FI58116C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT AKTIVA PARABIFENYLESTRAR AV PROSTAGLANDINSERIERNA E OCH F - Google Patents

Description

rBl KU RELEASE PUBLICATION

JETa IBJ (") UTLÄGGNINGSSKRIFT O O 1 Ί O

ijijpSik (^ Patent r-'iirlat (51) Kv.ik? /intci.3 c 07 C 177/00 // C 07 D 307Λ2, 333/16 FINLAND —FINLAND (M) ^ wnttlWcmm · —P) Mf «MBkiiing 31 + 1 * 4/73 (22) M * k # ml * pUvt — AnaSknlngtdtg 07.11.73 (23) ΑΙΙαιρβΜ — GIWth «then« 07.11.73 (41) Tullut lulkMuI - Bllvtt offentilf g ^ PMMttl · And the National Board of Registration (44 ) Date of publication of the month of issue.

Patent and Registration Office Anattkan υά «| 4 oeh uti ^ kmtm pubiinnd 29.08.80 (32) (33) (31) Requested« toik «is — Baglrd prlorltet q8.11.72 USA (US) 30 ^ 815 (71) Pfizer Inc. , 235 East 42nd Street, New York 17 »NY, USA (72) Michael Ross Johnson, Gales Ferry, Connecticut, Thomas Ken Schaaf,

Old Lyme, Connecticut, Jasjit Singh Bindra, New London, Connecticut, USA (7 * 0 Oy Kolster Ah

(5 * 0 Method for the preparation of parabiphenyl esters of therapeutically active prostaglandin series E and F - Förfarande för framställning av terapeutiskt aktiva parabiphenylestrar av prostaglandinserierna E och F

This invention relates to the preparation of certain novel analogs of naturally occurring prostaglandins, in particular novel 15-substituted MApentanorprostaglandins.

Prostaglandins are C-20 unsaturated fatty acids with various physiological effects. For example, E-series prostaglandins are potent vasodilators (Bergström et al., Acta Physiol, Scand. 64: 332-33, 1965 and Bergström et al., Life Sci. 6: 449- ^ 55, 1967) and lower intravenous vasodepression when administered intravenously (Weeks and King, Federation Proc. 23: 327, 196U; Bergström, et al., 1965 op. cit., Carlsson, et al., Acta Physiol, Scand. 75: 161-169> 1969). Another well-known physiological form of action for PGE1 and PGE1 is their function as bronchodilators (Cuthberth,

Brit, Med. J. 4: 723-726, 1969).

Yet another physiological role for natural prostaglandins is related to the reproductive cycle. PGEIs are known to have the ability to induce postpartum burns 58116 (Karim, et al., J. Obstet, Gynaec. Brit. Cwlth. 77: 200-210, 1970), to induce therapeutic miscarriage (Bygdeman, et al., Contraception, L, 293 (1971) and to be useful in the regulation of 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 Publication Nos. 75 ^ 158 and DE- U.S. Patent No. 2,031,611) and the use of PGFβ, Fβ, and Fβ to regulate the reproductive cycle (ZA Patent No. 69/6089) It has been shown that luteolysis can occur in PGF As a result of dosing (Labhsetwar, Nature 230 528 (1971)), and for this reason, prostaglandins have utility in the regulation of birth control through a process in which smooth muscle stimulation is not necessary.

Still other physiological activities for PGE2 include inhibition of digestive acid secretion (Shaw and Ramwell, In: Worcester Symp. On Prostaglandins,

New York, Wiley, 1968, pp. 55-6L) and also the prevention of platelet aggregation (Emmons, et al., Brit. Med. J. 2: ^ 68-1 + 72, 1967).

It is known that such physiological effects occur in vivo only shortly after prostaglandin administration. A considerable body of evidence shows that the reason for this rapid cessation of activity is that natural prostaglandin! deactivated rapidly and efficiently via carboxylic acid side chain β-oxidation and oxidation of the 15α-hydroxyl group (Anggrad, et al. Acta Physiol. Scand., 81, 396 (1971) and references cited herein). It has been shown that the introduction of a 15-alkyl group into prostaglandins increases the duration of action, possibly by inhibiting the oxidation of the C-hydroxyl (Yankee and Bundy, JACS 9I +, 3651 (1972); Kirton and Forbes, Prostaglandins, 1, 319 (1972)).

It was considered desirable to provide prostaglandin analogs with the same physiological activities as natural compounds, but with increased activity selectivity and duration of action. The selectivity of the increased 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) -

It was further considered necessary to provide compounds that would readily crystallize because the isolation and purification of non-crystalline products is cumbersome and inefficient.

These requirements are met by the novel compounds according to the invention, parabiphenyl esters of U-pentanorprostaglandins, having one hydrogen or methyl in the C-position and one substituent of the formula • 9 3 581 1 6

Ar- (CH-) - or - (CH 2 -OB 2 2 n 2 m 2 where n is an integer from 0 to 2; m is an integer from 1 to 1; R is alkyl of 1 to 3 carbon atoms; and Ar is -furyl, n1- or Λ-thienyl, or β-naphthyl] phenyl or monosubstituted phenyl substituted with methoxy, methyl or phenyl.

