyl alcohol / methylene chloride gave 6.85 g (42.8%) of the desired 2- / 3a-p-phenylbenzoyloxy-5oc-hydroxy-2β- (3-oxo-3- (2-indanyl)) -trans-1-propen-1-yl) cyclopent-loc-yl7-acetic acid} -f-lactone as white feathers melting at 170-172 ° C.

The infrared spectrum of the product (CHCl 3) showed absorptions at -1 -3 -1 1775 cm for the lacton carbonyl, at 1710 cm for the ester carbonyl, at 1670 and 1625 cm -1 for the ketonecarbonyl, and at 975 cm -1 for the trans double bond.

24 U3499 m in is t-σι σ> • t * o o cg cm

VO VQ Η H

• k * k O o

00 CO MO VO

✓Η Η H

i — 1 I ft. ft a o o

O HH

^ IS IS

Η H

cfl X} n ft CO 9 5 ti 0 s

IS IS

ΐά HH

H

§% fj «· S s; u a / ^ ° ° u! 'V> J i ϊ a ° "0f i s s n °

cS 0 = SO

^ f \\

M

t, r W

<D

d

H CM

dl

Η H

r *>

-P -P

d d

CO CO

ci S §

CO CO

d · ΰ cO to

1 I

Η H

EXAMPLE 5 iE225iilEE2E22illiil £ Z2i2E2S5ii2iii) 2 ^ -i222E2 - ^ - i-2i22_2S_.2; l3oc- £

A ^ SYl ^^^^ YiSiZr ^ a-hYdroxY ^ igg - ^^^ hYdroxY - ^ - ^ S-indanYll ^ trans-l-progen-l-Yl ^ cYclogent-la-Y ^ -acetic acid-Y-lactome

To a solution of 6.73 g (14.0 millimoles) of 2- (3a-p-phenylbenzoyl-oxy-5α-hydroxy-2β- (3-oxo-3- (2-indanyl) -trans-1-propylene) 1-yl) cyclopent-1-yl) acetic acid N-lactone in 67 ml of dry tetrahydrofuran in a dry nitrogen atmosphere at ambient temperature was added dropwise to 14.0 ml of a 0.5M zinc borohydride solution. After stirring at room temperature for 1.5 hours, a saturated sodium hydrogen tartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 minutes, then 150 ml of dry methylene chloride was added. After drying over magnesium sulfate and concentration (water jet pump), the resulting semi-solid was purified by column chromatography on silica gel (Baker "Analyzed" Reagent, particle size 0.074-0.250 mm) to obtain the use of mixtures of ethyl acetate and ether as eluent. After eluting minor polar impurities, a fraction containing 2.21 g (32.8% yield) of 2- (3α-β-phenylbenzoyl-oxy-5α-hydroxy-2β- (3α-hydroxy-3- (2- indanyl) -trans-1-propen-1-yl) cyclopent-1a-yl) acetic acid β-lactone and a fraction containing 1.79 g (26.6% yield) of 2- (3α-β-phenylbenzoyloxy-5α -hydroxy-2β- (3β-hydroxy-3- (2-indanyl) -trans-1-propen-1-yl) cyclopent-loc-yl) acetic acid-Y-laetone.

The IR spectrum (CHCl1) for both products showed strong absorption at 1770 cm “((lactone carbonyl) and 1705 cm“ ((ester carbonyl) and a mean absorption at 970 cm “^ (trans-alkene).

26 143499

_ ΙΑ ΙΑ O O

Jp IS C- C- E'- p o \ σ \ cj \ o \ S «► ·> ·>

S IA IA IA IA

Η Η Η H - S- S S S

Η Η Η H

® ti ai «*

IA in 1A 1A

s s s s

S S S S IN

M Η Η Η H

• k u · * æ h

O H * H

o cd O Pi fe, c *. Q) o) a> bo _ to tI ri ri φ o S .iHhhh s p ® * 1 i o o o φ cd H <i Sj iA s a a β I od o S '-N wl H II ti O CM m fe p

