FI58912C - ANALOGIFICANT FARMS FOR FRAMSTAELLNING AV NYA THERAPEUTIC ACTIVATING ACTIVITIES THEREOF PROSTAGLANDINSERIERNA E OCH F - Google Patents

Description

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Vi® (45) Fac-nt ·· -; l: t ^ ^ (51) Kv.ik.3 / im.a.3 C 07 C 177/00 FINLAND —FINLAND (21) l »ttuimih * k * mu .-P «*. Nau ^ knlnI 3 ^ 55/73 (22) H» k * ml * pttvt - An * eknlng * d «g 08.11. T 3 (23) AlkupiM — Glftl | Hut * l »f 08.11.73

(41) Interpreters Swept - Bllvlt affuntllg 09.05.7U

Patent ·] · r «ki <t« Hh * llitut / iA. . ,,.,, _ * (44) DIMM -

Patents and Trademarks AntOkm utktgd och uti. * Cryptocurrencies published 30.01.8l (32) (33) (31) Pyydutcy utuoikum — Buglrd priority 08.11.72 USA (US) 301 + 750 (71) Pfizer Inc., 235 East * + 2nd Street, New York, NY, USA (72) Hans-Jurgen Ernst Hess, Old Lyme, Connecticut, Thomas Ken Schaaf,

Old Lyme, Connecticut, USA (7 * 0 0y Kolster Ab

(5 * +) Analog method for the preparation of new therapeutically active prostaglandin series E and F compounds - Analogifarfarande för framställning av nya, therapeutiskttiva föreningar tillhörande prostaglandinserierna E och F

This invention relates to the preparation of certain novel analogs of naturally occurring prostaglandins. In particular, it is directed to the preparation of new 15-substituted-U / pentanorprostaglandins.

Prostaglandins are C-20 unsaturated fatty acids with various physiological effects. For example, E- and A-series prostaglandins are potent vasodilators (Bergström, et al., Acta Physiol. Scand. 6 * 1: 332-33, 1965 and Bergström et al., Life Sci. 6: UL9 ~ U55, 1967). and lower intravenous blood pressure (vasodepression) when administered intravenously (Weeks and King, Federation Proc. 23: 327, 196 ^ Bergström, et al., 1965, op.cit .; Carlson, et al., Acta Med. Scand. 183 : 1 + 23-1 + 30, 1968 and Carlson, et al., Acta Physiol. Scand. 75: 161-169 »1969). Another well-known physiological function for PGE1 and PGE1 is their function as bronchodilators (Cuthbert, Brit. Med. J. * +: 723-726, 1969).

Yet another important physiological role for natural prostaglandins is related to the reproductive cycle. PGE 1 is known to have the ability to induce 2,58912 postpartum burns (Karim, et al., J. Obstet. Gynaec. Britt. Cvlth. 77: 200-210, 1970), to induce therapeutic miscarriage (Bygdeman, et al., Contraception, 1+ , 293 (1971)) and to be useful in the regulation of fertility (Karim, Contraception, 3, 173 (1971¾). +1) and for PGFβ, Fβ1 and Fβ1 to regulate the reproductive cycle (ZA Patent Publication No. 69/6089).

Ch has shown that luteolysis can occur as a result of PGFgβ administration (Labhsewar, Nature, 230, 528 (1971)) and therefore prostaglandins have utility in birth control through a mechanism in which smooth muscle stimulation is not necessary.

Still other physiological activities known to PGEI include inhibition of digestive acid secretion (Shaw and Barnwell, In: Worcester Symp. On Prostaglandins, New York, Wiley, 1968, pp. 55-61 +) and inhibition of platelet aggregation (Emmons, et al. ., Britt. Med. J. 2: 1 * 68-1 + 72, 1967).

It is known that such physiological effects are produced in vivo only for a short time as a result of prostaglandin administration. There is ample evidence that the reason for this rapid cessation of activity is that natural nonprostaglandins are rapidly and efficiently deactivated metabolically through oxidation in the carboxylic acid side chain and through oxidation of the 155 (- hydroxyl group) (Anggard, et al., Acta Physiol. Scand. , 81, 396 (1971) and references therein) It has been shown that the addition of a · 15-alkyl group to prostaglandins increases the duration of action, possibly due to inhibition of C 1-4 hydroxyl oxidation (Yankee and Bundy, JACS, 9, 3651 (1972)). Kirton and Forbes, Prostaglandins, 1, 319 (1972).

It was considered desirable to provide analogs of prostaglandins that had the same physiological activities as natural prostaglandins, but with increased selectivity and duration of action. The increased selectivity of the effect could be expected to alleviate adverse side effects, especially in the gastrointestinal tract, which are often observed as a result of intravenous administration of natural prostaglandins (Lancet, 536, 1971) ·

The invention relates to an analogous process for the preparation of new therapeutically active prostaglandin series compounds E and F having the formula 3,581 2

M

v._I (CH) A (I) ii> N 2 n

P '^% H

wherein A is 1-adamantyl, 2- (1,2,3, U-tetrahydronaphthyl) which may be racemic or optically active or 2-indanyl which may be substituted by nitro; R is hydrogen or methyl; n is an integer from 0 to 2; W is a single bond or a cis double bond; Z is a single bond or a trans double bond; M is oxo, -N- or T-O, X is 5-tetrazolyl or a group of the formula -CONHSO4-CH3 or -COOR ', wherein R' is hydrogen, methyl, ethyl, biphenyl or 3-ethyl. cycloalkyl, and for the preparation of their C 1-4 epimers and for the esterification of any free, C 1-4 or C 1-4 hydroxy group with a lower alkanoyl or formyl, and for the preparation of pharmaceutically acceptable compounds of formula I wherein X is -C00H. The invention is characterized in that a) a compound of formula

J - L <0H 2> nA

THP (R) wherein A, n, M, R, W, X and Z have the same meaning as above and THP is 2-tetrahydropyranyl is reacted with aqueous acetic acid; b) reacting a compound of formula I wherein M is oxo with a suitable reducing agent to prepare such a compound of formula I

^^ __ ^ QJJ

si, where M οη <ΤΓ ΛΤΙ or ^ „and A, n» R, W, X and Z have the same meaning as "" // Un "////// n above, and the 9 * r and 9 ^ isomers c) a compound of formula I wherein A, R, n, M and X are as defined above, W is a single bond or a cis double bond when Z is a trans double bond and Z is a single bond when W is cis d) a compound of formula I wherein A, R, n, M and X are as defined above and W and Z are a single bond; M and X are as defined above and W and Z are a double bond, are selectively hydrogenated by reaction at one atmospheric hydrogen pressure in the presence of a palladium catalyst on 5 ~ carbon in absolute methanol to give a compound of formula I wherein A, R, n, M and Z has the same meaning as above, W is a single bond and Z is a trans double bond, and a compound of formula I wherein X is -COOH is optionally converted to an ester by reaction with a suitable esterifying agent; and from any free hydroxy group, if desired, preparing an alkanoyl or formyl ester of> 11 ° C or 15 ° C by reacting a compound of formula I with a suitable acylating agent; and converting a compound of formula I wherein X is -COOH, if desired, to a pharmaceutically acceptable salt.

It is further to be understood that as used herein, the term "zero series prostaglandin" refers to, e.g., PGEq prostaglandin in which the 5-6 and 13-1 ^ double bonds are saturated, i.e., the PGEq is 5.6-13.1 ^ - tetrahydroprostaglandiini. In addition, the terms "one-sets" or "two-sets" as used herein refer to the degree of unsaturation in the side chains, i.e., PGE 2 and PGF 2 are "two sets" of prostaglandins, while PGE 2 and PGF 2 are "one-set" prostaglandins. . As used herein and in the claims, the term prostaglandin encompasses both epimers in C 1-4. The term "lower alkyl group" as used herein further refers to alkyl groups containing 1-U carbon atoms.

The starting material for the various novel compounds prepared in accordance with this invention is commercially available or can be prepared by methods well known to those skilled in the art. For example, to prepare 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 a dry nitrogen atmosphere and then added dropwise under a nitrogen atmosphere. n-butyllithium in hexane. 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 gel-like material is combined with water, the aqueous phase is extracted with chloroform, and the combined organic extracts are washed, dried and concentrated to give the desired product.

To prepare the desired 15-substituted - # - pentanorprostaglandins, the appropriate acids are converted to esters as described below by known methods and then to phosphonates as described above for the 15- (2-indanyl) starting materials.

To prepare 15- (2 - (+) (1,2,3,4-tetrahydronaphthyl)) prostaglandins, (+) - 2- (1,2,3,1-naphthalene) carboxylic acid is prepared according to the procedure of Cohen, et al. by the method of J. Biol. Chem., 10, 266U (1969) »is converted to an ester and then to a phosphonate, as described in the 15- (2-indanyl) case.

To prepare 15- (2 - (-) - (1,2,3, U-tetrahydronaphthyl)) prostaglandins, (-) - 2- (1,2,3, U-naphthalene) carboxylic acid is prepared by Cohen, et al. by the method of J. Biol. Chem., 10, 266U (1969), is converted to the ester and then 5,58912 to the phosphonate as described for 15- (2-indanyl).

When 15- (2-indanyl) prostaglandins are desired, indane-2-carboxylic acid is prepared, e.g., by the method of Bergman and Hofftan, J. Org. Chem., 26, 3555 (1961), is converted to an ester and then to a phosphonate as described above; come your way.

To prepare 16- (2-indanyl) prostaglandins, 2-indanylacetic acid is prepared as described by Bergman and Hoffman, J. Org.

Chem., 26, 3555 (1961), is converted to an ester and then to a phosphonate as described in the 15- (2-indanyl) case.

To prepare 15- (2- (5,6-dimethoxyindanyl) prostaglandins, the necessary 5,6-dimethoxyindan-2-carboxylic acid must first be prepared. Condensation of N, 5-bis-chloromethylveratrol (prepared by Wood, Perry and Tung). J. Am. Chem. Soc., 72, 2989 (1950)) with ethyl t-butyl malinate in the presence of sodium hydride to give β-carbethoxy-2-carbo-t-butoxy-5,6-dimethoxyindan. treatment of the diester with p-toluenesulfonic acid in refluxing benzene followed by decarboxylation of the product affords ethyl 5,6-dimethoxyindan-2-carboxylate which is converted to the phosphonate as described for 15- (2-indanyl).

For the preparation of 16- (1-adamantyl) prostaglandins, (1-adamantyl) acetic acid is obtained from Aldrich Chem. From Col (No. 12, 727-2), is converted to an ester and then to a phosphonate as described for the 15- (2-indanyl) compound.

To prepare 17- (1-adamantyl) prostaglandins, 3- (1-adamantyl) propionic acid is prepared by the method of Fieser, et al., J. Med.

Chem., 10, 517 (1967), is converted to the ester and then to the phosphonate as described in connection with the 15- (2-indanyl) case.

When 16- (2-norbornyl) prostaglandins are desired, 2-norboroylacetic acid is obtained from Aldrich Chem. From Col (No. 12, 726-U), is converted to an ester and then to a phosphonate as described for the 15- (2-indanyl) compound.

To prepare 15- (2- (1) - (1,2,3, U-tetrahydronaphthyl)) prostaglandins, (1) -2- (1,2,3, U-naphthalene) carboxylic acid is prepared by the method of Cohen, et al. , J. Biol. Chem., 10, 266k (1969) * is converted to an ester and then to a phosphonate as described in the 15- (2-indanyl) case.

6

Scheme A

5891 2 0 0 Il t A “(CH2) n'COOCH3 - * A - (CH2) n-C-CH2-P (0CH3) 2 1 2 / ° / 3 °

__0 ^ V

/ M

'^? <*? ** + +

B

ό '

] A

T 58912

As shown in Scheme A, the first step (1-2) is to condense the appropriate ester with dialkylmethylphosphonate to give the ketophosphonate 2. Usually, the desired methyl ester is condensed with dimethyl methyl phosphonate.

