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IE43815B1 - 11-desoxy-15-substituted-16,17,18,19,20-pentanorprostaglandins - Google Patents

11-desoxy-15-substituted-16,17,18,19,20-pentanorprostaglandins

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Publication number
IE43815B1
IE43815B1 IE2635/75A IE263575A IE43815B1 IE 43815 B1 IE43815 B1 IE 43815B1 IE 2635/75 A IE2635/75 A IE 2635/75A IE 263575 A IE263575 A IE 263575A IE 43815 B1 IE43815 B1 IE 43815B1
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phenyl
deoxy
group
trans
acid
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IE2635/75A
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IE43815L (en
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Pfizer
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Priority to IE1534/78A priority Critical patent/IE43816B1/en
Priority to IE1535/78A priority patent/IE43817B1/en
Publication of IE43815L publication Critical patent/IE43815L/en
Publication of IE43815B1 publication Critical patent/IE43815B1/en

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Abstract

1508170 2-Formylcyclopentaneheptanoic acid derivatives PFIZER Inc 10 Dec 1975 [11 Dec 1974] 29061/77 Divided out of 1508168 Heading C2C The invention comprises 2-formylcyclopentaneheptanoic acid derivatives of the formula wherein R2 and R3 each are C 1-10 alkyl, C 7-9 aralkyl, or 1- or 2-naphthyl or phenyl optionally substituted by Cl, Br, F, C 1-6 alkyl, C 1-6 alkoxy or phenyl and their preparation by oxidizing the corresponding 2-hydroxymethylcyclopentaneheptanoic acid derivatives. Methyl 7 - [2# - hydroxymethyl - 5α - acetoxyla-cyclopentyl]heptanoate is prepared by the hydrogenation of methyl 7-[2#-benzyloxymethyl- 5α - acetoxy - 1α - cyclopentyl] - cis - 5 - heptenoate, resulting from the acetylation of methyl 7 - [2# - benzyloxymethyl - 5α - hydroxy - 1α- cyclopentyl] - cis - 5 - heptenoate, obtained by esterifying 7 - [2# - benzyloxymethyl - 5α- hydroxy - 1α - cyclopentyl] - cis - 5 - heptenoic acid which is made by reacting (4-carboxybutyl)- triphenylphosphonium bromide with 4#-benzyloxymethyl - 3,3a#,4,5,6,6a# - hexahydro - 2H- cyclopenta[b]furan-2-ol.

Description

This invention relates to ll-deoxy-15-substituted-16,17,18,19,20-pentanorprostaglandins and intermediate compounds useful for the preparation thereof. The prostaglandin compounds of this invention are analogues of the naturally ' occurring prostaglandins and have activity profiles comparable to the parent prostaglandins, but exhibit a greater tissue specificity of action.
The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. For instance, ) the prostaglandins of the E and A series are potent vasodilators (Bergstrom, et al, Acta Physiol Soand 64:332-33, 1965 and Bergstrom, et al. Life Sei 6:449-455, 1967) and lower systematic arterial blood pressure (vasodepression) on intravenous administration (Weeks and King, Federation Proc 23:327. 1964? Bergstrom, et al, 1965, op oit; Carlson, et al, Acta Med Soand 183:423-430, 1968? and Carlson et al, Acta Physiol Scand 75:161-169, 1969), Another well known physiological action for PGE^ and PGE2 is as a bronohodilator (Cuthbert, Brit Med J 4:723-726, 1969).
Still another important physiological role for prostaglandins is in connection with the reproductive cycle.
PGE2 is known to possess the ability to induce labour (Karim, et al, tf Obstet Gynaeo Brit Cwlth 77*200-210, 1970), to induce therapeutic abortion (Bygdeman, et al, Contraception - 2 4 3 815 4, 293 91971). PGEj has been used for control of fertility (Karim, Contraception, 3., 173 (1971)). Several prostaglandins of the E and F series are known as inducers of labour in mammals, and PGE^, ant3 F-j ate known for control of the reproductive cycle. It has been shown that luteolysis may take place as a result of administration of PGF^[Labhsetwar, Nature, 230, 528 (1971)] and hence prostaglandins have been used for fertility control by a process in which smooth muscle stimulation is not necessary.
Still other known physiological activities for PGE^ are in the inhibition of gastric acid secretion (Shaw and Ramwell, Ins Worchester Svmp on Prostaglandins, New York, Wiley, 1968, p 55-64) and also of platelet aggregation (Emmons, et al, Brit Med J 2s468-472, 1967).
It is now known that such physiological effects will be produced in vivo for only a short period, following the administration of a prostaglandin. Evidence indicates that the reason for this rapid cessation of activity is that the natural prostaglandins are quickly and efficiently metabolically deactivated by β-oxidation of the carboxylic acid side-chain and by oxidation of the 15a-hydroxy group (Anqgard, et al. Acta Physiol Scand 81, 396 (1971) and references cited therein). It has been shown that placing a 15-alkyl group in the prostaglandins has the effect of increasing the duration of action possibly by preventing the oxidation of the C15-hydroxyl [Yankee and Bundy, JACS 94, 3651 (1972)], Kirton and Porbes, Prostaglandins, 1, 319 (1972).
Accordingly, it has been considered desirable to - 3 prepare analogues; of the prostaglandins which would have physiological-activities equivalent to the'natural compounds, but in which the selevtivity of action and the duraotion of the activity would be increased. Increased selectivity of activity would be expected to alleviate the severe side effects, particularly gastro-intestinal side effects frequently observed following systemic administration of the natural prostaglandins (Lancet, 536, 1971).
It has how been found that these needs may be met 10 by ll-deoxy-16,17,18,19,20-pentanorprostaglandins or the E and Ρ series and Clg epimers thereof having ai; the 15 position a hydroxyl or oxo group and one substituent of the formula R I Ar—CH— as hereinafter defined.
Accordingly, the present invention provides an 11-deoxy16,17,18,19,20-pentanorprostaglandin of the E or F series having the formula:- wherein Ar is a- or β-thienyl; 5-phenyl-a- or β-thienyl; -lower alkyl-a- or β-thienyl; a or β-naphythyl; trcpyl, phenyl? 3,4dimethoxyphenyl; 3,4-methylenedioxyphenyl? 3,4-diehlorophenyl; 3,5-dimethylphenyl; or a mono-substituted phenyl group wherein the said substitutent is a bromine, chlorine or fluorine atom, or a trifluoromethyl, phenyl, lower alkyl or lower alkoxy group - 4 4 3 815 thereof; R is hydrogen or methyl; each of M and M' is H OH, or W is a single bond or cis double bond with the proviso that when R' is a hydrogen atom or an alkyl group and Ar is an unsubstituted phenyl, naphthyl or thienyl group or a 5- lower alkyl-thienyl group, a 3,4-dichlorophenyl or a 3,4dimethylphenyl group or a monosubstituted phenyl group where the substituent is a bromine chlorine, or fluorine atom, a trifluoromethyl group or a lower alkyl group, but excluding the case is oxo and M is OH or OH , w is not a single bond; Z is a single bond or trans double bond and R' is hydrogen, alkyl of from 1 to 10 carbon atoms; aralkyl of from 7 to 9 carbon atoms; e- or (5-naphthyl; phenyl or substituted phenyl wherein the said substituent is a chlorine, bromine or fluorine atom or a lower alkyl, lower alkoxy or phenyl group, and when R' is hydrogen, the pharmaceutically acceptable salts thereof.
The terms lower alkyl, lower alkoxy and lower alkanoyl used herein refer to groups having a to Cg alkyl chain.
The invention also includes the compound 11-deoxy16-phenyl-17,18,19,20-tetranor-PGEo and the optical antipode, racemates and pharmaceutically acceptable salts thereof. 4381S Examples of the prostaglandin analogues of this invention are the C,_ derivatives (as set out above) of !□ 11-deoxy-PGE2, -PGE^, -PGF^, -PGF^, -PGF^, -P®?^, -PGEq, PGF.-PGF -13,14-dihydro PGE.,-13,14-dihydro PGF. and OC& Op ri ZCt -13,14-dihydro and esters thereof wherein the esterifying group is R1, as defined above, and. the C,15 epimers and C^g oxo derivatives thereof having at the Imposition a hydroxy or oxo group and one substituent of the formula (i) herein.
An especially preferred series of novel compounds are represented by the formula: OH and its c^g epimer.
Another especially preferred series of novel compounds is represented by the formula: and its Clg epimer.
Still other especially preferred novel compounds are represented by the formula: - 6 4 3 8 15 COOR' and its C15 epimer.
Another especially preferred series of novel compounds are represented by the formula: OH COOR1 Another especially preferred series of novel compounds is represented by the formulasOH ZvX COOR' R I CH '•M il Still other especially preferred novel compounds are represented by the formula:- 7 43815 wherein Ar, W, z, R and R1 are as defined above.
Especially preferred are: ll-deoxy-16-phenyl-17,18,19,20-tetranor-PGEQ, ll-deoxy-16-phenyl-17,18,19,2o-tetranor-PGE2, rac-11-deoxy-16-(8-naphthvl)-17,18.19.20tetranor-PGE2, ll-deoxy-16-(5-phenyl-2-thienyl)-17,18,19,20-tetranorPGE2, ll-deoxy-15-((-)-1-phenylethyl)-16,17,18,19,20-pentanorPGE2, ll-deoxy-16-(m-tolyl)-17,18,19,20-tetranor-PGE2, 15epi-ll-deoxv-16-(m-tolvl)-17,18,19,2O-tetranor-PGE2, 9,15dioxo-16-(m-tolyl)-17,18,19,20-tetranor-prosta-cis-5-trans13-dienoic acid, ll-deoxy-13,14-dihydro-16-phenyl-17,18,19,20tetranor-PGE2, 15-epi-ll-deoxy-16-phenvl-17.18,19,20-tetranorPGE2, 11-deoxy-[15-((+)-1-phenylethyl)-16,17,18,19,20-pentanorPGE2, 15-epi-ll-deoxv-15-((+)-1-phenylethyl)-16,17,18,19,20pentanor-PGE2, rac-11-deoxy-16-(p, -chlorophenyl)-17,18,19,20tetranor-PGE2, rac-9,15-dioxo-16-(S-naphthvl)-17,18.19,20tetranQrorosta-cis-5-trans-13-dienolc acid and 15-epi-lldeoxy-16-(j3-ehloraphenyl)-17,18,19,20-tetranor-PGE2.
This invention further provides useful intermediates for the preparation of these prostaglandins of the formula:- 8 Μ and the C15 epimers thereof, wherein Ar is a- or β-thienyl; -phenyl-a- or β-thienyl; 5-lower alkyl-a- or β-thienyl; a or β-naphthyl; tropyl, phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4-dichlorophenyl; 3,5-dimethylphenyl or a monosubstituted phenyl group wherein the said substituent is a bromine, chlorine or fluorine atom or a trifluoromethyl, phenyl, lower alkyl or lower alkoxy group; R is hydrogen or methyl; and the pharmaceutically acceptable salts thereof and the esters thereof wherein the esterifying groups is: alkyl of from 1 to 10 carbon atoms; aralkyl of from 7 to 9 carbon atoms; aor β-naphthyl; phenyl or substituted phenyl wherein the said substituent is a chlorine, bromine or fluorine atom or a lower alkyl, lower alkoxy or phenyl group; R1 is hydrogen; alkyl of from 1 to 10 carbon atoms; aralkyl of from 7 to 9 carbon atoms; a- or βnaphthyl; phenyl or substituted phenyl wherein the said substituent is a chlorine, bromine or fluorine atom or a lower alkyl, lower alkoxy or phenyl group, and wherein W is a single bond or cis double bond; Z is a single bond or trans double bond; M is oxo, .OH or 'H and optionally where M is not oxo, the hydroxyl group is modified by being esterified; and R^ is 2-tetrahydropyranly or dimethyl-tert-butylsilyl.