«HK g O

O <D

^^ HH HU

Φ \ K ·. TJ Φ

S V P ti s P

. X £ S ra -P

S · * / \ ft H 0)

£ fln S <<J pQ W O

CQ \\ O CQ Qi 0

n; rf e: B

β ° \ 1 T) W

2 \ Zb S 5 i

S 0 = 0 ^ S H

o I S fe fe fe fe fe H

'H / \ W J g J g -H

sea ! § φ T cd ©

M A · I P

-j p t. o

H l () l <D CD H

fe ril P a o

g H fe O

i «* rl Φ ·· P s O ti Φ

a o P

m p p „® ra a

• ri Q) H

P P ·· cd to C \ u >> bo m ^ O H <P Φ cd Tl a τΙ

O -H

<1 Si

NI o bO

W Η Η H W S

k *> ίζ »Μ * £ j p 4J p p cd t!

P P P P H M

cd cd 3 cd Ti ® a a a a a h cd cd cd cd >> fe τι td tj ti p o cd cd cd cd to Ό C *

1-4 Η Η Η cd P

EXAMPLE 4 2- / 3α? 5o> Dihydroxy-2 (3- (3a-hydroxy-3- (2-indguai) -trins-1-priggen-1

ZLL £ Z2i2E®} irl "zZiZ® ^^ ®®ZE®iIii2Si22i

A heterogeneous mixture of 2.21 g (4.46 millimoles) of 2- [3oc-p-phenyl-benzoyloxy-5a-hydroxy-2β- (3oc-hydroxy-3- (2-indanyl) trans-1-propylene-1 -yl) cyclopent-1α-yl-acetic acid T-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 ° C. cooled solution was added 4.46 ml of 1.0N hydrochloric acid. After stirring at 0 ° C for a further 10 minutes, 75 ml of water was added while forming methyl p-phenyl benzoate, which was collected by filtration. The filtrate was concentrated by rotary evaporation and then extracted with ethyl acetate (3 times), and the combined organic extracts were dried over magnesium sulfate and concentrated to give 924 mg (66%) of viscous oily 2- dihydroxy-2β- (3α-hydroxy-3- (2-indanyl) -trans-1-propen-1-yl) cyclopent-1α-yl7-acetic acid-1β-lactone.

The IR spectrum (CHCl 3) showed a strong absorption at 1770 cm -1 for the lactone carbonyl and a mean absorption at 970 cm -1 for the trans double bond.

28 143499 p æ i-1

ISLAND

, -J ft Ί1 ®

cl P

O ®

w o ΙΓν ΙΛ ΙΓΊ IA S

Π— E ^ - C— t— C— cd ολ ον σ \ σ \ CTi ιι • p & πj »« “* * Λ S ooo in ai t- C · - C" C * - C "" Η Η ^ Η Η H ^

H

ISLAND

ft p t H *

a .S

u a «2 ff ^ ft

s | .1 φ φ Φ Φ Φ J

φ pj · Η · Η · Η · Η -Η 5 g] Η Η Η Η Η β m \ Ο Ο Ο Ο Ο · Ρ> 1-1 α). <2 «- ο Η c-g Η φ w 3 ΰ ο 3 rt ν 'C0 6 Vg ^ ι S / °« s «8% ο & ij & ^ & ® <V-,. / Κ g J S α S α> 2- x i — i y 3 \ _ «71 —-p P Ό Zj

Il ΰ h ^ s o PI O Η H CM CM a ra • r4 «Η cd p bo o

-P

CD

S

island

P

Λ

ISLAND

xa Η Η Η H W)

> »'>>>» >> CO

Η -P -P -P -P H

V, P P P β · ΰ

C; cd cd cd cd P

3 a a i s >>

ti cd cd cd ro IH

rj ti ti xl • h cd cd cd cd ^ i I I I I cd <J | CM ι-f Η Η H w 29 EXAMPLE 5 yloxyT7-3- (2-indanyl) -trans-1-propene-17yl) cyclopent-1-yl7-acetic acid