In reaction 2 to 3, the ketophosphonate 2 is reacted with a known aldhyde H (Corey et al. J. Am. Chem. Soc. 93, 1491 (1971)) to give, after chromatography or crystallization, the enone 3 * A compound in which p The -biphenylcarbonyl group is replaced by a p-biphenylcarbamoyl protecting group, is also useful as a H substituent, and has the additional advantage that a greater amount of the desired α-isomer is obtained in the reduction step (3-4).

Enone 3 can be converted to a mixture of alcohols 13 and 14 by tertiary reaction with the appropriate metalloalkyl and isomers 13 and 14 can be separated by column chromatography. Enos 3 can be reduced with zinc borohydride or lithium trialkylborohydrides such as lithium triethylborohydride to a mixture of alcohols 4 and 3 which can be separated as above. Ethers such as tetrahydrofuran or 1,2-dimethoxyethane are usually used as solvents in this reaction, although methanol is sometimes preferred to ensure specificity of the reduction. Additional conversions of 4 are shown in Figure B.

4-> 6 is a base catalyzed transesterification in which the p-biphenylcarbonyl protecting group is removed. This is preferably done with potassium carbonate in methanol or a mixture of methanol and tetrahydrofuran as solvent. 6-> 7 weathering involves the protection of two free hydroxyl groups with an acid-labile protecting group. Any sufficient acid-labile group is satisfactory; however, the most common is 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.

8

Scheme B 0 - (P

5 891 2 6> n oh i y / 6 o * p ~~ \

\ C (CHp) r-A

\ JL (CH) -A THP ° '^^ XoTH? THPO · 'N ^' N, ^ H "^ '* OTHP // 8 1 << o

-> \ _ /. (CH) -A

\ 7 thpo '£

) -C. . (CH) -A Hv '' OTHP

THPO- “JO.

£ ° H ° ^! ^ '(S "'

X-) - / ^ JCH2} n “A

(CH) -A H0 '

H ^ OH

- li 9 5891 2 7 -> 8 is the reduction of lactone 7 to hemiacetal 8 using drisobutylaluminum hydride in an inert solvent. Low reaction temperatures are preferred and the range between -60 ° and -70 ° is common. However, higher temperatures can be used as long as there is no over-reduction. If desired, purify by 8 column chromatography.

8 is a Wittig condensation in which 8 is reacted with e.g. (H-carbohydroxy-n-butyl) -triphenylphosphonium brinide in dimethyl sulfoxide in the presence of sodium methylsulfinylmethide. 9 is purified as above.

Conversion 9 -> 12 is the hydrolysis of tetrahydropyranyl groups. Any acid that does not cause degradation of the molecule during deprotection * can be used, however, this is most often done in a 65-night aqueous solution of acetic acid. The product is purified as above, 9 -> 10 is the oxidation of the secondary alcohol 9 to the ketone 10. This can be done using any oxidizing agent that does not affect the double bonds; however, Jones' reagent is usually preferred. The product is purified as above.

10 -> 11 is performed in the same way as 9- * 12. The product is purified as above. Reduction of compound 11 with sodium borohydride yields the 9/5 isomer of the F-series prostaglandin analogs, i.e., PGF # compounds. These can also be obtained by reduction with sodium borohydride followed by hydrolysis as described above for 10-> 11.

5891 2 10

Scheme C OH

i k k ('l' '' NOTT- / "" 'NX J2'

^ ^ 0a (ch2> n-A

HO "H0 <^ • A ...

“-------------------- ^ 3- / (CH_) -A 11 '2n

OH

\ x J6 TO 'R ^ -' oh

. - A XX

> V _ / ^ <CH2) n-A

A / ho ^ Oh OH _l6 'l

\ _ / (CH) A

A 2 n

^ H0 HO X

R

0 iu As- -> A /. (CH) -A * '^ 2 n

HO HO A \ D

K

”58912

As shown in Scheme C, H in Scheme B can be replaced with 5, 13, and 1 U to obtain prostaglandin derivatives 12 ', 11', 16, 17, 16 'and 17'.

Scheme D shows the synthesis of precursors of 13,1β-dihydro-15-substituted-α-pentanorprostaglandins.

Reduce the enone 3 to the tetrahydro compound using any of the complex metal hydride reducing agents, LiAlK 2, NaBH 4, KBH 2, LiBH 3 and Zn 2 H 2. NaBH 2 is particularly preferred. The products, 19 and 19 * are separated by column chromatography.

Further, compounds b and 5 of the scheme can be reduced from catalytic hydrogen to 19 and 19 *, respectively. The step of reducing the double bond is not critical and hydrogenation of Scheme B 6 or 7 also provides useful intermediates for the 13,11-dihydro-prostaglandin analogs of this invention. This reduction can be accomplished with either a homogeneous catalyst such as tris-triphenylphosphine chlorodhodium (i) or a heterogeneous catalyst such as platinum, palladium or rhodium. Similarly, precursors for 15-methyl-15-substituted-N-pentanorprostaglandins are synthesized by substituting 13 and 11 for U and 5 in the synthesis just described, respectively. Conversion of 19, 19 *, 20 'and 20 to the corresponding prostaglandins follows the route shown in Scheme B when U is replaced by 19, 19', 20 'and 20 of prostaglandin derivatives 13, To obtain 1β-dihydro-PGE 6 and PGF 4 series containing hydrogen or a lower alkyl group in carbon-15.

Scheme D

3 12 5891 2 I \ f H H1 H.

«J-Ck *’ * · * φ · ® φ 3 Φ 0 iS 19 »g £

Δ A U

dr

.V-O (CH2) n-A

• S: 0 toXr Θ - ϋ · go. ' 13 5891 2

Scheme E illustrates the differentiation of the preparation of precursors of reduced 15-substituted- (i> -pen-tanorprostaglandins).

19-> 22 is performed as described in Scheme B for 4-> 9 *.

22 can be used both as a precursor for "two-series" 13,14-dihydro-15-substituted- (o-pentanorprostaglandin) or as an intermediate for 23, which is a precursor for "ykai-earjoj" 13,14-dihydro-15-substituted-u> 22- ^ 23 is carried out by catalytic hydrogenation using the catalyst described for reduction 4-H9 in Scheme D. Intermediates of type 21 are prepared by selective reduction of 5 * 6 cis-double-amino acid at low temperature using the catalysts described in 4-9 and 17 to> 23. Particularly preferred for this purpose is the use of palladium on carbon as a catalyst and the reaction temperature is -20 °. rake 9 - * 15 »but they are also precursors for the 23-type compounds by the already mentioned route 22 -> 23 · from "two-series" prostaglandin analogs, by first protecting the hydroxyl dimethyl isopropylsilyl groups by introducing, selectively reducing the cis * double moiety, and removing the protecting group.

Scheme E

U 58912 iä £

• I

y v f «

-X-X c ^^! I2) n-A

TH? 0 Η ^ ΌΪΗΡ THPÖ ^ Χ, ΟΤΠ? SS '2i \ /

OH

Λ-VvV ·

J-L. \ / (CH2) n-A

23 '23 15.- 5 891 2

The introduction of the residual group is usually accomplished by treating the prostaglandin analog with dimethylisopropylchlorosilane and triethylamine, the reduction is performed as described above for 9- ^ 21, and the deprotection is performed by contacting the reduced compound with a mixture of acetic acid and water (3: 1) for 10 minutes. until or until the reaction is substantially complete.

The C 1-4 epimers of 21, 22 and 23 can be used as precursors for the 15-episeries of the prostaglandin derivatives described above and the 15 * n-ethyl-15-substituted-1β-pentanorprostaglan -dines and their C 1-4 epimers can be prepared from the appropriately eubstituted analogs of 9 and 19, the synthesis of which follows the synthesis shown in Schemes A and B.

13,11-dihydro-N-methyl-N-substituted-u'-pentanorprostaglandins and are obtained from appropriately substituted precursors via Scheme E.

% 16 5891 2

Scheme F

0 0 J.. 1 / \ = sss \ i C00H_. rN coor HO HO R H0 HO 'Έ 11 11 E * Λ 0 0 I]>, / / ^ IP ° THPO' R THPO 'THPO' '

10 10 E

Λ

OH 0H

1 Λ = / \ / \ 1 A = / x / \ i

COOH / N COOR

-> _l / v A I / n:

ΤΗΡ <ί THPO '' Ä THPÖ THPO '* R

9 9 E

OH V

^ «/ \ __ ^ κ \ χ \ ^ οο ^

/ L- \ ^ \ -_ A

HO />

HO 'R

12 E

, τ 5891 2

For example, Scheme F shows a different route to the ester NE ”.

In each case, the esterifying group is introduced by an esterification reaction which can be carried out by contacting a suitable prostaglandin analog or its precursor with an alcohol or phenol in the presence of a catalyst. Alternatively, the prostaglandin or its precursor may be treated with a diazoalkane or cycloalkane in a reaction-inert solvent to give the desired ester. Any prostaglandin analog can be used as a substrate for the esterification reactions described above, and in addition, prodrugs of such prostaglandins or prostaglandin analogs can be used, as shown in Scheme F. For example, 9 can be converted to 9E by the esterification reaction described above, and 9E can then be converted to 10E and 12E by the same methods used to convert to 9- + d0t and 12 as described above. Compound 10E can be converted to HE by the reactions described for conversion 10-> 11.

As indicated above, esters such as 9®, 10B, 11E, and 12E can be used as substrates for various reduction schemes previously described in connection with the preparation of "one-set" and "two-set" prostaglandin analogs.

The prostaglandin analogs of this invention that are acylated at C 1-4 and C 1-4 are readily prepared from the corresponding support by acylation, which is usually performed using carboxylic anhydride or carboxylic acid chloride as acylating agents.

Mixed anhydrides (formic acetic anhydride) are used to prepare formyloxy derivatives. C 1-4, C 1-4 and C 1-4 acyloxy-prostaglandin analogs and their esters are similarly prepared from the desired PGF precursor.

Various modifications are possible in the upper side chain of the prostaglandins of this invention. The 5-tetrazolyl moiety can be placed in the β-position as disclosed in U.S. Patent Application 177102 (filed September 1, 1971) and related examples. For example, compound Θ can be reacted from ((4-tetrazol-5-yl) -n-butyl) triphenylphosphonium bromide and with a ylide derived from sodium methylsulfinylmethide to give the C 1-4 tetrazole-substituted compound 9. The conversion of 9 to the corresponding prostaglandins takes place as described above.

Another upper side chain modification that can be performed in the prostaglandins of this invention is the replacement of the carboxylate extract at the β-position with a carboximide or carboxysulfonamide moiety. Methods for preparing these compounds are disclosed in U.S. Patent Application No. 8,591,260,572 (filed 7 * 6,199). For example, 8 can be reacted with a ylide derived from (methanesulfonylaminocarbonyl-n-butyl) -triphenylphosphonium bromide and sodium methylsulfinylmethide to give a C 1-4 -N-methanesulfonylcarboxamide-substituted compound 9. The conversion of 9 to the corresponding prostag

Alternatively, the novel compounds of this invention can be prepared, for example, from compounds 9 and 10 of Scheme B by reactions with the appropriate sulfonyl isocyanates, followed by hydrolysis with dilute acid.

In the above methods, if chromatographic purification is desired, suitable chromatographic ones are included. carriers include neutral alumina, silica gel and fluorasil. Chromatography is conveniently performed in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane, n-hexane and methanol, as further described in the following examples.

