NO754195L - - Google Patents

Description

"Process for the preparation of prostaglandin derivatives".

This invention relates to the production of certain new analogues of naturally occurring prostaglandins. In particular, it relates to the preparation of new 11-deoxy-15-substituted-u)-pentanorprostaglandins. Furthermore, it relates to various new intermediate products suitable for their production.

The prostaglandins are C-20 unsaturated fatty acids that have various physiological effects. The prostaglandins of the E and A series are e.g. powerful vasodilators (Bergstrøm et al., Acta Physiol. Scand. 64:332-33, 1965' and Bergstrøm, et al., Life Sei. 6:449-455, 1967) and lower the systemic arterial blood pressure (vasodepression)

by intravenous administration (Weeks and King, Federation Proe. 23: 327', 1964; Bergstrøm, et al., 1965, op. eit.; Karlson, et al., Acta Med. Scand. 183:423-430, 1968; .and Carlson et al., Acta Phusiol. Scand. 75:161-169, 1969). Another well-known physiological action for PGE-1 and PGE2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969). Another important physiological role for the natural prostaglandins is in connection with the reproductive cycle. PGE^ is known to have the ability to induce labor (Karim et al.,

J. Obstet. Gynaec. Brit. Cwlth. 77:200-210, 1970), to induce therapeutic abortion (Bygdeman, et al., Contraception, 4, 293 (1971)) and to be useful in the regulation of fertility (Karim, Contraception, 3, 173 (1971)). Patents have been obtained for a number of prostaglandins of the E and F series that induce labor in mammals (Belgian patent 754,158 and West German patent 2,034,641), and on PGE^ F2 and F^ for regulating the reproductive cycle (South African patent 69/ 6089). It has been shown that luteolysis can occur as a result of administration of PGF2a [Labhsetwar, Nature, 230, 528

(1971)], and prostaglandins are therefore useful for regulating fertility in a process where smooth muscle stimulation is not necessary.

Other known physiological effects of PGE are inhibition

of gastric acid secretion (Shaw and Ramwell, In: Worchester Symp. on Prostaglandins, New York, Wiley, 1968, pp. 55-64) and also of blood-platelet aggregate formation (Emmons, et al., Brit. Med. J. 2 :468-472, 1967).

It is now known that such physiological effects are elicited in vivo only for a short period after administration of a prostaglandin. Evidence suggests that the reason for this rapid cessation of action is that the natural prostaglandins are quickly and efficiently deactivated metabolically by 3-oxidation of the carboxylic acid side chain and by oxidation of the 15a-hydroxy group (Anggard, et al., Acta. Physiol. Scand. 81, 396 (1971). and the literature citations indicated there). It has been shown that the addition of a 15-alkyl group to the prostaglandins acts to increase the duration of action, possibly by preventing the oxidation of the C15-hydroxyl group [Yankee and Bundy, JACS 94, 3651 (1972)], Kirton and Forbes, Prostaglandins , 1, 319 (1972).

It was of course considered desirable to provide analogues of the prostaglandins which had a physiological effect corresponding to the effect of the natural compounds, but where the selectivity of action and the duration of action were increased. Increased selectivity of action would be expected to reduce the serious side effects, especially stomach and intestinal side effects, which are often obtained by systemic administration of the natural prostaglandins (Lancet, 536, 1971).

These requirements are fulfilled by 11-deoxy-w-pentanorprostaglandins and their C,^ epimers which have in the 15-position a hydroxyl or keto group and a substituent of the formula:

where Ar is α- or 3-thienyl; 5-phenyl-a- or -3-thienyl; 5-lower alkyl-α- or -3-thienyl; α- or 3-naphthyl; tropyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4-dichlorophenyl; 3,5-dimethylphenyl; and monosubstituted phenyl wherein the substituent is bromine, chlorine, fluorine, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; and R is hydrogen or methyl, and pharmaceutically acceptable salts thereof. Preferred compounds are 15-substituted-11-deoxy-a)-pentanor prostaglandins of the E and F series, their C^j- epimers and C^^-keto-

derivatives, and their esters where the esterifying group is alkyl with from 1-10 carbon atoms; aralkyl of 7-9 carbon atoms; α-or 3-naphthyl; phenyl or substituted phenyl where the substituent is lower alkyl, lower alkoxy, chlorine, bromine, fluorine or, phenyl.

Such preferred compounds have the formula:

where Ar is α- or 3-thienyl; 5-phenyl-a- or -3-thienyl; 5-lower alkyl-α- or -3-thienyl; α- or 3-naphthyl; tropyl, phenyl; 3,5 dimethylphenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4-dichlorophenyl; and monosubstituted phenyl wherein the substituent is bromine, chlorine, fluorine, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; R is hydrogen or methyl; and M and N are each

W is a single bond or cis-double bond; Z is a single bond or trans-double bond, and R' is hydrogen, alkyl with 1 - 10' carbon atoms, aralkyl with from 7-9 carbon atoms, α- or 3-naphthyl, phenyl or • substituted phenyl where the substituent is lower alkyl, lower alkoxy, chlorine, bromine, fluorine or phenyl.

In addition to 11-deoxy-prostaglandins where the 11-deoxy-prostaglandin is ll-deoxy-PGE„, -PGE,, -PGF„ , -PGF„n, -PGF, ,

22' 1 2a 23 let

-PGF1(3, -PGEq , -PGFQa, -PGFQ(3, -13,14-dihydro PGE2, -13,14-dihydro PGF2a and -13,14-dihydro PGF,,^, and their C^-esters where the esterifying group is alkyl with from 1-10 carbon atoms, aralkyl with from 7-9 carbon atoms, α- or 3-naphthyl, phenyl or substituted phenyl where the substituent is lower alkyl, lower alkoxy, chlorine, bromine, fluorine or phenyl, and their C ^^-epimers and C^-keto derivatives with a hydroxy or keto group in the 15-position and a substituent of the formula

wherein Ar is α- or '3-thienyl; 5-phenyl-a- or 3-thienyl; 5-lower-

alkyl-α- or -3-thienyl; α- or 3-naphthyl; tropyl, phenyl, 3,5-dimethylphenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4-dichlorophenyl; and monosubstituted phenyl wherein the substituent is bromine, chlorine, fluorine, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; and R is hydrogen or methyl,

A particularly preferred series of new compounds has the formula:

Another particularly preferred series of new compounds has the formula:

A further particularly preferred series of novel compounds

has the formula:

In the above formulas, W, R<1>, R and Z have the meanings indicated above.

Another particularly ^preferred series of new compounds has f nrmo 1 ar\ •

Another particularly preferred series of new compounds has the formula:

A further preferred series of new compounds has the formula:

In the above formulas, W, Z, R and R' have the meanings indicated above.