The present invention relates to a process for the preparation of therapeutically active parabiphenyl esters of the prostaglandin series E and F of the formula M w _ / \ C00R '

X ----- L (D

ho "R *" oh 2 wherein A is Ar 1 CH 2 - or - (CH 2) -OR, where n is an integer from 0 to 2, m is an integer from 1 to 1, R 1 is alkyl of 1 to 3 carbon atoms, Ar is «K-furyl, β-furyl, β-thienyl, β-thienyl, β-naphthyl, β-naphthyl, phenyl or monosubstituted phenyl substituted with methoxy, methyl or phenyl, R 'is para-biphenyl , R is hydrogen or methyl, W is a single bond or a cis double bond, Z is a single bond or a trans double bond and M is. _. C = 0 or C, '"' ΌΗ

The invention is characterized in that the precursor acid of the formula s 'N ··' \ C00H

_____ A 1 '

HO

R ~ 'where A, R, M, W and Z have the same meaning as above, is reacted with p-phenylphenol in the presence of dicyclohexylcarbodiimide.

P-biphenyl esters of 15-substituted-U1-pentanorprostaglandins, wherein said prostaglandin is PGF4, PGE2, 13,11-dihydro PGF4 and PGE2; PGF 2, PGE, 13,11-dihydro PGF 0 and PGE; particularly preferred according to the present invention 2 dot. The compounds prepared are the p-biphenyl esters of the following prostaglandins: 11,518,116-phenyl-dM; etranorprostaglandin N, N-dihydro-1-phenyl-N-tetranor PGE1, 16-phenyl-N-tetranor PGE1, 1-phenyl-tert-tetranor PGEQ, 17-phenyl-UAtetranor PGE 1,17-phenyl-4γ-trisnor PGF, 16β-naphthyl-β-tetranor PGE_, 16-o-tolyl-UAtetranor-PGEg, 16-p-tolyl-O-tetranor PGEg , 16-paraethoxyphenyl-tTetetranor PGE 2, 16-β-thienyl-β-tetranor PGE 2, 16β-thienyl-β-tetranor PGE 2 and other preferred compounds of this invention are 15-phenyl-13, N, N-dihydro-N, N-pentanor PGE 2, N-methyl-1-phenyl-N, N-dihydro-UA, tetranor PGE 2> 19-oxa PGE 2, 19-oxa PGF 2> 20-oxa-1 H -homo PGE, 17-branch PGF0, 16-phenyl-tt * -tetranor PGF, ISjlU-dihydro-

2 2 <λ 2cC

1-phenyl-tu-tetranor PGF0 / a, 16-parabiphenyl-OA-tetranor PGE0, 20-oxa-ltt-homo PGF '

2 / ¾ 2 2 <? C

and 16-thienyl- <ε * -tetranor PGE 2.

It is to be understood that as used herein, the term "zero" series of prostaglandins, e.g., PGEq, refers to a prostaglandin in which the 5-6 and 13-1U double bonds are saturated; i.e. PGEq is 5-6, 13-1 ^, tetrahydro PGE ^. 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 1 and PGF 2 are "two-set" prostaglandins, while PGE 1 and PGE 1 are "one-set" prostaglandins. . As used herein and in the claims, the term prostaglandin includes both epimers at the C 1-4 position. The term "lower alkyl group" as used herein further refers to alkyl groups having 1 to U carbon atoms.

Those skilled in the art will appreciate that stereochemistry on lactol carbon has not been incorporated into the structures describing hemiacetals.

The invention will be better understood by first referring to Reaction Schemes A-E, which, together with the accompanying description, illustrate the syntheses of (N-pentanorprostaglandins).

As shown in Scheme A, the first step (1-2) is the condensation of the appropriate ester with a dialkylmethylphosphonate to produce the ketophosphonate 2. Usually, the desired methyl ester is condensed with dimethyl methylphosphonate.

In 2- * 3, the ketophosphonate 2 is reacted according to known methods (Corey et al., J. Am.

Chem. Soc., 93, 1 91 (1971)) with aldehyde-H to give enone 3.

After chromatography or crystallization, enone 3 can be converted to a mixture of tertiary alcohols 13 and 1 by reaction with the appropriate lithium alkyl and isomers 13 and can be separated by column chromatography. Enone 3 can be reduced with zinc hydrochloride to a mixture of alcohols H and 5, which can be separated as above. Separation of the isomers at this stage is not absolutely necessary and the mixture of epimers can be introduced through successive steps into the final prostaglandin analogs, which can then be separated. Ethers such as tetrahydrofuran or 1,2-dimethoxyethane are used as solvents in this reaction, although methanol is sometimes preferred to ensure specificity of the reduction. Additional transformations of U are shown in Figure B.

It -? 6 is a base-catalyzed trans-esterification 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. 6-7 includes the protection of two free hydroxyl groups with an acid-labile protecting group. Any sufficiently 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 environment. The catalyst is usually p-toluenesulfonic acid.

Scheme A 0 9 "1 A-COOCH3 -» AC-CH2 ~ P (OCH3) 2 -, · 0 -—- 0 ^, 0 'C / Ί r'V © H 0' - '' - '- ό' · Λ ", -v / -V 0 W _ Λ © following c © · 0, ^ .—, o ^ ...„ 1. © K © - '11, 0 o \ /, 0.0 © IS' "" "11+ 6 58116

Scheme B

ö A

k HO '- Hr ΌΗ 6

<o- ^ ° ° H

rV3 _>

THPO \ ^ _ 7 A

H ^ '- OTHP THPO' '' '' j * '-

H ^ - OTHP

1 -

HO O

- · \ x - = ^^ '' - ^ '\ cooh' "COOH \ / -). * - .., ^. * THPO 'l ^ -OTHP THP0

OTHP

9 jo.