It is noted that the above formulas describe optically active compounds. It is clear, however, that the corresponding racemates show valuable biological activity due to the above-mentioned biologically active optical isomer they contain, and it is intended that the above formulas include such racemates both herein and in the claims.

Racemic mixtures are readily prepared by the same methods used to synthesize optically active forms, merely replacing the optically active starting materials with the corresponding racemic precursors.

Numerous in vivo and in vitro experiments have shown that novel prostaglandin analogs have selective physiological activities comparable to those shown by natural prostaglandins.

These experiments include e.g. effect study on guinea pig uterus, guinea pig ileum and rat uterus isolated from smooth muscle, stimulation of diarrhea in mice, inhibition of histamine-induced bronchospasm in guinea pigs, effect on canine blood pressure, inhibition of gastric acidity inhibition, Inhibition of ADP-induced platelet aggregation in rats and guinea pigs by luteolytic and non-luteolytic mechanisms.

The physiological interactions observed in these experiments are useful in determining the utility of test substances in the treatment of various natural and pathological phenomena. Such identified uses include: antihypertensive activity, bronchodilator activity, .9 5891 2 antithrombogenic activity, gastric ulcer activity, smooth muscle activity (useful as a contraceptive agent, inducer of maternal burns, and contraceptive). through luteolytic mechanisms that do not affect smooth-muscle, as well as the synchronization of the reproductive cycle in countries with economy animals.

The novel compounds of this invention have more selective activity profiles than their corresponding naturally occurring compounds.

With prostaglandins and are in many cases more potent and show a longer duration of action. For example, 15- (2-indanyl) -U-pentanorprostaglandin 11a, which exhibits guinea pig uterine smooth muscle stimulating activity comparable to PGFOJ, is only 8% of guinea pig ileum stimulating activity and is at least 30-fold more active than PGF in abortion activity rats.

The 15-substituted-β-pentano-prostaglandins of PGFβ, PGFβ and 13.1 U-dihydro PGFβ are similarly selective for smooth muscle stimulating activity.

The various modifications in the upper side chain of the prostaglandins prepared in accordance with this invention do not in themselves alter the basic biological activity, although they may further increase selectivity and duration of action and decrease toxicity.

Particularly useful for birth control, induction of miscarriage, and induction of labor burns are the 15- (2-indanyl) -1H-pentanorprostaglandins of the E0 and F1 series, 15 "(1, 2,3, ^ -tetrahydronaphthyl) - \ i> - pentanorprostaglandins, 17 '(1-adamantyl) -α-trisnorprostaglandin and 16- (1-adamantyl) -di> tetranorprostaglandins, based on potent smooth muscle stimulating activity and abortifacient activity in rats and concomitant reduced blood pressure.

Likewise, the substituted β1-pentanorprostaglandins of the PGE2, PGFg1-13,11 + -dihydro PGFβ series are useful in birth control, including miscarriage and induction of labor burns based on their selective smooth muscle stimulating activity. Novel prostaglandins with β-hydroxyl in C-15 are generally less potent, although often more selective than the corresponding c (hydroxyl epimers. In addition, prostaglandins with β-hydroxyl in C-15 are valuable intermediates for prostaglandins with c ( hydroxyl in C-15 via a recycling process involving oxidation and reduction in C-15. The novel prostaglandin analogs prepared in accordance with this invention, wherein said prostaglandins represent E or F series, »are useful birth control 2 ° 5 8 91 2 properties and are still useful in synchronizing the reproductive cycle in animals.

The novel 15-methyl compounds of this invention have the same activity profile as the novel prostaglandin analogs wherein R is hydrogen and from which they are derived. Their particular utility depends on the fact that their duration of action is greatly increased in relation to the above-mentioned compounds in which R is hydrogen and, in cases where this is essential, are generally considered to be the preferred 15-methyl compounds. Prostaglandin analogs having a beta-hydroxyl in C 1-4 and a C 1-4 methyl group have a similar effect as their epimers. In a few cases, however, the selectivity shown by these compounds exceeds the selectivity of the epimeric compounds.

Therapeutic comparative experiments I Experiments performed A. Spasmodic effect on the isolated uterus of the guinea pig: the experiment demonstrates the birth-regulating activity induced by uterine irritation.

B. Protection of guinea pigs against toxic aerosol administration of histamine by aerosol administration: the experiment shows bronchodilator activity.

C. Hypotonic effect of the drug in anesthetized dogs: the experiment shows anti-hypotonic activity.

B. Induction of diarrhea in mice: the experiment reveals the usual side effects caused by prostaglandins.

2. Inhibition of pentagastrin-stimulated gastric acid secretion: the experiment shows anti-secretory (anti-ulcer) activity.

F. Abortion activity in rats: The experiment demonstrates birth control activity induced by ectopic stimulation (e.g., luteol).

II. Test compounds

Natural PGE 2 and PGF 2 were used as reference compounds, and the results of numerous pharmacological and clinical experiments have been published.

1) 16-adamantyl-ft) -tetranor PGEg is a more selective birth control agent than PGEg due to its high uterine stimulating activity and low bronchodilator, hypotonic, and diarrhea-inducing effect.

2) 15-epi-16-adamantyl-ib-tetranor is more selective for birth control than PGEg due to its high uterine stimulating activity and low bronchodilator, hypotonic, and diarrhea-inducing effect.

3) ββ-adamantyl-γ1-tetranor PGFβ is a selective non-PEGgγ substance suitable for birth control and 5891 2 due to its high uterine stimulating activity and lower hypotonic and diarrheal effect.

1+) 17 ~ adamantyl-fi, rtrisnor PGEg is a more selective anti-secretory (anti-ulcer) agent than PGEg due to its higher anti-secretory activity and low uterine stimulating, bronchodilator and diarrhea-inducing effect.

5) 17-adamantyl-u1-trisnor PGFβ2 is a more selective agent for birth control than PGFβ because of its high abortifacient activity and low uterine stimulating, hypotonic and diarrhea-inducing effect.

6) 15- (2-indanyl) -β-pentanor PGEg is a more potent and selective birth control agent than PGE2 due to its high abortifacient activity and low uterine stimulating, hypotonic and diarrhea-inducing effect.

7) 15- (2-indanyl) -ft-pentanor PGF 2+ is a more potent and selective birth control agent than PGFβ due to its higher abortifacient activity and low uterine stimulating and diarrheal effect.

8) 15 "& (fa) -1,2,3,11-Tetrahydronaphthyl] -β / pentanor PGE ,, is a more effective and selective birth control agent due to its higher abortion activity and low bronchodilator, diarrhea-inducing and anti-secretory effect.

9) 15- £ 2- £ (R) -1,2,3,4-tetrahydronaphthyl ^ - << / - pentanor PGFβ is a more potent and selective birth control agent than PGFβ because of its greater uterine stimulating and abortive activity and low hypotonic and diarrheal effect.

10) 15- [2- (1S) -1,2,3,4-tetrahydronaphthyl] -4-yl] -pentanor PGFg4 is a more potent and selective birth control agent because of its higher abortifacient activity and low diarrhea effect .

11) 15 “(2-Indanyl) -o> -pent Anor PGF *, -p-bi phenyl ester is more potent and selective®! a substance suitable for birth control because it has a higher abortifacient activity and a low uterine stimulating, hypotonic and diarrheal effect.

12) 15- (E) - (S) -1,2,3,1 »“ tetrahydronaphthyl] -N-pentanor PGEg-p-biphenyl ester is a more potent and selective birth control agent due to its high abortifacient activity and low uterine stimulating and diarrheal effect.

13) 2-Descarboxy-2- (tetrazol-5-yl) -15- (2-indanyl) - <i> -pentanor PGF2c <is a more potent and selective birth control agent than PGFβ because of its high abortifacient activity and low uterine stimulating and diarrheal effect.

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cd x> Ο Ό (U dn 25 5891 2 The novel compounds prepared according to the present invention can be used in various pharmaceutical compositions containing the novel compound and can be administered in the same way as natural prostaglandins in various ways, such as 5a ^ onee n, ^ ah aJ ^ to, skin ai ai ses 11, s uun k help, mothers 11 me en, i nt ra— and extra-amniotic.

To induce miscarriage, the 15-substituted-t-pentanorprostaglandin prepared according to the present invention, such as tablets containing 15- (2-indanyl) -u'-pentar.prostaglandin, or an aqueous suspension or alcoholic solution may be administered orally in doses of about 0.1 to 20 mg. , using 1-7 daily doses. For vaginal administration, lactose tablets or tempo impregnated with the same substance are a suitable dosage form. Doses of about 0.1 to 20 mg / dose, using 1 to 7 daily doses, would be suitable for such treatments. For intra-amniotic administration, a suitable dosage form is an aqueous solution containing 0.05-10 mg / dose, using 1-7 doses daily.

A suitable dosage form for extra-amniotic dosing is an aqueous solution containing 0.005-1 mg / dose, using 1-5 doses daily. Alternatively, the 15-substituted-ttf-pentanorprostaglandins of this invention may be infused into a vein to induce miscarriage at doses of 0.05 to 50 ug / min. 1-2U per hour. To synchronize the reproductive cycle in piglets, sheep, cows or horses, administer a solution or suspension containing 0.03-30 mg / day of 15-substituted-W-pentanorproethylglandin, subcutaneously for 1-H days.

Various diluents, additives or carriers which are inert to the reaction can be used to prepare any of the above dosage forms and any of a myriad of other possible dosage forms. Such substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol, and other known carriers for drugs. If desired, these pharmaceutical compositions may contain additives such as preservatives, wetting agents, stabilizing agents, or other therapeutic agents such as antibiotics.

The following examples illustrate the invention. In these examples, all temperatures are expressed in degrees Celsius, all melting and boiling points are uncorrected.

26 5891 2

Example 19 9α, 11a, 15α-Trihydroxy-15- (2-indanyl) -cis-5-trans-13- (α) -pentanorep prostadienoic acid

A solution containing 602 mg of 9α-hydroxy-15α, 15α-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-traa-13-U) -pentanorprostadienolinic acid 10 in a mixture of glacial acetic acid and water (63:33) · was stirred under nitrogen at room temperature for 18 hours and then concentrated on a rotary evaporator. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7 100-22 mesh) using mixtures of chloroform and ethyl acetate as eluents. After elution of less polar impurities, 9α, 11α, 15α-trihydroxy-15- (2-indanyl) -cis-5-trans-13'β-trisprostradienadienoic acid was collected as a white solid weighing 156 mg ($ 39) and melted at 114-113 ° (from ethyl acetate).

The IH spectrum (KBr) of the product showed strong absorption at 5 to 77 yu for the acid carbonyl and moderate absorption at 10.23 yu for the Trane double bond.

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Example 2 9-Oxo-11α, 15α-dihydroxy-15- (2-indanyl) -c18-5-trans-8-13-pentanprostadienoic acid

A solution of 1.11 g of 9'-Okeo, 15α-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13-yl] -pentanorproate-dienadienoic acid in 15 ml a mixture of glacial acetic acid and water (6505) »was stirred under nitrogen at room temperature for 18 hours, then concentrated on a rotary evaporator. The resulting crude oil was purified by column chromatography on silica gel (Mallin-ckrodt CC-4 100-200 mesh) using mixtures of chloroform and ethyl acetate as eluents. After less polar impurities, 9-oxo-15α, 15α-dihydroxy-15- (2-indanyl) -cie-5-traa-13-t *> - pentanorproeta-dienoic acid was collected as a white solid weighing 288 mg ($ 37> ) and melting at 110-112 ° (from a mixture of ethyl acetate and hexane).

The IR spectrum (KBr) of the product showed strong absorptions at 5.68 for ketone carbonyl and at 5-84 for acid carbonyl and a moderate absorption at 10.25 for the trans double bond.