To a solution of 0.924 g (2.94 millimoles) of 2- / 3α, 5α-ά ^7άΓ0Χ7-2β- (3oc-hydroxy-3- (2-indanyl) -trans-1-propen-1-yl) cyclopentene Loc-yl-acetic acid-Y-lactone 49 ml of anhydrous methylene chloride and 0.86 ml of 2,3-dihydropyran at 0 ° C in a dry nitrogen atom 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 washed with saturated sodium hydrogen carbonate solution (1 x 15 ml) and then with saturated brine (1 x 15 ml), dried over anhydrous magnesium sulfate and concentrated to give 1 38 g (97.8%) of crude 2- / 5cc-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3β- / tetrahydro-pyran-2-yloxy7-3- (2-indanyl)) trans-l-propen-1-yl) cyclopent-loc-yl7 acetic acid-Y-lactone, which was used without purification.

The IR spectrum of the product (CHCl 3) exhibited a strong absorption at −1 ^ΊΊ 1755 cm for the lactone carbonyl and a mean absorption at 965 cm for the trans double bond.

30 U3499 u æ i — i o ft 0) u

<D

a rT “'a s o w o O O ΙΑ ΙΛ ¢. S S N. · * Ni σ \ σι ^ ^ <τ> m -p δ (tf «λ · * ·. · * F — t rj m o o m in o \ D N N N ft

pi C «- S S N S

© Η Η Η Η H © w

Ten

G

g 1 i s u c2 <·

^ G H

g S £ i §! . Imsi i r. \ W rj

© V · O I

© ov Γ 3 3 tw s g J h o vi ©

'H o + J

PU ø £ H file O Η H w N -p © j

* P H

£. i S λ ^ w • ri © bo

ISLAND

-P

«A o β Λ o © Η ιΗ Ηi H W) ^ ©

Η -P -P -P -P H

>> a s s a © c © © © © c © a a s a

© © © © -P

g © τ> τί τ) • η © © © © ^ i i i i i © <J | CVI Η Η Η H ^ 31 143499 EXAMPLE 6 2iZI “ihZ ^ £ 2iZl ^ 2lii®ii! ^ 2 ^ 22Zr§Sz2rZl222ji2g:; _ (3a ::; / ietrahydro2Yran ;; 2-

YiSiZZl ^ ii ^ indan ^ lj-trans ^ l ^ roEen-l-Yljcyclogent-la ^^ iZSSSiS ^ Sz »ZÉzXiil2 £ i2 £ 2i2li

A solution of 1.39 g (2.9 millimoles) of 2- [5a-hydroxy-3oc- (tetrahydro-pyran-2-yloxy) -2β- (3α / tetrahydropyran-2-yloxy7-3 ”(2-indanyl) ) -trans-1-propen-1-yl) cyclopent-1a-ylacetic acid-Y-lactone in 20 ml of dry toluene was cooled to -78 ° C in a dry nitrogen atmosphere. To this cooled solution was added 4.2 ml of 20% diisobutyl aluminum hydride in n-hexane dropwise at such a rate that the internal temperature never rose above -65 ° C (15 minutes). After a further 30 minutes of stirring at -78 ° C, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature and concentrated by rotary evaporation. The resulting oil was slurried in methanol and filtered to remove aluminum salts. Concentration of the filtrate gave the crude product which was purified by column chromatography on silica gel (Baker "Analyzed" particle size 0.074-0.250 mm) using mixtures of benzene and ethyl acetate as eluant. After removal of minor polar impurities, the desired 2- / 5oc-hydroxy-3α (tetrahydropyran-2-yloxy) -2β- (3α / tetrahydropyran-2-yloxy7-3- (2-indanyl) -trans-1- propen-1-yl) cyclopent-1a-yl7acetaldehyde-V-hemi-acetal as a viscous oil, weighing 1.17 g (84.3%).

The IR spectrum (CHCl3) of the purified product showed a mean absorption at 975 cm for the trans double bond and no carbonyl absorption.