Precursor compounds of these intermediates of the invention are the subject of Patent Specification No.
The canpcunds of this invention including the various intermediate compounds, may be prepared from known compounds by steps described hereinafter and illustrated by Reaction. Schemes A to F, wherein Ar, R, R^, and M are as defined above, R2 and Rg are each alkyl of 1 to 8 carbon atoms, phenylalkyl of up to 9 carbon atoms, phenyl, tolyl, a- or β-naphthyl or p-biphenyl-yl; and M' is As shewn in Scheme A, the first step (l-*2) is a condensation between the known aldehyde 1 (Garey and Ravindranathan, Tetrahedron lett. 1971, 4753) with an appropriate 3-axophosphdnate to produce enone 2. The oxophosphonate is usually produced by condensation of the appropriate carboxylic acid ester with a dialkyl irethylphosphonate. Typically the desired methyl ester is condensed with dimethyl msthylphosphonate.
Enone 2 is then reduced to enol _3 with zinc borohydtide or a kindred alkyl barohydride such, as lithium triethylborchydride or potassium tri-secbutylborohydride. This reduction produces a mixture of epimers both of which may be used as substrates for further reactions. The enol 2 is used to produce prostaglandin analogues having a α-hydroxyl at C^g. The epimer of 2 is used to produce prostaglandin analogues having a β-hydroxyl at C^g.
In addition, the mixture of C^g epimers may be used to produce 15oxcprostaglandin analogues. The epimers produced in the hydride reduction · can be separated by column, preparative thin layer, or preparative high pressure liquid chromatography. In the reduction reaction ethers such as tetrahydrofUran ot 1,2 dimethoxyethane or acetonitrile are usually employed as solvents.
Enone 2 may be reduced catalytically with hydrogen to ketone 6, a suitable starting material for the preparation of 13,14-dihydrcprostaglandin analogues of the present invention. This reduction may be achieved with either a homogeneous catalyst such as trls-trl-thSnvlthosphinerhodlum chloride or with a heterogeneous catalyst system such as platinum, palladium or rhediun. The stage at which the reduction is carried out is not critical as will be seen below. . - 10 43815 Scheme A - 11 43815 Enone 2 may also be reduced with borohydride ion to produce alcohol 7 in a single step or alternatively, enol 3. may be catalytically reduced to produce alcohol 7. using conditions described above. (3.->4) involves the protection of the free hydroxyl group with an acid labile protecting group. Any sufficiently acid labile group is satisfactory, however, the most usual ones are 2-tetrahydropyranyl or dimethyl-tert-butvlsilvl groups which can be incorporated in molecule by treatment with dihydropyran and an acid catalyst, usually p-toluenesulfonic acid, in an anhydrous medium or dimethyl-tert-butylsilyl chloride and imidazole, respectively. (4->5_) is a reduction of the lactone 4 to hemiacetal 5. using a suitable reducing agent such as diisobutylaluminium i hydride in an inert solvent. Low reaction temperatures are preferred and -60 to -80°C are usual. However, higher temperatures may be employed if over reduction does not occur. 5. is then purified if desired by column chromatography. As indicated in Scheme A, compounds 4 and 5 may be catalytically reduced to 8 and 9 respectively, by the procedure outlined above.
The conversion of follows that already outlined by the conversion of (2->5.) · The remainder of the synthesis of the two-series prostaglandin analogs of this invention is outlined in Scheme B. (5 ->10) is a Wittig condensation in which hemiacetal 5 is reacted with (4-carboxybutyl)triphenylphosphonium bromide (22) in dimethyl sulfoxide in the presence of sodium methylsulfinylmeth-yl-ide. 10 is then purified as above. The conversion of 10—11 is an acid catalyzed hydrolysis of protecting group. Any acid may be used which does not cause destruction of the molecule in the course of the removal of the protecting group, however this is accomplished most often by the use of 65% v/v aqueous acetic acid. Alternatively, the dimethyl-tert-butvlsilvl protecting group may be removed by the action of tetraalkylammonium fluoride in a solvent such as tetrahydrofuran. The product is purified as above. is an ll-deoxy-15-substituted-16,17,18,19,20-pentanorprostaglandin of the F2a series. The prostaglandin analogues of the E2 series of this invention (13) are prepared from intermediate 10 which may be oxidized by any reagent capable of oxidizing hydroxyl groups which does not attack double bonds. However, the Jones reagent is usually preferred. The product is purified as above to produce intermediate 12. Intermediate 12 may be converted into the prostaglandin analogues of the E2 series (13.) of this invention in the same manner as described for (10-»ll). Furthermore, intermediate 12 may be reduced with eodium borohydride to a mixture of intermediate 15 and its Cg epimer which are separable by column, preparative thin layer, or preparative high pressure liquid chromatography and which can be converted into prostaglandin analogues of the F2q and F,„ series of this invention by the methods given for (10->ll). Alternatively, compound 13 may be reduced with sodium borohydride to provide the F2a and F2p prostaglandin analogues of this invention directly* This epimeric mixture may be separated as described above for 15 to provide pure PGF2a and PGF2P· 43315 Scheme Β -14 43815 The various reduced prostaglandin analogues of this invention, that is, prostaglandins of the one, zero and 13,14-dihydro-two series are produced as shown in Scheme C. Intermediate 6 may be converted to 19 by the steps already outlined for the conversion of (2->10). 19 may then be converted to 20 by the steps discussed above for the conversion of 10->15. 20 may be catalytically reduced to produce 18 which is the precursor for the prostaglandin analogues of the zero series of this invention by the steps previously outlined. (16-»17) is a selective catalytic hydrogenation of the 5-6 cis double bond at low temperature using catalysts such as those described above. Especially preferred for this reduction is the use of palladium on carbon as a catalyst and a reaction temperature of -20°C. 17 is not only a precursor for the prostaglandin analogues of the one series of this invention but also for the zero series since 17 may be reduced to 18 using the methods described for (4-v8). Similarly, 16 may be reduced to 18 by the same procedure. The removal of the protecting groups is carried out as previously described and 17, 18, and 20 may be deproteoted in this way to produce prostaglandins of the one, zero, and 13,14-dihydro-two series of this invention. The production of prostaglandins of the E and E series wherein said prostaglandin is of zero, one, or 13,14-dihydro-two series from 16, 17, 18, 19 and 20 follows that previously described for the conversion of 10-»ll, 12, 13, 14, and 15. 8lS Scheme C OH ψ Furthermore, the 15-substituted-16,17,18,19,2O-pentanorprostaglandin analogues of the E^, F^g, and F^o Series may be obtained directly from the corresponding prostaglandin analogue of the 2-series, by first protecting the hydroxyl by introducing dimethylisopropylsilyl groups reducing selectively the cis double bond, and removing the protecting group.
The reduction is usually accomplished as discussed above for 16-»17 and removal of the protecting group is accomplished - 16 43815 by contacting the reduced protected compound with 3:1 v/v acetic acid:water for 10 minutes or until reaction is substantially complete.
The ll-deoxy-15-substituted-16,17,18,19,20-pentanor5 prostaglandin analogues of the one series of this invention may be prepared by the alternative synthesis summarized in Scheme D. For the first step in the preparation of the above-named prostaglandin analogues the hemiacetal 2-[5ahydroxy-2p-benzyloxymethyloyclopent-la-yl]-acetaldehyde, γ10 hemiacetal is reacted with the disodium salt of (4-carboxybutyl)triphenylphosphonium bromide (22) as described above for 5->10. This intermediate may be converted by procedures described in detail in the appended Examples as summarized below.
As shown in Scheme D, hemiacetal 21 is reacted with the reagent 22 to produce 23.
Scheme D - 17 43815 Scheme D (continued) OH t 23—»24 involves esterifying the carboxyl group with diazomethane to form a methyl ester intermediate. Other blocking groups may be used provided the group is stable to hydrogenation and mild acid hydrolysis and removable by mild basic hydrolysis. Such groups include alkyl of from 1 to 8 carbons, phenalkyl of up to 9 carbons, phehyl, tolyl, p-biphenyl-yl or a- or β-naphthyl. Acylation of the methyl ester intermediate with acetic anhydride and pyridine forms an acetate intermediate. Other blocking groups may be used provided the group is stable to hydrogenation and mild acid hydrolysis. Such groups include alkanoyl of from 2 to 9 carbons, phenalkanoyl of up to 10 carbons, benzoyl, toluoyl, p-phenylbenzoyl or a- or β-naphthoyl. The protected benzyl ether upon reduction with hydrogen and palladium on carbon in an appropriate solvent containing a suitable acid catalyst, ethanol and acetic acid or ethyl acetate and hydrochloric - 18 4 3 815 acid being especially preferred, affords a hydroxy compound oxidation of which with Collins' reagent yields aldehyde 24. 24->17 XZOH Ή involves treatment of 24 with the sodium salt of the appropriate 3-oxophosphonate under conditions described for l->2, to form an enone reduction of which with a hindered alkyl borohydride such as lithium triethylborohydride or potassium tri-sec-butylborohydride or zinc boro10 hydride forms an enol. The hydroxyl group is then protected by treatment with dihydropyran to form a 2-tetrahydropyranyl ether. Other protecting groups may be employed provided they are stable to mild basic hydrolysis and easily removable by mild acid hydrolysis. Such groups 15 include 2-tetrahydrofuryl, or dimethyl-t-butylsilyl.
This protected compound is then contacted with aqueous sodium hydroxide to yield 17. The conversion of 17 to the 11-dioxy-15-substituted-16,17,18,19,20-pentanorprostaglandins of the one series of this invention follows the procedure outlined above.
Scheme Ε - 20 43815 9,15-Dioxo-15-substituted-16,17,18,19,20-pentanorprostaglandins E and derivatives of this invention may be prepared as summarized in Scheme E. 25-»26 involves oxidation of the C,_ hydroxy group of 25 and, if necessary also of the C_ io y hydroxyl group. Any reagent capable of oxidizing hydroxyl groups which does not attack double bonds may be used, however, the Jones’ reagent is usually preferred. The 9,15-dioxo-derivatives of this invention of the 13,14-dihydro two-, one-, and zero- series may be prepared from compounds 27, 29 and 31 as described for 25->26 above.
