FI60389C - NYA 16-ARYLOXIS SUBSTITUTES OMEGA-TETRANORPROSTAGLANDINER VILKA AER ANVAENDBARA SAOSOM BEFRUKTNING FOERHINDRANDE MEDEL - Google Patents

Description

• ιΜμ · '| fftl / 1 «ADVERTISING PUBLICATION. Λ Λ

JwA W (1) UTLAGGNINGSSKRIFT 603 8 9 C Patent granted 11 01 1902

Patent eeddelat (51) Ky.ik.Wa3 C 07 C 177/00 SUOM I — FI N LAN D (21) p «un« jhuk «nu« —psuntmekning 3i + i + 3/73 (22) Hakemitpilvl —AMBknlnpdtg 07 · 11 «73 ^ ^ (23) AlkupUvt — GUtlghutsdaf 07 · 11.73 (41) Tullut lultdMkal - Bllvlt offtmllg 09 · 05 · 7 * +

Patent and Registration Office ,............ . .

_ ^. . (44) Date of initial assessment. - '0,

Patents and Registration Cases Airaekan utiagd och utl. 3 * »5 East l + 2nd Street, New York, NY, USA (72) Jasjit Singh Bindra, Groton, Connecticut, Michael Ross Johnson,

Gales Ferry, Connecticut, USA (7 * 0 0y Kolster Ah (5I +) New 16-aryloxy-substituted Q-tetranorprostaglandins useful as infertility inhibitors - Nya This invention relates to certain novel analogs of naturally occurring prostaglandins, i.e., novel 16-aryloxy-substituted (λ) -tetranorprostaglandins.

Prostaglandins are C-unsaturated fatty acids with various physiological effects.

One important physiological effect of naturally occurring prostaglandins is related to the reproductive cycle. PGE 1 is known to have the ability to induce postpartum burns (Karim, et al., J.0bstet Gynaec. Brit. Cwlth 77 * 200-210. 1970) to induce therapeutic miscarriage (Bygdeman, et al., Contraception, U, 293 (1971)). and be useful in birth control (Karim, Contraception, 3, 173 (1971)),

Several series E and F prostaglandins have been patented as inducers of postpartum burns in mammals (BE patent 75 * + 158 and DE patent 2 03 * + 61 + 1) and for PGF1, F1 and F1 to regulate the reproductive cycle ZA Patent Publication 69 (6089).

^ 0339

It is now known that physiological effects occur only shortly after in vivo prostaglandin administration. Numerous evidence indicates that the reason for this rapid cessation of activity is that natural prostaglandins are metabolically inactivated rapidly and efficiently through carboxylic acid side chain / S oxidation and oxidation of the 15β-hydroxyl group (Anggard, et al., Acta. Physiol. Scand., 81, 396 (1971) and references therein).

It was considered desirable to provide prostaglandin analogs that would have equivalent physiological activity to natural compounds, but with increased selectivity and duration of activity. Increased selectivity of action could be expected to bring with it adverse side effects, particularly in the gastrointestinal tract, which are often observed as a result of intravenous administration of natural prostaglandins (see Lancet, 536, 1971).

The present invention relates to novel 16-aryloxy-substituted (/} -tetranorprog taglandins useful as fertility inhibitors and having the formula: __I .. (I) H0V \ O-Ar

OH

wherein Ar is phenyl or monosubstituted phenyl substituted with halogen, trifluoromethyl, lower alkyl or lower alkoxy; W is a single bond or a cis double bond; Z is a single bond or a trans double bond;

—H _____--- OH

M is oxo or;

//// 'OH "" "/ H

X is tetrazolyl or a group of the formula; 0 ft -C-O-R ', wherein R' is hydrogen or p-biphenyl, provided that R 'is not hydrogen when W is a cis double bond or X is a group of the formula;

O

tt -CNHR ', wherein R "is acetyl, benzoyl, alkylsulfonyl having 1 to 3 carbon atoms or phenylsulfonyl, and their C 1-4 epimers.

3 60389

The novel compounds of formula I can be prepared as follows: a) a compound of formula:

O

(II) THPO '"'" '0_Ar

SqTHP

wherein Ar, M, W, X and Z are as defined in formula I and THP is 2-tetrahydropyranyl, is reacted with aqueous acetic acid; b) a compound of formula I or a trialkylsilyl ester thereof wherein X is COOH and Ar and M are as defined above and W and Z are a double bond are selectively hydrogenated with hydrogen in the presence of a palladium on carbon catalyst to give a compound of formula I wherein Ar, X and M is as defined above, W is a single bond and Z is a trans double bond, and the resulting compound wherein X is COOH is converted, if desired, to an ester for reaction with a suitable esterifying agent.

The intermediates used in the preparation of PGFs are those of the formula:

OH

THPO "" "* wherein THP is 2-tetrahydropyranyl and Ar, W, Z and X have the same meaning as in formula I; and their C 1-4 and C 1-4 epimers.

Z is a single sod or trans double bond.

Intermediates of formula IIA may be prepared by the following procedure: a) A compound of formula

OH

K

il ... VA

THPO ^ N ^^ V ^^ O-Ar

% OTHP

li 60389 wherein Ar, THP and Z have the same meaning as above, is reacted with a ylide of the formula: (cgH) 3p = ch-ch2-ch2-ch2-x where X has the same meaning as above, provided that when X = C and W is a cis double bond, and then the compound thus formed, if desired, is hydrogenated to give a compound of formula IIA wherein Ar, X and Z are as defined above and W is a single bond; b) a compound of formula IIA above, wherein Ar and X are as defined above, W is a cis double bond and Z is a trans double bond, is hydrogenated to form a compound of formula IIA wherein Ar is as defined above and W and Z are simple bonds; c) a compound of formula IIA above wherein Ar and X are as defined above, W is a cis double bond and Z is a trans double bond is selectively hydrogenated to form a compound of formula IIA wherein Ar and X are as defined above, W is a single bond and Z is a trans double bond.

The compounds used as intermediates in the preparation of PGE compounds are compounds of the formula: 0

"v \ W

\ _ / z ^ \ ji; i ^ \ //, SssO-Ar

THPO

^ "'OTHP

n 60389 wherein W, Z, X and THP are as defined above, and their C-epimers.

Intermediates of formula IIB may be prepared as follows: (a) a compound of formula:

OH

if w ΤΗΡ0 0_Ar

'' OTHP

wherein Ar, THP, X, W and Z have the same meaning as above, are reacted with chromic acid in aqueous sulfuric acid and acetone.

Other intermediates used in the preparation of the compounds of the invention include the compounds of formulas III, IV, V and VI below. Intermediates with the formula:

... III

QO 0 O-Ar 0 wherein Ar is phenyl or monosubstituted phenyl substituted with halogen, trifluoromethyl, lower alkyl or lower alkoxy; and Q is p-biphenylcarbonyl; can be prepared as follows: a compound of the formula O * o- \ QO '' CH0 wherein Q is as defined above is reacted with a compound of the formula: 60389 lower alkyl-O "· ^ ^ ^, P-CH- C- (CH) -O-Ar 2 [| 2 n

lower alkyl-O 0

where Ar means the same as above.