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Example 3 p-Biphenyl-9-oxo-11α, 15α-dihydroxy-15- (2-indanyl) -cis-5-trane-13- (b-pentanorprostadienoate

To a mixture of 60 mg (0.15 mmol) of 9 “oxo-11 ', 15e-dihydroxy-15- (2-indanyl) -c18-5-trans-13β-pentanorprostadienoic acid and 255 g (1.5 mmol) p-phenylphenol 6 ml of uniformly dry methylene chloride, 1.65 ml of a 0.1 molar solution of dicyclohexylcarbodiimide in methylene chloride were added. 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 (Baker, "Analyzed" 60-200 mesh) using mixtures of chloroform and ethyl acetate as eluents. After removal of the less polar impurities, solid p-biphanyl-9-oxo, 15β-dihydroxy-15- (2-indanyl) -cis-5-trans-13-α-pentanorproethadienoate, weighing 43 mg and melting at temperature, was collected 103-104 »5 ° (from a mixture of methylene chloride and hexane).

The IR spectrum (KBr) of the product showed strong adsorptions at 5.65 yu for ketone carbonyl and at 5 * 70 yu for ester carbonyl and moderate absorption at 10.35 yu for the trans double mixture.

Example 4 p-Biphenyl-9-oxo-11α, 153-dihydroxy-15 (2-indanyl) -cis-5-trans-13-β-ρ entanorpradioleate

To a mixture of 60 mg (0.15 mmol) of 9-oxo, 158-dihydroxy-15- (2-indanyl) -cis-5-trans-13-N-pentanorprostadienoate and 255 ®g (1, 5 mmol) of p-phenylphenol in 6 ml of dry methylene chloride, 1.65 ml of 0.1 molar dicyclohexylcarbodiimide in methylene chloride were added. The mixture was stirred for 16 hours at room temperature under nitrogen and concentrated. Purification of the solid residue by chromatography on silica gel (Baker "Analyzed" 60-200 mesh) using mixtures of chloroform and ethyl acetate as eluents. After removal of less polar impurities, solid p-biphenyl-9-oxo, 15β-dihydroxy-15- (2-indanyl) -cis-5-trans-13-i *> - pentanorprostadienoate weighing 34 mg was collected and melted. at a temperature of 98-100 ° (from a mixture of methylene chloride and hexane).

The 1H spectrum (KBr) of the product showed strong absorptions at 5.66 yu for ketone carbonyl and at 5.77 yu for ester carbonyl and a moderate absorbance at 10.35 yu for the trans double bond.

Example 5 p-Biphenyl-9α-15α-15α-trihydroxy-15α- (2-indanyl) -cie-5-trans-13β-pentanorprostadienoate

To a mixture of 60 mg (0.15 mmol) of 9a, 11a, 15α-trihydroxy-3 '5891 2 15- (2-indanyl) -cis-5 "trans-13-trans-pentanorprostadienoate and 255 mg ( 1.5 mmol) of p-phenylphenol in 6 ml of dry methylene chloride, 1.65 ml of a 0.1 molar solution of dicyclohexylcarbodiimide in methylene chloride were added, the mixture was stirred for 16 hours at room temperature under nitrogen, then concentrated. "60-200 mesh) chromatographically using mixtures of chloroform and ethyl acetate as eluents yielded less polar impurities after removal of solid p-biphenyl-9 ° F, 11 *, 15 </ - trihydroxy-15 ~ (2-indanyl) -ci s ~ 5 "trans-13 ~ W pentanorprostadienoate weighing 1 + 1 mg and melting at 13-135 ° (from a mixture of methylene chloride and hexane).

The IR spectrum (KBr) of the product showed strong absorption at 5.68 μ for ester carbonyl and moderate absorption at 10.35 μ for the trans double bond.

Example 6 p-Biphenyl-9-x, 11 ° <, 15/0-trihydroxy-15 “(2-indanyl) -cis-5-trans-13” u-pentanorprostadienoate

To a mixture of 60 mg (0.15 mmol) of 11 -, 1%> (- trihydroxy-15- (2-indanyl) -cis-5-trans-13-i (p-pentanorprostadienoate) and 255 mg (1, 5 mmol) of p-phenylphenol in 6 ml of dry methylene chloride, 1.65 ml of a 0.1 molar solution of dicyclohexylcarbodiimide in methylene chloride were added.

The mixture was stirred for 16 hours at room temperature under nitrogen, then concentrated. Purification of the solid residue by silica gel (Baker "Analyzed" 60-200 mesh) chromatography using mixtures of chloroform and ethyl acetate as eluents afforded less polar impurities after removal of solid p-biphenyl 11-9, 1H, 15 / $ - trihydroxy-15 "( 2-Indanyl) -cis-δ-trans-SU 2 pentanorprostadienoate, which weighed 10 mg and melted at 98-100 ° (from a mixture of methylene chloride and hexane).

The IR spectrum (KBr) of the product showed strong absorption at 5.65 μ for ester carbonyl and moderate absorbance at 10.20 μ for the trans double bond.

32 5891 2

Example 7 N-Methanesulfonyl-9α, 11α, 15α-trihydroxy-15- (2-indanyl) -cie-5-trans-15-β-pentanostrostadienainide

A solution of 500 mg of N-methanesulfonyl-9α-hydroxy-11α, 15α-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-15-β-penta-norprostadienamide 10 In 1 ml of a mixture of glacial acetic acid and water (65:35) »was stirred under nitrogen at room temperature for 1 vä hour and then concentrated on a rotary evaporator. The resulting crude oil was purified by column chromatography on silica gel (Hallinckrodt CC7 100-200 mesh) using mixtures of chloroform and ethyl acetate as eluents. After elution of less polar impurities, N-methanesulfonyl-9α (11α, 15α-trihydroxy-15- (2-indanyl) -cis-5-trans-13-t *> - pentanorprostadienamide was collected as a viscous oil weighing 257 mg (69 * 6 #).

The IE spectrum of the product (CHCl 3) showed strong absorption at • 1 μl for the 1705 cm carbonyl group and moderate absorption at 965 cm 3 for the Trane cacolate solution.

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Example θ N-Methanesulfonyl-9-ocolo-15α, 15α-dihydroxy-15- (2-indanyl) -βB-5-trans-13-β-pentanorprostadienamide

A solution of 371 mg of N-methanesulfonyl-9-oxo-15α-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13-β-pentanorethadienamide 10 in a mixture of glacial acetic acid and water (63:33), stirred under nitrogen at room temperature for 16 hours and then concentrated on a rotary evaporator. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7 100-200 mesh) using mixtures of chloroform and ethyl acetate as eluents. After elution of less polar impurities, H-methanesulfonyl-9-oko, 15α-dihydro-15- (2-indanyl) -cis-5-trans-13- (N-pentanorprostadienamide) was collected as a viscous oil weighing 63 mg (23, 8 56).

The IR spectrum of the product (CHCl 3) showed strong absorbances at -1 * -1 for 1740 cm for ketone carbonyl, 1720 cm for sulfonimide dicarbonyl and at 970 cm for the trans double mixture.

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Example 9

16- (1-adamantyl) -11β-tetranorprostaglandin-F

To a nitrogen- and ice-cooled solution of 100 mg (0.233 mmol) of 16- (1-adamantyl) -α-'- 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 stirred at 0 ° for 20 minutes, then at room temperature for 1.0 hour. The solution was quenched by the addition of 2.0 mL of water and the methanol was removed on a rotary evaporator. The resulting aqueous solution was supersaturated with ethyl acetate (10 mL), acidified by the addition of 10 # hydrochloric acid, and extracted with ethyl acetate (x x 5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (anhydrous magnesium sulfate) and concentrated. Purification of the crude residue by silica gel chromatography using mixtures of methylene chloride and methanol as eluents afforded 16- (1-adamantyl) ttf-tetranorprostaglandin F0 (1 + 9 mg) and 16- (1-adamantyl) -f / tetranor - prostaglandin F '(39 mg) f / 3 .. ...

Other prostaglandin F analogs of this invention are similarly prepared from the corresponding E precursors.

Example 10

17- (1-adamantyl) -β-trisnorprostaglandin F

2P

To a nitrogen-ice-cooled solution of 100 mg (0.225 mmol) of 17- (1-adamantyl) -β-trisnorprostaglandin E2 in 10 ml of absolute methanol was added an ice-cooled solution of 300 mg of sodium borohydride in methanol. The solution was stirred at 0 ° for 20 minutes, then at room temperature for 1.0 hour. The solution was quenched by the addition of 2.0 mL of water and the methanol was removed on a rotary evaporator.

The resulting aqueous solution was supersaturated with ethyl acetate (10 mL), acidified by the addition of 10% hydrochloric acid and extracted with ethyl acetate (x x 5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (anhydrous magnesium sulfate) and concentrated. Purification of the crude residue by silica gel chromatography using mixtures of methylene chloride and methanol as eluents afforded 17- (1-adamantyl) -this-trisnorprostaglandin F (28 mg) and 17- (1-adamantyl) -

"K

co-trisnorprostaglandin F0 (28 mg).

2β

Other prostaglandin I) 5 analogs of this invention are prepared in a similar manner from the corresponding E precursors.

Example 11

Cyclooctyl 9-ol, 11t, 15ol-trihydroxy-17- (1-adamantyl) -5-cis-13-trans-tert-norprostadienoate 37 5 8 91 2

To a solution of 130 mg (0.30 mmol) of 9 °, 11β, 15β-trihydroxy-17β- (1-adamantyl) -5-cis-13-trans-1β-trisnorprostadienoic acid in 7 ml dry methylene chloride, 33 mg (0.33 mmol) of triethylamine are added.

The mixture is stirred for 5 minutes, then 36 mg (0.33 mmol of pi-photoyl chloride) are added. The solution is stirred for 5 minutes at room temperature under nitrogen, then 192 mg (1.5 mmol) of cyclooctyl alcohol and 225 [mu] l of pyridine are added. The diluted solution is washed with water (2x) and brine (1x), dried (anhydrous magnesium sulfate) and concentrated. The purification of the crude residue by silica gel chromatography affords cyclo 9x »1 K» 15 ° trihydroxy-17- (1-adamantyl) -5-cis-13-trans-trans-enoate.

Other prostaglandin cyclooctyl esters of this invention are similarly prepared from the corresponding E or F precursors.

Example 12 Ethyl ester of 15-epi-16- (1-adamantyl) - <# - tetranorprostaglandin

To a solution of 15-epi-16- (1-adamantyl) -β-tetranorprostaglandin E2 (25 mg) in 5 mL of ether was added ethereal diazoethane 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 the eluent, afforded the desired ethyl ester of 15-epi-16- (1-adamanyl) -W-tetranorprostaglandin Eg, weighing 22 mg.

Other prostaglandin ethyl esters of this invention are similarly prepared from the corresponding E or F precursors.

Example 13

Methyl 9b <, 11c <, 150 <c-trihydroxy-16- (2-indanyl) -5-cis-13-trans-?-Tetranorprostadienoate

To a solution of 75 mg of 9'-11β, 15 <* - trihydroxy-16- (2-indanyl) -5-cis-13-trans-6i) -tetranoic acid amino acid in 10 ml of ether is added a yellow ether solution of diazomethane (prepared N-methyl-K'-nitro-N-nitrosoguanidine) dropwise until a yellow color persists for 5 minutes. Concentration of the solution and purification of the crude residue by silica gel chromatography affords methyl 9β, 11α, 15α, trihydroxy-16- (2-indanyl) -5-cis-13-trans-tU-t et r anorp roe t adi enoaat in.

Other prostaglandin methyl esters of this invention can be prepared in a similar manner from the corresponding E or F precursors.