32 143499 ti æ

tH

ISLAND

Ή H Q) ti

S CD

w 8

II

ti &

+3 S

cd in in in ία ία ti isisnisis CFv (Ti (Tv (Ti (Tv Η β

H

o ft

<D

ti ti r * ^ fi Ή

® S

! å £, ->] • d i Ifeaiai o Λ (4 o

S X

0) H

H <j> Φ i * rj ti fi. ti • H <, +> tø ΓΊ φ O ®.

tfj O (X <Η ύ M cd s Vs

o g (S.

H V "* <V H

—1 * ti | O Η H CM C \ j H

v c, / 1 -ti fc / ;, i / - ° S a Ϊ * o

They w 01

E-1 -H

<H

cd thaw ha o

-P

cd a o ti -ti

ISLAND

CQ

P Η Η Η 5P

ί> ϊ ϊ> ί i> i cd

Η -P -P -P P H

> »Ti ti ti ti" 2 ti cd cd cd cd ti cd s a s a j >>

ten cd cd cd cd H

ti τ3 · 0 τΙ τ) ti cd cd cd * ^ I I I I I ® <a; | C \ I rl rti i-1 H s ^ / 33 EXAMPLE 7 ^ il ^ ZÉESiYzliiiiSa-bis- ^ tetrah ^ drug-g-Ylox ^ J-lS - ^ - indan ^ l ^ -cis-5-trans-13 -Uj -pentanorprostadienic acid:

To a solution of 3.21 g (7.24 millimoles) of (4-carboxy-n-butyl-triphenylphosphonium bromide in 6.0 mL of dry dimethyl sulfoxide under a dry nitrogen atmosphere was added 6.96 mL (14.0 millimole) of a 2 , 1M solution of sodium methylsulfinylmethide in dimethylsulfoxide To this red ylide solution was added dropwise a solution of 1.16 g (2.41 millimoles) of 2-5a-hydroxy-3 3α-17Eetrahydropyran-2-yloxy7-3- (2-indanyl) -trans-1-propen-1-yl) cyclo-pent-1α-yl7acetaldehyde-γ-hemiacetal in 2.0 ml of dry dimethyl sulfoxide over 20 minutes. After a further 2.0 hours of stirring at room temperature, the reaction mixture was poured into ice-water, the basic aqueous solution acidified to pH about 3 with 10% hydrochloric acid, the acidic solution extracted with ethyl acetate (3 times) and the combined organic extracts washed with water (2 times), dried over magnesium sulfate and evaporated to give a solid residue. This solid residue was triturated with ether and filtered, and the filtrate was concentrated 1.99 g (> 100%) of 9 <xhydroxy-11α, 15α-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5 “trans-13 -Cd-pentanorprostadioic acid, which was used without further purification.

The IR spectrum (CHCl,) of the purified product showed a strong absorption at 1710 cm ”" for the acid carbonyl and a mean absorption at 970 cm “^ for the trans double bond.

143499 34 • u æ

H

ISLAND

P.

H

in β)

S P

o φ ^ a

o o o o o II

p * · P · * Γ * - Γ - "* P *** pj +> σ \ o \ o \ o \ σ * g CO .....

P UT O O O O

O O O "-I t-l ·> ώ ps. Ρ». P- * p> »r- j, H - · ·“ · • * "4 ·“ * '—C g

H

up.

(1)

P

T)

P

• H

3

S

H H

t §

U.S

ten in Cd Λ

^ tg ti N- / H

. CNi / '- n U PM ^ P «* rrt -P 0 ^ 4 ffiS» 43i-ia, 2 o w Λ a, o £

/ v λ P

t, <v K. -P

3 <,? 'IS' *

ϊ x "Ή I

^ \ · Η ni 'tt Ώ

L O C | O r-l - * CM OJ O

5 S s ™ H *

* 1 CQ

£ i! 0) Tj

S S

^ WJ

o -μ

cO

a o k X! o 03 & 0

CO

r-1 r-l r-l H _l

^ rH

r-l 4J U 4J -U y

Ps c c a c g β td cd cd cd> * <d g g E £ E- <• o cd cd cd cd β * u Ό Ό * o Λ

• ri d cd cd Cd W

I I I I I ® <j | N Η Η Η H N— EXAMPLE 8

A solution of 602 mg of 9α-hydroxy-11α, 15α-bis (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13-UJ-pentanorprostadienic acid in 10 ml of a mixture of glacial acetic acid and water in the 65:36 volume ratio 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", particle size 0.074 - 0.149 mm) using mixtures of chloroform and ethyl acetate as eluant. After eluting minor polar impurities, 9a, 11cc, 15oc-trihydroxy-15- (2-indanyl) -cis-5-trans-13-w-pentanorprostadioic acid was collected as a white solid weighing 156 mg (39%) and melted at 114-115 ° C (from ethyl acetate).