Intermediates of the formula: wherein Ar is phenyl or monosubstituted phenyl substituted with halogen, trifluoromethyl, lower alkyl or lower alkoxy; Q * is hydrogen or p-biphenylcarbonyl, can be prepared as follows: a compound of formula 0

o '' ... III

Qo '' ^ | /// ^ NXs'0-Ar

O

wherein Ar and Q are as defined above, is reduced to give a compound of formula IV wherein Ar and Q are as defined above, if desired, the 8 and 8β isomers are separated; and a compound of formula IV wherein Ar is as defined above and Q is biphenylcarbonyl, optionally treated with 1 CO 2 to give a compound of formula IV wherein Q is hydrogen; and, if desired, separating the 8 oC and 8/3 isomers.

Intermediates with the formula: 7 6 O 3 8 9 Υ γ9 THPO O-Ar

OTHP

wherein Ar is phenyl or monosubstituted phenyl substituted with halogen, trifluoromethyl, lower alkyl or lower alkoxy; THP is 2-tetrahydropyranyl; Z is a single bond or a trans double bond; and

<H

; can be prepared as follows:

OH

a compound of the formula:

Y

ΓΛ ... iv I_I z ho '

OH

wherein Ar and Z are as defined above and Y = 0, is reacted with 2,3-tetrahydropyran in the presence of an acid catalyst to give a compound of formula V wherein Ar and Z are as defined above and Y = 0; a compound of the above formula V wherein Ar and Z are as defined above and Y = O is reacted with di-iso-butylaluminum hydride to give a compound of formula V wherein Ar and Z are as defined above and Y is: above a compound of formula IV wherein Ar is as defined above, Z is a trans double bond and Y = O, is catalytically reduced to give a compound of formula V wherein Ar is as defined above, Y = 0 and Z is a single bond.

Intermediates of the formula:

Ar-O-CH2-C-CH2-Pl ^^ ... VI

^^ OCH

wherein Ar is phenyl or monosubstituted phenyl in which the substituent is halogen, trifluoromethyl, lower alkyl or lower alkoxy, can be prepared by lowering an alkyl ester of the formula:

B

Ar-O-CH 2 -C 0-lower alkyl wherein Ar is as defined above is reacted with a dialkylmethylphosphonyl of the formula:

T

(lower alkyl-O) 2 P-CH 2 ·

Preferred compounds of the invention are 16-phenoxy-PGE2-p-biphenyl ester and 16-phenoxy PGFβ-β-biphenyl ester and 16-phenoxy-βGF-β-biphenyl ester. Other preferred prostaglandins are the following compounds: A compound of formula I wherein X is a group of the formula:

O

f! -CNHR ", wherein R" is acetyl; W is a cis double bond and Ar is phenyl.

A compound of formula I wherein X is tetrazolyl, W is a cis double bond, Z is a trans double bond and Ar is phenyl.

A compound of formula I wherein X is a group of the formula:

M

-CNHR ", wherein R" is methylsulfonyl; W is a cis double bond, Z is a trans double bond and Ar is phenyl.

60389

A compound of formula I wherein X is a group of the formula: -CNHR "wherein R" is methylsulfonyl; W is a cis double bond, Z is a trans double bond and Ar is m-methoxyphenyl.

A compound of formula I wherein X is a group of the formula: wherein R "is acetyl; W is a cis double bond, Z is a trans double bond and Ar is m-methoxyphenyl.

The starting materials for the novel compounds of the invention are commercially available or can be prepared by methods well known to those skilled in the art. For example, in the preparation of dimethyl 2-oxo-3-phenoxypropyl phosphonate, a starting material for the synthesis of 1-phenoxy-prostaglendins, a solution of dimethyl methylphosphonate in tetrahydrofuran is cooled to -70 ° C in a dry nitrogen atmosphere and then lithium-lithium is slowly added dropwise. After standing at -78 ° for 3-1 + hours, 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.

The preparation of 16-phenoxy-prostaglandins requires substituted phenoxyacetic acids prepared by condensing the appropriate phenol with a haloacetic acid or ester in the presence of a base, as described by J.M. Petersen, Acta Chem. Scandinavic, 5, 519 (1951) or M. Beroza, Agri.

Food Chem., H, 1 + 9 (1956). Condensation of bromomethyl with cresol in the presence of sodium methoxide affords the methyl ester of 3, 4-methylenedioxyphenoxyacetic acid. Correspondingly, p-chlorophenoxyacetic acid, 3,1 +, 5-trimethoxyphenoxyacetic acid and p-phenylphenoxyacetic acid can be prepared.

The various steps in the preparation of the compounds of the invention are shown in the following reaction scheme.

10 k 60389> ν '"· y l.n * V—« 9 ° \ p CQJ \ / n n / * 33 S3 33 Γ 1 ^ s * \ \ O O / -x Q ^ \ \ / O J V ·.>

Cv »I O · * * <ö \ _J a“ V loi '·· -1 $

r1 ° ί V

i 1 rS Λ§ t v · .. f ψ Vy> J ...- / H X i <\ -A jo].

tn '331 s.>'

S3 O \ / O

y <^ -i mi o crru Q = o f- 0 0 o Λ Λ 5 [oj [o 60389 11

As shown in Scheme A, the first step in the complete synthesis (_1 → → E) is the condensation of the appropriate ester with a dialkyl methyl phosphonate to provide the ketophosphonate 2. These esters are obtained as described above.

In the reaction, the ketophosphonate is reacted with a known (Corey et al., J. Am. Chem. Soc., 93, 191 (19T1)) aldehyde H to give the enone by chromatography or crystallization. after.

Enone 3 can be converted to a mixture of tertiary alcohols J 3 and 3 by reaction with the appropriate metal alkyl and isomers 13 and III can be isolated by column chromatography. Enone 3 can be reduced with zinc borohydride or trialkyl borohydrides such as triethyl borohydride to a mixture of alcohols h and 5 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. Further transformations of U are shown in Scheme B.

E - β 6 is base catalyzed hydrolysis in which the p-biphenylcarbonyl protecting group is removed. This is preferably done with potassium carbonate using methanol or a mixture of methanol and tetrahydrofuran as the solvent.

E -> 7 includes protection of two free hydroxyl groups with an acid labile protecting group. Any acid labile group is satisfactory; however, the most common is tetrahydropyranyl, which can be introduced into the molecule by treatment with tetrahydropyranyl and an acid catalyst in an anhydrous medium.

The catalyst is usually p-toluenesulfonic acid.

1-> 8 is the 7th reduction hemiacetal of the lactone E using diisobutylaluminum hydride in an inert solvent. Low reaction temperatures are preferred and the temperature range is between -6 ° and -70 °. However, higher temperatures can be used as long as no over-reduction occurs. If desired, purify by 8 column chromatography.

E is a Wittig condensation in which hemiacetal 8 is reacted with (1-carbohydroxy-n-butyl) triphenylphosphonium bromide in dimethyl sulfoxide in the presence of sodium methylsulfinylmethide. £ cleaned as above.

The conversion from ε to 1212 is the acid hydrolysis of tetrahydropyranyl groups. Any acid that does not cause degradation of the molecule during deprotection may be used; however, this is most often performed in an aqueous solution of 65% acetic acid. The product is purified as above.

60389 £ - ^ 10 is the oxidation of the secondary alcohol £ to the ketone 10.

This can be done using any oxidizing agent that does not affect the double bonds; however, Jones' reagent is generally preferred. The product is purified as above.

10 is performed in the same manner as £ --y12. The product is purified as above.