38 5 891 2

Other prostaglandin phenethyl ethers of this invention are prepared in a similar manner from the corresponding E-f or 7 ··· i products.

i

Example 14

Cyclopropyl 9α, 11α, 15α-trihydroxy-15- (2- (1,2,3,4-tetrahydronaphthyl)) -5-cis-13-trans-β-pentanorprostadienoate To a solution containing 82 mg (0, 20 mmol) 9α, 11a, 15α-trihydroxy-15- (2- (1,2,3 * 4-tetrahydronaphthyl)) - 5-cis-13-trans-β-pentanorprostadienoic acid (12a) in 5 ml dry methylene chloride, 22 mg (0.22 mmol) of triethylamine are added. The mixture is stirred for 5 minutes, then 24 mg (0.22 mmol) of pivaloyl chloride are added. The solution is stirred for 43 minutes at room temperature under nitrogen, then 58 mg (1.0 mmol of cyclopropyl alcohol and 150 of pyridine) are added. The mixture is stirred at room temperature for a further 2.0 hours, then diluted with ethyl acetate. The diluted solution is washed with water (2x) and dried over brine (1x), dried (anhydrous magnesium sulfate) and concentrated. )) - 5-cis-13-trans-U) -pentanor-prostadienoate.

Other prostaglandin cyclopropyl esters of this invention are prepared in a similar manner from the corresponding E or 7 products.

Example 15 Tris-hydroxymethylaminomethane salt of 9β, 11α, 15α * trihydroxy-17- (1-adamantyl) -5-cis-13-trans-u) -trisnor-prostadienoic acid To a solution heated to 80 ° containing 319 mg (0.70 mmol) ) 93, 11a, 15α-Trihydroxy-17- (1-adamantyl) -5-cis-13-Trane - (») - tri8-norprostadienoic acid (12b) in 35 ml of dry acetonitrile is added with vigorous stirring 86 mg (0, 86 mmol) solution of trisnor-hydroxymethylaminomethane in 0.15 ml of water · The mixture is allowed to cool to room temperature and 93, Ha, 15α-trihydroxy-17- (1-adamantyl) -5-cis-13-trans-α the triehydroxymethylaminomethane salt of tris-norpostadienoic acid is assembled Example 16

To a solution of 80 mg (0.2 mmol) of 9α, H, 15α-trihydroxy-15- (2-indanyl) -5-cis-13-Trane-α-pentanorprostadienoic acid in 1 ml of pyridine is added 120 mg (1 .0 mmol) pivaloyl chloride. The solution is stirred for 4 hours at 43 ° under nitrogen and cooled to room temperature. 36 mg (2.0 mmol) of water are then added to the solution. The solution is then stirred at room temperature for 2.0 hours, then diluted with ethyl acetate. The diluted solution is washed with 0.1 N hydrochloric acid (2x), water (1x) and saturated brine (1x), dried (anhydrous magnesium sulfate) and concentrated. Purification of the crude residue by silica gel chromatography affords 9 · λ, 11 «*, 150 ',“ trispivaloyloxy-15- (2-indanyl) -5-ciB-13-trans-fcd-pentanorprostadienoic acid.

Example 17 9-Oxo-11β, 15β-bisformyloxy-15- (2- (5,6-dimethoxyindanyl)) - 5-cis-13-trans-1H-pentanorprostadienoic acid

To a solution of U6 mg (0.1 mmol) of 9-oxo-11 *, 15'-dihydroxy-15- (2- (5,6-dimethoxyindanyl)) -5-cis-13'-trans pentanorprostadienoic acid in 0.5 ml of dry tetrahydrofuran, 29 mg (0.33 mmol) of formic acetic anhydride and 35 mg (0.33 mmol) of 2, β-lutidine are added. The solution is stirred for 1 hour under nitrogen at room temperature, then 36 mg (2.0 mmol) of water are added. The mixture is stirred at room temperature for a further 1.0 hour, then diluted with ethyl acetate. The diluted solution is washed with 0.1 N hydrochloric acid (1x), water (1x) and saturated brine (1x), dried (anhydrous magnesium sulfate) and concentrated. Purification of the crude residue by silica gel chromatography affords 9-oxo-11ος, 15 · Λ ~ bi s fornyloxy-15- (2- (5,6-dimethoxyindanyl)) -5-cis-13-trans- Ju-pentanor-prostadienoiinihapon.

Example 18 9-Oxo-11β-1,1'-dihydroxy-16- (2-indanyl) -13-trans- & tetranor-prostanoic acid

A solution of 7 * + mg (0.18 mmol) of 9-oxo-1H, 15o (dihydroxy-16- (2-indanyl) -cis-5-trans-13-to-tetranorprostadienoic acid in 6 ml of anhydrous ether, treated with hg mg (3.6 mmol) of dimethylisopropylchlorosilane and 36.0 mg (3.6 mmol) of triethylamine at room temperature under nitrogen for U8 hours The reaction mixture is cooled to 0 °, methanol and the resulting solution are added. washed with water, dried (anhydrous magnesium sulfate) and concentrated, the residue is dissolved in methanol (6 ml), 5% palladium on carbon (30 mg) is added and the resulting heterogeneous mixture is stirred at -22 ° under one hydrogen atmosphere for 1+ hours. After filtration (Celite) and concentration of the filtrate, the residue is dissolved in a mixture of acetic acid and water (65:35). · The solution is stirred for 10 minutes at room temperature, then diluted with water and extracted with ethyl acetate (1x). sulfa tti) and concentrated, after purification by silica gel chromatography, to give 9-oxo-1H, 15β-dihydroxy-16- (2-indanyl) -13-trans-tU-tetranorprostenoic acid.

Other prostaglandin E 1 analogs of this invention are similarly prepared from the corresponding Eg precursors.

ta 58912

Example 19 N-Methanesulfonyl-9β, 11α,> 150-trihydroxy-15- (2- (5,6-dimethoxyindanyl)) -1,3-trans-N-pentanorprostenamide

A solution of 58 mg of N-methanesulfonyl-9,11f, 15/5-trihydroxy-5- (2- (5,6-dimethoxyindanyl) -5-cis-13-trans-1H-pentanorprostadienamide 6 per ml of anhydrous ether, treated with ΗΛ8 mg (3.6 mmol) of dimethylisopropylchlorosilane and 36.0 mg (3.6 mmol) of triethylamine at 25 ° for 18 hours. The reaction mixture is cooled to 0 °, methanol and The resulting solution was washed with water, dried (anhydrous magnesium sulfate) and concentrated. The residue was dissolved in methanol (6 mL), treated with 5'-aldlaldium on carbon (30 mg), and the resulting slurry was hydrogenated for 1 hour at -22 °. ) and after concentrating the filtrate, the product is hydrolysed in 2 ml of a mixture of acetic acid and water (65 = 35) for 10 minutes, diluted with water and extracted with ethyl acetate. 9o <, 11o, 15 / 6'trihydroksi-15- ( To obtain 2- (5,6-dimethoxyindanyl)) - 13-trans-N-pentanorprostanoic acid after purification by silica gel chromatography.

At the same time, other prostaglandin Fs of this invention are prepared

or Fn or F0 precursors corresponding to F., analogs.

1P c-Oc d ff

Example 20

1T- (1-adamantyl) -this-trisnorprostaglandin F

A heterogeneous mixture of II7 mg (1.0 mmol) of 15-epi-17 (1-adamantyl) -α-trisnorprostaglandin FgA and 5 g of activated manganese dioxide in 1 + 5 ml of dry methylene chloride is stirred overnight at room temperature. filtered and concentrated to give 15-keto-17- (1-adamantyl) -β-trisnorprostaglandin F, which is used without purification.

To an ice-cooled solution containing 223 mg (0.50 mmol) of 15 "keto-17- (1-adamantyl) -N-trisnorprostaglancinline F in 22 ml of absolute methanol is added an ice-cooled solution containing 669 mg of sodium borohydride. In 85 ml of 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 on a rotary evaporator and the resulting aqueous solution is supersaturated with ethyl acetate, acidified with 10 # hydrochloric acid and further extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (anhydrous magnesium sulfate) and concentrated. Purification of the crude residue by silica gel chromatography affords 17- (1-adamantyl) -ii) -trisnorprostaglandin F1 and 15-ep.- 17- (1-adamantyl) -N-trisnorprostaglandin F1. .of.

, 58912 41

Other 15-epi-prostaglandins of the present invention which do not have a previous alkyl group in C 1-4 can be similarly converted to their C 1-4 epimers by the above method.

Example 21 2-Descarboxy-2- (tetrazol-5-yl) -9-oxo-11β, 150-dihydroxy-16- (2'-indanyl) -N-tetanorprostanoic acid.

Heterogeneous mixture containing 120 mg of 2-descarboxy-2- (tetrazol-5-yl) -9-oxo-11β, 15C * t-dihydroxy-16- (2-indanyl) -5-cis-13- irans-α'-tetranor-prostadienoic acid and 12 mg of 5 # palladium on carbon in 12 ml of absolute methanol are stirred in one atmosphere of hydrogen at 0 ° for 3 hours. The reaction mixture is filtered (Celite) and concentrated. The crude residue is purified by silica gel chromatography to give 2-descarboxy-2- (tetrazol-5-yl) -9-oxo-110 ', 1'-dihydroxy-16- (2-indanyl) 1H-atetranorprostanoic acid.

By the above method, other prostaglandin analogs of the E, Foe, or F / 3 types of the single, double, or 13,1 ** -dihydro-2 series can be converted to the corresponding "zero" series analogs.

Example 22 9-Oxo-11α, 15,5-dihydroxy-16- (1-adamantyl) -N-tetranorprostanoic acid

A heterogeneous mixture containing 150 mg of 9-oxo-1 lev, 15/6 "dihydroxy-16- (1-adamantyl) -5-cis-13" trans-13 "N-tetranorprostadienoic acid (11a) and 15 mg of $ 5 of palladium on carbon in 15 ml of absolute methanol, stirred under a single atmosphere of hydrogen at 0 ° for 3 hours. The reaction mixture is filtered (Celite) and concentrated. The crude product is purified by silica gel chromatography to give 9-oxo-110e, 15S-dihydroxy-16- (1-adamantyl) -U-tetranorprostanoic acid.

By the method described above, other prostaglandin analogs of the present invention of the E, Fcr or F / J type of the other single, double or 13,1 ** dihydro double series can be converted to corresponding zero series analogs of the present invention.

Manufacture of starting materials

Example I

Dimethyl-2-oxo-2- (2-indanyl) ethyl phosphonate

A solution of 20.1 * g (16 ** mmol) of dimethyl methylphosphonate (Aldrich) in 200 ml of dry tetrahydrofuran was cooled to -780 in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 82.6 mL of a 2.25 molar solution of n-butyllithium in hexane (Alfa Inorganics, Inc.) dropwise over 20 minutes at such a rate that no reaction mixture was present. . - once the temperature had risen above -65 · 5 minutes after further stirring at “70 °, 1 **, ** g (73.5 mmol) of methyl indane-2-carboxylate was added dropwise at such a rate that the reaction temperature remained below -70 ° (20 minutes). After 1.0 h 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 gel-like material was taken up in 50 ml of water, the aqueous phase was extracted with 75 ml portions of methylene chloride (U x), the combined organic extracts were washed (75 ml HgO), dried (MgSO 4) and concentrated (water jet pump) to a crude residue and distilled, b.p. . 150-160 ° (0.1 mm) to give 17.0 g (86.0%) of dimethyl 2-oxo-2- (2-indanyl) ethylphosphonate.

The NMR spectrum (CDCl 3) of the distilled product showed a single line of 7.15 ό for aromatic protons, a dashed line of 3.76 ό (J = 11 cps) for OCH 2, a single line of 3.25 for benzyl protons, a couple of lines at 3 , 18?