Particularly preferred compounds are: 11-deoxy-16-phenyl-u-tetranor PGEq, 11-deoxy-16-phenyl-co-tetranor PGE2 , rac-11-deoxy-16-(3-naphthyl)-u-tetranor PGE2' 11-deoxy-16-(5-phenyl-a-thienyl)-u-tetranor PGE2'11-deoxy~15~

((1)-1-phenyl- -ethyl)-u-pentanor PGE2, 11-deoxy-16-(m-tolyl)-u-tetranor PGE2>15-epi-11-deoxy-16-(m-tolyl) -w-tetranor PGE2'11_ desoxy-15-keto-16-(m-tolyl)-u-tetranor PGE2'H_desoxy~l3/14~ dihydro-16-phenyl-u-tetranor PGE2, 15-epi-ll-deoxy -16-phenyl-u-tetranor PGE2, 11-deoxy-15-((+)-1-phenyl-1-ethyl)-w-pentanor PGE2, 15- ipi-11-deoxy-15-((+)- 1-phenyl-1-ethyl)-u-pentanor PGE2'rac-11_ desoxy-16-(p-chlorophenyl)-to-tetranor PGE2' rac-H-desoxy-15-keto-16-(3-naphthyl) -u-tetranor PGE2 and 15-epi-11-deoxy-16-(p-chlorophenyl)-u-tetranor PGE2*

Valuable intermediates for the production of these compounds are the following:

a compound with the formula:

where R<1> is 2-tetrahydropyranyl or dimethyl-tert-butylsilyl, and M, W, Z, Ar, R' and R are as indicated above...

A compound with the formula:

and C,r the epimers thereof, where Q is =0 or

and R"<*>" is 2-tetrahydropyranyl, dimethyl-tert-butylsilyl or hydrogen.

A compound with the formula:

where R, Z and Ar are as indicated above. ..A compound with the formula:

where R 2 and R 3 are each alkyl with from 1 to 8 carbon atoms, phenylalkyl

with up to 9 carbon atoms, phenyl, tolyl, α- or 3-naphthyl or β-biphenyl, and R 3 may also be hydrogen.

According to the invention, a method is provided for the production of an 11-deoxy-to-pentanorprostaglandine with the formula:

'where Ar is α- or 3-thienyl, 5-phenyl-α- or -3-thienyl, 5-lower-alkyl-α- or -3-thienyl, α- or 3-naphthyl, tropyl, phenyl, 3, 4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4-dichlorophenyl, 3,5-dimethylphenyl and monosubstituted phenyl where the substituent is bromine, chlorine, fluorine, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; R is hydrogen or methyl; and R' is hydrogen. alkyl with 1 to 10 carbon atoms, aralkyl with 7-9 carbon atoms, α- or 3-naphthyl, phenyl or substituted phenyl where the substituent is lower alkyl, lower alkoxy, chlorine, bromine, fluorine or phenyl; and W is a single bond or cis-double bond; Z is a single bond or trans double bond; and N and M are each keto,

and the pharmaceutically acceptable salts thereof. The procedure charac- terized by a 15-blocked prostaglandin with the formula:

where R<1>., M, W, Z, R and Ar are as above, and R"*" is 2-tetra hydropyranyl or dimethyl-tert-butylsilyl, is hydrolyzed to form a compound of formula I wherein N is

and when M in the hydrolysis product is keto, it is reduced if desired to the final product where M is

and if N in formula I is to be keto, the hydrolysis product is oxidized while M is protected during the oxidation in the case of the end products where M contains OH, and when R' is an ester, an end product is esterified where R' is H, and optionally when R<1> is H, the pharmaceutically acceptable salts are formed.

As shown in Scheme A, the first step (I—*-2) is a condensation between the known aldehyde 1 (Corey and Ravindranathan, Tetrahedron, Lett., 1971, 4753) with an appropriate 3-keto-phosphate for

to form the enone 2. The ketophosphate is usually formed by condensation of the appropriate carboxylic acid ester with a dialkyl methyl phosphonate. Typically, the desired methyl ester is condensed with dimethylphosphonate.

The enone 2 is then reduced to the enol 3^ with zinc borohydride or a hindered alkylborohydride such as lithium triethylborohydride or potassium tri-sec-butylborohydride. The reduction leads to a mixture of epimers, both of which can be used as starting materials for further conversions. Compound 3^ is used to form prostaglandin analogs with an α-hydroxyl group at C^^. The epimer of _3 is used to form prostaglandin analogues with a 3-hydroxyl group at . In addition, the mixture of C-1 epimers can be used to form 15-keto-prostaglandin analogs. The epimers produced by the hydride reduction can be separated by column, preparative thin-layer or preparative high-pressure liquid chromatography. In the reduction, ethers such as tetrahydrofuran or 1,2-dimethoxyethane or acetonitrile are usually used as solvents.

The enone 2 can be catalytically reduced with hydrogen to the ketone 6, a suitable starting material for the preparation of 13,14-dihydro-prostaglandin analogues of formula I. This reduction can be achieved with either a homogeneous catalyst such as tris-triphenylphosphinerhodium chloride or with a heterogeneous catalyst system such as platinum, palladium or rhodium. The step at which the reduction is carried out is not critical, as will be seen from the following.

The enone 2 can also be reduced with borohydride ion to form

an alcohol 7 in a single step, or alternatively the enol 3_ can be catalytically reduced to form the alcohol 2 using the conditions described above.

( 3_ ^ 4_) includes protection, of the free hydroxyl group which is an acid-labile protecting group. Any sufficiently acid-labile group is satisfactory, but the most common are however tetrahydropyranyl or dimethyl-tert-butylsilyl which can be introduced into the molecule by treatment with respectively dihydropyran and an acid catalyst, usually p-toluenesulfonic acid, in an anhydrous medium or dimethyl-tert-butylsilyl chloride and imidazole.

(4_ -> 5_) is a reduction of the lactone 4 to the hemiacetal

5_ using a suitable reducing agent such as diisobutylaluminum hydride in an inert solvent. Low reaction temperatures are preferred, and -60 to -80°C is common. However, higher temperatures can be used if overreduction does not take place. 1 5_ is then possibly purified by column chromatography. As indicated in scheme A, compounds 4 and 5 can be catalytically reduced to £5 and 9_, respectively, by the method described above.

The conversion of C6 ^ 90 follows that which has been explained

by the transformation of ( 2 -> _5) .