Scheme F summarizes the preparation of the 9-hydroxyl5-oxo-15-substituted-16,17,18,19,20-pentanorprostanoic acid derivatives of this invention. 33->34 involves acylation of 33 with acetic anhydride and pyridine to form an acetate intermediate. Other blocking groups may be used provided the group is stable to mild acid hydrolysis. Such groups include alkanoyl of from 2 to 9 carbons, phenalkanoyl of up to 10 carbons, benzoyl, toluoyl, p-phenylbenzoyl, or a- or βnaphthoyl. The protecting group at C^5 is then removed as described above to provide a second intermediate. The next step involves oxidation of the hydroxyl group to provide a third intermediate. Any reagent capable of oxidizing hydroxyl groups which does not attack double bonds may be used, however, the Jones' reagent is usually preferred.
The last step in this sequence involves hydrolysis of the protecting group at Οθ.
Scheme F This is usually done by treatment with anhydrous potassium carbonate in an alcoholic solvent such as methanol, which affords the 9-hydroxy-15-oxo-derivative of this invention. The 9-hydroxy-15-oxo-derivative of the present 5 invention of the 13,14-dihydro-two-, one-, and zero- series may be prepared from compounds 35, 37 and 39 as described for 33 to 34. It should be noted that the stereo-chemistry of the hydroxyl group at C15 is unimportant for the preparation of all 15-oxo compounds of the present invention; 15β, 15α, or an epimeric mixture will all afford the same -oxo analogue.
In the foregoing procedures, where purification by column chromatography is desired, appropriate chromatographic supports include neutral alumina and silica gel and 60-200 mesh silica gel is generally preferred. The chromatography is suitably conducted in reaction-inert solvents such as diethyl ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane, as further illustrated in the specific Examples. Where purification by high pressure liquid chromatography is desired, appropriate supports include Corasil, Porasil, and Lichrosorb with inert solvents such as diethyl ether, chloroform, methylenechloride, cyclohexane and n-hexane being employed. (The words Porasil and Lichrosorb are Trade Marks).
It will be seen that the foregoing formulae depict optically active compounds. It is intended that both optical antipodes, e.g, 8,12-nat and 8,12-ent, be embraced by the foregoing formulae herein and in the appended claims. 43SlS The two optical antipodes are readily prepared by the same methods by mere substitution of the appropriate optically active precursor aldehyde. It will be clear, however, that the corresponding racemates will exhibit valuable biological activity by virtue of their content of the above-mentioned biologically active optical isomers, and it is intended that such racemates also be embraced by the foregoing formulae herein and in the appended claims. The racemic mixtures are readily prepared by the same methods ) employed herein to synthesize the optically active species, by mere substitution of corresponding racemic precursors in place Of optically starting materials. It will be seen, in addition, that the foregoing formulae include an optical centre at c-16 whenever R is methyl. It is intended that both C-16 optical antipodes (e.g. R and S) be embraced by the foregoing formulae herein and in the appended claims. The two c^6 optical antipodes are readily prepared by the same methods by mere substitution of the appropriate optically active precursor phosphonate.
In numerous in vivo and in vitro tests we have demonstrated that the new prostaglandin analogues possess physiological activities comparable but much more tissue selective and longer acting than those exhibited by the natural prostaglandins (see'above). These tests include, among others, a test for effect on isolated smooth muscle from guinea pig uterus, guinea pig ileum and rat uterus, inhibition of histamine-induced bronchospasm in the guinea pig effect, effect on dog blood pressure, inhibition of stress-induced ulceration in the rat, effect on mouse 43818 diarrhoea, and inhibition of stimulated gastric acid secretion in rats and dogs.
The physiological responses observed in these tests are useful in determining the utility of the test substance for the treatment of various natural and pathological conditions. Such determined utilities includes vasodilator activity, antihypertensive activity, bronchodilator activity, antiarrythmic activity, cardiac stimulant activity, antiulcer activity, and in nan-human animals, antifertility activity.
An advantage possessed by 11-deoxyprostaglandins of the E series in general is their increased stability as compared with such as PGE2· a<3<34t4on novel 11-deoxy15-substituted-16,17,18,19,20-pentanorproetaglandins of this invention possess highly selective activity profiles compared with the corresponding naturally occurring prostaglandins and, in many cases, exhibit a longer duration of action. The novel prostaglandin analogues of this invention possess useful vasodilator activity. A prime example of the therapeutic importance of these prostaglandin analogues is the efficacy of ll-deoxy-16-phenyl-17,18,19,20-tetranorprostaglandin-Eo and 15-epi-ll-deoxy-15-(m-tolyl)-17,18,19,2O-tetranorprostaglandin-E2 which exhibits hypotensive activity of greatly enhanced potency and duration as compared with PGE2 itself. At the same time, the smooth muscle stimulating activity is markedly depressed in comparison with pGE2· In a similar manner, other E and Fg analogues of this invention exhibit desirable hypotensive activity.
In addition, ll-deoxy-16-(m-tolyl)-17,18,19,20-tetra- 25 norprostaglandin-E2 and 11-deoxy-16-(5-phenyl-thienyl)17,18,19,20-tetranorprostaglandin-E2 exhibit high bronchodilator activity with reduced non-vascular smooth muscle activity. In similar fashion, other ll-deoxy-15-substituted5 16,17,l8,19,20-pentanorprostaglandin-E2 analogues of the present invention display desirable bronohodilator activity.
Another outstanding example of the therapeutic importance of. these prostaglandin analogues in the potent, selective antiulcer and antisecretory activity displayed by the ll-deoxy-16-(p-naphthyl)-17,18,19,20-tetranor-PGE2 and 9,15-dioxo-16-(β-naphthyl)-17,18,19,20-tetranorproata-cife5-trans-13-dienoic acid. Similarly, the other PGE and 15-oxo analogues of this invention possess these desirable gastrointestinal activities. - .
The phenyl and naphthyl esters of the prostaglandin analogues of this invention are prepared from the corresponding acids by contacting them with the desired phenol or naphthol in the presence of dicyclohexyl-carbodiimide in an inert reaction solvent. The alkyl or aralkyl preferably phenalkyl esters of the prostaglandin analogues of this inventionare prepared from the corresponding acids by contacting them with the appropriate diazo compound in the presence of a reaction inert solvent. Such esters possess the activity of the acid from which they are derived.
The esters of the prostaglandin analogues of this invention which are acylated at the Cg and/or C^g positions can be readily prepared from the corresponding parent compound by acylation which is typically carried out using a carboxylic acid anhydride or carboxylic acid chloride as the acylation - 26 agent. Suitable acyl groups include lower alkanoyl, benzoyl and substituted benzoyl wherein the substituent is halogen, trifluoromethyl, lower alkoxy or phenyl or formyl. Such esters generally possess the activity of the prostaglandin analogues from which they are derived.
The prostaglandin analogues which have a beta hydroxyl at have action which is similar to their epimers. In some cases, however, the selectivity that these compounds display, such as the hypotensive activity of the 15-epi-16m-tolyl PGE2 analogue, exceeds that of the epimeric compounds. Pharmacologically-acceptable salts useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminium 2inc, and iron, are within the scope of this invention.
Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines.
Examples of suitable amines are methylamine, dimethylamine, triethylamine, ethylarnine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, β-phenylethylamine, ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to - 27 43815 about 18 carbon atoms, as well as heterocyclic amines, e.g.; piperidine, morpholine, pyrrolidine, piperazine, and loweralkyl derivatives thereof, e.g., l-methylpyrrolidine, 1,4dimethylpiperazine and 2-methylpiperidine,.as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, Nbutyl-ethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3propanediol, 2-amino-2-methyl-l-propanol, tris(hydroxymethyl)aminomethane, N-phenylethanolamine, N-(p-tert-amylohenvl) diethanolamine, galactamine; N-methylglucattine, N-methylglucosatttine, epherdrine, phenylephrine, epinephrine and procaine.
Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetrarnethylammonium, tefcraethylammonlum, benzyltrimethylammoniuni and phenyltriethy!ammonium.
The compounds of this invention may be used in a variety of pharmaceutical preparations which contain the compound or a pharmaceutically acceptable salt thereof, and they may be administered in the same manner as natural' prostaglandins by a variety 6f routes, such as intravenous, oral and topical, including aerosol, intravaginal and intranasal, among others.
Accordingly, the present invention further provides a pharmaceutical composition comprising, as the active ingredient, an ll-deoxy-le,17,18,19,2Q-pentanorproat&glandin. of the invention or a pharmaceutically-acceptable salt or ester thereof in admixture with a pharmaceutically-acceptable carrier. - 28 43815 To produce bronchodilation or to increase nasal potency, an appropriate dosage form would be an aqueous ethanolic solution of ll-deoxy-16-Ar-substituted-17,18,19,20tetranor-PGE^ or -PGE^ employed as an aerosol using fluorinated hydrocarbons as propellant in an amount of from 3 to 500 ug/dose.
The 16-Ar-substituted-17,18,19,20-tetranorprostaglandin analogues of the E„, E and 13,14-dihydro E. or Fe series of 2 0 2 p the present invention are useful hypotensive agents. For treatment of hypertension these drugs appropriately may be administered as an intravenous injection at doses of 0.5 to 10 |ig/kg or preferably in the form of capsules or tablets at doses of 0.005 to 0.5 mg/kg/day.
The 15-oxo-16-Ar-substituted-17,18,19,20-tetranorprostanoic acid derivatives or 16-Ar*-substituted-17,18,19,20tetranorprostaglandin E analogues of the present invention are useful antiulcer agents. For treatment of peptic ulcers these drugs may be administered in the form of capsules or tablets at doses of 0.005 to 0.5 mg/kg/day.
To prepare any of the above dosage foims or any of the numerous other forms possible, various pharmaceuticallyacceptable diluents, excipients or carriers may be employed. Such substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol and other known carriers for medicaments. If desired, the pharmaceutical compositions of the invention may contain auxiliary substances such as preserving agents, wetting agents, stabilizing agents, or - 29 43815 other therapeutic agents, such as antibiotics.
The following Examples VII, X to XII, XIX to xxii, xxiv, XXVI to XXX, XXXIV and XXXV illustrate the invention and the manner in which it may be performed.. In the Examples it will be appreciated that all temperatures are expressed in degrees Centigrade and all melting and boiling are unoorrected. Examples I to vi, vnr, IX, Xinto XVIII,. XXIII, XV and XXXI to XXXIII describe the preparation of intermediates and starting materials, EXAMPLE I. 2-[2p-Benzyloxymethyl~5a-hydroxyayclopent-la‘-yl}acetaldehyde, γ-hemiacetal (21).
To a stirred solution, cooled to -78°, of 10.0 g (40.5 mmoles) of 2-[2p-benzyloxymethyl~5a-hydroxycyclopentla-yl] acetic aoid γ-lactone in 100 ml of toluene was added dropwise 55.5 ml of a 20% w/v solution of diisobutylaluminium hydride in hexane. The solution was stirred in the cold under nitrogen for 40 minutes then was quenched by the dropwise addition of methanol until gas evolution ceased. The quenched mixture was warmed to room temperature, then was concentrated. The resultant oil was slurried with hot methanol, filtered, and the filtrate was concentrated. Purification of the crude product by silica gel chromatography using mixtures of benzene:ethyl acetate as eluents provided the colourless, oily 2-[2p-benzyloxymethyl-5a- . hydroxyeyelopent-lct-yl]acetaldehyde, γ-hemiacetal (21) weighing 8.91 g (86% yield).