\ /

'V

OH

', 0 V' ^ \ - == ^^ \ ^^ '' \ coOH

\ / \] \ C00H

H ° 'H ^' "OH Η0"> OH

n il 21 7 58116 7—> 8 is the reduction of lactone 7 to hemiacetal 8 using diisobutylaluminum hydride in an inert solvent. Low reaction temperatures are preferred and a temperature range of -60 to 7070 ° C is common. However, higher temperatures can be used if no over-reduction occurs. If desired, purify by 8 column chromatography. 8 -> 9 is a Wittig condensation in which hemiacetal 8 is reacted with (U-carbohydroxy-n-butyl) triphenylphosphonium bromide in dimethyl sulfoxide in the presence of sodium methylsulfinyl. 9 is purified as above.

Conversion 9-> 12 is 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 accomplished using 65 ~ aqueous 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 accomplished using any oxidizing agent that does not affect the double bonds; however, it is commonly used in Jones' reagent. The product is purified as above.

10—> 11 is performed in the same manner as 9— ^ 12. The product is purified as above.

β 58116

Scheme C

OH

^ \ / A 12 'H0' ^ hcT 'ή 5 (^^ Ύ' "'Ννχ == ^^

\,, ^. and OJ

H0 HO ^ Mi

OH

<^ '^ y' 'COOH

\ - A ^^ / A - R ^ '' ΌΗ 11 '0

"" -'- A * V COOH

j \ _y / A ϋ HO ''

R ^ OH OH

A - r r - = - / '-' \ cooh

^ _ / a J6L

HO '

HO '-R

1+ "O

Ay · '^ = / ^ / ^ cooh ^ HO' '

HO VR

9 581 1 6

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

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

At 3-> 19 + 19J, the enone 3 is reduced to the tetrahydro compound using any reducing agent in the complex metal hydride, LiAlH 2,

NaBH ^, KBH ^, LiBH ^ and ΖηίΒΗ ^) ^. NaBH 2 is particularly preferred. The products, 19 and 19 'are separated by column chromatography.

Furthermore, compounds 1 * and 5 of Scheme A can be catalytically reduced with hydrogen to products 19 and 19 '. The step of reducing the double bond is not critical and the hydrogenation of Schemes B 6 and 7 also provides useful intermediates for the 13.1 ^ - dihydroprosta analogs. This reduction can be accomplished with either a homogeneous catalyst such as tris- (triphenylphosphine) chloride I or a heterogeneous catalyst such as platinum, palladium or rhodium. In a similar manner, precursors for 15-lower alkyl-15-substituted compounds 13 and 1U, respectively, are prepared by substituting h and 5 for compounds 13 and 1U, respectively, in the synthesis just described. 19 = n, 19 ', 20' and 20 i

S

10 581 1 6

Scheme D

3 II

.0- £ j. } / 0 ^ 0 .0 ^ 0 0 O Λ fV ·, 'Λ--

"'<9 // A \ / \ V

C "° '^ 0 = C-0' '^ </ v. A

I, "Λ, ^ X. ° r '^.

O y P

9 'O

19 191 20 Λ il, 9 o o <Cf, o-- c-o ho ^ - '. R ί Φ

I! O

The conversion of 1 1 201 11 58116 to the corresponding prostaglandins follows the pathway shown in Scheme B when U is replaced by 19: 11a, 19 ', 11', 20 'and 20: 11a to give the series of prostaglandin derivatives ISjI-dihydro-PGEg and PGF1, containing in carbon # a hydrogen or a lower alkyl group.

Scheme E depicts the preparation of precursors of various reduced 15-substituted-uA-pentanor prostaglandins.

19—> 22 is performed as described in Scheme B for U-> 9.

22 can be used as a precursor for 13,1-dihydro-15-substituted-2-pentanorprostaglandin as a precursor to "two-series" and as an intermediate for 23-^ -dihydro-15-substituted-UA- pentanorprostaglandins. 2223 is carried out as catalytic hydrogenation using the catalyst used in reaction U-> 19 of 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 U-> 19 and 17-> 23. Particularly preferred in this reduction is the use of a palladium-on-carbon catalyst and a reaction temperature of -20 °. The 21-type intermediates are not only precursors to the "one-set" 15-substituted-μl-pentanorprostaglandins of Scheme B, route 9-> 15, but are also precursors to the 23-type compounds of the aforementioned route 22-> 23. Furthermore, the 15-substituted-UAprostaglanins of the E1 and F1 series can be obtained directly from the corresponding prostaglandin analogs of the "two series", first by protecting the hydroxyl group by introducing dimethylisopropylsilyl groups, selectively reducing the cis double bond and removing the protecting group.

Scheme E

19 9

1 I

OH OH

X .. i ^ .C00H

1 "Y" ^ ^ ^ cooh / \ · '

'J__! A ___I A

THPO'- 'H ^ OTHP ^^ 0ΐΗρ 22 21 \> ur

OH

THP0 ”'" ^^ η' ^^ οτηρ 23 12 581 1 6

Deprotection is usually accomplished by treating the prostaglandin analog with dimethyl isopropylchlorosilane and triethylamine, reduction is performed as described above for Reaction 9 -> 21, and deprotection is accomplished by contacting the reduced, protected compound with a mixture of acetic acid and water (3: 1). for ten minutes or until the reaction is substantially complete.

15-Methyl-15-substituted-1-pentanorprostaglandins reduced at the 5,6- and / or 13,1-position can be prepared from appropriately substituted analogs of 9 and 19, the syntheses of which follow the syntheses shown in Schemes A and B.

13,1U-Dihydro-15-n-ethyl-N-pentanorprostaglandins are obtained from appropriately substituted precursors via Scheme E.

The synthesis of natural prostaglandins has been performed by prof. E.J. Corey et al. (Corey et al., J. Amer. Chem. Soc., 92, 2586 (1970); and references cited herein) and prostaglandins made by this reaction series and other reaction series or isolated from natural material are suitable for use as precursors to the compounds of this invention. .