The rest of the syntheses of the two series of prostaglandin analogs of formula I are. illustrated in scheme B. (5_ > 1_0) is a Wittig condensation where the hemiacetal 5_ is reacted with 4-(carboxy)butyltriphenylphosphonium (22) bromide in dimethyl sulfoxide in the presence of sodium methylsulfinyl methide. 10 is then cleaned as above. The conversion of JJD 1_1 is an acid-catalyzed hydrolysis of the protecting group. Any acid which does not cause destruction of the molecule during the removal of the protecting group can be used, but usually 65% aqueous acetic acid is used. Alternatively, the protecting dimethyl-tert-butylsilyl group can be removed by the action of tetraalkylammonium fluoride in a solvent such as tetrahydrofuran. The product is cleaned as above. 11 is a 11-deoxy-15-substituted-co-pentanorprostaglandin of the F2a_series. The prostaglandin analogues of the E2~ series with formula I ( 13) are prepared from the intermediate _10 which. can be oxidized by any reagent which can oxidize hydroxyl groups and which does not attack double bonds. Generally, imide lertide Jones reagent is preferred. The product is purified as above to form the intermediate 12. The intermediate _12_ can be converted to the prostaglandin analogs of the E2 series (L3) of formula I in the same manner as described for ' (10_ 1_1) . Furthermore, intermediate 12^ can be reduced with sodium borohydride to a mixture of intermediate 15 and its Cg-epimer which can be separated by column, preparative thin-layer or preparative high-pressure liquid chromatography, and which can be converted into prostaglandin analogues of the F_ - and F_0 series ^ ^ r 2a ^ 23 with formula I by means of the methods indicated for (10_ 11) . Alternatively, compound 13_ can be reduced with sodium borohydride to give F2a~°^F23~Prosta9^an^n9ana-'-09ené me<^ formula I directly. This epimeric mixture can be separated as described for L5 to give. pure PGF2a and PGF^ The various reduced prostaglandin analogs produced according to the invention, i.e. prostaglandins of the one-, zero- and 13,14-dihydro-two series are formed as shown in scheme C. The intermediate 6^ can be converted to 19_ by means of the steps which is described above for the transformation of ( 2 > . 10) . 19_ can then be converted to 20 using the steps discussed above for the conversion of 10 > 15_. 20_ can be catalytically converted to give 18 (P^= THP or (CH^^Si C(CH^)^) which is the precursor of the prostaglandin analogues of the null series, by means of the steps described above.

( 16 > 17) is a selective catalytic hydrogenation of

5-6 the cis double bond at low temperature using such catalysts as described above. Particularly preferred for this reduction is the use of palladium-on-charcoal as catalyst and a reaction temperature of -20°C. 11_ (R^= THP or (CH^^ Si C(CH-j).j) is not only a precursor of the prostaglandin analogs of the "one" series of formula I, but also of the "zero" series, since 17_ can be reduced to 18 using the methods described for (£ ^ 8^) . Similarly, 16_ can be reduced to 18_ by the same procedure. Removal of the protecting groups is carried out as described previously, and 17, 18, 19 and 20_ where R1= THP or (CH3) 2 Si C8CH3)^ can be "deprotected" in this way to form prostaglandins of the "one", "zero", and 13,14-dihydro-two series of formula I. Preparation of prostaglandins of the E and F series where the prostaglandin is of the "zero", "one" or 13,14-dihydro-two series from 16, 17, 18, 19 and _2_0 follow the method previously described for conversion of 1£ ->11 , 1_2, 13, 14^and 15.

Furthermore, the 15-substituted-pentanorprostaglandinananalogs of the E^-, F^^- and F^^-series can be obtained directly from the corresponding prostaglandin analogue of the "2-series", by first protecting the hydroxyl group by introducing dimethylisopropylsilyl groups and selectively reducing the cis double bond, and removing the protecting group.

The reduction is usually carried out as discussed above for 1_6 and removal of the protecting group is achieved by contacting the reduced protected compound with 3:1 acetic acid:water for 10 minutes until the reaction is nearly complete.

The 11-deoxy-15-subst in tuert-to-pentanorprostaglandinana loges of the "one" series can be prepared by the alternative synthesis illustrated in Scheme D. For the first step in the preparation of the above prostaglandin analogs, the hemiacetal 2 -[ 5α-hydroxy-23-benzyloxymethylcyclopent-la-yl]-acetaldehyde, γ-hemiacetal to react with the disodium salt of 4-(carboxy)butyltri-phenylphosphonium bromide (2_2) as described above for _5 10 . This intermediate can be converted by methods described in detail in the example as shown below.

As shown in Scheme D, the hemiacetal 21 is reacted with the reagent 2_2 to form 23.

23 2_4 involves esterification of the carboxyl group with diazomethane to form a methyl ester intermediate. Other blocking groups can be used provided that the group is stable to hydrogenation and mild acid hydrolysis and can be removed by mild base hydrolysis. Such groups include alkyl with from 1-8 carbon atoms, phenylalkyl with up to 9 carbon atoms, phenyl, tolyl, p-biphenyl or α- or 3-naphthyl. Acylation of the methyl ester intermediate with acetic anhydride and pyridine leads to the formation of an acetate intermediate. Other blocked groups may be used provided that the group is stable to hydrogenation and mild acid hydrolysis. Such groups include alkanoyl with from 2-9 carbon atoms, phenylalkanoyl with up to 10 carbon atoms, benzoyl, toloyl, p-phenylbenzoyl or α- or 3-naphthoyl. On reduction with hydrogen and palladium-on-charcoal in a suitable solvent containing a suitable acid catalyst, ethanol and acetic acid or acetyl acetate and hydrochloric acid being particularly preferred, the protected benzyl ether gives a hydroxy compound which, on oxidation with Collin's reagent, gives the aldehyde 24_. 24 * ±1_ involves treatment of 2A_ with the sodium salt of the appropriate 3-ketbphosphonate under conditions described for 1V 2_, to form an enone, which by reduction with a hindered alkylborohydride such as lithium triethylborohydride or potassium tri-sec-butylborohydride' or zinc borohydride, gives an enol. The hydroxyl group is then protected by treatment with dihydropyran to form a tetrahydropyranyl ether. Other protecting groups can be used provided they are stable to mild base hydrolysis and can be easily removed by mild acid hydrolysis. Such groups include tetrahydrofuryl or dimethyl-t-butylsilyl. This protected compound is then contacted with aqueous sodium hydroxide to give .The conversion of 17 to 11-deoxy-15-substituted-w-pentanorprostaglandins of the "one" series follows the process described above.

11-deoxy-15-keto-15-substituted-w-pentanorprostaglandins E of formula I can be prepared as summarized in Scheme E. _2J5 * 26 involves oxidation of the C. ,- alcohol portion of 25. Any reagent

which can oxidize hydroxyl groups and which do not attack double bonds, can be used, but Jones<1> reagent is usually preferred. The 15-keto-prostaglandin-E analogues of formula I of the 13,14-dihydro-two-, one- and zero-series can be prepared from compounds 2_7, 29_ and 3_1 as described for 2_5 and 26^ above.