EXAMPLE II. 7-[2β-Benzyloxymethyl-5 α-hydroxycyclopent-1α-yl]-cis-5heptenoic acid (23).
To a solution of 4.96 g (11.2 mmoles) of (4-carboxy5 butyl)triphenylphosphonium bromide (22) in 8.85 ml of dimethyl sulfoxide is added dropwise 9.73 ml (21.2 mmoles) of a 2.18 M solution of sodium methylsulfinylmethylide in dimethyl sulfoxide. To the resultant red ylide solution is added a solution of 1.12 g (4.50 mmoles) of 2-[2B-benzyloxymethyl10 5α-hydroxycyclopent-la-yl]acetaldehyde, γ-hemiacetal (2) in ml of dimethyl sulfoxide. After being stirred for an additional 45 minutes the reaction is poured onto ice-water. The basic aqueous solution is extracted with a 2:1 v/v mixture of ethyl acetate:diethyl ether is then covered with ethyl acetate, and is acidified with 1.0 N hydrochloric acid to pH~3. The aqueous layer is extracted further with ethyl acetate; the combined ethyl acetate extracts are washed with water, are dried (anhydrous magnesium sulfate), and are concentrated. Purification of the crude product by silica gel chromatography affords the desired 7-[2p-benzyloxymethyl-5a-hydroxycyclopent-la-yl]-cis-5-heptenoic acid (23).
EXAMPLE III.
Methyl 7-[28-benzyloxymethyl~5a-hydroxycyclopent-los-yl]cis-5-heptenoate.
A solution of 1.41 g (4.06 mmoles) of 7-|^-benzyloxymethyl-5a-hydroxyeyclopent-la-yl]-eis-5-heptenoic acid (23) in 17.5 ml of anhydrous diethyl ether is titrated at room temperature with an ethereal diazomethane solution until the yellow colour persisted for 5 minutes. The reaction is then decolorized by the dropwise addition of glacial acetic acid. The ethereal solution is then washed with saturated sodium bicarbonate and saturated brine, is dried (anhydrous -/magnesium sulfate), and is concentrated to afford the desired methyl 7-[2β-benzyloxymethyl-5a-hydroxy-cyclopentan-la-yl] cis-5-heptenoate.
EXAMPLE IV.
Methyl 7-[2p-benzyloxyiriethyl-5a-acetoxycyclopent--la~yl] cis-5-heptenoate.
A mixture of 1.28 g (3.54 mmoles) of methyl 7-[Σβbenzvloxvmethvl-5a-hvdroxvcvclopent-la-vl1 -cis-5-heptenoate prepared in Example ill, 5.0 ml of pyridine, and 0.736 ml (7.78 mmoles) of acetic anhydride is stirred under nitrogen ' - -: - r. ----at 50° overnight- The mixture is then cooled to room temperature and diluted with diethyl ether (75 ml). The ethereal solution is washed with water (lx) and with saturated copper (II) sulfate (3x), is dried (anhydrous magnesium sulfate), and concentrated to afford the desired , methvl' 7-r2S-benzvloxvmethvi-5a^aoetoxvcvcl0Pent-ia-vi1 -cis- F . j 5-heptenoate.
EXAMPLE V. ' ' Methyl 7-[2p-hydroxymethyl-5a-acetoxyeyclopent-la-yl]heptenoate. : ; • · - ' ' ' A heterogeneous mixture of 1.27 g (3.14 mmoles) of - ' - . - ., -:. · ' · — I methyl 7- [2 β-benzyloxymethyl-5α-acetoxycyclopent-1 ά-yl] -cis- - . 5-heptenoate prepared in Example IV, 305 mg of 10% palladium on carbon, ahd .13 ml of a 20:1 v/v mixture of absolute ethanol:glacial'acetic acid is stirred at room temperature under one atmosphere of hydrogen for 20 hours. The mixture - 32 4381S is then filtered through Celite 545 and the filtrate is concentrated to afford the desired methyl 7-[2p-hydroxymethyl-5a-acetoxycyelopental-la.-yl] heptenoate. (Celite is a Registered Trade Mark).
EXAMPLE VI.
Methyl 7-[2p-formyl-5a-acetoxycyclopent-la-yl]heptanoate (24). To a mechanically stirred solution of 3.37 ml (41.7 mmoles) of pyridine in 50 ml of methylene chloride cooled to 10 to 15° under nitrogen is added portionwise over a period of 30 minutes 1.89 g (18.9 mmoles) of chromium trioxide. The dark burgundy solution was then let warm to room temperature then is cooled to 0°. To the cold solution is added a solution of 747 mg (2.37 mmoles) of methyl 7-[2p-hydroxymethyl-5a-acetoxycyclopent-la-yl]heptanoate prepared in Example V in 7.0 ml of methylene chloride with the concomitant formation of a dense black precipitate. The suspension is stirred in the cold for 15 minutes then 7.21 g (52.2 mmoles) of finely ground sodium bisulfate monohydrate is added. After being stirred for 10 minutes 6.25 g (52.2 mmoles) of anhydrous magnesium sulfate is added. After being stirred for 5 minutes the dark suspension is filtered through a pad of Celite, the pad is washed with methylene chloride, then the filtrate concentrated by rotary evaporation to afford the crude, methyl 7-[2p-formyl-5a-acetoxycyclopent-la-yl] heptanoate (24) which is used without purification.
EXAMPLE VII.
Methyl 9 α-acetoxy-l5-oxo-l6- (p-chlorophenvl) .-13-tran b17,18,19,20-tetranorprostenoate.
To a suspension of 110 mg (2.61 mmoles) of a 57.0% dispersion Of sodium hydride in mineral oil in 20 ml of tetrahydrofuran is added 740 mg (2.61 mmoles) of dimethyl 2-oxo-3-(p-chlorophenyl) propylphosphohate. ' The mixture is then stirred at room temperature for 1 hour under nitrogen. To this mixture is added a solution of 744 mg (2.37 mmoles) of the crude methyl 7-[23-£ormyl-5a-aeetoxycyclopent-la-yli— heptenoate (24) in 4 ml of tetrahydrofuran. The resultant reaction mixture is stirred at room temperature for 2.0 hours under nitrogen. The reaction is then quenched by the addition of glacial acid to pH~7 and is concentrated by rotary evaporation. The crude product is purified by chromatography on silica gel to provide the desired methyl 9 g-acetoxv-i 5-oxo-16-(p-chlorophenvl)-13-trans-17.18,19,20tetranorprostenoate.
EXAMPLE VIII. ' Methyl 9a-acetoxv-15a-hvdroxv-16-(p-ehlorophenvl) -13-trans17,18,19,20-tetranorprostehoate and methyl 9a-acetoxy-15phydroxy-16-(p-chlorophenyl)-13-trans-17,18,19,20-tetranorprostenoate.
To a solutioii, cooled under nitrogen to -78°, of 900 mg (2.0 mmoles) of methyl9a-acetoxy-15~oxo-16-(]3-chlorophenvl )-13-trans-17.18.19.20-tetranorproatenoate prepared in Example VII in 30 ml of tetrahydrofuran is added 2.0 ml of a 1.0 m solution of lithium triethylborohydride in.tetrahydrofuran. The reaction mixture is stirred in the cold - 34 4381S for 30 minutes then is quenched by the addition of 1 ml of a 9:1 v/v mixture of water:acetic acid. The quenched reaction mixture is allowed to warm to room temperature, then is concentrated. The resultant product is diluted with ethyl acetate; the organic layer is extracted with water and saturated sodium bicarbonate, is dried (anhydrous magnesium sulfate), and is concentrated. Purification of the resultant product by silica gel chromatography affords the methyl 9a-aoetoxy-15p-hydroxy-16-(p-chlorophenyl)-13trans-17,18,19.20-tetranorprostenoate and the methyl 9aacetoxy-15a-hydroxy-16-(p-chlorophenyl)-13-trans-17,18,19,20tetranorprostenoate . The 15β product of this example may be converted into the 15-epi-11-deoxy-16-p-chlorophenyl17,18,19,20-tetranorprostaglandin E^, P1(j, and compound of this invention by the procedures of examples IX-XII, XXIII, and XXVI.
EXAMPLE IX. 9a, 15a-Dihydroxy-16-(p-chlorophenyl)-13-trans-17,18.19,20tetranorprostenoic acid (17a).
A mixture of 100 mg of methyl 9a-acetoxy-l'5a-hydroxy16-(p-chlorophenyl)-l3-trans-17.18,19,20-tetranorprostenoate prepared in Example VIII, 1.0 ml of 1.0 N aqueous sodium hydroxide, 1.0 ml of tetrahydrofuran, and 1.0 ml of absolute methanol is stirred under nitrogen at room temperature for 1.5 hours. The solution is then acidified by the addition of 1.0 ml of 1.0 N aqueous hydrochloric acid (pH of acidified solution was ca. 5). The acidified solution is then extracted with ethyl acetate. The combined extracts are dried (anhydrous magnesium sulfate) and concentrated.
Purification of the crude product provides the 9a,15adihydroxy-16-(p-chlorophenyl)-13-trans-17,18,19,20-tetranorprostenoio acid (17a).
EXAMPLE X.
Methyl 9 a-acetoxy-15 a- (tetrahydropyran-2-yloxy) -16-(p-chlorophenylj -1-3 -trans-17,18,19,20-tetranorprostenoate.
A mixture of 453 mg (1,0 mmole) of the methyl 9aacetoxy-15a-hydroxy-16-(p.-chlorophenyl)-13-trans-17.18,19,20tetranorprostenoate prepared in Example VIII, 0.14 ml (1.53 mmoles) of dihydropyran, 4.2 ml of methylene chloride,and 1 crystal of p-toluenesulfonic acid monohydrate is stirred at room temperature under nitrogen for 20 minutes.· The reaction mixture is then diluted with diethyl ether, washed with saturated 'aqueous sodium bicarbonate, dried (anhydrous :. magnesium sulfate), and concentrated to give the methyl 9αaceto3cz-15α-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)13-trafiS-17,18,19,20-tetranorprostenoate.
EXAMPLE XI. 9a-hydroxy-15a-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl}13-trans-17,18,19,20-tetranorprostenoic acid (17a).
A homogeneous solution of 537 mg (1.0 mmole) of methyl 9a-acetoxy-l5a-(tetrahydropyran-2-yloxy)-16-(g,-chlotophenyl) 13-trans-l7.18.19.20-tetranorprostenoate prepared in Example X 3.0 ml (3.0 mmoles) of a 1.0 N aqueous sodium hydroxide solution, 3.0 ml of methanol, and 3.0 ml of tetrahydrofuran is stirred under nitrogen overnight. The reaction is then quenched by the addition of 3.0 ml (3.0 mmoles) of a 1.0 N aqueous hydrochloric acid solution. Ihe quenched solution is diluted with, ethyl acetate. The organic layer is dried ' . . - 36 4 381s (anhydrous magnesium sulfate) and concentrated. The crude product is purified by silica gel chromatography to afford the desired 9a-hydroxy-15a-(tetrahydropyran-2-yloxy)-16-(pchlorophenyl)-13-trans-17.18.19,20-tetranorprostenoic acid (17a).
EXAMPLE XII. 9-oxo-15 a-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)-13trans-17,18,19,20-tetranorprostenoic acid (17a).