The IR spectrum of the product (KBr) showed a strong absorption at 5.77 µm for the acid carbonyl and a mean absorption at 10.25 µm for the trans double bond.

36 143699 ro

H

u g o ^ Λ 1? ^ m ^ tn µ m _ _ w 7 O S 3 i i 3 s g ^ g ^^ p · © ^ tn v «η in n, - 'cm cm cm © tn .o' · -— m

cd η * o Γ '. o o <D

ij O 't-l CT> r-t r-1 g

* ..... II

Ό -i O -d- vi £) «- <oo Ι-t ro oo & nj Is». h »'- p H tn r-4 tn ΙΛ» u 8

H

O O O

in oo ft tn vo HH © 1 1 h in in ti

• | Q) · »Q)« 0) C

pJ -H m -H n- -H H

al h tn h vo h a

CQI O Η O Η O II

d s Φ a d S 9 fi-l ^ 4 Ό ro ~ jj

S W S H S H S I

s I

H 8 <D φ ^ W Ci_l

β CVJ \ J

#rj O

o U <£ / * ^ o (^ ®

Ci_i \ ώ +3

\ O * H

© / X «d ^ \ V® 3

S)] l in C | o> -t r-l CM CM O

• H / \ B

u V-f © © / rj "d si / Γ *

> * oi »<* H

\ cd \ ίπ% ω w o

-P

cd a o u Λ o to

bO

CD

t — I »—I · - <· - · r-I

^ ih ^ rrj ^ u u u U £ >> ti d C ti β d td td td cg> i «g g g g E-t * o cd nj <d nj e ό * 2 Ή" 2 ^ -n

• h ca td <d td M

I I I I I CO

<J | CM it rM * - · · · · - 143499 37 EXAMPLE 9 2l222l! I “il5a-Lis- ^ tetrahYdro] 2Yran-2-; £ i2 ^ 1“ i £ li2ii2 <i £ 2Zi} l £ i2l5-trans. 13-l-2-tentanorgrostadiens ^ re_:

To a solution of 1.32 g (2.34 millimoles) of 9α-hydroxy-11cc, 15α-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13-U penta-prostadioic acid in 15 ml of reagent pure acetone, cooled to -10 ° C under nitrogen, was added dropwise 1.17 ml of Jones' reagent. After 15 minutes at -10 ° C, 1.17 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes, then combined with ethyl acetate, washed with water (2 times), dried over magnesium sulfate and concentrated to give 1.11 g (84.2%) of 9-oxo-11cc, 15a-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13-N-pentanorprostadioic acid, which was used without purification.

U3A99 38 g Η

ISLAND

ft <1>

U

Q)

S

II

"V

u æ

H

o ft Q) cl

C

• H

p

II

ft ^, i <D o p * ^ £ l ^ ώ cd

H

S Ih ti Φ o -µ 'µ ω tJ ® o? m S cd ti p

O _ CD

ta w p

Hq · Η

ω g H

'P, <H

£ /

• H \ CM C | O> -l r-l CM O

ti / U Pj <2 \ vi 3 fe {S 's bO' i_ / b0

* H / "* O

Η o— / I +5 ti ° = <cd © \ e> * é>. h PLI Λ w o h ta

bD

i — t »—i t — i i — i cd ί * ι t N | - | jj ti -u u y> ·, c c c c ^

, ff ra ni «ns C

§ ε g e g >> tø tu ni <3 Eh β Ό Ό Ό Ό., 4 itf d <S <β

i i i i M

<| EXAMPLE 10 39 143499 9-Qxo-11a, 15a-dihydroxy-15- (2-indanyl) -cis-5-trans-13-lu-pentanor-prostadic acid