Scheme F summarizes the preparation of the 11-deoxy-15-keto-15-substituted-co-pentanorprostaglandin F2a and F2^ analogs of formula I. 3_3 ——> 3_4 involves acylation of 3_3 with acetic anhydride and pyridine to form an acetate -intermediate product. Other blocking groups can be used provided that the group is stable to mild acid hydrolysis. Such groups include alkanoyl of from 2-9 carbon atoms, phenylalkanoyl of up to 10 carbon atoms, benzoyl, toloyl, p-phenylbenzoyl or α- or (3-naphthoyl. The protecting group at C-^^ is then removed as described above to give another intermediate. The next step involves oxidation of the C-,j-alcohol moiety to form a third intermediate. Any reagent capable of oxidizing hydroxyl groups and which does not attack double bonds can be used, but Jones<1> reagent is normally preferred. The final step of this series includes transesterification of the protecting group with Cn.

This is usually achieved by treatment with anhydrous potassium carbonate in an alcoholic solvent such as methanol, which gives the 15-keto-F 2 Q or -F 2 ^ analogs of formula. The 15-keto-prostaglandin FQ or F^ analogs of the 13,14-dihydro-two, one, and zero series can be prepared from compounds 35, _37, and 3_9 as described for 3_3_34. It should be understood that the stereochemistry of the hydroxyl group at C^j. is' unimportant for the preparation of all the 15-keto compounds, and 153-, 15a- or an epimeric mixture will all give the same 15-keto analogue.

When purification by column chromatography is desired in the foregoing methods, suitable supports for chromatography include neutral alumina and silica gel and 60-200 mesh silica gel is generally preferred. Chromatography is conveniently carried out in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane, as also illustrated in the examples. When purification by high pressure liquid chromatography is desired, suitable carriers include "Corasil", "Porasil" and "Lichrosorb", which are used with inert solvents such as ether, chloroform, methylene chloride, cyclohexane and n-hexane.

It will be seen that the preceding formulas include optically active compounds. It should be understood that both optical antipodes, for example in 8,12-nat and 8,12-ent, are covered by the formulas in the description and claims. The two optical antipodes are easily prepared by the same methods by simply using the appropriate optically active precursor aldehyde. However, it will be clear that the corresponding racemates will have a valuable biological effect due to its content of the above-mentioned biologically active optical isomers, and also such racemates are therefore covered by the preceding formulas and in the claims. The racemic mixtures are easily prepared by the same methods used here to prepare the optically active compounds, by simply using the corresponding racemic precursors instead of optically active starting material. It will also be seen that the preceding formulas include an optical center at C-16 when R is methyl. Both C-16 optical antipodes (e.g. R and S) are covered by the formulas given here. The two C, , optical antipodes are easily prepared by the same methods by simply using the appropriate optically active precursor phosphonate.

In numerous in vivo and in vitro experiments, we have shown that the new prostaglandin analogues have physiological effects that can be compared with, but are much more tissue-selective and long-lasting than the effects that natural prostaglandins have (see above). These experiments include, among other things, an experiment on the effect on isolated smooth muscle from guinea pig uterus, guinea pig small intestine and rat uterus, inhibition of histamine-induced bronchospasm in guinea pigs, effect on blood pressure in dogs, inhibition of stress-induced ulceration in rats , effect on diarrhea in mice, and inhibition of stimulated gastric acid secretion in rats and dogs.

The physiological reactions observed in these experiments,

are valuable in determining the utility of the test compounds for the treatment of various natural and pathological conditions. Such particular uses include: vasodilator activity, anti-hypertensive activity, bronchodilator activity, antiarrhythmic activity, cardiac stimulant activity, antifertility activity

and antiulcer activity.

An advantage of 11-deoxy-prostaglandins of the E series in general is their increased stability compared to the likes of PGE2.

In addition, the new 11-deoxy-15-substituted-0)-pentanorprostaglandins have very selective activity profiles compared to the corresponding naturally occurring prostaglandins and in many cases have a longer duration. The new prostaglandin analogues have useful vasodilator activity. An important example of the therapeutic importance of these prostaglandin analogues is the effectiveness of 11-deoxy-16-phenyl-w-tetranorprostaglandin Eo and 15-epi-ll-deoxy-16-(m-tolyl)-(jj-tetranorprostaglandin E2) which have hypotensive activity with much increased strength and duration compared to PGE2 itself.At the same time, the stimulating activity on smooth muscles is clearly reduced compared to PGE2- In a similar way, other E and F^ analogues have beneficial hypotensive activity.

In addition, 11-deoxy-16-(m-tolyl)-w-tetranorprostaglandin-E2 and 11-deoxy-16-(5-phenyl-a-thienyl)-w-tetranorprostaglandin-E2 have high bronchodilator activity with reduced non-vascular smooth muscle activity. Similarly, other 11-deoxy-15-substituted-pentanorprostaglandin E 1 and E 2 analogues have beneficial bronchodilator activity.

Another good example of the therapeutic importance of

the new prostglandin analogues are the strong, selective anti-ulcer and

antisecretory action exhibited by 11-deoxy-16-(3-naphthyl)-t-tetranor-PGE2 and 11-deoxy-15-keto-16-(3-naphthyl)-w-tetranor-PGE2.

Similarly, the other new PGE and 15-keto analogues have these desired

gastrointestinal effects.

the phenylesters of the prostaglandin analogs are prepared from the corresponding acids by contacting them with the desired phenol in the presence of dicyclohexylcarbodiimide in an inert reaction solvent. The C-1 alkyl or p enalkyl esters of the new prostaglandin analogs are prepared from the corresponding acids by contacting them with the appropriate diazo compound in the presence of a reaction-inert solvent. Such esters have the effect of the acid from which they are derived. The esters of the new prostaglandin analogues which are acylated at C 8 and/or C 5 are easily prepared from the corresponding acid by acylation which is usually carried out using carboxylic acid anhydride or carboxylic acid chloride as acylating agent. Such acyl groups are lower alkanoyl, benzoyl and substituted benzoyl where the substituent is halogen, trifluoromethyl, lower alkoxy or phenyl or formyl. Such esters have the activity of the prostaglandin analogue from which they are derived.

The prostaglandin analogues which have a (3-hydroxyl group at

C^i- and have a C^,- lower alkyl group, have an action corresponding to the action of their epimers. In some cases, however, the selectivity exhibited by these compounds, such as the hypotensive activity of the 15-epi-16-m-tolyl-PGE 2 ~ analog, will exceed the action 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.