To a solution, cooled under nitrogen to -15 to -20°, of 199 mg (0.371 mmole) of 9a-hydroxy~15a-(tetrahydropyran2-yloxy)-16-(p-chlorophenyl)-13-trans-17,18,19,20-tetranorprostenoic acid (17a) in 4.0 ml of acetone is added dropwise 0.163 ml (0.408 mmole) of Jones' reagent. The reaction is stirred in the cold for 15 minutes then is quenched by the addition of 0.194 ml of isopropanol. The quenched reaction is stirred in the cold for 5 minutes and then is diluted with ethyl acetate. The organic solution is washed with water and saturated brine, dried (anhydrous magnesium sulfate), and concentrated to afford the 9-oxo-15a-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)-13-trans-17,18,19« 20tetranorprostenoic acid (17a) which is used without purification.
EXAMPLE XIII. 9-oxo-15a-hydroxy-16-(p-chlorophenyl)-13-tranB-17,18,19,20tetranorprostenoic acid (17a).
A homogeneous solution of 175 mg (0.328 mmole) of the 9-oxo~15a-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl,)13-trans-17.18,19,20-tetranorprostenoic acid (17a) in 5 ml of a 65:35 v/v mixture of acetic acid:water is stirred 438 IS under nitrogen for 20 hours. The reaction is concentrated by rotary evaporation followed by oil pump. The crude product is purified by silica gel chromatography to provide the 9-oxo-15g-hydroxy-16-(p-chlorophenyl)-13-trans-l7.18.19.20tetranorprostenoic acid (17a). The product of this example (17a) may be reduced as described in Example XXIII to provide the. corresponding PGF2a an<^ PGP2p analo9ueSl EXAMPLE XIV.
Dimethyl 2-oxo-3~phenylpropylphosphonate.
A solution of 6.2 g (50 mmoles) dimethyl methylphosphonate (Aldrich) in 125 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 21 ml of 2.37 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes' stirring at -78°, 7.5 g (50.0 mmoles) methyl phenyl-, acetate was added dropwise at a fate that kept the reaction temperature less than -70° (20 minutes). After 3.3 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 nil acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50.cc K^O), dried (MgSO^), and concentrated (water aspirator) to a crude residue and distilled, .b.p. 134-5° (<0.1. mm) to give 3.5 g (29%) dimethyl 2-oxo-3-phenylpropylphosphonate (2).
The nmr spectrum (CDCl^) showed a doublet centered at 3.76 (J=11.5 cps, 6H) for II (CHO)-P- , a triplet centered at 3.37 6 (2H) for CHg-O-CHg-C^-, a singlet at 3.286 (3H) for CH3~O-CH2-, a doublet centered at 3.146 (J=23 cps, 2H) 0 I! II — c -ch2- P — , a singlet at 3.96 (2H) for II -ch2-c_ and a broad singlet at 7.26 (6H) for CgHg-.
EXAMPLE XV. (nat.)-2-Γ 5 a-Hvdroxv-2 B-(3-oxo-4-phenvl-trans-1-butenvl) cyclopent-lci-yl] acetic acid, γ-lactone (2b).
Dimethyl 2-oxo-3-phenylpropylphosphonate (6.93 g, 28.6 mmole) in 420 ml anhydrous THE was treated with 1.21 g (28.6 mmole) 57% sodium hydride in a dry nitrogen atmosphere at room temperature. After 60 min. of stirring, 2-[5a-hydroxy2p-formylcyelopent-la-yl]acetic acid, ϊ-lactone (1) in 50 ml anhydrous THF was added. After 95 minutes the reaction mixture was quenched with 4.2 ml glacial acetic acid, filtered, evaporated and combined with 250 ml ethyl acetate which was washed successively with 100 ml saturated sodium bicarbonate solution (2x), 150 ml water (lx), 150 ml saturated brine (lx), dried (Na2SO^) and evaporated to yield 2.51 g (nat)-2-Γ5a-hvdroxv-2S-(3-oxo-4-phenyl-trans- 39 43815 l-butenyl)oyclopent-la-yl]acetic acid,, γ-lactone (2b) as a solid after column chromatography (Silica gel. Baker 60-200 mesh), m.p. 52-56°, [a]D25 = +35.0° (C = 0.8, CHCLg).
The nmr spectrum (CDCip exhibited a doublet of doublets centered at 6.80δ (1h, J=7, 16 ops) and a doublet centered at 6.276 (IH, J-16 ops) for the olefinic protons, a broad singlet at 7.266 (SH) for CcH_— CH-— C— , a singlet at 3.82δ (2H) for II c6h5-ch2_c~, and multiplets at. 4,78-5.186 (IH) and 1.2-2,86 (SB), for the remainder of the protons. ' .
EXAMPLE XVI. (nat.) 2-[5 a-hydroxy-2 β-(3a-hydroxy-4-phenyl-trans-1-butenyl)eyclopent-la-yl]acetic acid, γ-lactone (3b) To a solution of 2.5 g (9.25 mmole) (nat.) 2-[5ahvdroxv-2B-(3-oxo-4-phenvl-trans-l-butenvl)cvclOPent-la-vl1 acetic-acid, γ-lactone (3) in 30 ml dry THF in a dry nitrogen atmosphere at -78° was added dropwise 9.25 ml of a l.QM lithium triethylborohydride solution. After stirring at -78° for 30 min, 20 ml of acetic acid/water (40:60 v/v) was added. After the reaction came to room temperature, 40 ml of wafer was added and the reaction was extracted with . methylene chloride (3 x 50 ml), washed with brine (2x5 ml), dried (Na2S04) and concentrated (water aspirator). The resultant oil-was purified by column chromatography on - 40 4381S silica gel (Baker Analyzed Reagent 60-200 mesh) ueing cyclohexane and ether as eluents. After elution of less polar impurities a fraction containing 365 mg (nat.) 2-[5ahydrozy-2 β-(3 a-hydroxy-4-phenyl-trans-1-butenyl)cyclopentΙα-yl] acetic acid, Ύ-lactone (3b), a 578 mg fraction of mixed 3b and epi-3b and finally a fraction (489 mg) of (nat.) 2-[5a-hydroxy-2 β-(3β-hydroxy-4-phenyl-trane-1-butenyl) cyclopent-Ια-yl]acetic acid, γ-lactone epi 3b were obtained.
The (nat.) 3b had [α]β25 = +6.623° (G s 1.0 CHClg) and (nat.) epi-3b had [a]D25 = +24.305° (C = 1.69, CHClg).
The 15-epi product of this example (epi-3b) can be converted into the 15-epi-11-deoxvprostaglandins of this invention by the procedures of examples XVII-XXX and XXXIIXXXV.
The products of this Example (3b and epi-3b) may be converted into the 13,14-dihydro-ll-deoxyprostaglandin twoseries analogues of this invention by the procedures of Examples XXXIX, XVIII-XXI, XXIII, XXVI, XXVII-XXX and XXXIV-XXXV.
EXAMPLE XVII. (nat.) -2-[5α-ηγάΓθχγ-2β- (3 α- (tetrahydropyran-2 -yloxy) -4phenvl-trans-1-butenyl)cyclopent-Ια-yl]acetic acid, γ-lactone (4b).
To a solution of 805 mg (2.96 mmole) (nat.) 2-[5ahydroxy-2 β-(3 a-hydroxy-4-phenyl-trans-1-butenyl)cyclopentla-yl]acetic acid, γ-lactone (3b) in 20 ml anhydrous methylene chloride and 0.735 ml of 2.,3-dihydropyran at 0° in a dry nitrogen atmosphere was added 35.3 mg p.-toluenesulfonic acid, raonohydrate. After stirring for 35 minutes, - 41 43815 the reaction mixture was combined with 150 ml ether, the ether solution washed with saturated sodium bicarbonate (2 x 100 ml) then saturated brine (1 x 100 ml), dried (N&2S04) and concentrated to yield 1.2 g (-^100%) crude (nat.) 2-[5a-hydroxy-2p-(3a-tetrahydropyran-2-yloxy)-4phenvl-trans-1-butenvl)cvclopent-1g-vll acetic acid, γlactone (4b).
The ir (CHCl^) spectrum had a medium adsorption at 975 cm 1 for the trans-double bond and a strong adsorption at 1770 cm 1 of the lactone carbonyl.
EXAMPLE XVIII. (nat.)-2-t5a-hydroxy-2p-(3a-(tetrahydropyran-2-yloxy)-4phenyl-trans-1-butenyl)cyclopent-la-yl]acetaldehyde, Y-hemiacetal (5b).
A solution of 1.1 g (2.96 mmole) 2-[5α-)ιγόΙτοχγ-2β-(3α(tetrahydropyran-2-yloxy)-4-phenyl-tr ans-1-butenvl)cyolopentΙα-yl]acetic acid, Y-lactone (4b) in 15 ml dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution was added 4.05 ml of 20% diisobutylaluminium ) hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never rose above -65° (15 minutes). After an additional 30 minutes of stirring at -78°, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture wae combined with 150 ml ether, washed with 50% w/v sodium potassium tartrate solution (2 x 50 ml), brine (1 x 75 ml), dried (Na2SO4) and concentrated to yield 883 mg (nat.)-2-[5a-hydroxy-2β(3a-(tetrahydropyran-2-yloxy)-4-phenvl-trans-l-butenyl) - 42 £3815 cyclopent-la-yl]acetaldehyde, γ-hemiacetal (5b) after column chromatography.
EXAMPLE XIX. 9a-hydroxy-15a-(tetrahydropyran-2-yloxy)-16-phenyl-5-cis13-trans-17.18.19.20-tetranorprostadienoic acid (10b) To a solution of 3.83 g (4-carboxybutyl)-triphenylphosphonium bromide (23) in a dry nitrogen atmosphere in 10 ml dry dimethyl sulfoxide was added 11.9 ml of a 2.1M solution of sodium methylsulfinylmethylide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 1.2 g (3.3 mmole) 2-[5a-hydroxy-2p-(3a(tetrahydropyran-2-yloxy)-4-phenyl-trans -1-butenv1)cyclopent-la-yl] acetaldehyde, γ-hemiacetal (5b) in 15.0 ml dry dimethyl sulfoxide over a period of 20 minutes. After an additional 20 hr stirring at room temperature, the reaction mixture was poured onto ice water, 10% HC1 (60 ml), and ethyl acetate (100 ml). The acidic solution was extracted with ethyl acetate (2 x 100 ml) and the combined organic extracts washed with water (1 x 100 ml), brine (100 ml), dried (MgS04) and evaporated to a residue. The residue was purified by column chromatography on silica gel (Baker Analyzed Reagent 60-200 mesh) using chloroform and ethyl acetate as eluents. After removal of high Rf impurities, 2.0 g of 9a-hydroxy-15a-(tetrahydropyran-2-yloxy)-16-phenyl5-cis-13-trans-17,18,19,20-tetranorprostadienoic acid (10b) was collected.