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Example II

2 «(3c ^ p-phenylbenzoyloxy-5 <rhydroksi * 2 ^ - (3-oxo-3- (2-indanyl) -trans-l-propen-l-yl) -cyclopent-LCC-yl) acetic acid; γ-lactone To a solution cooled in ice under a nitrogen atmosphere containing 17.2 mL (32.6 mmol) of a 1.90 molar solution of n-butyllithium in hexane and 150 mL of dry 1,2-dimethoxyethylene was added dropwise 9 # 2 g (34 * 3 mmol) of dimethyl 2-oxo-2- (2-indanyl) ethylphosphonate. The solution was stirred in the cold for 10 minutes, then 11.9 g (33 * 3 mmol) of the known 2- (3O-p-phenylbenzoyloxy-5H-hydroxy-2,3-formylcyclopentyl) -acetic acid were added. γ-lactone. The ice bath was removed; the mixture was stirred for 1 hour, then quenched with glacial acetic acid (pH about 3). 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) and saturated sodium chloride solution (50 ml), dried (anhydrous magnesium sulfate) and concentrated to a semi-solid. Recrystallization of the product from a mixture of isopropyl alcohol and methylene chloride afforded the desired 2- (3α-ρ-phenylcenzoyloxy-5α-hydroxy-2β- (3-oxo-3- (2-indanyl) -trans-1-propen-1 -yl) cyclopent-1-yl) acetic acid, 6-lactone as white feathers, melting at 170-720 and weighing 6.85 g (42.8 56).

The 1H spectrum of the product (CHCl 3) showed absorbances at 1773 cm -1 for lactone carbonyl, at 1710 cm -1 for ester carbonyl, at 1670 and 1625 cm -1 for ketone carbonyl and at 975 cm -1 for the trans double bond.

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Example III

2- (5α-p-phenylbenzoyloxy-5α-hydroxy-2β- (3α-hydroxy-3- (2-indanyl) -trans-1-propyn-1-yl) cyclopnt-1α-yl) acetic acid , γ-lactone and 2- (3a-p-phenylbenzoyloxy-5a-hydroxy-3- (2-indanyl) -) - trans-1-propen-1-yl) cyclopentyl-1-yl) acetic acid, Y gamma-lactone

To a solution of 6.75 g (14 * 0 mmol) of 2- (3a-p-phenylbenzoyloxy-5α-hydroxy-28- (3-oko-3- (2-indanyl) -trans-1-propene) was added. 1-yl) cyclo-pent-1-yl) acetic acid, γ-lactone in 67 μl of dry tetrahydrofuran in a dry nitrogen atmosphere at ambient temperature, 14.0 ml of a 0.5 molar solution of zinc borohydride were added dropwise. After stirring at room temperature for 1.5 hours, saturated sodium bi-tartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was allowed to stir for 5 minutes, at which time 150 mL of dry methylene chloride was added. After drying (MgSO 4) and concentration (water jet pump), the resulting semi-solid was purified by column chromatography on silica gel (Baker Analyzed Reagent 60-200 mesh) using mixtures of ethyl acetate and ether as eluents. , 21 g (32.8% yield) of 2- (3'-phenylbenzoyloxy-5α-hydroxy-2β- (3'-hydroxy-3- (2-indanyl) -trans-1-propen-1-yl) cyclopentene 1α-yl) acetic acid, γ-lactone and a fraction containing 1.79 g (26.6%) of 2- (3α-p-phenylbenzoyloxy-5α-hydroxy-2β- (3α-hydroxy-3- ( 2-indanyl) -trans-1-propenyl) cyclopentyl-1'-yl) acetic acid, lactones.

The IR spectra (CHCl 3) of both products had strong adsorption at 1770 cm -1 (lactone carbonyl) and 1705 cm ** 1 (ester carbonyl) and moderate adsorption at 970 cm -1 (trans-olefin).

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2- (3α-5α-dihydroxy-2β- (3β-hydroxy-3- (2-indanyl) -trans-1-propen-1-yl) cyclopent-1α-yl) acetic acid β-lactone

Heterogeneous mixture # containing 2 # 21 g (4.46 mmol) of 2- (3a-p-phenylbenzoyloco-5α-hydroxy-2β- (3α-hydroxy-3- (2-indanyl) -trans-1-propene -1-yl) cyclopent-1a-yl) acetic acid, γ-lactone, 40 ml of dry tetrahydrofuran # 40 ml of absolute methanol and 0.61 g of finely ground anhydrous potassium carbonate, stirred for 1 hour at room temperature # then cooled to 0 °. To the cooled solution was added 4.46 ml of 1.0 N aqueous hydrochloric acid. After stirring for a further 10 minutes at 0 °, # 73 ml of water was added # while methyl p-phenylbenzoate was formed simultaneously # which was collected by filtration. The filtrate was concentrated on a rotary evaporator and extracted with ethyl acetate (3x), the combined organic extracts dried (MgSO 4) and concentrated to 924 mg (66f) of viscous, oily 2- (3aα-5α-dihydroxy-2β- (3aα-hydroxy-3). - (2-indanyl) -trans-1-propen-1-yl) cyclopent-1-yl) acetic acid, to give γ-lactone.

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

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Example 7 2- (5α-Hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3α-tetrahydropyran-2-yloxy) -3- (2-indanyl) -trans-1-propene 1-yl) cyclopent-1α-yl) acetic acid, γ-lactone

To a solution containing 0.924 g (2.94 mmol) of 2- (3α, 5α-dihydroxy-2β- (3α-hydroxy-3- (2-indanyl) -trans-1-propen-1-yl) cyclopentene -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, a few crystals of p-toluenesulfonic acid τ · monohydrate were added. After stirring for 13 minutes, the reaction mixture was combined with 100 mL of ether, the ether solution was washed with saturated sodium bicarbonate (1 x 19 mL), then brine (1 x 19 mL), dried (MgSO 4) and concentrated to 1.38 gm (97 x 8 mL). 6) crude 2- (5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -28- (3α- (tetrahydropyran-2-yloxy) -3- (2-indanyl) -trans-1-propen-1-yl ) - cyclopent-1α-yl) acetic acid, to give γ-lactone, which was used without purification.

The IR spectrum (CHCl 3) of the product showed strong adsorption at .1.13 for 1733 cm-lactone carbonyl and moderate absorption at 963 cm-1 for the Trane double bond.

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s a i w u '3 § ^ § - £ 3 f — I Λ · Η H S · Η • H ® ^ O' ö •• ”3 Ö Ö

• H * H

* I H

: θ5 · Η O

43 m, C

• H ^ O

a; O · η * h »h * h M

-p 43 rH cH r — I 1 — l 1—1 .2 5 § £ & & fc f λ bvSSSS ^ >> g I S g ® g d aj π3 ^ § § § § to

4J

.h ή - oJ <β a3 aj 3 I I I I I I —-

S <oJOJ '-'-'-'- M

52 5891 2

Example YI

2- (5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3α- (tetrahydropyran-2-yloxy) -3- (2-indanyl) -trans-1- propen-1-yl) cyclopent-1α-yl) acetic acid, γ-hemiacetal 1.39 g (2.9 mmol) of 2- (5α-hydroxy-N- (tetrahydropyran-2-yloxy)) -2β- (3α- (tetrahydropyran-2-yloxy) -3- (2-indanyl) -trans-1-propen-1-yl) cyclopent-1-yl) acetic acid, γ-lactone in 20 ml of digging toluene was cooled to -76 ° in a dry nitrogen atmosphere. To this cooled solution was added 4.2 ml of 20 diisobutylaluminum hydride n-hexane (Alfa Inorganics) dropwise at such a rate that the temperature of the mixture never rose above -63 ° (15 minutes). After further stirring at -78 °, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature and concentrated on a rotary evaporator. The resulting oil was soaked in ethanol and then filtered to remove aluminum salts. Concentration of the filtrate afforded the crude product which was purified on silica gel (Baker "Analyzed" 60-200 mesh) by column chromatography using mixtures of benzene and ethyl acetate as eluents. After removal of the less polar impurities, the desired 2- (5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3α- (tetrahydropyran-2-yloxy) -3- (2-indanyl) -trans-1 -propen-1-yl) cyclopent-1-yl) acetaldehyde, γ-hemiacetal as a viscous oil weighing 1.17 g (84.3%) *

The IR spectrum (CHCl 3) of the purified product showed moderate absorbance at 973 cm for the trans double bond and showed no carbonyl absorption.

53 5891 2 ö * 0) β «- c α> i · η c S Η · η 3 3 ä H« 1

4J OH

g * &. .

«3! § C

| LP »O LT \ LPv t / \ ΙΓ \ Β'Ώ K t— t— t— t— t— t— ö g

H 0 \ 0 \ 0 \ ONO \ 0 \ (UH

3 - s

> · <U

Il II

a i! «5

rH

<”Cö e! g ö>

~ \ J I

/ o tn / u S Λ * s \ · * -p o 2 05¾ o

C [H C OO ^^ CMOJ

g 1 s s * '3 § H £ 05 £ a Ή λ

rH Ö * H

• H 3 H

O 13

· <- »CC

• H * rH

Ä I rH

! Q) Ή O

+? CQ rC

• H Λ O

<D O · Η · Η · Η · Η, Μ

-p -p pH rH rH rH rH

.2 S § & § £ & f £ i -i! 1 i I ® 05 Is0. § I § 3 ^

p C IA T5 Tl tj W

• h · Η 'o5 <d o5 o) 5 I I t I I 1 -r · 2 <! OJcvl '-'-'-'- o) 5I * 5 8 91 2

Example VII

9 α-hydroxy-11α, 15α-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13-β-pentanorprostadianoic acid

To a solution of 5 (21 g (7 (24 mmol)) of (4-carbohydroxy-n-butyl) triphenylphosphonium bromide in a dry nitrogen atmosphere in 6.0 mL of dry dimethyl sulfoxide was added 6.96 mL (14.0 mmol) of 2.01 To this red ylide solution was added dropwise a solution of 1.16 g (2.41 mmol) of 2- (5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β-) in a red solution of sodium methylsulfinylmethide in dimethyl sulfoxide. (3 '- (tetrahydropyran-2-yloxy) -3- (2-indanyl) -trans-1-propen-1-yl) cyclopent-1-yl) acetaldehyde, γ-hemiacetal in 2.0 ml dry dimethyl sulfoxide over 20 minutes After stirring for an additional 2.0 hours at room temperature, the reaction mixture was poured into ice water, the basic aqueous solution was acidified to pH about 3 ° C with aqueous hydrochloric acid, extracted with ethyl acetate (5x) and the combined organic extracts washed with water (2x), dried MgSO 4) and evaporated to a solid residue, which solid was triturated with ether. and filtered. The filtrate was concentrated with 1.99 g (100 f) of 9e-hydroxy, 15o-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13-w-pentanorprostadienoic acid. which was used without further purification.

The IR spectrum (CHCl 3) of the purified product showed strong absorption at 1710 cm-1 for the acid carbonyl and moderate absorption at 970 cm-1 for the trans-kakeol bond.