60389

K

Scheme B '\ i -> HO' / “Ar 6 H ΌΗ Λ · \, _I. C \ THPO ‘O-Ar Cv. ✓ · H 'CTHP 7 ^ Γ THPO' 'N ^ XX-Ar 8 / ·

/ - H OTHP

.L-X ^^ fi THPO 'O-Ar,' V ^ χ \ χ \ γ ti OTHP 9 I] j THPO '* ^ V ^^ X ^^ O-Ar

OH ψ, 10 H OTHP

OCX J

HO · '\ 0-Ar ϋ 11 0H Jk .-' V - / ^ vA.

HO 'XX ^ O-Ar 11 /

± - H OH

60389] Λ

As shown in Scheme C, E can be substituted with the silicon shown in Scheme B to give prostaglandin derivatives 12 'and 11'.

Scheme C

"Un ho 'ö —-> - 1 111 HO ^

B

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

3. At 19. + 191, the enone is reduced to the 3. tetrahydro compound using any of the complex metal hydride reducing agents, LiAlH 2, NaBH 4, KBH 2, LiBH 2 and ΖηίΒΗ ^) ^. NaBH 2 is particularly preferred. The products, _] _ £ and 19 'are separated by column chromatography.

Furthermore, the compounds shown in Scheme A can be catalytically reduced to 19 and 191 with hydrogen, respectively. The step of reducing the double bond is not critical and the hydrogenation of 6 or 7 shown in Scheme B also provides useful intermediates for the 13,1-dihydroprostaglandins of this invention. This reduction can be performed with either a homogeneous catalyst such as tris (triphenylphosphine) chlorodhodium or a heterogeneous catalyst such as platinum, palladium or rhodium.

15 60389 c o

X

yw, K ° X °> ro | - ^ u <o

VK

.s Y 'ri 51 «- ·« \ ° __ anos ^ / /> \ i6 60389 Conversion of 19 and 191 to their corresponding prostaglandins follows the path shown in Scheme B, replacing 19: Ha and 19' 13, 11, To obtain prostaglandin derivatives of the 1β-dihydro-PGE 2, PGA 2 and PGF 2 series.

Scheme E depicts the preparation of various reduced 15-substituted β-pentanorprostaglandin precursors: I? -> 22 is performed as shown in Scheme B for b-) 9. 22 can be used both as a precursor for 13,1U-dihydro-15-substituted-60-tetranorprostaglandin in the "2-series" and as an intermediate for 23, which is a 13,1-dihydro-15-substituted compound in the "1-series". -pentanorprostaglandin precursor.

22-> 2_3 is carried out by catalytic hydrogenation using the catalyst described in connection with the reduction reaction J + - »19 in Scheme D. Intermediates of type 21 are prepared by selectively reducing the 5,6-cis double bond at low temperature using the catalysts described for reactions - * J_9 and -> 23.

Particularly preferred for this reduction is the use of a palladium-on-carbon catalyst and a reaction temperature of -20 °. The 21-type intermediates are precursors not only to the 15-substituted-1J-pentanorprostaglandins of the "1-series" via thi 2-H1, but also as precursors to the 23- -type compounds by the method already mentioned in connection with 22-> 23.

X

60389

IT

/ VJ

/ </ o Qj

\ M

\ / kM

\ / H

. > <o β>) / \ /.

Λ / a V- / sl) a s- <4 XS i1> ¢ - \ / ml X \ _ / </ ° S g \ / s ä) k / I a ^ p »/ aa / X o --- · '\ M «m \ \

O

04

M

B

18 60389

Furthermore, the 15-substituted C 1-6 pentanorprostaglandins of the E 1 and series can be obtained directly from the corresponding prostaglandin analog of the "2 series", first by protecting the hydroxyl by introducing dimethyl isopropylsilyl groups, selectively reducing the cis double bond and removing the protecting group.

Deprotection is usually accomplished by treatment of the prostaglandin analog with dimethylisopropylchlorosilane and triethylamine, reduction is performed as described in Reaction 9-> 2J_, and deprotection is accomplished by contacting the reduced protected compound with a mixture of acetic acid and water (3: 1). for one minute or until the reaction is substantially complete.

The C1-4 epimers of 21, 22 and 23 can be used as precursors for the 15-epi series of prostaglandin derivatives described above.

In those of the above methods in which chromatographic purification is desired, neutral alumina and silica gel are included in suitable chromatographic supports, and a silica gel of 60 to 200 mesh is generally preferred. Chromatography is conveniently performed in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane, as described in the following examples.

It is noted that the above formulas describe optically active compounds. However, it is clear that the corresponding racemates have valuable biological activity due to their above-mentioned biologically active optical isomer content, and it is intended that such racemates fall within the above schemes and the following claims. Racemic mixtures are readily prepared by the same methods as optically active species, simply using the corresponding racemic precursors instead of optically active starting materials.

Numerous in vivo and in vitro experiments have shown that novel prostaglandin analogs have physiological activity comparable to that of natural prostaglandins. These experiments include e.g. effect test on smooth muscle isolated from guinea pig uterus, piglet ileum and rat uterus.

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

Particularly useful in the regulation of fertility are the 16-phenoxy-60-tetranorprostaglandins of the E ^, γ and F ^ series, based in particular on their remarkable smooth muscle stimulating activity and concomitant antihypertensive effects. Likewise, the substituted O-pentanor prostaglandins of the PGE 2, PGF 2, β, and 13,1H-dihydro-PGF 2+ series are useful in regulating fertility based on their smooth muscle stimulating activity.

60389 19

Novel prostaglandins with β -OH at the 15-position are less potent, although often more selective than the corresponding β-hydroxyl epimers. In addition, prostaglandins having β-hydroxyl at C-15 are valuable intermediates for prostaglandins having β-hydroxyl at C-15 through a recycling process involving oxidation and reduction at C-15.

The novel compounds of this invention can be used in a variety of pharmaceutical compositions containing the compound and can be administered as well as natural prostaglandins in a variety of ways, such as e.g. intravenously, orally, intravaginally, and intraamniotically and extraamniotically.

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

Various modifications in the upper side chain of the prostaglandins of this invention are possible; such modifications generally do not alter the biological activity of prostaglandin, although they may further increase the selectivity and duration of action and reduce toxicity. For example, the tetrazolyl group may be in the C 1-4 position.

Another upper side chain modification that can be performed on the prostaglandins of this invention is the replacement of the carboxylate group at the C 1-4 position with a carboxamide group. Alternatively, the novel compounds of formula I of this invention wherein X is:

O

M

CNHR ", where R" is as defined above, is prepared from compounds 9 and 10 (or corresponding 15-epimers or 15-lower alkyl derivatives of 9 and 10) shown in Scheme B by reaction with the appropriate isocyanates, followed by hydrolysis with dilute acid . For example, the use of N-methylsulfonyl-1-phenoxy-PGE 2 -carboxamide is the same as that of 1-phenoxy-PGE 2 -esters.

20 60389

One particularly useful ester is p-biphenyl ester. Such esters are prepared in the following examples simply by adding p-phenylphenol to prostaglandin in methylene chloride in the presence of a debriding agent, e.g. dicyclohexylcarbodiimide, and stirring overnight. Although the compounds were not more potent in in vitro soft muscle experiments, the evaluation of 16-phenoxy-00 -tetranor-PGE_ and PGF .. biphenyl esters as abortifacient showed 2 2 o that these substances have significantly higher physiological activity than free acids.