The product of this Example (10b) may be hydrolyzed by the procedure of Example XXI to the 9a,15a-dihydroxy-16phenvl-5-cis-13-trans-l7.18,19,20-tetranorprostadienoic acid (lib). The product of this Example (10b) may also be converted by the procedures of Examples XXIV and XXV into I the 9 a, 15 g-dihvdroxv-16-ohenvl-13-trans-17 >18,19,20-tetranorprostenoio acid (17b). by the procedures of Examples XXII l , , and XXI into the 9a, 15a-dihydroxy-16-phenyl-17,18,19,20tetranorprostanoic acid (18b), or by the procedures of Examples XXI and XXVI into the 9,15-diox0-16-phenvl-5-cisX3-trana-17.I8,19,20-tetranorprostadienoic acid (34b).
EXAMPLE XX. 9-oxo-15a-(tetrahydropyran-2-yloxy)-16-phenyl-5-cis-13trans-17.18.19,20-tetranorprostadienoic acid ' (12b). · To a solution cooled to -10° under nitrogen Of 1.33 g (2.9 mmole) 9a-hydroxy-15a-(tetrahydropyran-2-yloxy)-16phenvl-5-cis-13-trans-l7,18.19.20-tetranorprOstadienoic acid (lob) in 30 ml reagent grade acetone was added dropwise to 1.26 ml of Jones’ reagent. After 5 minutes at -10° 1.0 ml 2-propanol was added and the reaction mixture, was allowed to stir an additional 5 minutes at which time it was combined with 100 ml ethyl acetate, washed with water (3 x 50 ml), brine (lx 50 ml), dried (MgS04) and concentrated to give 1.3 g of 9-oxo-15a-(tetrahydropyran-2-yloxy)-16-phenyl-5ciB-13-tr.ans-17.i8.19.20-tetranorprostadienoic acid (12b).
• The product of this Example (12b) may be converted by the procedures of Examples XXIII and XXI into the- corresponding 11-deoxy prostaglandin F2ctan^ F2P analogues of this invention. The product of this Example (12b) may also he converted by the procedures of Examples XXII and XXI into the 9-oxo-15a-hydroxy-16-phenyl-l7,18,19,20-tetranorprostanoic acid (18b). - 44 43815 EXAMPLE XXI. 9-oxo-15 α-hydroxy-16-phenyl-5-ci s-13-tran s-17,18,19,20tetranorprostadienoic acid (13b) A solution of 1.3 g of 9-oxo-15a-(tetrahydropyran-2yloxy)-16-phenyl-5-cis-13-trans-17. j.8,19,20-tetranorprostadienoic acid (12b) in 20 ml of a 65.35 v/v mixture of o glacial acetic acidzwater was stirred under nitrogen at 25 for 18 hours then was concentrated by rotary evaporation.
The resultant crude oil was purified by column chromatography on silica gel [Mallinckrodt ( Trade Mark)! using chloroform and ethyl acetate as eluents. After elution of less polar impurities the desired 9-oxo-15 ahvdroxv-16-phenvl-5-cis"13-trans-17,18,19,20-tetranorprostadienoic acid (13b) weighing 450 mg was collected. The ir spectrum (CHClg) exhibited a broad hydroxyl absorption (3200-3650 cm-1), strong carbonyl absorptions at 1740 cm 1 (ketone) and 1710 cm-1 (acid) and a medium absorption at 970 om 1 for the trans double bond.
EXAMPLE XXII. 9-oxo-15a-hydroxy-16-phenyl-17,18,19,20-tetranorprostanoic acid (18b).
A heterogeneous mixture of 800 mg of 9-oxo-15a-hydroxy16-phenvl-5-cis-13-trans-17,18,19,20-tetranorprostanoie acid (13b) and 100 mg of 10% palladium on carbon in 50 ml of methanol is stirred under 1 atmosphere of hydrogen for 2.0 hours. The mixture is then filtered through a pad of Celite and the filtrate concentrated. Purification of the crude product by silica gel chromatography using chloroform as eluent provides the desired 9-oxo-15a-hydroxy-16-phenyl- 45 17,18,19,20-tetranorprostanoic acid (18b).
EXAMPLE XXIII. 9a, 15a-dihydroxy-16-phenyl-17,18,19,20-tetranorprostanoie acid (18b) and 9p-15a-dihydroxy-16-phenyl-17,18,19,20-tetranorprostanoic acid (18b).
To a solution of 100 mg of 9-oxo-15a-hydroxy-16-phenyll· 17,18,19,20-tetranorprostanoic aoid (18b) in 30 ml of methanol, cooled to 0°, was added a solution of 500 mg of sodium horohydride in 50 ml of methanol eoole.d to 0°. The reaction was let stir at 0° for 20 minutes then for 1.0 hour at room temperature. The reaction was then diluted with 6 ml of water and was concentrated. The concentrated solution was overlaid with ethyl acetate then acidified to pH 3 with 10% hydrochloric aoid. The ethyl acetate layer was washed with water (2 x 10 ml) and saturated brine (10 ml), was dried (sodium sulfate) and was concentrated. The crude residue was purified by silica gel column chromatography using mixtures of chloroformsmethanol as eluents to provide first 9a, I5a-dihydroxy-16-phenyl-l7,18,19,20-tetranorprostanoic acid (18b) as a viscous oil weighing 16 mg, 58 mg of a mixture of Cg epimers, and finally 9p,i5a-dihydroxy-16phenyl-17,18,19,20-tetranorprostanoic acid' (18b) as a viscous oil weighing 10 mg, EXAMPLE XXIV. 9-οχο-15β-(tetrahydropyran-2-yloxy)-16-(m,-tolyl)-13-trans17,18,19,20-tetranorprostenoio acid (17c).
A solution of 200 mg (0.445 mmole) 9t EXAMPLE XXV 9-oxo-15 8-hydroxy-16-(m-tolyl)-13-trans-17,18,19,20-tetranorprostenoic acid (17c).
A solution of 200 mg (0.445 mmole) of 9-οχο-15β·(tetrahvdropvran-2-vloxv)-16-(m-tolvl)-13-trans-17,18.19,20tetranorprostenoic acid (17c) in 10 ml of a 65:35 v/v mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 18 hours then concentrated by rotary evaporation.
The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7) using methylene chloride and ether as eluents. After elution of less polar impurities the desired 9-oxo-15 8-hvdroxv-16-(m-tolvl)-13-trans-17.18,19, 20-tetranorprostenoic acid (17c) weighing 50 mg was collected.
The ir spectrum (CHClg) exhibited a broad hydroxyl absorption at (3650-3200 cm-1), strong carbonyl absorption at 1740 cm 1 and 1710 cm1 for the ketone and acid respectively and -1 absorption at 970 cm for the trans double bond.
EXAMPLE XXVI. 9.15-dioxo-16-(m-tolvl)-5-cis, 13-trans-17,18,19,20-tetranorprostadienoic acid (26c).
To a solution, cooled to -10° under nitrogen, of 130 mg (0.35 mmole) 9-oxo-15a-hvdroxv-16-(m-tolyl)-5-cis, - 47 4 3 815 13-trans-17,18,19,20-tetranorprostadienoic acid (25c) in 20 ml reagent grade acetone was added 0.14 ml Jones1 reagent. After 3 minutes at 0°, 5 drops of 2-propanol were added and the reaction mixture allowed to stir an additional 5 minutes at which time it was diluted with 50 ml ethyl acetate, washed with water (2 x 20 ml), brine (lx 20 ml), dried (Na2S04) andconcentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Brinkman). After elution of less polar > impurities, the desired 9,15-dioxo-16-(m-tolvl)-5-cia, 13-trana-17.18.19.20-tetranorprostadienoic acid (26e) weighing 100 mg was collected. The ir spectrum (CHCl^) exhibited strong carbonyl absorption at 1740 cm-1 for the ketone, 1710 cm 1 for the acid and at 1660 cm"^ and 1610 ί cm 1 for the enone.
EXAMPLE XXVII. 9a-aeetoxy-l5a-(tetrahydropyrah-2-yloxy)-16-(m-tolvl)-5-cis, 13-trans-17,18,19,2O-tetranorprOstadienoic acid.
A mixture of 300 mg (0.625 mmole) 9a-hydroxy-15a(tetrahydropyran-2-yloxy)-16-(m-tolvl)-5-cis, 13-trans17.18.19.20- tetranorprostadienoio acid (33c), 1.88 ml pyridine and 0.28 ml acetic anhydride was stirred under N2 at 50° for 5 hours then poured onto ioe-water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water (1 x 20 ml), and brine (1 x 20 ml), dried (Na2S04) and concentrated to give 306 mg 9a-acetoxy-15a(tetrahydropyran-2-yloxy)-16-(ffl-tolyl)-5-ois, 13-trans17.18.19.20- tetranorprostadIenoio acid. - 48 4 3 815 EXAMPLE XXVIII. 9a-acetoxy-15ci-hydroxy-16-(m-tolyl)-5-cis-13-trans-17,18,19,20 tetranorprostadienoic acid.
A solution of 306 mg 9a-acetoxy-15a-(tetrahydropyran~ 2-yloxy)-16-(m-tolyl)-5-cis-13-trans-17,±8,19,20-tetranorprostadienoic acid in 10 ml of a 65:35 v/v mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 18 hours then concentration by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Baker) using ethyl acetate and methylene chloride as eluents. After elution of less polar impurities, the desired 9a-acetoxv-15a-hvdroxv-16-(m-tolvl)-5-cis-13trans-17,18,19.20-tetranorprostadienoic acid weighing 85 mg was collected. The ir spectrum (CHCl^) exhibited carbonyl absorption at 1730 cm1 and broad hydroxyl absorption at (3650-3200).
EXAMPLE XXIX. 9a-acetoxy-15-oxo-16-(m-tolyl)-5-cis-13-trans-17,18,19,20tetranorprostadienoic acid.
To a solution cooled to -10° under N2 of 85 mg (.19 mmole) 9a-acetoxy-15a-hydroxy-16-(m~tolyl)-5-cis-13-trans17,18,19,20-tetranorprostadienoic acid in 10 ml of reagent grade acetone was added 0.07 ml Jones' reagent. After 3 minutes at 0°, 5 drops 2-propanol were added and the reaction mixture allowed to stir an additional 5 minutes at which time it was diluted with 50 ml ethyl acetate, washed with water (2 x 20 ml), brine (1 x 20 ml), dried (Na2S04) and concentrated to give 80 mg 9a-acetoxy-15~oxo-16-(m-tolyl)5-cis-13-trans-17,18,19,20-tetranorprostadienoic acid. - 49 43815 EXAMPLE XXX. 9a-hydroxy-15-oxo-16-(m-tolyl)-5-cis, 13-trans-17,18,19,20tetranorprostadienoic acid (34c).
A mixture of 80 mg (.18 mmole) 9a-acetoxy-15-oxo-16~ (m-tolyl) -5-cis.-13-trans.-17,18,19,20-tetranorprostadienoic acid 0.5 ml 1.0N aqueous sodium hydroxide, 2 ml of tetrahydrofuran and 1.5 ml methanol was stirred at 27° for 12 hrs. The reaction was concentrated by rotary evaporation and the crude product was purified by chromatography On silica gel ) (Mallinckrodt CC-7) eluting with methylene chloride and ethyl acetate. After elution of less polar impurities, the 9a-hydroxy-15-0X0-16-(m-tolyl)-5-cis-13-trans-17,18,19,20 tetranorprostadienoic acid (34c) weighing 18 mg was collected The ir spectrum exhibited strong carbonyl absorption at 1660 -1 —1 cm and 1610 cm for the enone and broad hydroxy absorption at (3650-3200 cm1).