A solution of 1,11 g of 9-oxo-11a, 15a-bis (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13-ω-pentanorprostadlenoic acid in 15 ml of a mixture of glacial acetic acid and water in the 65:35 volume ratio were 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 (,, Mallinckrodi ^ fcc-4 ", particle size 0.074-0.149 mm) using mixtures of chlorodorm and ethyl acetate as eluent. After elution of less polar impurities, 9-oxo was collected. 11a, 15a-dihydroxy-15- (2-indanylίο in s-5-trans-13-uJ -pentanorprostadioic acid as a white solid weighing 288 mg (37%) and melting at 110-112 ° C (from ethyl acetate / hexane).

The IR spectrum (KBr) product showed strong absorptions at 5.68 µm for the ketone carbonyl and at 5.84 µm for the acid carbonyl and a mean absorption at 10.25 µm for the trans double bond.

143499 40 o o o o o ί§

H C1— C— C— C— H

I & o \ o \ o \ 0 \ O

o «*» * »» W o o o o o ® Η Η Η O H & at c— c ^ - t— C— C1— o)

+> ι-j Η Η Η H S

CO ..

tw .. »» “· II

o lf \ ΙΛ in 1Λ ai fo fo fo fo Oj

h S

Η Η Η Η H

• t h 8

H

ISLAND

ft p | 0)

Hl tu ® ® Φ Q>

CO -H -H j j j 'O

Ti Η Η Η H ti 0 O O O O · Η

S

S »a (¾

S J

? *

«H

i J Λ I

S o O S

s <Λ 3 M \ S *! B S ^ S »-3 S I H / o g

5 J> 8 S

W <**) - (+ * ® 5

h o = (S.

© \ ij li * 5 Ϊ · S g 0 »d µ

'* M

• H

dl O Η H CM CM * H

1 at

U

bO

ISLAND

-P

that s o

X

ta Η Η Η H U) ·>,> »>. S <g

H -H -P -g + J H

& § § § § B

1 § S of J &

d · ϋ Ό τ) tJ

• η λ co ca at I I I I I, c «

<J | CM Η -Η Η H

EXAMPLE 11 41 143499 [α] ³²gyGγj - 9-Oxo-11α, 15β-dihydroxy-15- (2-indanyl) -cls-5-trans-2,3-W-gentanorgrostadienoate

To a mixture of 60 mg (0.15 mmol) of 9-oxo-11a, 15a-dihydroxy-15- (2-indanyl) -cis-5-trans-13- ** - pentanorprostadienic acid and 255 mg (1.5 mmol ) p-phenylphenol in 6 ml of dry methylene chloride was 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 chromatography on silica gel ("JTBaker®Analyzed", particle size 0.074-0.250 mm) using mixtures of chloroform and ethyl acetate as eluant. After removal of less polar impurities, the solid p-biphenyl-9-oxo was collected -lla, 15a-dihydroxy-15- (2-indanyl) -cis-5-trans-13-u-pentanor-prostadienoate, weighing 45 mg and melting at 103-104.5 ° C (from methylene chloride / hexane) .

The IR spectrum of the product (KBr) showed strong absorptions at 5.65 µm for the ketone carbonyl and 5.70 µm for the ester carbonyl and a mean absorption at 10.35 µm for trans double bond.

EXAMPLE 12

PzgiE SBiii ^ ^ ^ i.i ^ iSSSrii Pidihydroxy-LS-Ig indanylJ ^ cis-S-trans

To a mixture of 60 mg (0.15 mmol) of 9-oxo-11α, 156-dihydroxy-15- (2-indanyl) -cis-5-trans-13-io-pentanorprostadioic acid and 255 mg (1.5 mmol) p-phenylphenol in 6 ml of dry methylene chloride was added 1.65 ml of a 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 chromatography on silica gel ("J.T.Baker®Analyzed", particle size 0.074-0.250mm) using mixtures of chloroform and ethyl acetate as eluant. After removal of minor polar impurities, the solid p-biphenyl-9-oxo-11α: 150-dihydroxy-15- (2-indanyl) -cis-5-trans-13-OJ-pentanorprostadienoate which was weighed was collected. 34 mg and melted at 98-100 ° C (from methylene chloride / hexane).