Scheme F shows the route to p-biphenyl esters ("PBE").

The parabiphenyl group is introduced by an esterification reaction performed by contacting the appropriate precursor acid with about 1-10 moles of p-biphenyl ester in the presence of 1-2 moles of dicyclohexylcarbodiimide in a reaction inert solvent, typically methylene chloride.

Scheme F

° U

s' 'γ - "\ / ^ \. C00H S' N - '' q \

l .............. i A -} .'------- V, -A

HO H0- '

n 11 PBE

13 581 1 6

In the above methods, if chromatographic purification is desired, suitable chromatographic supports include neutral alumina as the silica gel, and 60-200 mesh silica gel is usually preferred. The chromatography is conveniently carried out in a reaction-inert solvent such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane or n-hexane, as described in the following examples.

Therapeutic properties

In vivo and in vitro experiments can show that the novel p-biphenyl esters of prostaglandins and their analogues have a physiological activity comparable to that of natural prostaglandins. These trials include, but are not limited to, effects on guinea pig uterus, canine and rat uterine smooth muscle isolated, inhibition of norepinephrine-induced lipolysis in isolated rat adipocytes, prevention of histamine-induced bronchospasm in rat guinea pigs, and prevention of platelet aggregation induced in dogs and ADP or collagen.

The physiological reactions observed in these experiments are useful in determining the utility of a substance in the treatment of various natural and pathogenic conditions. Such identified uses include: antihypotensive activity, bronchodilator activity, antithrombogenesis activity, antiulcer activity, smooth muscle effect (useful as a contraceptive, contraceptive and miscarriage), and contraceptive activity, through luteolytic mechanisms.

The p-biphenyl esters prepared according to the invention have the same activity as the prostaglandin from which they are derived, but in addition have much smaller side effects. In this respect, the most important feature of the parabiphenyl esters prepared according to the invention is that they cause considerably less diarrhea compared to the free acids from which they are derived. In addition, these specific esters are valuable because they crystallize easily, thus they can be obtained in very pure form and in high yield, whereas prostaglandins generally have difficult crystallization problems. For example, the methyl and p-methylphenyl esters of 16-phenyl-ULtetranor PGEI are non-crystalline, while the p-biphenyl esters of the same 1 + 58116 same prostaglandin analog are highly crystalline. Such esters have shown a reduced tendency for gastrointestinal side effects in in vivo experiments. Furthermore, the new parabiphenyl esters have a uniform activity-time curve, which is often advantageous. A major example of the therapeutic importance of the compounds of the invention is the β-biphenyl ester of highly crystalline 1β-phenyl-β-tetranorprostaglandin EQ, which has a markedly increased hypotensive activity and duration of activity compared to PGE1 itself. At the same time, the smooth muscle stimulating activity is significantly reduced compared to PGE 2.

Another example of the high activity, specificity and crystallinity of the novel compounds of the invention is 19-oxaprostaglandin E 1 in p-biphenyl ester, which has high activity in smooth muscle, which is useful for contraceptive and miscarriage purposes. The novel 15-methyl compounds have the same activity profile as the novel prostaglandin analogs in which R is hydrogen and from which the former are derived.

Their particular utility is related to the fact that the duration of action is greatly increased compared to the above-mentioned compounds in which R is hydrogen; and in cases where this is important, 15-methyl compounds are generally preferred.

The p-biphenyl esters of natural prostaglandins are similarly easily crystallized and have the same therapeutic properties as the prostaglandins from which they are derived.

The optimum dose for each patient will be determined by the attending physician, and the dosages will generally be within the range indicated below.

To induce miscarriage, an aqueous suspension of E-series or F-series 17-substituted t-bisphenylprostaglandin p-biphenyl ester or tablets containing the same substance may be suitably administered in oral doses of about 1 to 20 mg, using 1 to 7 doses daily. For such treatment, oxaprostaglandin p-biphenyl esters may be conveniently administered at a level of about 5 to 100 mg, using 1 to 5 oral doses daily. A suitable dosage form for vaginal administration may be lactose tablets containing the same substances or a tempo impregnated with them. A suitable dosage range for such treatments is about 1-20 mg for the p-biphenyl ester of the 17-phenyl-PGE 4 derivative, about 10-200 mg for the p-biphenyl ester of the 17-phenyl-PGF derivative, using 1-7 doses, or about 10-100 mg oxaprostaglandin p-biphenyl ester using 1-2 doses.

15 581 1 6

Alternatively, to induce miscarriage, p-biphenyl esters of 17-substituted-N 2 -trisnorprostaglandin can be administered intraperitoneally in doses of 5-1.0 mg, 1-5 times daily, or infused intravenously at doses of 5-500 pg / min for about 1-2 hours.

Another suitable application for p-biphenyl esters of 17-, 18-, 19-, and 20-Ar-substituted Prostaglandin analogs and oxaprostaglandins is as a cause of maternity burns. For this purpose, an ethanol-saline solution of 17-substituted-β-trisnor-PGFβ or p-biphenyl ester of β-bisphenyl can be used infused intravenously in an amount of about 0.05 to 50 pg / min for about 1 to 10 hours.

To achieve bronchodilation or nasal cavity opening, a suitable dosage form is an aqueous ethanol solution of 16-Ar-substituted-U'-tetranor-PGE.) Or p-biphenyl ester of -PGE 4 as an aerosol, using fluorinated hydrocarbons as propellants at about 3-500 pg / ml. dose.