Particularly 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 cations of other metals, e.g. aluminium, zinc and iron can also be used.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-f enylethylamine, (3-f enylethylamine, ethylenediamine, diethylenetriamine, and similar aliphatic, cycloaliphatic and araliphatic amines containing up to about 18 carbon atoms, as well as heterocyclic amines, e.g. piperidine, morpholine, pyrrolidine, pip-erazine and lower alkyl derivatives thereof, e.g. 1- methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like as well as

amines containing water-solubilizing or hydrophilic groups, e.g. mono-, di-, and triethanolamine, ethyldiethanolamine, N-butyl-ethanolamine, 2-amino-l-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-l-propanol , tris(hydroxymethyl)aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephedrine, epinephrine, procaine, and the like.

Examples of proper pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

The new compounds can be used in a variety of different pharmaceutical preparations containing the compound or a pharmaceutically acceptable salt thereof, and they can be administered in the same manner as natural prostaglandins in a variety of ways, such as intravenously, orally and topically, including aerosol, intravaginally and intranasally .

To produce bronchodilation or to increase nasal activity, a suitable dosage form would be an aqueous ethanolic solution of 11-deoxy-16-Ar-substituted-ui-tetranor-PGE-^ or -PGE2 applied as an aerosol using fluorinated hydro- carbons as propellant, in an amount of from approx. 3 - 500 yg/dose.

"The new 16-Ar-substituted-w-tetranorprostaglandin analogs

of the ' Eo~°913,14-dihydro-E2~or -F^ series are useful hypotensive agents. For the treatment of hypertension, these agents can conveniently be administered as an intravenous injection in doses of approx. 0.5 - 10 ug/kg, or preferably in the form of capsules or

tablets in doses of 0.005 - 0.5 mg/kg/day.

The new 15-keto-16-Ar-substituted-w-tetranorprostaglandin analogs or 16-Ar-substituted-αi-tetranorprostaglandin-E analogs are useful antiulcer agents. For the treatment of peptic ulcers, these agents can be administered in the form of capsules or tablets in doses of 0.005 - 0.5 mg/kg/day.

To prepare any of the above dosage forms or the other numerous forms that are possible, various reaction-inert diluents, excipients or carriers can be used. Such substances include e.g. water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, polyalkylene glycols, petroleum jelly, cholesterol and other known carriers for medicines. Optionally, these may be pharmaceutical preparations containing such auxiliary substances as preservatives, wetting agents, stabilizing agents or other therapeutic agents such as antibiotics.

The following examples shall serve to further illustrate the invention. In these examples, all temperatures are in °C, and all melting points and boiling points are uncorrected.

EXAMPLE 1

2-[23-Benzyloxymethyl-5α-hydroxycyclopent-la-yl]acetaldehyde, α-hemiacetal (21).

To a stirred solution, cooled to -78°, of 10.0 g

(40.5 mmol) 2-[23_benzyloxymethyl-5a-hydroxycyclopent-la-yl]-acetic acid-a-lactone in 100 ml toluene was added dropwise 55.5 ml of a 20% solution of diisobutylaluminum hydride in hexane. The solution was stirred in the cooled state and under nitrogen i

40 minutes, and the reaction was then stopped by dropwise addition of methanol until gas evolution ceased. The mixture

was then warmed to room temperature and concentrated.

The resulting oil was slurried with our methanol, filtered,

and the filtrate was concentrated. Purification of the crude product by silicic acid-oil chromatography using mixtures of benzene:ethyl acetate as eluents gave colorless oily 2-[23-benzyloxymethyl-5α-hydroxy-cyclopen-lct-yl] acetaldehyde, γ-hemiacetal (21 ) with a weight of 8.91 g (86% yield).

EXAMPLE 2

7-[23-Benzyloxymethyl-5α-hydroxycyclpent-la-yl]-cis-5-heptenoic acid (23).

9.73 ml (21.2 mmol) of a 2.18 M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To the resulting red ylide solution is added a solution of 1.12 g (4.50 mmol) of 2-[23-benzyloxymethyl-5a-hydroxycyclpent-la-yl]-acetaldehyde, a-hemiacetal (2) in 11 ml of dimethylsulfoxide . After stirring in

for a further 45 minutes, the reaction mixture is poured into ice water.

The basic aqueous solution is extracted with a 2:1 mixture of ethyl acetate:ether, and then covered with ethyl acetate and acidified with 1.0 N hydrochloric acid to pH 3. The aqueous layer is further extracted with ethyl acetate, the combined ethyl acetate extracts are washed with water, dried (anhydrous magnesium sulfate) and concentrated. Purification of the crude product by silica gel chromatography gives the desired 7-[23-benzyloxymethyl-5a-hydroxycyclopent-1a-yl]-cis-5-heptenoic acid (23).

EXAMPLE 3

Methy 1-7-[23-benzyloxymethyl-5α-hydroxycyclopent-la-yl]-cis-5-heptenoate.

A solution of 1.41 g (4.06 mmol) of 7-[23-benzyloxymethyl-5a-hydroxycyclopent-la-yl]-cis-5-heptenoic acid (23) in 17.5 ml of anhydrous ether is titrated at room temperature with an ethereal diazomethane solution until the yellow color remains for 5 minutes. The reaction mixture is then decoloured by the dropwise addition of glacial acetic acid. The ether solution is then washed with saturated sodium bicarbonate and saturated brine, dried (anhydrous magnesium sulfate) and concentrated to give the desired methyl 7-[23-benzyloxymethyl-5α-hydroxy-cyclopentan-la-yl]-cis-5-heptenoate.

EXAMPLE 4

Methyl 7-[23-benzyloxynethyl-5a-acetoxycyclopent-la-yl]-cis-5-heptenoate.

A mixture of 1.28 g (3.54 mmol) methyl-7-[23-benzyloxy-. methyl 5α-hydroxycyclopent-la-yl]-cis-5-heptenoate prepared in example 3, 5.0 ml of pyridine and 0.736 ml (7.78 mmol) of acetic anhydride are stirred under nitrogen at 50° overnight. The mixture is then cooled to room temperature and diluted with ether (75 ml). The ether solution is washed with water (1 time) and with saturated copper (II) sulfate (3 times), dried (anhydrous magnesium sulfate) and concentrated to give the desired methyl-7-[23-benzyloxymethyl-5a-acetoxycyclopent-la-yl ]-cis-5-heptenoate.

EXAMPLE 5

Methyl 7-[23-hydroxymethyl-5α-acetoxycyclopent-la-yl]-heptenoate.

A heterogeneous mixture of 1.27 g (3.14 mmol) of methyl 7-[23-benzyloxynethyl-5a-acetoxycyclopent-la-yl]-cis-5-heptenoate prepared in Example 4, 305 mg of 10% palladium-on- charcoal and 13 ml of a 20:1 mixture of absolute ethanol:glacial acetic acid are stirred at room temperature under an atmosphere of hydrogen for 20 hours. The mixture is then filtered through Celite 545 and the filtrate is concentrated to give the desired methyl 1-7-[23-hydroxymethyl-5α-acetoxycyclopental-la-yl]heptenoate.