EXAMPLE XXXI. 2-[5a-Hydroxy-2p-(3-oxo-4~(m-tolyl)butyl)cyelopent-Ια-yl]acetic acid, γ-lactone (6c).
A heterogeneous mixture of 6.8 g of 2-[5a-hydroxy-2β(3-oxo-4-(m-tolyl)-trans-1-butenyl)cyclopent-1α-yl] acetic acid, γ-lactone (2 c) and 670 mg of 10% palladium on carbon in 55 ml of ethyl acetate was shaken in a Parr Shaker for 30 minutes. The mixture was then filtered through a pad of Celite and was concentrated. Purification of the crude residue by silica gel chromatography using 10% ethyl acetate in benzene as eluent afforded the desired 2-[5a-hydroxy-2β(3-oxo-4-(m-tolyl)butyl)cyclopent-la-yl] acetic acid, γlactone (6c) as a solid melting at 60.5-62.5° and weighing 2.9 g. - 50 43815 The product of this Example (6c) may be converted into the 13,14-dihydro prostaglandin two-series analogues of this invention by the procedures of Examples XVI-XXI, XXIII, XXVI-XXX and XXXIV-XXXV.
EXAMPLE XXXII. 2-[5 a-Hydroxy-2 β-(3 a-(tetrahydropyran-2-yloxy)-4-phenylbutyl)-cyclopent-la-yl]acetic acid, γ-lactone (8b).
A heterogeneous mixture of 500 mg of 2-[5a-hydroxy-2P(3a-(tetrahydropyran-2-yloxy)-4-phenyl-trans-1-butenyl) cyclopent-la-yl] acetic acid, (4b) and 50 mg of 5% rhodium on alumina in 5 ml of ethyl acetate is stirred under 1 atmosphere of hydrogen for 2 hours. The mixture then is filtered through a pad of Celite then is concentrated. Purification of the crude residue by silica gel chromatography affords the desired 2-[5a-hydroxy-2p-(3a-(tetrahydropyran-2-yloxy)-4-phenylbutyl)cyclopent-la-yl]acetic acid, γ-lactone (8b).
The product of this Example (8b) may be converted into the 13,14-dihydro-prostaglandin two-series analogues of this invention by the procedures of Examples XXVIIIXXI, XXIII, XXVI-XXX, and XXXIV-XXXV.
EXAMPLE XXXIII. 2-[5 a-hydroxy-2 β-(3 a-dimethyl-tert-butylsilyloxy-4-(3,5dimethylphenyl )-trans-1-butenyl)cyclopent-layl] acetic acid, γ-laetone (4d).
A solution of 1.47 g (4.95 mmoles) of 2-[5a-hydroxy2 β-(3 a-hydroxy-4-(3,5-dimethylphenyl)-trans-1-butenyl) cyclopent-la-yl]acetic acid, γ-lactone (3d), 945 mg (6.3 mmoles) of dimethyl-tert-butylsilyl chloride, and 910 mg (13.4 mmoles) of imidazole in 2.5 ml of dimethylformamide was stirred under nitrogen at 37° for 18 hours. The solution was then concentrated, the residue was diluted with methylene chloride, and the organic layer was washed with water (3x), was dried (anhydrous magnesium sulfate), and was concentrated. Purification of the crude residue by silica gel chromatography using chloroform as eluent provided the desired 2-Γ5a-hydroxy-2 β-(3 α-dimethvl-tertbutylsilyloxy-4-(3,5-dimethvlphenvl)-trans-1-butenvl) cyclopent-la-yl]acetic acid, γ-lactone (4d) as a viscous oil weighing 1.67 g.
The product of this Example (4d) may be converted into the corresponding 11-deoxy prostaglandins of this invention by the procedures of Examples XVIII-XXX, XXXII, and XXXIV-XXXV.
EXAMPLE XXXIV. p-Biphenylyl (ent)-9-oxo-15a-hydroxy-16-phenyl-5-cis-l3trans-17.18,19,20-tetranorprostadienoate.
To a solution of 365 mg (1.02 mmole) of (ent)-9-oxo15a-hvdroxv-16-phenvl-5-ciB-13-trans-17,18.19,20-tetranorprostadienoic acid in 40 ml of methylene chloride was added 11.7 ml of an 0.1 M solution of l-(3-dirnethylaminopropyl)-3ethylcarbodiimide in methylene chloride. The solution was stirred under nitrogen for 18 hours then is concentrated.
The residue was purified by silica gel chromatography using mixtures of benzene:chloroform as eluents to provide the desired £-biphenylyl (ent)-9-oxo-15α-hvdroxv-l6-phenyl-5cls-13-trans-17.l8,19,20-tetranorprostadienoate as a white solid melting at 68-70° and weighing 200 mg.
EXAMPLE XXXV. n-Decyl (rac)-9-oxo-15α-hvdroxv-16-phenvl-5 -ci s -13 -tr an s 17,18,19,20-tetranorprostadienoate.
To a solution of 30 mg of (rac)---oxo-12a-hydroxy-16phenvl-5-cis-13-trans-17,18.19,20-tetranorprostadienoic acid in 25 ml of diethyl ether was added a solution of diazodecane in diethyl ether (the reaction was followed by tic using 10% methanol in methylene chloride as eluent: R^ starting material 0.33, R^ product 0.82). The solution was then concentrated and the crude product purified by column chromatography to provide the desired n-decyl (rac)9-oxo-15a-hvdroxv-16-phenvl-5-cis-13-trans-17,18,19,20tetranorprostadienoate as a viscous oil weighing 5 mg. trans double bond; S = single bond 381S X X X X X X XX XX X X ^**s Z~«. z—1 z-x z-x z-x CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN ·— x-* CN tn CO O in rH to CO to co Φ o O o rH rH pH cn σ» CN Φ rH • pH on M CO CO ft-» m CO CN CO CN CO cn A Φ b •H 4J rt » n co CN Q TJ ZX K β V β a 1 0 o 1 O -t=& u 1 rH rt β 0 V o==»o •H 1 & +» K — 0 .G TO X Ώ H & rt! Λ X X X X X \ \x xx X X z*x Z-X ZX in in in in m tn in tn in in in tn • » • rH rH rH rH rH rH rH rH rH pH pH tH H rH rH rH rH rH rH rH pH x—z X—z χ·ζ >-z X— X-Z Χ-Ζ» x—z x^ m in ci to 00 rH CO rH Γ CN p* Γ·* r* P- r* t- r> • · p- 00 • Oi cn cn cn cn cn on oi cn cn cn oi pH ΪΒ □ rH ϋ a u ΙΛ 00 O <*> CN CN + 1 β g o Sh o & ϋ Λ Ο 43 Oi ft g • Sh rt >« i® g o Λ H -° ΰ X En 0 0 tn CN o *O 0 in p* Ό O • CN Φ 4J to m· Φ +J ρ to •H rt 1 7 •rl rt X pH mh g Tt· in Ή § 1 1 •H O to •Η O Cl CO Μ M M U o in 8 5 & Qj 3 Λ 00 rH Or 0 & g ft 0 rH β β rH rH g O >1 Ο >ι U JS ο -5 ft ft CN >i W >1 Φ • fi g π ο Ό Ο <0 cn Φ 4J Φ +J co • •H rt Η id co p μη Β ή ε rH X •pH Ο Η Ο 1 0 μ y H Η in β Λ ο 5 co r> ft 0 ft υ rH pH & I JZ 4J rt II S r s s Φ *H Λ V CN I & Φ *Λ ?· tn H £ +j & pH & Φ XJ g pM Λ <& rH & ω I •y β V di & Φ ft >.
C Φ §* n I-l Ό I Ti* rH & Φ £ cu 'i i? t! .§ in methoxy protons 8 VO O O VO o 8 8 VO o O vo o O vo CO 01 in co σ» m co co <0 co co CO co co r-l I o K O * ιή * m in d O w 0 b b b b b b b b σ» oi σι 01 σι 01 01 σι O O O s o % O O O O b b b b b b b b b b b b b b b b H i-i rH H H H H rt O O o o CN CN CM CN 4J 4J +} 4J Ή W W >9i § § XSi w te - « Additional Compounds H-chlorophenyl H α-OH D DP H0Et O 1770, 970, 3598 3 613 Additional Compounds .
S’ I u rt A rd & Φ i? ϊ φ £ >1 a ! (ent) H α-OH D LP EtjO/cyclohexane 1760, 960, 3600 (ent) H 0—OH D MP 1760, 960, 3600 «I H H H H >1 δ* >1 ΪΗ C ΰ ci c: Φ φ φ Φ Φ £i Λ .Ci £ £ A A A A A o o to in w in cn *. * m m σι O r-» r* H ·» O r* rH Additional Compounds Solvent system for column chromatography isomer separation Additional Compounds. m-methylphenyl a-OTHP H D 1770, 970 m-methylphenyl β-ΟΤΗΡ H D 1770, 970 o-biphenylyl a-OTHP H D 1770, 970 o-biphenylyl β-ΟΤΗΡ H D 1770, 970 5-phenyl-2-thienyl a-OTHP H D 1770, 970 5-phenyl-2-thienyl β-ΟΤΗΡ H D 1770, 970 β-naphthyl a-OTHP H D 1770, 970 β-naphthyl β-ΟΤΗΡ H D 1770, 970 g-ehlorophenyl a-OTHP H D 1770, 970 p-chlorophenyl β-ΟΤΗΡ H D 1770, 970 p-t-bu tylpheny1 α-ΟΤΠΡ H D 1770, 970 p-t-butylphenyl β-ΟΤΗΡ H D 1770, 970 phenyl a-OTHP (+)Me D 1770, 970 phenyl β-ΟΤΗΡ (+)Me D 1770, 970 phenyl a-OTHP (-)Me D 1770, 970 phenyl β-ΟΤΗΡ (-)Me D 1770, 970 phenyl (ent) a-OTHP H D 1760, 960 phenyl (ent) β-ΟΤΗΡ H D 1760, 960 3,5-dimethylphenyl a-ODMTBS H D 1760, 965 3,5-dimethylphenyl a-ODMTBS H D 1760, 965 / D is trans double bond; S is single bond - 59 43815 Additional Compounds Ar T R Ζ/ XR data m-methylph enyl ct-OTHP Η D 970 m-methylphenyl β-ΟΤΗΡ Η D 970 p-biphenylyl α-ΟΤΗΡ Η D ?70 o-biphenylyl β-ΟΤΗΡ Η D 970 5-phenyl-2-thienyl α-στΗΡ Η D 970 5-phenyl-2-thienyl β-ΟΤΗΡ Η D 970 β-naphthyl α-ΟΤΗΡ Η D 970 β-naphthyl β-ΟΤΗΡ Η D 970 p-chlorophenyl α-ΟΤΗΡ Η D 970 p-chlorophenyl β-ΟΤΗΡ Η D 970 p-t-butylphenyl α-ΟΤΗΡ Η D 965 p-t-butylphenyl β-ΟΤΗΡ Η D 965 phenyl α-ΟΤΗΡ (+)Me D 975 phenyl β-ΟΤΗΡ (+)Me D 975 phenyl α-ΟΤΗΡ (-)Me D 975 phenyl β-ΟΤΗΡ (-)Me D 975 phenyl(ent) α-ΟΤΗΡ Η D 970 phenyl(ent) β-ΟΤΗΡ Η D 970 3,5-dimethylphenyl a-ODMTBS Η D 965 3,5-dimethylphenyl a-ODMTBS Η D 965 / D is trans double bond; S is single bond.