The p-biphenyl esters of the Eq and 1,3,1-dihydro-Eβ series? -Ar-substituted-n-tetranorprostaglandins are useful hypotensive agents. Similarly, β-biphenyl esters of E-series 15 5-Ar-substituted-β-pentanorprostaglandins are useful bronchodilators. For the treatment of overexertion, these drugs are suitably administered intravenously in doses of about 0.5 to 10 pg / kg or preferably in the form of capsules or tablets at doses of about 0.005 to 0.5 mg / kg / day, I. Comparative experiments performed A. Spasmodic effect on isolated guinea pig uterus: stimulation-induced birth control activity.

B. Protection of Marsini against a toxic dose of histamine given as an aerosol by aerosol administration: the experiment demonstrates bronchodilator activity.

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

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

E. Inhibition of stress-induced ulcers in rats: the experiment shows anti-ulcer activity.

F. Abortion Activity in Rats: II Test Compounds 1. ip-Oxo-PGE 2 -p-biphenyl ester is useful as an antihypotensive agent and vasodilator.

2. 1-Phenyl-N, N-dihydro-β-pentanor-PGEg-β-biphenyl ester is useful as a bronchodilator.

16,581 1,6 3. 15-epi-13,1lt-dihydro-16-phenyl-PGE4β-biphenyl ester is useful as an antiulcer agent.

16-p-Biphenyl-PGE2-biphenyl ester is useful as a bronchodilator.

5. 16- (N-Naphthyl) -PGE 2 -β-biphenyl ester is useful as an antihypotensive agent.

6. 16- (o-1-enyl) -PGE2-p-bi phenyl ester is useful as an antiulcer agent.

7. 17-Phenyl-UAtrisnor-PGE2-p-biphenyl ester is useful as a birth control agent because of its high selective spasmodic effect on the uterus.

8. 7 - ((<-furyl) -UAtrisnor-PGE20-β-biphenyl ester is useful as a birth control agent and for synchronizing estrone in mammals because of its abortifacient activity.

9. 15-Methyl-16-phenyl-1,3,3-dihydro-UF-tetranor-PGE 2β-biphenyl ester is useful as an antihypotensive agent and a vasodilator.

10. 1-Phenyl-β-dihydro-β-tetranor-PGF-β-biphenyl ester is useful as an antihypotensive agent and a vasodilator.

11. 16-Phenyl-13,11-dihydro-N'-tetranor-PGA-β-biphenyl ester is useful as an antihypotensive agent and a vasodilator.

12.? -Phenyl-it-tetranor-PGEg-p-biphenyl ester is useful as an antihypotensive agent and a vasodilator.

13. 16-Phenyl-1,3,3-dihydro-N-tetranor-PGE 1-p-biphenyl ester is useful as an antihypertensive agent and a vasodilator.

1U. 16- (p-tolyl) -d, ε-tetranor-PGE2-p-biphenyl is useful as an antihypotensive agent and vasodilator.

15- 16- (o-tolyl) -it-tetranor-PGE2-p-biphenyl ester is useful as an antihypotensive agent and a vasodilator.

16. 16- (p-Methoxyphenyl) -tr-tetranor-PGE2-p-biphenyl ester is useful as an antihypotensive agent and a vasodilator.

17 · 16- (oi-thienyl) - <?: - tetranor-PGE2-p-biphenyl ester is useful as an antihypotensive agent and a vasodilator.

18. 16- (β-thienyl) -N-tetranor-PGE2-β-biphenyl ester is useful as an antihypotensive agent and a vasodilator.

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Table 2

Biological and Physical Values No. Compound M.D. ^ 8 ^ A.U. ^^ Sp.

11,6-Phenyl-1,3,1-dihydro-β-tetranorostagaglandin E 1 -phenyl ester 170 0.51 oil (reference compound) c 216-phenyl-13,14-dihydro-U1-tetranorostagaglandin -Eg-β-tolyl ester 31 0.51 oil (reference compound) 3'-phenyl-β-dihydro-Uf-tetranor-

prostaglandin N-β-biphenyl ester 0.25A 104-105 ° C

(Compound of Example 14) N-16-phenyl-N-tetranorprostaglandin-N-and-tolyl ester (reference compound) 100 oil 5 16-phenyl-N-tetranorprostaglandin

E2-E-biphenyl ester (Example 22 3 120-121 ° C

"compound)

Subscripts of Table 2 (a) Relative diarrhea effect in mice (PGE ^ = 100) (h) Antiulcer effect in rats at oral doses of 2 x 0.5 mg (A '= active, I = ineffective).

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

Example 1 p-Biphenyl-9-oxo-11,10β-bis- (tetrahydropyran-2-yloxy) -1,6-phenyl-cis-5-trans-13-dimethyl-ethananepro st adenoate i

A solution of 9-oxo-11β, 15α-bis- (tetrahydropyran-2-yloxy) -16-phenyl-cis-5-trans-13β-tetranorprostadienolic acid ((10a) 1 equivalent), p-phenylphenol ( 10 equivalents) and dicyclohexylcarbodiimide (1.25 equivalents) in methylene chloride, can be stirred overnight, concentrated (in vacuo) and purified by column chromatography p-biphenyl-9-oxo-11 ° <, 15 <* "bis- (tetrahydropyran). To give 2-yloxy) -6-phenyl-cis-5-trans-13-tetranorprostadienoate.

Accordingly, using the above methods, other substituted E-series dApentanorprostaglandin p-biphenyl esters of this invention can be obtained by substituting the appropriate 11,15-bis- (tetrahydropyran-2-yloxy) -15-substituted-N-pentanorprostaglandin compound of the above example for the appropriate compound 10 of the above example.