The following preparations describe the preparation of the reaction components and intermediates used in the preparation of the compounds of the invention, and the examples illustrate the preparation of the compounds of the invention. It should be noted that in the preparations and examples, temperatures are expressed in degrees Celsius, melting and boiling points are uncorrected.

Preparation A

Dimethyl-2-oxo-3-fenoksipropyylifosfonaatti:

A solution of 33.2 grams (268 mmol) of dimethyl methylphosphonate (Aldrich) in 3βθ ml of dry tetrahydrofuran was cooled to -78 ° under a dry nitrogen atmosphere. To the stirred phosphonate solution was added 118 mL of a 2.3 M molar solution of n-butyllithium in hexane (Alfa Inorganics, Inc.) dropwise over 18 minutes at such a rate that the reaction temperature never rose above -65 ° · After stirring for an additional 5 minutes at - 78 °, 22.2 grams (13 + mmol) of methyl 2-phenoxyacetate was added dropwise at such a rate that the reaction temperature was kept below 7070 ° (20 minutes). After standing at -78 ° for 3.5 hours, the reaction mixture was allowed to warm to ambient temperature, neutralized with 1U of acetic acid and rotary evaporated to a white gel. The gel-like material was taken up in 175 ml of water, the aqueous phase was extracted with 100 ml portions of chloroform (3x), the combined organic extracts were washed countercurrently (50 L H 2 O), dried (MgSO 4) and concentrated (water jet vacuum) to a crude residue. and distilled, b.p. 172-175 ° (0.5 mm) to give 2.6 g of dimethyl 2-oxo-3-phenoxypropylphosphonate.

The NMR spectrum (CDCl 3) showed a 3.75 / concentrated dashed line (J = 11.5 cps for 6H (CH 2) 0, one line for k, 7? (2H) C 6 HCO-CH 0 -CO-, .3 ff O 7 d -P- for 3 »2U / for the concentrated dashed line (J = 23 cps, 2H) 0 and for the aromatic protons in the range 6.8-7.5 / (5H) of the polyline t1. -

Preparation B ^ 2a (32''-p-phenylbenzoylthioxy-5H-hydroxy-2 / 3- (3-oxo-U-phenoxy-trans-1-buten-1-yl) cyclopent-1-yl) acetic acid, V "lactone: 60389 21

Dimethyl 2-oxo-3-phenoxypropylphosphonate (5.5 * g, 21 mmol) in 200 mL of anhydrous ether was treated with 7.9 mL (19 mmol) of 2.5 M n-butyllithium in n-hexane (Alpha Inorganics, Inc.) in a dry nitrogen atmosphere at room temperature. After stirring for 5 minutes, an additional 1 x 00 mL of anhydrous ether was added, followed by 6.0 g (17 mmol) of 2- (3H-phenylbenzoyloxy-5H-hydroxy-2β-formylcyclopentan-1-yl) acetic acid. lactone in one portion and 50 ml of anhydrous ether. After 35 minutes, the reaction was quenched with 5 mL of glacial acetic acid and washed with 100 mL of saturated sodium bicarbonate solution (1x), 100 mL of water (2x), 100 mL of saturated brine (1x), dried (MgSO 4). and evaporated 5.2 grams of 2- (3β-phenylbenzoyloxy-5-hydroxy-2 - (3-oxo-1-phenoxy-trans-1-buten-1-yl) cyclopent-1-yl) -acetic acid, to give the V ”lactone as a solid after column chromatography on silica gel, Baker, 60-200 mesh) and m.p. 112-111 ° after crystallization from methylene chloride-hexane.

The IR spectrum (KBr) of the product showed absorption lines at 1775 cm -1 (strong), 1715 cm -1 (strong), 1675 cm -1 (medium) and 1630 cm -1 (medium) due to carbonyl groups and at 970 cm -1 due to trans double the bond.

Preparation C

2- (3β-Phenylbenzoyloxy-5H-hydroxy-2β- (3H-hydroxy-1 * -phenoxy-trans-1-buten-1-yl) cyclopent-1H-yl) acetic acid, V " -lactones:

To a solution containing 5.1 grams (10.5 mmol) of 2- (3β-phenylbenzoyloxy-5N-hydroxy-2β- (3-oxo-1 * -phenoxy-trans-1-butene) 1-yl) cyclopent-1-yl) acetic acid, β-lactone In 30 ml of dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was added dropwise 11 ml (5.5 mmol) of a 0.5 molar solution of zinc borohydride. After stirring at room temperature for 2 hours, saturated sodium bitartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was allowed to stir for 5 minutes during which time 250 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 ether as eluent. After elution of less polar impurities, 896 mg of 2- (3γ-p-phenylbenzoyloxy-5H-hydroxy-20- (3R-hydroxy-1 * -phenoxy-trans-1-buten-1-yl) cyclopent-1-yl) were obtained. yl) acetic acid, a fraction comprising γ-lactone, a 600 mg fraction mixed with 1 * and 5 and finally 2- (3β-phenylbenzoyloxy-5H-hydroxy-2 (3- (3Y-hydroxy-1 + -phenoxy - trans-1-butenyl) cyclopent-1-yl) acetic acid, lactone (1.5 g) fraction.

The IR spectrum (CHCl 1) of 22 60389 i + rn had strong carbonyl absorptions at the sites. -1 ^ -1.

1770 and 1715 cm and absorption at 970 cm for the trans double bond.

Preparation D

2- (3Y, 5Y-dihydroxy-2S- (3-hydroxy-4-phenoxy-trans-1-buten-1-yl) cyclo-pent-1 2Γ-yl) acetic acid N-lactone :

A heterogeneous mixture containing 8 * * 6 mg (1.7 mmol) of 2- (3Y-p-phenyl-benzoyloxy-5H-hydroxy-2β- (3β-hydroxy-1+ -phenoxy-trans-1 -buten-1-yl) cyclo-pent-1,2-yl) acetic acid, N'-lactone, 10 ml of absolute methanol and 120 mg of finely ground anhydrous potassium carbonate were stirred at room temperature for 20 hours, then cooled to 0 °. To the cooled mixture was added 1.75 ml of 1.0 N aqueous hydrochloric acid. After stirring at 0 ° for a further 10 minutes, 10 ml of water was added along with the simultaneous formation of methyl p-phenylbenzoate, which was collected by filtration.

The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (1+ x 10 mL), the combined organic extracts were washed with saturated sodium bicarbonate (10 mL), dried (MgSO 4) and concentrated to 1 + 5 mg of viscous, oily 2- (3Y, 5 Y to obtain dihydroxy-2β- (3X -hydroxy-U-phenoxy-trans-1-buten-1-yl) -cyclopent-1K "-yl) -acetic acid-Y" -actone. IR spectrum (CHCl 3) showed -1. .

strong absorption for lactone carbonyl at 1772 cm and moderate absorption for the trans double bond at 969 cm 1.