5 891 2 ö a) a »- Ö Φ

'a t .S

z § a OOOOOOH CÖ

-p t— t— t— t— t— t— O H

0 0 \ CT \ CT \ ChC »N0 \ ft0> ft t I o» ft Λ »» 3 uNoooooosroc 1 OOOO '"' -» ^ K c— ε— t— t— t— t— gg XX 0) i (Ö ö> · φ

II II

a a w <<u a a)

O - · - rH

O OJ - 'H

/ δ £ .2 \ ~ \ a s a a a a a a s <") ο ω \ / °

/> I

--f M

/ w §- / ° \ s

'O

a, 3

0) Eh O

β COO ’-’- CVJCM

C W

Φ P

• a 3 * -Ö o r ~ I p> · Η 3 I ^ o »ö • n) ö ö • Η · Η

• I rH

: 00 · Η O

+3 U1 XS

• H .¾ O

Φ Ο · Η · Η · Η »H

Η-3 Η-3 rH rH rH rH r—]

.3 H I & & fe I

Ό >> · Η -p +3 +3 +3 .H

xx k -ö g 0 0 0 β> 3 g 1 § g g 5 <u os i i i i m +3 β u> tJ nd> ϋ τ) pq • η · η - aJ <d cd οβ

P I I I I I I O

S raJCMCVJr- * ”· · - r-n) 56 5891 2

Example VIII

9-Oxo-110S 150f-bis- (tetrahydropyran-2-yloxy) -15 "(2-indanyl) -cis-5" trans-13-N-ent anorepropenadinoic acid To a solution cooled to -10 ° under nitrogen containing 1.32 g (2.3 mmol of α) 9β-hydroxy-11β, 150 * -1> β- (tetrahydropyran-2-yloxy) -15 '(2-indanyl) -cis-5' trans-13β-pentanorprostaclienoenoic acid in 15 ml of reagent-pure acetone, 1.17 ml of Jones reagent was added dropwise. After 15 minutes at -10 °, 1.17 ml of 2-propanol was added and the reaction mixture was allowed to stir for a further 5 minutes. after which time it was combined with ethyl acetate, washed with water (2x), dried (MgSO 4) and concentrated to give 1.11 g (8U, 2%) of 9-oxo-1 lev, 15t-bis- (tetrahydropyran). To obtain 2-yloxy) -15- (2-indanyl) -cis-5-trans-13-chlorocanadprostadienoic acid, which was used without purification.

57 5891 2

Other compounds with structure: CO 2h

J_ "W

TBP ° Up A n TLC (a)

2-indanyl 0 MP

2- (5,6-dimethoxyindanyl) 0 LP

1-adamantyl 1 LP

1-adamantyl 1 MP

1-adamantyl 2 LP

1-adamantyl 2 MP

a) Mobility of ester alcohol for thin layer chromatography.

LP * less polar. MP = more polar

Example IX

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

To a stirred suspension of nitrogen containing 12.9 g (306 mmol) of a 57% sodium hydroxide suspension in 280 mL of dry tetrahydrofuran was added dropwise 28.8 g (153 mmol) of ethyl t-butyl malonate. After the addition was complete, the solution was stirred for an additional 20 minutes, then 2.49 g (15 mmol) of potassium iodide was added, followed by a solution of 58.0 8 91 2 36.0 g (153 mmol) of 1,2-dimethoxy-4,5-brine. -chloromethylbenzene in 180 ml of dry tetrahydrofuran. The mixture was heated at reflux for 2.5 hours, then allowed to cool, and concentrated on a rotary evaporator. The resulting slurry was dissolved in methylene chloride (300 mL), washed with water (2 x 100 mL), and dried (anhydrous magnesium sulfate), and concentrated to give the desired crystalline 2-carboethoxy-2-carbo-t-butoxy-5,6-dimethoxyindan, which weighed 46.2 g (86.2 96) and melted at 70-73 ° (from ether).

The XB spectrum (KBr) of the recrystallized product showed strong absorption at 5 → 77 for the carbonyl groups.

Example X

2-carboxy-5,6-dimethoxy-indan-2-carboxylic acid

A solution of 46.2 g (132 mmol) of 2-carbocaethoxy-2-carbo-t-butoxy-5,6-dimethoxyindan and 2.25 g (13.2 mmol) of p-toluenesulfonic acid monohydrate 460 in benzene, was heated to reflux using a Deans-Stark trap for 4 hours. The solution was allowed to cool, washed with water (3 x 50 mL), dried (anhydrous magnesium sulfate) and concentrated to give the desired crystalline 2-carboethoxy-5,6-dimethoxyindan-2-carboxylic acid weighing 38.9 g (100 #) and melted at 146-148 ° (from a mixture of ethyl acetate and cyclohexane).

The IR spectrum (KBr) of the recrystallized product showed strong absorption at 5.77 for ester carbonyl and at 5.67 for acid carbonyl.

Example XI

Ethyl 5,6-dimethoxyindan-2-carboxylate A 46.8 g (159 mmol) portion of 2-carboethoxy-5,6-dimethoxyindan-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 and weighed 29.6 g ($ 74.6), b.p. 170-176 °, at a pressure of 1.0 mm; mp. 46-48 °.

The XR spectrum (KBr) of the product showed strong absorption at 5.75 for ester carbonyl.

Example XII

N-methanesulfonyl-9α-hydroxy-11α, 15ββis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13β-pentanorprostadienamide

To a solution of 2.37 g (4 to 56 mmol) of (methanesulfonylaminocarbonyl-n-butyl) triphenylphosphonium bromide in a dry nitrogen atmosphere in 5.0 mL of dry dimethyl sulfoxide was added 4.50 mL (8.62 mmol) 59 5 891 2 1.90 molar solution of sodium methylsulphinylmethide in dimethylsulphoxide. To this red ylide solution was added dropwise a solution of 735 mg (1.52 mmol) of 2- (5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2B- (3α- (tetrahydropyran-2- yloxy) -3- (2-indanyl) -trans-1-propen-1-yl) cyclopentyl-1-yl) acetaldehyde, γ-hemiacetal in 6.0 ml of dry dimethyl sulfoxide. After stirring for another hour at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was acidified to pH with about $ 10 in 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 and ethyl acetate as eluents. After removal of high Rf impurities, 899 mg (81.3-6) of N-methanesulfonyl-9o hydroxy-IIa, 15a-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13-w pentanorprostadienamidia.

The IR spectrum of the product (CHCl 3) showed moderate absorbances at -1 '-1 for the 1710 cm carbonyl group and at 970 cm for the trans double bond.

Treatment of the above hemiacetal with an ylide derived from (4- (tetrazol-5-yl) n-butyl) triphenylphosphonium bromide gives a product which can be converted to 2-descarboxy-2- (tetratolol-5-yl) prostaglandins.

'. 60 5891 2 (Η

S

o

• P S

? - ä 0 “* O M O 'W r>. r ·· r »•“ 'O' M O 'd Φ ö d ©

• a -S

% a

H (Q

0 H P <O

P *: S d rt g: rt ^ ¢ 4 CU CU s g o ij> j j φ a M MM Ä Φ: rt d t »Φ

1 I

a a «P ή υ 'll« M .3 52—53 S 52 = 53 * 5 · I 35 1 1 {«, *> y \% γ \«! s (i * a g> x s 2 s \ V s -s *) 4, ö § <7 5 rt) | d MK / Ä

1 — I o I | if O

o \ _ d o 00 “'d * _ 01

: rt g H

-p rt • h S ^> φ ^ -h m d

P h «H

ai S S 3

• H γϊ rt * H

ό d d -h

Λ rt rt M

>> Ό> ö rt -S -S 5

+ J I I M

• H Ή -H O

d Φ O jC

g Λ * O

O O M

• P -P M

• h Φ «rt

rH aa I

S Ή, * H · Η

P * Xf X) M

SI I ® VO VO + »« O> * (0 a v

• H> w 'W

I II ^ -S

CM CM CM rt 61 5891 2

Example XIII

• N-Methanesulfonyl-9-ocolo-15α, 15α-bis- (tetrahydropyran-2-yloxy) -15- (2-indaryl) -cis-5-Trane-13-yl] -pentanorpr 031 adi enamide To Temperature - 10 ° N under nitrogen In a cooled solution containing 399 ®e (0.62 mmol) of N-methanesulfonyl-9a * “by] dibroca, 15a-bi8- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis- 5 "trans-13 - (*> - pentanorprostadienamide in 15 ml of reagent-pure acetone, 0.31 ml of Jones reagent was added dropwise. After 15 minutes at -10 °, 0.31 ml of 2-propanol was added and the reaction mixture was allowed to stir for 5 minutes, then combined with ethyl acetate, washed with water (2x), dried (MgSO 4) and concentrated with 371 mg (93%) of N-methanesulfonyl-9-oxo, To obtain β-bi- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13-yl-penta-norprostadienamide, which was used without purification.

Other compounds with structure:

\ I (CHo) ^ A

TKPO ^ - '

OTHP

A n X He (a)

2-indanyl 0 χ, Ν-Ν LP

B

(a) ester-alcohol mobility by thin-layer chromatography.

LP less polar MP * more polar ♦ 62 5891 2

Example XIV

Dimethyl 2-oxo-3- (2-indanyl) propyl phosphate A solution of 20.4 gsn (164 mmol) of dimethyl methylphosphonate (Aldrich) in 200 ml of dry tetrahydrofuran is cooled to -78 ° under a dry nitrogen atmosphere. To the stirred phosphonate solution is added 82.6 mL of a 2.23 molar solution of n-butyllithium in hexane (Alfa Inorganics, Inc.) dropwise over 20 minutes at such a rate that the reaction temperature never rises above -63 °. After stirring for an additional 3 minutes at -78 °, 14.0 g (73 x 5 mmol) of methyl (2-indanyl) acetate are added at a rate that maintains the reaction temperature below -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 evaporated to a white gel. The gel-like material is taken up in 30 ml of water, the aqueous phase is extracted with 73 ml portions of methylene chloride (4x), the combined organic extracts are washed (73 → 1 HgO), dried (MgSO4) and concentrated (in a water-jet vacuum) to give a crude residue and distilled, dimethyl 2-oxo-3- (2-indanyl) propylphosphonate.

The product of this reaction is the starting material for the synthesis of E- or F-series 16- (2-indanyl) -β-tetranorprostaglandins. Other precursors required for the synthesis of the 17-20 substituted prostaglandin analogs of this invention are similarly prepared from the appropriate methyl ester. 1

Example XV

Bimethyl 2-oxo-2- (2- (1,2,3,4-tetrahydronaphthyl) ethylphosphonate A solution of 20.4 g (164 mmol) of dimethylmethylphosphonate (Aldrich) in 200 ml of dry tetrahydrofuran is cooled to -78 ° in dry nitrogen. To the stirred phosphonate solution is added dropwise 82.6 mL of a 2.23 molar solution of n-butyllithium in hexane (Alfa Inorganics, Inc.) over 20 minutes at such a rate that the reaction temperature never rises above -63 °. «After stirring for 3 minutes at -78 ° , 14.0 g (73.5 mmol) of methyl 2- (1,2,3,4-tetrahydronaphthylcarboxylate) are added dropwise at a rate which keeps the reaction temperature below -70 ° (20 minutes). After 0 hours at -78 °, the reaction mixture is allowed to warm to ambient temperature, neutralized with 20 ml of acetic acid and rotary evaporated to a white gel. The organic extracts are washed with 63 5891 2 (75 ml H 2 O) #, dried (MgSO 4) and concentrated (water jet pump) to a crude residue and distilled to give 2-oxo-2- (2- (1,2,3,4-tetrahydronaphthyl) ethyl acetate). to obtain a phosphonate.

The product of this reaction is the starting material for the synthesis of 15- (2- (1,2,3,4-tetrahydronaphthyl)) - o-tetranorprostaglandins of the E »or F-ear. Other precursors required for the synthesis of the 16-2C substituted prostaglandin analogs of this invention are similarly prepared from the appropriate methyl esters.