Example 2 p-Biphenyl-9β-hydroxy-1β, 15β-bis- (tetrahydropyran-2-yloxy) -1,6-phenyl-cis-5-trans-1S-tα-tetranorprostatienoate

A solution of 9,4-hydroxy-11β, 15β-bis- (tetrahydropyran-2-yloxy) -2,282,116-phenyl-cis-δ-trans-1S-tetranorprostadienoic acid (9a) (1 equivalent) p-phenylphenol (10 equivalents) and dicyclohexylcarbodiimide (1.25 equivalents) in methylene chloride, stirred overnight, concentrated (in vacuo) and purified by column chromatography p-biphenyl-11 «« <- hydroxy-1 15 <* - bis- (tetra - to obtain hydropyran-2-yloxy) -16-phenyl-cis-5-trans-1S-tetranorprostadienoate.

Using the above procedure, other 1-substituted-pentanorprostaglandin p-biphenyl esters of this invention are similarly obtained by substituting the appropriate 11,15-bis- (tetrahydropyran-2-yloxy) -15-substituted-α-pentanor-prostaglandin of compound 9a of the above example.

Example 3 p-Phenylphenol ester of non-thienyl-tetranorprostaglandin-Egrn

A solution containing 2 kg (0.65 mmol) of 16 -? - thienyl-β-tetranorprostaglandin-Eg, 680 mg (1+ mmol) of p-phenylphenol) + 12 mg (1 mmol) of dicyclohexylcarbodiimide in methylene chloride and 15 mL of methylene chloride, was stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 60 mg of 1-o-thienyl-ttf-tetra-norprostaglandin-E 2 in p-phenylphenol ester, m.p. was 115-117 ° »after crystallization (ether-pentane as solvent).

In a similar manner, p-phenylphenol ester of 1β-thienyl-β-tetranorprostaglandin-E 2 was prepared, m.p. 126-8 °.

Example 1+ 17 ~ 0 <~ Furyl-uAtrisnorprostaglandin-PGF0 and p-phenylphenol ester det

A solution of 177 mg (0.35 mmol) of N-N-furyl-trisnorprostaglandin, 668 g (0.39 mmol) of p-phenylphenol, 1+, 95 ml of 0.1 M dicyclohexylcarbodiimide in methylene chloride and 15 ml of methylene chloride was stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 28 mg of 17 - * - furyl-UAtrisnor prostaglandin p-phenylphenol ester, m.p. 122-2) + ° after crystallization, (ether-pentane as solvent).

Example 5 p-Phenol Phenol Ester of 16- [3-Naphthyl-β-Tetranorprostaglandin-E2

A solution of 200 mg of (O) (7 mmol) N, N-naphthyl-N-tetranorpropaglandin-E, 900 mg (5.3 mmol) of p-phenylphenol, 7 ml of 0.097 molar dicyclohexylcarbodiimide in methylene chloride and ml of methylene chloride, 23 5 81 1 6 was stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 72 mg of 16-β-naphthyl-β-tetranorprostaglandin-E2 p-phenylphenol ester, m.p. 79-02 °, after crystallization (ether-pentane as solvent). The IR and mass spectra confirmed the putative structure for the substance.

Example 6 13.1 '+ Dihydro-15-methyl-16-phenyl-ε-tetranorprostaglandin E2 p-phenylphenol ester

A solution of 50 mg (0.388 mmol) of N, N-dihydro-N-methyl-1-phenyl-N-tetranorprostaglandin-Eg, 61 + 5 mg (3.8 mmol) of p-phenylphenol, 1+ ml of , 1 molar dicyclohexylcarbodiimide in methylene chloride and 12 ml of methylene chloride were stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded? Tk-J ° t after crystallization (ether-pentane as solvent).

The IR and mass spectra confirmed the putative structure for the substance. Separation of the 15 R and 15 S epimers was accomplished by liquid chromatography.

Example J

P-Phenylphenol ester of 19-oxa-prostaglandin E2

A solution of 167 mg (0.1 + 7 mmol) of 19-oxa-prostaglandin E2, 800 mg (1 +, 7 mmol) of p-phenylphenol, 6 ml of 0.1 molar dicyclohexylcarbodiimide in methylene chloride and 20 ml of methylene chloride, stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 53 mg (23 L) of p-phenylphenol ester of 19-oxa-prostaglandin E2, m.p. 87-87.5 °, after crystallization (ether-pentane as solvent). The IR spectrum confirmed the putative structure for the substance.

Example 8 p-Phenylphenol ester of 19-oxa-prostaglandin F

A solution of 180 mg (0.55 mmol) of 19-oxa-prostaglandin-F0.91 + 0 mg (5 → 5 mmol) of p-phenylphenol, 7 ml of 0.97 molar dicyclohexylcarbodiimide in methylene chloride and 20 ml of methylene chloride was stirred. overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 156 mg (56%) of 19-oxa-prostaglandin.

F-p-phenylphenol ester, m.p. 10U-5 °, after crystallization (ether as solvent). d oC

The IR spectrum confirmed the putative structure for the substance.

211 5 8116

Example 9 p-Biphenyl 9-oxo-11®-1,15β-dihydroxy-16-phenyl-cis-5-trans-13-titetranetrostadienoate

A solution of 200 mg (0.535 mmol) of 9-oxo-1-lot, 15 ° -dihydroxy-16-phenyl-cis-5-trans-13-β-tetranorprostadienoic acid (11a), 900 mg (5.3 mmol) of lia) p-phenylphenol, 7 ml of 0.097 molar dicyclohexylcarbodiimide in methylene chloride and 20 ml of methylene chloride were stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) using chloroform first, then ethyl acetate as eluents afforded tetranorprostadienoate, m.p. 120-121 ° (ether-pentane).