Preparation E

2- (5 Y-hydroxy-3 N- (tetrahydropyran-2-yloxy-2 - 3- (3 Y-tetrahydropyran-2-yloxy-U-phenoxy-trans-1-buten-1-yl) cyclopent-1Y) -yl) acetic acid V "lactone:

To a solution of 1 * U5 mg (1, 6 mmol) of 2- (3γ, 5β-dihydroxy-N- (3β-hydroxy-1H-phenoxy-trans-1-butenyl) cyclopent-1H) -yl) acetic acid N-lactone in 5 ml of anhydrous methylene chloride and 0.1 ml of 2,3-dihydropyran at 0 ° in a dry nitrogen atmosphere, 5 mg of p-toluenesulfonic acid monohydrate were added. After stirring for 15 minutes, the reaction mixture was combined with 100 mL of ether, the ether solution was washed with saturated sodium bicarbonate (1 x 15 mL), then brine (1 x 15 mL), dried (MgSO 4) and concentrated to 752 mg (> 100%) of 2- (5 N- (tetrahydropyran-2-yloxy-U-phenoxy-trans-1-buten-1-yl) cyclopent-1-yl) acetic acid Ϋ'-lactone.

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

60389 23

Preparation F

2- (5H-hydroxy-3H- (tetrahydropyran-2-yloxy) -2/3- (3H-tetrahydropyran-2-yloxy -1 * -phenoxy-trans-1-buten-1-yl) cyclopent 1Y-yl) acetaldehyde-4-hemiacetal:

Solution containing 690 mg (1t6 mmol) of 2- (5Y-hydroxy-3Y- (tetrahydropyran-2-yloxy) -2- (3- (3H-tetrahydropyran-2-yloxy-U-phenoxy) trans -1-buten-1-yl) cyclopent-1Y-yl) acetic acid N-lactone in 8 ml of dry toluene was cooled to -70 ° C in a dry nitrogen atmosphere, to which was added 2.0 ml of 20% diisobutylaluminum hydride. in n-hexar (Alfa Inorganics) dropwise at such a rate that the internal temperature never rose above -65 ° (15 minutes) After stirring at -18 °, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. combined with 100 mL of ether, washed with 50% sodium potassium tartrate solution (x 20 mL), dried (Na 2 SO 4) and concentrated to give 613 mg of 2- (5H-hydroxy-3Y-tetrahydropyran-2-yloxy) - 2 β- (3 N-Tetrahydropyran-2-yloxy-1-phenoxy-trans-1-buten-1-yl) -cyclopent-1-yl J to obtain acetaldehyde-^ - hemiacetal.

Preparation G

9H-hydroxy-11H, 15H-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis-5-trans-13-tetranor-prostadienoic acid r

To a solution of 1.6 g (3.5 mmol) of (1-carbohydroxy-n-butyl) triphenylphosphonium bromide in a dry nitrogen atmosphere in 6.0 mL of dry dimethyl sulfoxide was added 3.2 kg (6.5 mmol) of A 2.0 molar solution of sodium urethylsulfinylmethide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 613 mg (1.29 mmol) of 2- (5H-hydroxy-3Y- (tetrahydropyran-2-yloxy) -2β- (3β-tetrahydropyran-2-yloxy-1 * -phenoxy-trans-1-buten-1-yl) cyclopent-1-yl) acetaldehyde-N-hemiacetal in 5.0 ml of dry dimethyl sulfoxide over 20 minutes. After stirring for an additional 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (20 mL) and acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 20 ml) and the combined organic extracts were washed once with water (10 ml), dried (MgSO 4) and evaporated to a solid residue.

This solid residue was triturated with ethyl acetate and the filtrate was concentrated to give 75 L + mg of 9 Y-hydroxy-11Y, 15 Y-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis-5-trans-13-1d-tetranorprostadienoic acid. Infrared spectrum (CHCl 3)

-1 J

showed a strong band for the carboxyl group at 1720 cm k · * 2h * 60389

Preparation H

9-oxo-11,15β-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis-5-trans-13β-tetranorprostadienoic acid:

To a solution cooled to -10 ° under a nitrogen atmosphere containing 751 * mg (1.3 mmol) of 9β-hydroxy-11β-15β-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy- cis-5-trans-13-CO-tetranorprostadienoic acid in 13 ml of reactive acetone, 0.56 ml (1.0 U mmol) was added dropwise

Jones' reagent. After standing at -10 ° for 20 minutes, 0.260 ml of 2-propanol was added and the reaction mixture was allowed to stir for a further 5 minutes, then combined with 75 ml of ethyl acetate, washed with water (3 x 10 ml), dried (MgSO 4) and concentrated to give 752 mg of 9-oxo-11/15 / -bis- (tetrahydropyran-2-yloxy) -6-phenoxy-cis-trans-13-C-β-tetranor-prostadienoic acid, which was chromatographed on silica gel using ethyl acetate as eluent, to give 505 mg of pure 10.

Preparation I

2- (3H-p-phenylbenzoyloxy-5H-hydroxy-2R- (3-hydroxy-3-methyl-1 + -phenoxy-trans-1-buten-1-yl) cyclopent-1-yl) ) acetic acid / lactone: To a solution of 2- (3β-phenylbenzoyloxy-5H-hydroxy-2,3- (3-oxo-U-phenoxy-trans-1-buten-1-yl) cyclopent -1H-yl) acetic acid / lactone in ether-THF cooled to 7878 ° was added dropwise 1 equivalent of a 2N solution of methyllithium in ether. After stirring at -78 ° for 15 minutes, the reaction was quenched by the addition of sufficient glacial acetic acid to adjust the pH to 7. The mixture was diluted with methylene chloride, washed with water, brine, dried (NaSO 4) and concentrated to give oily epimer alcohols. The crude product was purified by column chromatography on silica gel to give the desired 2- (3'-p-phenylbenzyloxy-5H-hydroxy-2 / - (3-hydroxy-3-methyl-U-phenoxy-trans-1-buten-1-yl) cyclopentene). 1 # -yl) acetic acid, to obtain the V * "'lactone.

Preparation J

2- (3H-phenylbenzoyloxy-5H-hydroxy-2-hydroxy-U-phenoxy-but-1-yl) cyclopent-1-yl) acetic acid β-lactone:

A heterogeneous solution containing 2.5 g of 2- (3β-phenyl-benzoyloxy-5H-hydroxy-2β- (3γ-hydroxy-4-phenoxy-trans-1-buten-1-yl) cyclopentene- 1-yl) -acetic acid β-lactone and 0.25 g of 5% palladium on carbon in 30 ml of absolute methanol were stirred under a hydrogen atmosphere for k hours. The mixture was then filtered and concentrated with 2- (3H-phenylbenzoyloxy-5H-hydroxy-2R - (3-oxo-N-phenoxy-but-1-yl) cyclopent-1-yl) acetic acid N-lactone to obtain.

60389 25

To a solution of 1.9 g of the crude hydrogenation product described above in 20 ml of absolute methanol was added excess sodium borohydride, and the solution was stirred at room temperature under nitrogen for 2 hours and then concentrated. The residue was diluted with 0.1 N hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na 2 SO 4) and concentrated. Purification of the crude residue by silica gel chromatography afforded 2- (3'-p-phenylbetyloxy-5H-hydroxy-2β- (3H-hydroxy-1 + -phenoxy-but-1-yl) cyclopent-1-yl) acetic acid, N, Lactin and 3β-hydroxyepimer.

This was converted to the 13,1β-dihydro Eg and ^ compounds using the methods used in Preparations E-H.