EXAMPLE 6

Methyl 7-[23-formyl-5α-acetoxycyclopent-la-yl]heptanoate (24).

To a mechanically stirred solution of 3.37 ml (41.7 mmol) of pyridine in 50 ml of methylene chloride cooled to 10 to 15° under nitrogen, 1.89 g (18.9 mmol) of chromium trioxide is added portionwise over a period of 30 minutes. The dark, burgundy colored solution was then warmed to room temperature and cooled to 0°. To the cold solution was added a solution of 747 mg (2.37 mmol) of methyl 7-[23-hydroxymethyl-5a-acetoxycyclopent-1a-y1]heptanoate prepared in Example 5 in 7.0 ml of methylene chloride with accompanying end formation of a dense, black precipitate. The suspension was stirred in the cold state for 15 minutes, and then 7.21 g (52.2 mmol) of finely ground sodium bisulfate monohydrate was added. After stirring for 10 minutes, 6.25 g (52.2 mmol) of anhydrous magnesium sulfate was added. After stirring for 5 minutes, the dark suspension was filtered through a pad of Celite, washed with methylene chloride and then concentrated by rotary evaporation to give crude methyl 7-[23-formyl-5a-acetoxy-cyclopent-la-yl]heptanoate (24), which was used without purification.

EXAMPLE 7

Methyl 9α-acetoxy-15-oxo-16-(p-chlorophenyl)-13-trans-α-tetranorprostenoate.

To a suspension of 110 mg (2.61 mmol) of a 57.0% dispersion of sodium hydride in mineral oil in 20 ml of tetrahydrofuran 740 mg (2.61 mmol) of dimethyl-2-oxo-3-(p- chlorophenyl)propyl phosphonate. 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 mmol) of the crude methyl 7-[23-formyl-5a-acetoxy-cyclopent-la-yi]-heptenoate (_24) in 4 ml of tetrahydrofuran. The resulting reaction mixture is stirred at room temperature for 2.0 hours under nitrogen. The reaction is then stopped by the addition of glacial acetic acid to pH ~* 7, and the reaction mixture is concentrated using a rotary evaporator. The crude product is purified by chromatography on silica gel to give the desired methyl 9α-acetoxy-15-oxo-16-(p-chlorophenyl)-13-trans-co-tetranorprostenoate.

EXAMPLE 8

Methyl 9a-acetoxy-15a-hydroxy-16-(p-chlorophenyl)-13-trans- -tetranorprostenoate and methyl 9a-acetoxy-15(3-hydroxy-16-(p-chlorophenyl)-13-trans- -tetranorprostenoate.

To a solution, cooled under nitrogen to -78°, of

900 mg (2.0 mmol) of methyl 9a-acetoxy-15-oxo-16-(p-chlorophenyl)-13-trans-co-tetranorprostenoate prepared in example 7 in 30 ml of tetrahydrofuran is added to 2.0 ml of a 1, 0 m solution of lithium triethylborohydride in tetrahydrofuran. The reaction mixture is stirred in a cold state for 30 minutes, then the reaction is stopped by the addition of 1 ml of a 9:1 mixture of water:acetic acid. The reaction mixture is warmed to room temperature and then concentrated. The resulting product is diluted with ethyl acetate, the organic layer is washed with water and saturated sodium bicarbonate, dried (anhydrous magnesium sulfate) and concentrated. Purification of the resulting product by silica gel chromatography gives methyl 9α-acetoxy-150-hydroxy-16-(p-chlorophenyl)-13-trans-α)-tetranorprostenoate and methyl 9α-acetoxy-15α-hydroxy-16-( p-chlorophenyl)-13-trans-to-tetranorprostenoate. The 153 product in this example can be converted into the 15-epi-11-deoxy-16-p-chlorophenyl-co-tetranorprostaglanding-E.^ , -F.^ - and -F^ compound of formula I according to Examples 9 - 12, 23 and 26.

EXAMPLE 9

9α,15α-dihydroxy-16-(p-chlorophenyl)-13-trans-tetranorprostenic acid (17a)

A mixture of 100 mg methyl 9α-acetoxy-15α-hydroxy-16-(p-chlorophenyl)-13-trans-w-tetranorprostenoate prepared in Example 8, 1.0 ml 1.0 N aqueous sodium hydroxide, 1.0 ml tetrahydrofuran and 1.0 ml of absolute methanol are stirred under nitrogen at room temperature for 1.5 hours. The solution is then acidified by adding 1.0 ml of 1.0 N aqueous hydrochloric acid (pH of acidified solution was approx.

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 yields 9α,15α-dihydroxy-16-(p-chlorophenyl)-13-trans-w-tetranorprostenic acid ( 17a).

EXAMPLE 10

Methyl 9α-acetoxy-15α-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)-13-trans-oj-tetranorprostenoate.

A mixture of 453 mg (1.0 mmol) of methyl 9α-acetoxy-15α-hydroxy-16-(p-chlorophenyl)-13-trans-u-tetranorprostenoate prepared in Example 8, 0.14 ml (1.53 mmol ) dihydropyran, 4.2 ml methylene chloride and 1 crystal of p-toluenesulfonic acid monohydrate are stirred at room temperature under nitrogen for 20 minutes. The reaction mixture is then diluted with ether, washed with saturated aqueous sodium bicarbonate, dried (anhydrous magnesium sulfate) and concentrated to give methyl 9α-acetoxy-15α-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)-trans- 13-oj-tetranorprostenoate.

EXAMPLE 11

9α-hydroxy-15α-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)-13-trans-to-tetranorprostenic acid ( 17a) .

A homogeneous solution of 537 mg (1.0 mmol) of methyl 9α-acetoxy-15α-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)-13-trans-α)-tetranorprostenoate prepared in Example 10, 3.0 ml (3.0 mmol) of one 1.0 N aqueous sodium hydroxide solution, 3.0 ml methanol and 3.0 ml tetrahydrofuran are stirred under nitrogen overnight. The reaction is then stopped by the addition of 3.0 ml (3.0 mmol) of a 1.0 N aqueous hydrochloric acid solution. The solution is then diluted with ethyl acetate. The organic layer is dried (anhydrous magnesium sulfate) and concentrated. The crude product is purified by silica gel chromatography to give the desired 9a-hydroxy-15a-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)-13-trans-u-tetranorprostenic acid (17a).

EXAMPLE 12

9-oxo-15α-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)-13-trans-. oj-tetranorprostenic acid (17a) .