Example 10 p-Phenylphenol ester of 15-epi-16- (3-naphthyl-U) tetranorprostaglandin E2

A solution of 200 mg (0.47 mmol) of 15-epi-16- [N-naphthyl-N-tetraorprostaglandin-E, 900 mg (53 mmol) of p-phenylphenol, 7 ml of 0.097 molar dicyclohexylcarbodiimide in methylene chloride and 20 ml of methylene chloride were stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 50 mg of p-phenylphenol ester of 15-epi-16- [5-naphthyl-tetranorprostaglandin-E 2, m.p. 101-3 °, after crystallization from ether-pentane.

In a similar manner, β-phenylphenol ester of δ-γ-naphthyl-tfAtetranorprostaglandin E 2 was prepared, m.p. 79-82.

Example 11 p-Phenylphenol ester of 16-phenyl-13,1β-dihydro-β-tetranorprostaglandin E 1

A solution of 120 mg (0.32 mmol) of 1-phenyl-N, N-dihydro-UA-tetranorprostaglandin-N, 5.5 * 5 mg (3.2 mmol) of p-phenylphenol, U, 1 ml of 0.097 molar dicyclohexylcarbodiimide in methylene chloride and 18 ml of methylene chloride were stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 75 mg (LU%) of p-phenylphenol ester of 16-phenyl-13,1β-dihydro-ftA-tetranorprostaglandin E, m.p. 90.1-92 °, after crystallization from ether-pentane. IR, NMR and mass spectra confirmed the putative structure.

Analysis: Calculated for C 18 H 28 N 2 O 2: C 77.53, H 7.27 Found: C 77.23, H 7.31.

25 581 1 6

Example 15 p-Phenylphenol ester of 16- [3-thienyl-β-tetranorprostaglandin-E2

A solution of 130 mg (0.3 mmol) of 16- [3-thienyl- * O-tetranorprog taglandin, 653 mg (0.38 mmol) of p-phenylphenol, U, 85 ml of 0.1 molar dicyclohexylcarbodiimide in methylene chloride and 15 mL of methylene chloride, was stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 17 mg of 16- [3-thienyl-fcf-tetranorprostaglandin p-phenylphenol ester, mp, 126-28 °, after crystallization from ether-teripentane. IR, mass, NMR, and UR spectra confirmed the putative structure.

Example 12 p-Phenylphenol ester of 13.1 U-dihydro-16-phenyl-ΔTetranorprostaglandin E.

A solution of 36 mg (0.096 mmol) of N, N-dihydro-1-phenyl-N-tetranorprostaglandin-E., 6 mg (0.96 mmol) of p-phenylphenol, 1.5 ml of 0.097 molar dicyclohexylcarbodiimide in methylene chloride and 5 ml of methylene chloride, was stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 10 mg of 13,1β-dihydro-1-phenyl-β-tetranorprostaglandin-E. p-phenyl ester, m.p. 96-100 °, after crystallization (ether-pentane as solvent).

Example 13 p-Phenylphenol ester of 13,1β-dihydro-15-phenyl-α-pentanorprostaglandin E2

A solution of 1U6 mg (0.05 mmol) of 13.1 U-dihydro-15-phenyl-M / S-pentanorprostaglandin-E, 770 mg (U, 53 mmol) of p-phenylphenol in 6 ml of 0.097 molar dicyclohexylcarbodi- imide in methylene chloride and 15 ml of methylene chloride were stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 76 mg of 13,1β-dihydro-15-phenyl-tt * -pentanorprostaglandin-E2 p-phenylphenol ester, m.p. 87-90 °, after crystallization (ether-pentane as solvent). IR and mass spectra confirmed the hypothesized structure. The 15 (R) and 15 (S) epimers were separated by thin layer chromatography.

Example 1U

P-Phenylphenol ester of 16-phenyl-dAtetranorprostaglandin E

A solution of kk mg (0.12 mmol) of? -Phenyl-β-tetranorprostaglandin-E1, 20k mg (1.2 mmol) of p-phenylphenol, 2.6 ml of 0.097 molar dicyclohexylcarbodiimide in methylene chloride and 5 ml of methylene chloride , was stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded the p-phenylphenol ester of 16-phenyl-β-tetranorpropaglandin-E1, m.p. 95-6 °, after crystallization (ether-pentane as solvent).

26 581 1 6

Example 15 16-p-Methoxyphenyl-tfM: etranorprostaglandin p-phenylphenol ester

A solution of 76 mg (0.19 mmol) of 16-p-methoxyphenyl-6H-tetranor-prostaglandin-Egj in 322 mg (1.9 mmol) of p-phenylphenol in 2.27 ml of 0.097 molar dicyclohexylcarbodiimide in methylene chloride and 10 ml of methylene chloride, stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 26 mg (25%) of p-phenylphenol ester of 16-p-methoxyphenyl-β-tetranorprostaglandin-E 2, m.p. 100-110 °, after crystallization (ether-pentane as solvent).

Example 16 p-Phenylphenol ester of 16-p-tolyl-O-tetranorprostaglandin-E2

A solution of 200 mg (0.52 mmol) of 1β-p-tolyl-tetranorprostaglandin-E2> 875 mg (5-2 mmol) of p-phenylphenol, 6.2 ml of 0.097 molar dicyclohexylcarbodiimide in methylene chloride and 20 ml of ml of methylene chloride, stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 75 mg (27%) of 16-p-tolyl-tff-tetranorprostaglandin-Eβ p-phenylphenol ester, m.p. 10 U °, after crystallization (ether-pentane as solvent).