Preparation K

9β-Hydroxy-11β-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-13-trans-CO -tetranorprostanoic acid:

A heterogeneous mixture containing 800 mg of 9β-hydroxy-11,15β-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis-5 'trans-13-CO-tetranorprostadienoic acid and 80 mg 5% palladium on carbon in 10 ml of absolute methanol was stirred in one atmosphere of hydrogen at -22 ° for 5 hours. The mixture was then filtered and the filtrate was concentrated to give 9β-hydroxy-11,15β-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-13-trans-β-tetranorprostenoic acid.

Hydrolysis with acetic acid and water in the usual manner gave 16-phenoxy-PGFiy ·

Preparation L

h- (tetrazol-5-yl) butyltriphenylphosphonium bromide A mixture of 5-bromovaleronitrile (16.2 g, 0.10 mol), triphenylphosphine (26.2 g, 0.10 mol) and toluene (100 ml) was heated to reflux. and stirring under nitrogen for 16 hours. The resulting white thick suspension was cooled to room temperature and filtered. The residue was washed with benzene and air dried to give 33.0 g of a white crystalline solid, m.p. 230-232 °, which was U-cyanobutyltriphenylphosphonium bromide.

Analysis. Calculated for C 18 H 18 BrNP: C, 65.10; H, 5.7; N, 3.30, Found: C, 65.01; H, 0.5; N, 3.19-

The above phosphonium salt (10.0 g, 23.5 mmol), ammonium chloride (1.6 g, 30.0 mmol), lithium chloride (0.032 g, 0.76 mmol), sodium azide (1.91 g, 29.3 mmol) ) and dimethylformamide (50 ml) were heated to 127 ° (with an oil bath) under nitrogen with stirring for 18 hours. The resulting suspension was cooled and filtered. The residue was washed with dimethylformamide and the combined filtrate and washings were concentrated (water jet pump pressure, ca. U5 °).

2660389 The oily residue was crystallized from water at 0 ° and air dried to give a white crystalline solid (8.11 g), m.p. 100-102 °. The product was recrystallized from methanol-ether to give white prisms (7.18 g), m.p. 197-206 °: An analytical sample was prepared by recrystallization from 2-propanol to give a white crystalline powder, m.p. 212-123 °, which was N- (tetrazol-5-yl) -butyltriphenylphosphonium bromide.

Analysis. Calculated for C23H2LH1PBr: C, 59.10; H, 5.17; N, 11.99. Found: C, 59.35; H, 5.28; N, 12.31; P, 6.78; Br, 17.26.

Preparation M

1- (Tetrazol-5-yl) -4,9-hydroxy-11β-bis-tetrahydropyran-β-yloxy) -1,6-phenoxy-cis-5-trans-13β-trans prostatrienoic:

To a solution of 1- (tetrazol-5-yl) butyltriphenylphosphonium bromide (1.1 + 9 g) in a dry nitrogen atmosphere in 6.0 mL of dry DMSO was added 3.2b mL of a 2.0 M solution of sodium methylsulfinylmethide in DMSO: in. To this solution was added dropwise a solution containing 615 mg of 2- (5'-hydroxy-3- (tetrahydropyran-2-yloxy) -2- (3'-tetrahydropyran-2-yloxy) -U-phenoxy-trans-1- buten-1-yl) cyclopent-1-yl) acetaldehyde-N-hemiacetal in 5.0 ml of dry DMSO over 20 minutes. After stirring for a further 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was acidified with 0.1 N hydrochloric acid and extracted with ethyl acetate. The residue obtained after evaporation of the solvent was chromatographed on pure 1- (tetrazol-5-yl) -9X-hydroxy-11-15'bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13- (jJ). -tetranor to obtain prostadiene.

Preparation N

A mixture of (L- (methanesulfonylaminocarbonyl) butyl) triphenylphosphonium bromide containing 0.950 g (0.01 mol) of methanesulfonamide and 1.80 g (0.01 mol) of 5-bromovaleric acid chloride was heated on a steam bath until gas evolution ceased (about 5 minutes). The brown reaction mixture was allowed to cool and dissolved in methylene chloride. The methylene chloride solution was treated with Darco, filtered and diluted with hexane under cooling to give white crystalline N-methanesulfonyl-5-bromovaleramide weighing 2.22 g (86.0% yield), m.p. 88-89 ° · NMR spectrum (CDCl 3) showed a broad single line at δ, 26-3.95 for NH, a polyline at 3.66-3.23 for CH 2 Br, a single line at 3.31 S SO 2 CH ^, for a polyline at 2.63-2.20 & -CH2CO and at a multiline at 2.12-1.52 for CH2-CH2O. The IR spectrum (CHCl 3) showed strong absorption at 1720 cm due to the carbonyl group.

60389 27

A solution of 2.20 g (8.57 mmol) of N-methanesulfonyl-5-bromovaleramide prepared as described above, 2.2 h g (8.57 mmol) of triphenylphosphine and 20 mL of acetonitrile was heated at reflux under nitrogen overnight.

The solution was then concentrated on a rotary evaporator and the resulting solid was triturated with hot benzene (U x). The triturated solid was recrystallized from a mixture of azolytic ethanol and ether to give white crystalline (1- (methanesulfonylaminocarbonyl) butyl) triphenylphosphonium bromide weighing 2.80 g (63.7% yield) and melting at 190-191 ° · Product IR spectrum (KBr) showed strong absorption at 5.85 microns due to the carbonyl group. The NMR spectrum (CDCl 3) showed a complex polyline at δ, 7.27 ° for aromatic protons, a polyline at U, 00-3.30 & -CH 2 P, a private line at 3.12 δ -SO 2 CH 2. for multiline at 3.00-2.38 for CH 2 CO 2 and multiline for 2.23-1.38 for CH Titration of the solid product showed a pKa 1/2 of 5.25-

Preparation 0 1- (Tetrazol-5-yl) -4,9-hydroxy-11β-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-yl) -tetranorprostadiene To a solution of U- (tetrazol-5-yl) butyltriphenylphosphonium bromide (1.1 + 9 g) (in a dry nitrogen atmosphere) in 6.0 mL of dry DMSO was added 3.2 h mL of a 2.0 M solution of sodium methylsulfinylmethide in DMSO. . To this solution was added dropwise a solution of 615 mg of 2- (5,26-hydroxy-3 '- (tetrahydropyran-2-yloxy) -2β- (3' - (tetrahydropyran-2-yloxy) -U-phenoxy-trans- 1-buten-1-yl) cyclopent-1X-yl) acetaldehyde-γ-hemiacetal in 5.0 ml of dry DMSO over 20 minutes.

After stirring for an additional 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was acidified with 0.1 N hydrochloric acid and extracted with ethyl acetate. After evaporation of the solvent, the residue was chromatographed to give 680 mg of pure colorless oils, 1- (tetrazol-5-yl) -9β-hydroxy-11β, 2β-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5 trans-13 "6ohtetranorprostadieeniä.

Preparation P

1- (Tetrazol-5-yl) -9-oxo-11α-15 N-dihydroxy-16-phenoxy-cis-5-trans-13-U) -tetranor-prostadiene

A solution of 508 mg of 1- (tetrazol-5-yl) -9-oxo-11β, 26-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13,6-tetranor -prostaxylene in 10 ml of a mixture of glacial acetic acid and water (65:35), stirred under nitrogen at 25 ° for 20 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 than 28 60389 polar impurities, a colorless oily 1- (tetrazol-5-yl) -9-oxo-11-15-dihydroxy-16-phenoxy-cis-5-trans-13-60 -tetranor-prostadiene was obtained, which weighed 2l + 0 mg.