To a solution, cooled under nitrogen to -15 to -20°, of 199 mg (0.371 mmol) of 9α-hydroxy-15α-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)-13-trans-w- tetranorprostenic acid (17a) in 4.0 ml of acetone is added dropwise 0.163 ml (0.408 mmol) of Jones<1> reagent. The reaction mixture is stirred in a cold state for 15 minutes, and then the reaction is stopped by the addition of 0.194 isopropanol. The reaction mixture is stirred in a cold state for 5 minutes and then diluted with ethyl acetate. The organic solution is washed with water and brine, dried (anhydrous magnesium sulfate) and concentrated to give 9-oxo-15α-(tetrahydropyran)-2-yloxy)-16-(p-chlorophenyl)-13-trans-w-tetranorprostenic acid (17a)

which is used.without purification.

EXAMPLE 13

9-oxo-15α-hydroxy-16-(p-chlorophenyl)-13-trans-u-tetranorprostenic acid (17a) .

A homogeneous solution of 175 mg (0.328 mmol) of 9-osco-15a-(tetrahydropyran-2-yloxy)-16-(p-chlorophenyl)-13-trans-w-tetranorprostenic acid ( 17a) in 5 ml of a 65:35 mixture of acetic acid:water is stirred under nitrogen for 20 hours. The reaction mixture is concentrated by rotary evaporation followed by an oil pump. The crude product is purified by silica gel chromatography to give 9-oxo-15a-hydroxy-16-(p-chlorophenyl)-13-trans-u-tetranorprostenic acid (17_cxi . The product according to this example (17a) can be reduced as described in example 23 for to give the corresponding PGF2q and PGF^ analogs<:>.

EXAMPLE 14

Dimethyl 1-2-oxo-3-phenylpropyl phosphate.

A solution of 6.2 g (50 mmol) of dimethyl methylphosphonate (Aldrich) in 125 ml of dry tetrahydrofuran was cooled to -78°C 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 with

such a rate that the reaction temperature did not rise above -65°. After a further 5 minutes of stirring at -78°, 7.5 g (50.0 mmol) of methylphenylacetate was added dropwise at a rate of

kept the reaction temperature below -70° (20 minutes). After 3.5 hours at -78°, the reaction mixture was heated to ambient temperature, neutralized with 6 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml water, the aqueous phase was extracted with 100 ml portions of chloroform (3 times), the combined organic extracts were backwashed (50 ml H20), dried (MgSC<4) and concentrated (water aspirator) to an impure residue and distilled, b.p. 134-5° (*v0.1 .mm) to give 3.5 g (29%) .dimethyl-2-oxo-3-phenyl propyl phosphate (2^) .

The nuclear magnetic resonance spectrum (CDC1-.) showed a

J 0 doublet centered at 3.76 (J=11.5 eps, 6H) for q)-P- a tri-spot centered at 3.376 (2H) for CH3-0-CH2-CH2", a singlet at 3.286q( 3H) £or.CH3-0-CH2-, a doublet centered at 03.146 (J=23 eps,

2H) " '„ " , a singlet at 3.96 (2H) for „„ " and a wide

—L—L*ti 2~ " — 2~

singlet at 7.26 (6H) for CgH5-.

EXAMPLE . 15

(nat.)-2-f 5α-hydroxy-23-(3-oxo-4-phenyl-trans-1-buten-1-y1)cyclopent-la-yl]acetic acid,γ-lactone (2b).

Dimethyl-2-oxo-3-phenylpropylphosphonate (6.93 g, 28.6 mmol)

in 420 ml of anhydrous THF was treated with 1.21 g (28.6 mmol) of 57% strength sodium hydride in a dry nitrogen atmosphere at room temperature. After stirring for 60 minutes, 2-[5α-hydroxy-23-formylcyclopentan-la-yl]acetic acid, γ-lactone (1) in 50 ml anhydrous THF was added. After 95 minutes, the reaction was quenched with 4.2 ml of glacial acetic acid, the reaction mixture was filtered, evaporated and mixed with 250 ml of ethyl acetate, and the mixture was washed successively with 100 ml of saturated sodium bicarbonate solution (2 times) 150 ml (1 time), 150 mL saturated brine (1 time), dried (Na 2 SO 4 ) and evaporated to give 2.51 g (nat)-2-.

[50-hydroxy-23-(3-oxo-4-phenyl-trans-1-buten-1-yl)cyclopent-la-yl]-acetic acid, γ-lactone (2b) as a solid after column chromatography

(siika gel, Baker 60-200 mesh) , sm.p. 52 - 56°, [cx] 5 = +35.0° (C=0.8 CHCl 3 ).

The nuclear magnetic resonance (nmr) spectrum (CDCl^) showed a doublet of doublets centered at 6.806 (1H, J.=7, 16 eps) and a doublet centered at 6.276 (1H, J=16 eps) for the olefinic protons, a wide singlet at 7.266 (5H) for^H _ ru , a

6 5 2

singlet, at 3.826 (2H) for „ u, and multiplets at C ^ ri^ —L-n 2 —,

4.78-5.186 (1'H) and 1.2-2.86 (8H) for the rest of the protons.

EXAMPLE 16

(nat.).2-[5α-hydroxy-23_(3α-hydroxy-4-phenyl-trans-l-buten-l-yl)-cyclopent-la-yl]acetic acid, γ-lactone (3b).

To a solution of 2.5 g (9.25 mmol) (nat.) 2,[5α-hydroxy-23-(3-ox0-4-phenyl-trans-1-buten-1-yl)cyclopent-la- yl]acetic acid, γ-lactone (3_) in 30 ml of dry THF (tetrahydrofuran) in a dry nitrogen atmosphere at -78° was added dropwise 9.25 ml of a 1.0 M lithium triethylborohydride solution. After stirring at -78° for 30 minutes, 20 ml of acetic acid/water (40:60) was added. After the reaction mixture had reached room temperature, 40 ml of water was added, and the reaction mixture was extracted with methylene chloride (3x50 ml), washed with brine (2x5 ml), dried (Na 2 SO 4 ) and concentrated (water aspirator). The resulting oil was purified by column chromatography on silica gel (Baker "Analyzed" Reagents 60-200 mesh) using cyclohexane and ether as eluents. After elution of less polar impurities, a fraction was obtained containing 365 mg (nat.) 2-[5α-hydroxy-23~(3α-hydroxy-4-phenyl-trans-1-buten-1-yl)cyclopent-la-yl ] acetic acid, γ-lactone (3b), a 578 mg fraction of (mixed 3b and epi-3b and finally a fraction (489 mg) of

(nat.) 2-[5α-hydroxy-23-(33~hydroxy-4-phenyl-trans-l-buten-l-yl)-cyclopent-la-yl]acetic acid, γ-lactone epi 3b.

(nat.) 3b had [a]^5=+6.623° (C=1.0 CHC13) and (nat.) epi-3b had [a]^5 =+24.305° _(C=1.69, CHC13 ).

The 15-epi product according to this example (epi-3b) can be converted into the new 15-epi-11-deshydroxyprostaglandins by the method according to examples 17 - 30 and 32 - 35.