Example 17 p-Phenylphenol ester of N-phenyl-N-trisnorprostaglandin F

A solution of 50 mg (0.13 mmol) of 17-phenyl-NJ-trisnorprostaglandin-F, 220 mg (1.30 mmol) of p-phenylphenol, 1.79 ml of 0.10 molar dicyclohexylcarbodiimide in methylene chloride and 5 .0 ml of methylene chloride, was stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 63 mg (90.5 L) of p-phenylphenol ester of 17-phenyl-ii-trisnorprostaglandin F0, m.p. 116-117 °, c. Λ after crystallization (methylene chloride-hexane as solvent). The IR spectrum confirmed the putative structure.

Example 18 p-Phenylphenol ester of 1β-phenyl-U, tetranorprostaglandin E,

A solution of 200 mg (0.535 mmol) of 16-phenyl-tu-tetranor-prostaglandin-E2> 900 mg (5.3 mmol) of p-phenylphenol, 7 ml of 0.097 molar dicyclohexylcarbodiimide in methylene chloride and 20 ml of methylene chloride was stirred. overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 185 mg (66.5%) of 16-phenyl-β-tetranorprostaglandin E-p-phenylphenol ester, m.p. 120-1 °, after crystallization (ether-pentane as solvent). IR, mass and UV spectra confirmed the putative structure.

27,581 1 6

Example 19 p-Phenylphenol ester of 1-o-tolyl-MZ-tetranorprostaglandin E

A solution of 77 mg (0.20 mmol) of 16-o-tolyl-.beta.-tetranorprostaglandin-Eβ, 3 * + 0 mg (2.0 mmol) of p-phenylphenol in 2.58 ml of 0.097 molar dicyclohexylcarbode -imide in methylene chloride and 7> 7 ml of methylene chloride, was stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 1OU mg (97%) of p-phenylphenol ester of 16-o-tolyl-U -'-tetranorprostaglandin-E, m.p. 9-9.15 °, after crystallization (ether-pentane as solvent). The IR spectrum confirmed the putative structure.

Example 20 p-Phenylphenol ester of 17-phenyl-ttt-trisnorprostaglandin-E2

A solution of 50 mg (0.13 mmol) of 17-phenyl-UM, risnorprostaglandin-E 2, 220 mg (1.30 mmol) of p-phenylphenol, 1.79 ml of 0.10 molar dicyclohexylcarbodiimide in methylene chloride and 5 ml of methylene chloride, stirred overnight at room temperature. Concentration (in vacuo) and column chromatography on silica gel (Baker, 60-200 mesh) afforded 51 mg (73.6%) of p-phenylphenol ester of 17-phenyl-N-trisnor-prostaglandin E2, m.p. 11.5.5-115.5 °, after crystallization (methylene chloride-hexane as solvent). The IR spectrum confirmed the putative structure.

Prostaglandin parabiphenyl esters prepared according to the previous examples:

Melting point ° C

16-phenyl-N-tetranorprostaglandin E2 120-121 13,1β-Dihydro-16-phenyl-N-tetranor PGE-108-16-phenyl-N-tetranor PGE1 95-96 16-Phenyl-tetranor PGE 100 n-phenyl-tert-tetranor PGE ^ 11 **, 5-115.5 n-phenyl-t-tetranor PGE ^ 116-117

17o <-furyl-1H-trisnor PGF0. 122-12U

1S-naphthyl-N-tetranor PGE ^ 79-82 16-o-tolyl-t-tetranor PGE ^ 91.91.5

16-p-tolyl-β-tetranor PGE 2 10U

16-paramethoxyphenyl-β-tetranor PGE 2 108-110 16 β-thienyl-β-tetranor PGE 1 115-117-16,5-thienyl-β-tetranor PGEg 126-128 -i ^ -pentanor PGEg 87 ~ 90 28 5811 6

Melting point ° C

15-methyl-16-phenyl-13,1β-dihydro-N--tetranor PGE 2 87-87.5 19-branch PGF0 10 * * -105 20-oxa-tHHiamo PGE 2 72-73 17-branch PGF 3 93- 9 * 1.5 13.1 * + - Dihydro-15-epi-16-phenyl-Ultetranor PGF2 111.5-113.5 13,11-Dihydro-1-phenyl-N--tetranor PGF ^ 129-131 1α-parabiphenyl-β-tetranor PGE2 107-109 15-epi-16γS-naphthyl-β-tetranor PGE2 101-103 20-oxa-β-homo PGF2o -121 16-phenyl-u / -tetranor PGF2öt 117-119

Claims (1)

»58116 Claim: A process for the preparation of parabiphenyl esters of therapeutically active prostaglandin series E and F of formula I .A (I) R '' OH 2 wherein A is AriCH 2 - or - (CH 2) -OR, where n is an integer 0- 2, m is an integer from 1-U, R 1 is alkyl of 1 to 3 carbon atoms, Ar is N-furyl, N-furyl, N-thienyl, N-thienyl, N-naphthyl, N-naphthyl, phenyl or monosubstituted phenyl substituted with methoxy, methyl or phenyl, R 'is para-biphenyl, R is hydrogen or methyl, W is a single bond or a cis double bond, Z is a single bond or a trans double bond, and M is. 0 or ^ C, X 't.' ΌΗ characterized in that the precursor acid of the formula '' '._1 ^ .A HO' 'R ^% OH where A, R, M, W and Z have the same meaning as above, reacted with p-phenylphenol in the presence of dicyclohexylcarbodiimide.