Preparation Q

N-Methanesulfonyl-9β-hydroxy-11} 6,15β-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis-5-trans-13-60-tetranor-prostadienamide

To a solution of 1.7 g of (1 + -methanesulfonylaminocarbonyl-butyl) -triphenylphosphonium bromide in a dry nitrogen atmosphere in 6.0 mL of dry DMSO was added 3.2 mL (6.5 mmol) of a 2.0 molar solution of sodium methylsulfinylmethide in DMSO: in. To this red ylide solution was added dropwise a solution of 610 mg (1.29 mmol) of 2- (5,6-hydroxy-3Y- (tetrahydropyran-2-yloxy) -2A- (3R- (tetrahydropyran-2-yloxy)). 1 + -phenoxy-trans-1-buten-1-yl) cyclopent-11-yl-acetaldehyde, N, N-hemiacetal in 5 ml of dry DMSO over 20 minutes After further stirring at room temperature for 2 hours, the reaction mixture was poured into ice water. twice with ethyl acetate (3 x 20 ml) and the combined organic extracts were washed once with water (10 ml), dried (Na 2 SO 4) and evaporated to an oil, chromatography on silica gel afforded 681+ mg of pure oils of N-methanesulfonyl-9,26-hydroxy-11β. 26 26-bis- (tetrahydropyran-2-yloxy) -6-phenoxy-cis-5-trans-13-60-tetranor-prostadienamide.

Preparation R

N-Methanesulfonyl-9-oxo-115β-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-CO-tetranor-prostadienamide

To a solution of 1 + 00 mg in 8 ml of reagent-pure acetone cooled to -10 ° under nitrogen was added dropwise 0.1+ ml of Jones reagent. After standing at -10 ° for 30 min, 0.1+ ml of 2-propanol was added and the reaction mixture was allowed to stir for a further 5 minutes, then combined with 60 ml of ethyl acetate, washed with water (3 x 10 ml), dried (Na 2 SO 4). SO 2) and concentrated to give 380 mg of colorless oils from N-methanesulfonyl-9-oxo-1116,15β-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis-5-trans-13- (4-tetranor -prostadienamidia.

Preparation S

N-acetyl-9β-hydroxy-11β-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis-5-trans-13,6-tetranor-prostadienamide

To a solution of 5.32 g of (1 + -acetamidocarbonyl) butyl) -triphenylphosphonium bromide in a dry nitrogen atmosphere in 10 ml of dry DMSO was added 17.7 ml of a 2.0 molar solution of sodium methylsulfinylmethide in DMSO. To this red ylide solution was added dropwise a solution containing 0.52 L + g (1,1-ramol) of 2- (5H-hydroxy-3N- (tetrahydropyran-2-yloxy) -2) - (3'-tetrahydropyran). 2- (60389) 2-yloxy) -phenoxy-trans-1-buten-1-yl) cyclopent-1'-yl) acetaldehyde, 1H-hemiacetal in 10 ml of dry DMSO over 20 minutes. After stirring for an additional 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (3 x 25 ml) and the combined organic extracts were washed once with water (10 ml), dried (Na 2 SO 4) and evaporated to an oil. Chromatography on silica gel afforded 0.66 g of pure oils of N-acetyl-9β-hydroxy-11β-15β-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis-5-trans-13-yl'-tetranor- prostadienamidia.

Preparation T

N-acetyl-9-oxo-11β-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-6) -tetranorostadienamide

To a solution cooled to -10 ° under nitrogen containing 39 mg of N-acetyl-9β-hydroxy-11,5,5β- his- (tetrahydropyran-2-yloxy) -16-Tenoxy-cis-5-trans-13-GO- tetranor-prostadienamide in 10 ml of reagent-pure acetone, 0.27 ml of Jones reagent was added dropwise. After standing at -10 ° for 30 minutes, 0.1 ml of 2-propanol was added and the reaction mixture was allowed to stir for a further 5 minutes, after which it was combined with 60 ml of ethyl acetate. Washed with water (3 x 10 mL), dried (Na 2 SO 4) and concentrated to give 390 mg of colorless oils N-acetyl-9-oxo-11β-bis (tetrahydropyran-2-yloxy) -16-phenoxy -cis-5-trans-13 - (\) - tetranor-prostadienamidia.

Example I

p-Biphenyl-9-oxo-11β-15Y-dihydroxy-16-phenoxy-cis-5-trans-13-CO-tetra norprostadienoate:

To a solution of 50 mg (0.13 mol) of 9-oxo-11β-15β-dihydroxy-16-phenoxy-cis-5-trans-13-60-tetranor-Prosta dienoic acid and 63 mg (0.1 U mmol) ) p-phenylphenol in 10 ml of dry methylene chloride, 825 mg (0.1 mmol) of dicyclohexylcarbodiimide were added and the solution was stirred overnight at room temperature. After concentration, the crude product was purified by silica gel chromatography to give the desired p-biphenyl ester, m.p. 100-102 °.

Analysis: Calculated for C 18 H 18 O 2: C, 75.53; H 6.71 Found: C, 75.65; H, 6.83

Example II

p-Biphenyl-12β-trihydroxy-16-phenoxy-cis-5-trans-13-O-tetranorep prostadienoate:

To a solution of 106 mg of 9β-trihydroxy-16-phenoxy-cis-5-trans-13-U tetranorprostadienoic acid and 189 mg of p-phenylphenol in 30 ml of dry methylene chloride was added 600 mg of dicyclohexylcarbodiimide and the solution. stirred overnight at room temperature. After concentration, the crude product was purified by silica gel chromatography to give 80 mg of pure p-biphenyl ester, m.p. 101-103 °.

Analysis: Calculated for: C, 75 »25; H, 7.06 Found: C, 75.38; H, 7.30.

Additional features are shown in Table 1 below.

Example III

1- (Tetrazol-5-yl) ~ 9 11 11 15 15 -trihydroxy-16-phenoxy-cis-5-trans-13β-tetranor-prostadiene

A solution of 300 mg of 1- (tetrazol-5-yl) -7,7-hydroxy-11R, N, N-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis-5-trans-13 CC0-tetranor-prostadiene in 6 ml of a mixture of glacial acetic acid and water (65:35) was stirred under nitrogen at 25 ° 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, 100-200 mesh) using mixtures of chloroform and ethyl acetate as eluent. After elution of less polar impurities, a colorless, oily 1- (tetrazol-5-yl) -9β-trihydroxy-16-phenoxy-cis-5'-trans-1-3,6-tetranorprostadiene weighing 220 mg ( 80% yield). The biological properties of the compound are shown in the table below (Sample 6).

Example IV

N-Methanesulfonyl-9β-11β-trihydroxy-16-phenoxy-cis-5-trans-13-tetranor-prostadienamide

A solution of 250 mg of the intermediate described in Preparation Q in 5 ml of a mixture of glacial acetic acid and water (65:35) was stirred under nitrogen at 25 ° for 18 hours and then concentrated to a crude oil which 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, a colorless oily M-methanesulfonyl-9β, 15β-trihydroxy-16-phenoxy-cis-5-trans-13β-tetranor-prostadienamide weighing 180 mg was collected. The product proved to be homogeneous by liquid-liquid chromatography. The biological properties of the compound are shown in Table 2 below (sample k).