The IR spectrum of the product (KBr) showed strong absorptions at 5.66 µm for the ketone carbonyl and 5.77 µm for the ester carbonyl and a mean absorption at 10.35 µm for the trans double bond.

EXAMPLE 13 p-Biphenyl-9g, 11a, 15g-trihydroxy-15- (2-indanyl) -cis-5-trans-13- (3-pentanorprostate)

To a mixture of 60 mg (0.15 mmol) of 9α, lloc, 15α-trihydroxy-15- (2-indanyl) -cis-5-trans-13β-pentanorprostadioic acid and 255 mg (1.5 mmol) p-phenylphenol in 6 ml of dry methylene chloride was added 1.65 ml of a 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 chromatography on silica gel ("J.T.Bakei® Analyzed", particle size 0.074-0.250 mm) using mixtures of chloroform and ethyl acetate as eluant. After removal of minor polar impurities, the solid p-biphenyl-9cc, 11a, 15a-trihydroxy-15- (2-indanyl) -cis-5-trans-13-tu at 134-135 ° C (from methylene chloride / hexane).

The IR spectrum of the product (KBr) showed a strong absorption at 5.68 µm for the ester carbonyl and a mean absorption at 10.35 µm for the trans-double bond.

EXAMPLE 14 2Si 2 S 2 S 2 S 2 S 2 S 2 5 5-TrihydroxY-15-(2-indanil) cis-5-trans-13; pentanorprostadienoate

To a mixture of 60 mg (0.15 mmol) of 9a, 11a, 15β-trihydroxy-15- (2-indanyl) -cis-5-trans-13-tho-pentanorprostadioic acid and 255 mg (1.5 mmol) phenylphenol in ml of dry methylene chloride was added 1.65 ml of a 0.1M solution of dicyclohexylcarbodiimide in methylene chloride. The mixture was stirred for 1 h at room temperature under nitrogen and then concentrated. The solid residue was purified by chromatography on silica gel ("JTBake® Analyzed", particle size 0.074-0.250 mm) using mixtures of chloroform and ethyl acetate as eluant. After removal of less polar impurities, the solid p-biphenyl-9cc, 11α was collected , 15β-Trihydroxy-15- (2-indanyl) -cis-5-trans-13-U-pentanorprostadienoate, which weighed 40 mg and melted at 98-10O ° C (from methylene chloride / hexane).

The IR spectrum of the product (KBr) showed a strong absorption at 5.65 µm for the ester carbonyl and a mean absorption at 10.20 µm for the trans double bond.

EXAMPLE 15 2zP® Scarbo ^ -2- {tetrazol-5-Yl2-9oc = hydroxy-11a15oc: bis = _ (tetra.Y; rostatic acid

To a solution of 2.13 g (4.56 mmol) (4- (tetrazol-5-yl) -n-butyl) -triphenylphosphonium bromide in 5.0 ml dry dimethyl sulfoxide under a dry nitrogen atmosphere was added 4.50 ml (8, of a 1.90M solution of sodium methylsulfinylmethide in dimethnylsulphoxide To this red ylide solution was added dropwise a solution of 755 mg ^ 1.52mmol; 2- / 5a-hydroxy-3a (tetrahydropyran-2-yloxy) - 2β- (3α / tetrahydropyran-2-yloxy7-3- (2-indanyl) -trans-1-propen-1-yl) -cyclopent-1-yl7acetaldehyde-γ * -hemiacetal in 6.0 ml After a further 1 hour stirring at room temperature, the reaction mixture was poured into ice-water. The basic aqueous solution was acidified to pH about 3 with 10 # hydrochloric acid. The acid solution was extracted with ethyl acetate (3x combined organic extracts washed once with water (10 ml), dried over magnesium sulfate and evaporated to give a solid residue. The crude product was purified by column chromatography on silica gel ("JTBakeinalyzed Reagent" , particle size 0.074-0.250 mm) using mixtures of chloroform and ethyl acetate as eluant. After removal of high Rf impurities, 825 mg (81.5 #) of 2-descarboxy-2- (tetrazol-5-yl) -9a-hydroxy-11a, 15a-bis- (tetrahydropyran-2-yloxy) - was collected. 15- (2-indanyl) -cis-S-trans - ^ - ^ - pentanorprostadioic acid.