Example XVI

Dimethyl 2-oko-2- (2- (R, 2,3,4-tetrahydronaphthyl)) ethylphosphonate A solution of 20.4 g (164 mmol) of dimethylmethylphosphonate (Aldrich) in 200 ml of dry tetrahydrofuran is cooled to -78 ° in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 82.6 ml of a 2.25 molar solution of n-butyllithium in hexane (Alfa Inorganics Inc.) dropwise over 20 minutes at such a rate that the reaction temperature never rises above -65 °. After stirring for a further 5 minutes at -78 °, 14.0 g (73.5 mmol) of methyl 2- (R1, 2,3,4-tetrahydronaphthylcarboxylate) are added dropwise at a rate which keeps the reaction temperature below -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 evaporated to a white gel. The gel-like material is taken up in 50 ml of water, the aqueous phase is extracted with 75 ml portions of methylene chloride (4 z), the combined organic extracts are washed (75 ml of H 2 O), dried (MgSO 4) and concentrated (water jet pump) to a crude residue which is purified by column chromatography. dimethyl 2-oxo-2- (2- (R, 2,3,4-tetrahydronaphthyl)) ethylphosphonate.

The product of this reaction is the starting material for the synthesis of 15- (2- (R-1,2,3,4-tetrahydronaphthyl)) -? - tetranorprostaglandins of E- or F-sarphs. From the mold, the precursors required for the synthesis of the 16-20 substituted prostaglandin analogs of this invention are similarly prepared from the appropriate methyl esters.

Example XVII

Dimethyl 2-oxo-2- (2- (S1, 2,3,4-tetrahydronaphthyl)) ethyl phosphonate 5891 2 6h A solution of 20 g (16 mmol) of dimethyl methyl phosphonate (Aldrich) in 200 ml of dry tetrahydrofuran is cooled to -780 in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 82.6 mL of a 2.25 molar solution of n-butyllithium in hexane (Alfa Inorganics, Ind.) Dropwise over 20 minutes at such a rate that the reaction temperature never rises above -65 ° · After stirring for another 5 minutes at ~ T8 °, add dropwise 1.0 g (T3.5 mmol) of methyl-2- (S ~ 1,2,3, * + “tetrahydronaphthyl) at a rate that keeps the reaction temperature below -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 evaporated to a white gel. The gel-like material is taken up in 50 ml of water, the aqueous phase is extracted with 75 ml portions of methylene chloride (4x), the combined organic extracts are washed (75 ml of HgO4), dried (MgSO4) and concentrated (water jet pump) to a crude residue which is purified by column chromatography. to obtain dimethyl 2-oxo-2- (2- (S-1,2,3,7-tetrahydronaphthyl)) ethylphosphonate.

The product of this reaction is the starting material for the synthesis of E- or F-series 15- (2- (S-1,2,3,3-tetrahydronaphthyl)) -N-tetranorprostaglandins. Other brochure products required for the synthesis of 16-20 substituted prostaglandin analogs of this invention are similarly prepared from the appropriate methyl esters.

Example XVIII

N-Methanesulfonyl-9CX-hydroxy-11H, 15c * -bis- (tetrahydropyran-2-yloxy) -15- (2- (1,2,3,4-tetrahydronaphthyl)) - N-pentanorprostanamide

A heterogeneous mixture containing 1.52 g of N-methanesulfonyl-9-hydroxy-110 ', 15 * * -bis- (tetrahydropyran-2-yloxy) -5-cis-13-trans-15- (2- (1,2 (3,3-tetrahydronaphthyl)) -cy-pentanorprostadienamide and 152 mg of 5 to 5 palladium on carbon in 15 ml of absolute methanol are stirred together under a hydrogen atmosphere at 0 ° for four hours. The reaction mixture is filtered (Celite) and concentrated to N-methanesulfonyl-St <-hydroxy-11c *, 15t-bis- (tetrahydropyran-2-yloxy) -15- (2- (1,2,3 »U-tetrahydronaphthyl)) - ^ / - pentanorprost to give the amide.

Example XIX

2- (50'-hydroxy-3α- (tetrahydropyran-2-yloxy) -2,3- (3α-tetrahydropyran-2-yloxy) -8- (1-adamantyl) oct-1-yl) cyclopent -loEacetic acid, T ~ lactone (2Ue)

A heterogeneous mixture containing 2.39 g (* +, 2 mmol) of 2- (5-y-hydroxy-3-y- (tetrahydropyran-2-yloxy) -2H- {30- (tetrahydropyran-2-yloxy) - 8- (1-adamantyl) -trans-1-octen-1-yl) cyclopent-1-yl) acetic acid, β-lactone and 239 mg of 5 # palladium on carbon in 25 ml of absolute methanol, ¢ 5 5 8 91 2 is stirred together under a hydrogen atmosphere for 2 hours. The reaction mixture is filtered (Celite) and concentrated 2- (5c * -hydroxy-3C * - (tetrahydropyran-2-yloxy) -2H- (3x- (tetrahydropyran-2-yloxy) -8- (1-adamantyl) oct -1-yl) cyclopent-1 (γ-yl) acetic acid, to give the T-lactone.

Example XX

2- (3- & 3-Phenylbenzene oxyloxy-hydroxy-2 / 5- (3c / -hydroxy-3/5-methyl-5- (1-adamantyl)) -trans-1-penten-1-yl) cyclopent-Icx-yl) acetic acid. γ-lactone and 2- (3α * -ρ-phenylbenzyl oxyloxy-5α-hydroxy] -2 / 3- (3β-hydroxy-30β-methyl-5- (1- adamantyl) -trans-1-penten-1-yl) cyclopent-10-yl) -acetic acid, γ-lactone

To a solution of 2.15 g (* + .0 mmol) of 2- (3β-phenylbenzoyloxy-5Cyr-hydroxy-2 / 6- (3-oxo-5- (1-adamantyl) trans) 1-penten-1-yl) -cyclopent-IQA-yl) acetic acid, γ-lactone in 21 ml of anhydrous ether and 20 ml of tetrahydrofuran in a dry nitrogen atmosphere at -78 °, is added dropwise 1+, 0 ml (1, 0 molar) methyl lithium solution in ether (Alpha). After stirring at -78 ° for 15 minutes, quench with glacial acetic acid until the pH of the mixture is about 7 · The mixture is then diluted with methylene chloride and the diluted organic solution is washed with water and brine, dried (anhydrous magnesium sulfate) and concentrated to give epimeric alcohols.

The crude product is purified by column chromatography on silica gel with 2- (SO1-p-phenylbenzoyl) oxy-hydroxy-N- [S- (SP-hydroxy-S / methyl-? - (1-adamantyl) -trans-1-penten-1-yl) ) cyclopent-10-yl) acetic acid, γ-lactone and 2- (3β-phenylbenzoyloxy-5α-hydroxy-2 / 3- (3H-hydroxy-SfX-methyl-5- (1-adamantyl)) - trans-1-penten-1-yl) cyclopent-1β-yl) acetic acid, γ-lactone.

Example XXI

2- (N, N-dihydroxy-N- (3-N-hydroxy-3- (2-indanyl) -trans-1-propen-1-yl) cyclopent-1- (X-yl) acetaldehyde, γ-hemiacetal) To a solution cooled to -78 ° containing 750 mg (1.5 mmol) of 2- (3'-p-phenylbenzoyloxy-5H-hydroxy-2 / e- (30'-hydroxy-3- (2-indanyl)) - trans-1-propen-1-yl) cyclopent-1 (X-yl) acetic acid, γ-lactone in 15 ml of toluene, 7 to 5 ml of a 20 .mu.l solution of diisobutylaluminum hydride in hexane (Alpha) are added. The reaction mixture is stirred in the cold for 1.0 hour, then quenched by the addition of methanol until gas evolution ceases, the quenched mixture is allowed to warm to room temperature, then concentrated, the residue is stirred with methanol (3x) and concentrated. - (N, N-hydroxy-3- (2-indanyl) -trans-1-propen-1-yl) cyclopent-NX-yl) acetaldehyde, γ-hemiacetal.

66 5 8 91 2

The above product can be converted to the 15- (2-indanyl) -β-pentanor PGF 4 analogs of this invention. Other F-type prostaglandin analogs of this invention can be prepared by the above procedure.

Claims (1)

67 5891 2 Claim: An analogous process for the preparation of new therapeutically active prostaglandin series compounds E and F of the formula MZ (CH-) A (*) RX OH wherein A is 1-adamantyl, 2- (1,2,3Λ-tetrahydronaphthyl) ), which may be racemic or optically active or 2-indanyl, which may be substituted by methoxy; R is hydrogen or methyl; n is an integer from 0 to 2; W is a single bond or a cis double bond; Z is a single bond or a trans double bond: M is oxo,-^ 7 „„ or -r; ; X is 5-tetrazolyl or a group of the formula * Un '*> x1 -CONHSO8CH2 or -C00R', wherein R * is hydrogen, methyl »ethyl-biphenyl or cycloalkyl having 3 to 8 carbon atoms, and their C 1-4 epimers for the esterification of any free hydroxy group in the C 1-4, C 1-4 or C 1-4 position with a lower alkanoyl or formyl, and for the preparation of pharmaceutically acceptable salts of the compounds of the formula I in which X is -C00H, characterized in that a ) a compound of formula M (CH 2 -A --- 2 n THPO R / N 'OTHP wherein A, n, M, R, W, X and Z are as defined above and THP is 2-tetrahydropyranyl is reacted b) a compound of formula I wherein M is oxo is reacted with a suitable reducing agent to produce a compound of formula I wherein M is or * i, and A, n, R, W, X and Z have the same meaning as above, and the 9 <X. ~ and S $ isomers ** are separated if desired; c) a compound of formula I wherein A, R, n, M and X are as defined above, W is a single bond or a cis double bond when Z is a trans double bond and Z is a single bond when W is a cis double bond, is catalytically hydrogenated to prepare a compound of formula I wherein A, R, n, M and X are as defined above and W and Z are a single bond; 66 5 891 2 d) a compound of formula I wherein A, R, n, M and X have the same meaning as above and W and Z represent a double bond is selectively hydrogenated by reaction at one atmospheric hydrogen pressure in the presence of a palladium catalyst having 5 to # carbon in absolute in methanol to prepare a compound of formula I wherein A, R, n, M and Z are as defined above, W is a single bond and Z is a trans double bond; and a compound of formula I wherein X is -COOH is optionally converted to an ester by reaction with a suitable esterifying agent; and, if desired, preparing a 1H- or l-lower alkanoyl or formyl ester from any free hydroxy group by reacting a compound of formula I with a suitable acylating agent; and converting a compound of formula I wherein X is -COOH, if desired, to a pharmaceutically acceptable salt. 69 5891 2 Analogous derivatives for the preparation of a therapeutically active compound for the treatment of prostaglandic compounds E and F with the formula M w, *! - 1 R- '' "'OH color A and 1-adamantyl, 2- (1,2,3, ^ -tetrahydronaphthyl), which can be racemic or optically active, or 2-indanyl, which can be substituted by methoxy; For each of these or trans-double bonds, M is oxo, H ———— OH or X is 5 or 5-tetrazolyl or a group of the formula -C0NHSO0CHO and d3 or -C00R ', color R1 is methyl, methyl, ethyl , which is phenyl or cycloalkyl with 3 to 8 chlorates; föreningarna med formuleln I, color X är -C00H, kännete cknat därav, att a) en förening med formuleln M TT ___ (CH2) nA THPÖ 'R' '-0THP color A, n, M, R, W, X oc h Z is an angiven betydelse och THP är 2-tetrahydropyrahy1, omsättes med vattenhaltig ettiksyra; (b) in the case of formula I, color M and oxo, in the case of a reduced reduction medium for the formulation in the form of formula I, in the form of M, H OH nu or 'A, n, R, W, X and Z har ovan .engiven betydelse, och "UH '' ttn n om sä önskas, 9 ° *“ och 9 / 3risomererna separeras; with enabling or with cis-duplicating with Z and with trans-duplicating and Z with enabling of W with cis-duplicating, hydrolytic catalytic for the production of formulas I, color A, R, n, VL and X har (d) in the case of formulas I, color A, R, n, M and X har ovan.