Example V

N-Methanesulfonyl-9-oxo-1115 N-bis-dihydroxy-16-phenoxy-cis-5-trans-13-C-tetranor-prostadienamide

A solution of 260 mg of the intermediate described in Preparation R in 6 ml of a mixture of glacial acetic acid and water (65:35) was stirred under nitrogen at 25 ° for 20 hours and then concentrated to a crude oil which was purified by column chromatography on silica gel (Mallinckrodt CC-7, 100-200 mesh) using mixtures of chloroform and ethyl acetate as eluents. Elution of less polar impurities 31 60389 gave colorless N-methanesulfonyl-9-oxo-11V15 Y-bis-dihydroxy-16-phenoxy-cis-5-trans-13 - (*) - tetranor-prostadienamide weighing 130 mg. The product crystallized from ether as colorless crystals, m.p. 76 °. The biological properties of the compound are shown below.

Example VI

N-Methanesulfonyl-9-oxo-11β-Y-dihydroxy-5-cis-13β-trans-16-phenoxy-β'-tetranor-prostadienamide to 1.0 mmol of 9-oxo-11β-Yβ-bis- (tetrahydropyran) Preparation of 2-yloxy) -1,6-phenoxy-cis-5 'trans-13-CO-tetranor-prostadienoic acid In 10 ml of THF, 2 ml of triethylamine were added. After stirring at room temperature for 15 minutes, 10.0 mL of 0.1 M methanesulfonyl isocyanate in THF was added.

After a further hour of stirring, the reaction mixture was neutralized with acetic acid and the solvent was removed by evaporation (in vacuo). The resulting residue was taken up in methylene chloride and washed successively with water and sodium bicarbonate to give, after drying and evaporation of the solvent, N-methanesulfonyl-9-oxo-11β-15,26-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis- 5-trans-13-O--tetranor-prostadienamide. This intermediate was then hydrolyzed overnight with a mixture of acetic acid and water (as in Example IX) and purified by column chromatography to give the desired N-methanesulfonyl-9-oxo-11β-dihydroxy-5-cis-13-trans-16-phenoxy-CO tetranor-prostadienamide. The spectral properties of the compound are shown in Table 1 below.

Example VII

N-acetyl-9 Y 1 1 Y 15 Y-trihydroxy-16-phenoxy-cis-5-trans-13-tetranor-prostadienamide

A solution of 0.39 g of N-acetyl-9 Y-hydroxy-11 Y-15 Y'-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-W- tetranorprostadienamidia in 5 ml. a mixture of glacial acetic acid and water (65:35) »was stirred under nitrogen at 25 ° for 18 hours and then concentrated to a crude oil which was purified by column chromatography on silica gel (CC-7) using mixtures of chloroform and ethyl acetate as eluents. After elution of less polar impurities, a colorless oil, N-acetyl-N, N-Y-trihydroxy-1-phenoxy-cis-trans-13-CO-tetranor-prostadienamide, weighing 95 mg, was collected. The spectral properties of the compound are shown in Table 1 below.

32 60389

Example VIII

N-acetyl-9-oxo-11β-N'-bis-dihydroxy-N-phenoxy-cis-N-trans-13,6'-tetranor-prostadienamide

A solution of 390 mg of N-acetyl-9-oxo-11β, 15β-bis- (tetrahydropyran-2-yloxy) -1,6-phenoxy-cis-5-trans-13-N-tetranor-prostadienamide in 8 ml of ice-cold a mixture of vinegar and water (65:35) was stirred under nitrogen at 25 ° for 20 hours and then concentrated to a crude oil which was purified by column chromatography on silica gel using mixtures of chloroform and ethyl acetate as eluents. After elution of less polar impurities, a colorless oily N-acetyl-9-oxo-11-β-bis-dihydroxy-1-phenoxy-cis-β-trans-IS-β-tetranor-prostadienamide weighing 76 mg was obtained. The spectral properties of the compound are shown in Table I below.

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36 60389

Infertility activity of the novel compounds of formula I.

I. Biological tests used.

A. Determination of the convulsive effect on the uterus of a guinea pig in vitro test for inhibition / abortifacient activity.

B. Blood pressure assay for anesthetized dogs - a test for a rare side effect of prostaglandins.

C. In vivo assay for diarrhea in mice - a test for the common side effect of prostaglandins.

D. In vivo assay of abortifacient activity in rats - non-smooth muscle mechanism of infertility prevention / abortion activity11a. test for luteolytic activity.

II. Superiority of the new compounds over the known compounds.

The abortifacient model of rats, in which PGF γ is more potent than PGE 2, operates by a luteolytic mechanism. Thus, it is expected that the active compounds will be inhibitors of fertilization according to this mechanism. The results of the biological experiments are shown in Table 2 ^ 37 (o) (o) € 60389

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The results show that the compounds of formula I are 3-1,000 times more potent than PGFβ (sample 1). Sample 5 had a significantly smaller effect (10x) on blood pressure than PGFβ. Samples 2 and 3 have a much more favorable therapeutic index for ordinary diarrheal activity than PGFβ.

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Ia. Biological experiments used.

Experiments A, B and C were the same as above D. Determination of abortifacient activity in vivo in guinea pigs - an experiment demonstrating the smooth muscle mechanism of fertilization inhibition / abortifacient activity11a (i.e. uterine stimulation).

The results of the biological experiments are shown in Tables 3-6.

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Ha. Superiority of the new compounds over the known compounds. Tables 3-6 show that the new compounds (samples 8-27) are clearly more potent and selective than PGE 2 (sample 7) and the compound 1-phenoxy-cu-tetranor-PGEg (sample 28). Thus, it is expected that the new compounds will be by far superior fertility inhibitors and abortifacients.

Changes in blood pressure are sometimes observed as a side effect of administration of the known compound PGE2 to humans. Because the effect of the new compounds on blood pressure is UO-7200 times less than the effect of PGEI (U-720 is smaller than that of the ICI compound); this side effect is much less common in humans.

When prostaglandins are given to humans, perhaps the most common side effect is diarrhea. Although the diarrhea side effect of the new compounds is comparable to that of known analogs, the abortifacient effect of the new compounds is significantly greater than the corresponding effect of PGE 1 (10-300 times) or the corresponding effect of the ICI analog (10-300 times). The therapeutic index of the compounds according to the invention is 20-1875 times higher than that of PGEI and 10-937 times higher than that of the compounds of ICI.

Claims (1)

U8 60389 Claim: Novel 16-aryloxy-substituted '0-tetranorprostaglandins useful as fertility inhibitors and having the formula: M ____L z (I) HO \ .. Λγ "OH wherein Ar is phenyl or monosubstituted phenyl with substituent halogen, , lower alkyl or lower alkoxy, W is a single bond or a cis double bond, Z is a single bond or a trans double bond, M is H OH oxo, or '' 1 '* n-OH "" "' HX is tetrazolyl, a group , of the formula -C00R ', wherein R' is hydrogen or p-biphenyl, provided that R 'is not hydrogen when W is a cis double bond; or X is a group of the formula wherein O "is acetyl, benzoyl, alkylsulfonyl having 1 to 3 carbon atoms or phenylsulfonyl, and C 1-4 epimers thereof.