Additional Compounds.
OH j Ar T R W/ z/ IR data cm 1 m-methylphenyl a-OTHP H D D nmr consistent m-methylphenyl β-ΟΤΗΡ H D D nmr consistent o-biph enylyl a-OTHP H D D nmr consistent o-biphenylyl β-ΟΤΗΡ H D D nmr consistent 5-phenyl-2-thienyl a-OTHP H D D nmr consistent p-naphthyl a-OTHP H D D nmr consistent β-naphthyl p-OTHP H D D nmr consistent p-chlorophenyl a-OTHP H D D nmr consistent 2-chlorophenyl P-OTHP H D D nmr consistent p-t-butylphenyl a-OTHP H D 0 1710, 970 p-t-butylphenyl P-OTHP H D D 1710, 970 phenyl a, p-OTHP (+)Me D D 1705, 965 phenyl a, p-OTHP (-)Me D D 1705, 965 phenyl(ent) a-OTHP H D D 1700, 965 phenyl(ent) β-ΟΤΗΡ H D D 1700, 965 / D is cis double bond; S is single bond.
/ D is trans double bond; S is single bond. 3815 Additional Compounds.
Ar T R W/ z/ m-methylphenyl α-ΟΤΗΡ Η 3 m-methylphenyl β-ΟΤΗΡ Η D D o-biphenylyl α-ΟΤΗΡ Η D D o-biphenylyl β-ΟΤΗΡ Η D D 5-phenyl-2-thienyl α-ΟΤΗΡ Η D D β-naphthyl α-ΟΤΗΡ Η D D β-naphthyl β-ΟΤΗΡ Η D D 2,-chlorophenyl α-ΟΤΗΡ Η D D p-chlorophenyl β-ΟΤΗΡ Η D D a-t-butylphenyl α-ΟΤΗΡ Η D D 2,-t-butylphenyl β-ΟΤΗΡ Η D D phenyl α-ΟΤΗΡ (+)Me D D phenyl β-ΟΤΗΡ (+)Me D D phenyl α, β-ΟΤΗΡ (-)Me D D phenyl(ent) α-ΟΤΗΡ Η D D phenyl(ent) β-ΟΤΗΡ Η D D / D is cis double bond? S is single bond.
/ D is trans double bond; S is single bond.
Additional Compounds.
Ar T R w/ 2/ -1 IR data cm m-methylphenyl a-OH H D D consistent nmr m-methylphenyl β-ΟΗ H D D consistent nmr o-biphenylyl a-OH H D D 1735, 1710, 975 p-b iphenylyl β-ΟΗ H D D consistent nmr 5-phenyl-2-thienyl a-OH H D D β-naphthyl a-OH H D D 1730, 1705, 960 β-naphthyl β-ΟΗ H D D 1735, 1710, 965 p-ohlorophenyl a-OH H D D 1730, 1710, 970 p-ehlorophenyl β-ΟΗ H D D 1730, 1710, 970 p-t-butylphenyl a-OH H D D 1730, 1715, 970 p-t-butylphenyl β-ΟΗ H D D 1730, 1715, 970 phenyl a-OH (+) Me D D 1730, 1705, 970 phenyl β-ΟΗ (+) Me D D 1730, 1705, 970 phenyl a-OH (-)Me D D 1730, 1710, 965 phenyl β-ΟΗ (-)Me D D 1730, 1710, 965 phenyl(ent) a-OH H D D 1730, 1710, 960 phenyl(ent) β-ΟΗ H D D 1730, 1710, 960 phenyl a-OH H D S 1735, 1710 3,4-dimethoxyphenyl a-OH H S S 1730, 1710, 965 o-methylphenyl a-OH H S S 1730, 1715 / D is cis double bond; S is single bond.
/ D is trans double bond; S is single bond. 43818 Additional Compounds.
Ar R w/ 2/ -1 IR date om β-naphthyl H D D consistent nn·. phenyl H D D 1735, 1700, 1680, 1625, phenyl (+)Me D D 1735, 1700, 1670, 1625, o-biphenylyl H D D consistent nmr / D is cis double bond; S is single bond.
/ D is trans double bond; S is single bond.

Claims (27)

1. A compound of the general formula:- wherein Ar is o- or β-thienyl; 5-phenyl-a- or β-thienyl; 5 5-lower alkyl-a- or β-thienyl; a- or β-naphthyl; tropyl, phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4dichlorophenyl; 3,5-dimethylphenyl or a monosubstituted phenyl group wherein the said substituent is a bromine, chlorine or fluorine atom or a trifluoromethyl, phenyl, lower alkyl or 10 lower alkoxy group; R is hydrogen or methyl; R' is hydrogen; alkyl of from 1 to 10 carbon atoms; aralkyl of from 7 to 9 carbon atoms; a- or β-naphthyl; phenyl or substituted phenyl wherein the said substituent is a chlorine, bromine or fluorine atom, or a lower alkyl, lower alkoxy or phenyl group, and 15 where in '! is a single bond or cis-double bond with the proviso thatf -when R' is a hydrogen atom or an alkyl group and Ar is an unsubstituted phenyl, naphthyl or thienyl group or a 5-lower alkyl thienyl group, a 3,4-dichlorophenyl or a 3,4-dimethylphenyl group or a monosubstituted phenyl group where the substituent 20 is a bromine chlorine or fluorine atom, a trifluoromethyl group or a lower alkyl group, but excluding the case M 1 is oxo and M is ,W is not a single bond; Z is a single bond or trans-double bond; ami each of M and M' is oxo, '•OH 'Ml and when R 1 is hydrogen, the pharmaceutically acceptable salts thereof.
2. A compound as claimed in claim I wherein M and/or M 1 is and wherein either or both of such hydroxyl groups is modii.-.d by being esterified.
3. A compound of the general formula:- 10 and the epimers thereof, wherein Ar R, R’, W and Z are as defined in claim 1. and the C^ 5 epimers thereof, wherein Ar R, R', W and Z are as .5 defined in claim 1.
4. 5. A compound of the general formula :- and the C 15 epimers thereof wherein Ar R, R', M and Z are as defined in claim 1. 5
5. 6. A compound of the general formula :-- wherein Ar R, R', W and Z are as defined in claim 1.
6. 7. A compound of the general formula :- 10 wherein Ar R, R', W and Z are as defined in claim 1.
7. 8. A compound of the general formula :67 wherein Ar R, R', W and Z are as defined in claim 1.
8. 9. A compound of the general formula:- 5 and the c^ 5 epimers thereof, wherein Ar is a- or β-thienyl; 5-phenyl-a- or β-thienyl; 5-lower alkyl-o- or β-thienyl; a- or β-naphthyl; t'ropyl, phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4-dichlorophenyl; 3,5-dimethylphenyl or a monosubstituted phenyl group wherein the said
9. 10 substituent is a bromine, chlorine or fluorine atom or a trifluoromethyl, phenyl, lower alkyl or lower alkoxy group; R is hydrogen or methyl; and the pharmaceutically acceptable salts thereof and the esters thereof wherein.the esterifying group Is: alkyl of from.l to 10 carbon atoms; aralkyl of 15 from 7 to 9 carbon atoms; a- or β-naphthyl; phenyl or substituted phenyl wherein the said substituent is a chlorine, bromine or fluorine atom or a lower alkyly, lower alkoxy or phenyl group: R is hydrogen; alkyl of from 1 to 10 carbon atoms; aralkyl of from 7 to 9 carbon atoms; a- or β-naphthyl; «13815 phenyl or substituted phenyl wherein the said substituent is a chlorine, bromine or fluorine atom or a lower alkyl, lower alkoxy or phenyl group, and wherein W is a single bond or cis double bond; Z is a single bond or trans double bond; M is oxo, Z OH ^OH and optionally where M is not oxo, the hydroxyl group is modified by being esterified, and R^ is 2-tetrahydropyranyl or dimethyl-tert-butyl silyl. 10. ll-deoxy-16-phenyl-17,18,19,20-tetranorprostaglandin-Eo.
10. 11. ll-deoxy-13,14-dihydro-16-phenyl-17,18,19,20tetranorprostaglandin-Ej.
11. 12. ll-deoxy-16-phenyl-17,18,19,20-tetranorprostaglandin-E 2 .
12. 13. ll-deoxy-15-((-)-1-phenylethyl)-16,17,18,19,20pentanorprostaglandin-E 2 .
13. 14. ll-deoxy-15-((+)-1-phenylethyl)-16,17,18,19,20pentanorprostaglandin-E 2 .
14. 15. (rac)-ll-deoxy-16-(p-chlorophenyl)-17,18,19,20tetranorprostaglandin-E 2 .
15. 16. ll-deoxy-16- (m-tolyl) -17,18,19,20-tetranorprostag landing.
16. 17. 15-epi-ll-deoxy-16-(m-tolyl)-17,18,19,20-tetranorprostaglandin-E 2 .
17. 18. 15-epi-ll-deoxy-l6-(p-chlorophenyl)-17,18,19,20tetranorprostaglandin-E 2 .
18. 19. (rac)-ll-deoxy-16-(β-naphthyl)-17,18,19,
19. 20tetranorprostaglandin-E 2 . 5 20. (rac)-9,15-dioxo-(β-naphthyl)-17,18,19,20tetranorprosta-cis-5-trans-l3-dienoic acid.
20. 21. ll-deoxy-16-(5-phenyl-2-thiehyl)-17,18,19,20tetranorprostaglandin-E 2 .
21. 22. 9,15-dioxo-16-(m-tolylJ-17,18,19,20-tetranorprosta0 cis-5-trans-13-dienoic acid.
22.
23. 15-epi-ll-deoxy-16-phenyl-17,18,19,20-tetranor-PGE 2 .
24. 15-epl-ll-deoxy-15-((+)-l-phenylethyl)-16,17,18,19,2Opentanor-PGE 2 .
25. ll-deoxy-16,17,18,19,20-pentanorprostaglandins and 5 esters thereof according to any one of claims 1 to 8 and lo and substantially as hereinbefore described with reference to any one of Examples Vii, XXI, XXVI, XXVIII to XXX, XXXIV and XXXV.
26. Compounds according to claim 9 and substantially as ι hereinhefore described with reference to the Examples X to XII, XIX, XX, XXIV and XXVII.
27. A pharmaceutical composition comprising, as the active ingredient, an ll-deoxy-16,17,18,19,20-pentanorprostaglandin, or a pharmaceutically-acoeptable salt or C^-ester thereof according to any one of claims 1 to 8 and 10 in admixture with a pharmaceutieally-acceptable carrier.
IE2635/75A 1974-12-11 1975-12-03 11-desoxy-15-substituted-16,17,18,19,20-pentanorprostaglandins IE43815B1 (en)

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