The IR spectrum of the product (CHCl 3) showed mean absorption at 970 cm -1 for the trans double bond. The thin-layer chromatographic mobility of ester-alcohol was less polar.

EXAMPLE 16 2zPescarbo ^ = 2- (tetrazole = 5zYl2z9aillai15aitrihyloxy = 15- {2; indanyl);: £ 15.5; trans-13-utE £ £ 5 £ 2EEE25 diacetic acid

A solution of 458 mg of 2-descarboxy-2- (tetrazol-5-yl) -9a-hydroxy-11a.) 15a-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5- trans-13-ui-pentanorprostadioic acid in 10 ml of a mixture of glacial acetic acid and water in the 65:35 volume ratio 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 ("Mallinckrodi® C7", particle size 0.074-0.149 mm) using mixtures of chloroform and ethyl acetate as eluant. After elution of minor polar impurities, 2-descarboxy-2- (tetrazol-5-yl) -9a, 11a, 15a-trihydroxy-15- (2-indanyl) -cis-5-trans-13-β-pentanorprostadienic acid was collected as a solid weighing 228 mg (69.6 #), m.p. 125-126 ° C.

45 143499

The IR spectrum (KBr) of the product showed a strong absorption at 10.25 µm. The thin-layer chromatographic mobility of ester-alcohol was less polar.

EXAMPLE 17 ^ zDescarboxy-g ^ Ctetrazol-yl ^ g-oxo-11a-11a-bis-tetrahydropylTan-2 = ylo ^ 2-15- (2-indanyl) -cis-5-trans-13;

To a solution of 366 mg (0.62 mmol) of 2-descarboxy-2- (tetrazol-5-yl) -9a-hydroxy-lloc, 15a-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) ) -cis-5-trans-13-Wx, pentanorprostadienic acid in 15 ml of reagent pure acetone, cooled to -10 ° C under nitrogen, was added dropwise 0.31 ml of Jones' reagent. After 15 minutes at -10 ° C, 0.31 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes, then combined with ethyl acetate, washed with water (2x), dried over magnesium sulfate and concentrated to give obtained 340 mg (93%) of 2-descarboxy-2- (tetrazol-5-yl) -9-oxo-11,15a-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5 -trans-13-w-pentanorprostadioic acid, which was used without purification.

The thin-layer chromatographic mobility of ester-alcohol was less polar.

EXAMPLE 18? LP§§2§r ^ 2 Zlilii®ir§52il5iYl) z9-oxo-11a11a-dihydroxy; 15- (2-indanyl) = cis-5-trans-13 rostadiensyre

A solution of 340 mg of 2-descarboxy-2- (tetrazol-5-yl) -9-oxo-11α, 15α-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans -13-w-pentanorprostadioic acid in 10 ml of a mixture of glacial acetic acid and water in the 65:35 volume ratio was stirred under nitrogen at room temperature for 16 hours and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel ("Mallinckrod-bc-", particle size 0.074-0.149 mm) using blends of chloroform and ethyl acetate as eluant. After eluting minor polar impurities, 2-descarboxy-2- (tetrazol-5-yl) -9-oxo-11a-15a-dihydroxy-15- (2-indanyl) -cis-5-trans-13-w ^ -pentanorprostadienic acid as viscous oil, weighing 58 mg (23.8 ^).

The IR spectrum of the product (CHCl3) showed strong absorptions at 1740 cm 2 for the ketone carbonyl and at 970 cm -1 for the trans double bond. The thin-layer chromatographic mobility of ester-alcohol was less polar.