. The products according to this example (3b and epi-3b) can be converted into the new 13,14-dihydro-11-deoxyprostaglandin two-series analogues by the methods according to examples 32, 18 - 21, 23, 26, 27 - • 30 and 34 - 35 . EXAMPLE 17■ (nat.)-2-[5α-hydroxy-23~(3α-(tetrahydropyran-2-yloxy)-4-phenyl-trans-l-buten-l-yl ) cyclopent-la-yl] acetic acid , y -lactone (4b). To a solution of 805 mg (2.96 mmol) (nat.) 2-[5a-hydroxy-23-(3a-hydroxy-4-phenyl-trans-l-buten-l-yl]cyclopent-la-yl] acetic acid, γ-lactone (3b) in 20 ml of anhydrous methylene chloride and 0.735 ml of 2,3-dihydropyran at 0° in a dry nitrogen atmosphere was added 35.3 mg of p-toluenesulfonic acid, monohydrate. After stirring for 35 minutes, the reaction mixture was mixed with 150 ml of ether, the ether solution was washed with saturated sodium bicarbonate (2x100 ml), then with the saturated brine (1x100 ml), dried (Na2SO4) and concentrated to give 1.2 g (>100%) of impure (nat.) 2 -[5α-Hydroxy-23~(3α-tetrahydropyran-2-yloxy)-4-phenyl-trans-1-buten-1-yl)cyclopent-la-yl]acetic acid, Y-lactone (4b).

The infrared spectrum (CHC1-.) had a medium absorption at 975 cm for the trans double bond and a strong absorption at 1770 cm for the lactone carbonyl group.

. EXAMPLE 18

(nat.)-2-[5a-hydroxy-23~(3a-(tetrahydropyran-2-yloxy)-4-phenyl-trans-l--buten-l-yl)cyclopent-la-yl] acetaldehyde, Y- hemiacetal (5b).

A solution of 1.1 g (2.96 mmol) of 2-[5a-hydroxy-23~(3a-(tetrahydropyran-2-yloxy)-4-phenyl-trans-l-buten-l-yl)cyclopent-la -yl] acetic acid , γ-lactone (4b) in 15 ml of dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution was added 4.05 ml of 20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate that the internal temperature did not rise above -65° (15 minutes). After a further 30 minutes of stirring at -78°, anhydrous methanol was added until gas evolution ceased, and the reaction mixture was warmed to room temperature. The reaction mixture was mixed with 150 ml of ether, washed with 50% sodium potassium tartrate solution (2x50 ml), with brine (1x75 ml), dried (Na2SO4) and concentrated to give 883 mg of (nat.)-2-[ 5a-hydroxy-23~(3a-(tetrahydropyran-2-yloxy)-4-phenyl-trans-l-buten-l-yl)cyclopent-l-yl]acetaldehyde, Y-hemiacetal (5b) after column chromatography.

EXAMPLE 19

9α-Hydroxy-15α-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-tetranorprostadic acid ( 10 b).

To a solution of 3.83 g of (4-carbohydroxy-n-butyl)tri-phenylphosphonium bromide (2_3) in a dry nitrogen atmosphere in 10 ml of dry dimethyl sulphoxide was added 11.9 ml of a 2.1 M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 1.2 g (3.3 mmol) of 2-[5α-hydroxy-23-(3α-(tetrahydropyran-2-yloxy)-4-phenyl-trans-1-butene- 1-yl) cyclopent-la-yl] acetaldehyde , Y-hemiacetal (^5b) in 15.0

ml of dry dimethylsulfoxide over a period of 20 minutes. After a further 20 hours of stirring at room temperature, the reaction mixture was poured into ice water, 10% HCl (60 ml) and ethyl acetate (100 ml).

The acidic solution was extracted with ethyl acetate (2x100 mL), and the combined organic extracts were washed with water (1x100 mL), brine (100 mL), dried (MgSO 4 ) and evaporated to a residue. The residue was purified by column chromatography on silica gel (Baker "Analyzied" Reagents 60-200 mesh) using chloroform and ethyl acetate as eluents. After removal of high Rf impurities, 2.0 g of 9α-hydroxy-15α-(tetrahydro-pyran-2-yloxy)-16-phenyl-cis-5-trans-13-α-tetranorprostadic acid (10b) was collected.

The product from this example (10b) can be hydrolysed by the method according to example 21 to 9a,15a-dihydroxy-16-phenyl-cis-5-trans-13-co-tetranorprostadic acid (11b). The product according to example (10b), can also be converted by the methods according to examples 24 and 25 to 9a,15a-didihydroxy-16-phenyl-trans-13-w-tetranorprostenic acid (17b), by the methods according to the examples

■22 and 21 to 9a,15a-dihydroxy-16-phenyl-w-tetranorprostanoic acid (18b) or by the methods according to examples 21 and 26 to 9,15-dioxo-16-phenyl-cis-5-trans-13-co -tetranorprostadic acid (34b) .

EXAMPLE 20

9-oxo-15a-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-u)-tetranorprostadioic acid (12b).

To a solution cooled to -10° under nitrogen, of 1.33 g

(2.9 mmol) 9a-hydroxy-11-deoxy-15a-(tetrahydropyran-2-yloxy)-16-phenyl-5-trans-13-w-tetranorprostadic acid ( 10b) in 30 ml of reagent grade acetone was added dropwise 1 .26 ml of Jones<1>reagent. After 5 minutes at -10°, 1.0 ml of 2-propanol was added, and the reaction mixture was stirred for another 5 minutes, and it was then mixed with 100 ml of ethyl acetate, washed with water (3x50 ml), with brine (1x50 ml) , dried (MgSO 4 ) and concentrated to give 1.3 g of 9-oxo-15a-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-u-tetranorprostadic acid (12b).

The product according to this example (12b) can be converted by the methods according to examples 23 and 21 to the corresponding 11-deoxy-prostaglandin-F2a_ and -F2^ analogues. The product according to this example (12b) can also be converted by the method according to examples 22 and 21 to 9-oxo-15a-hydroxy-16-phenyl-w-tetranorprostanic acid (18b).

EXAMPLE 21

9-oxo-15a-hydroxy-16-phenyl-cis-5-trans-13-tetranorprostadic acid (13b).

A single solution of 1.3 g of 9-oxo-15o-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-prostadioic acid (12b) in 20 ml of a 65:35 mixture of glacial acetic acid: water was stirred under nitrogen at 25° for 18 hours and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7) using chloroform and ethyl acetate as eluents. After elution of the less polar impurities, the desired 9-oxo-15a-hydroxy-16-phenyl-cis-5-trans-13-tetranorprostadic acid (13b) with a weight of 450 mg was collected. The infrared spectrum (CHC1-.) showed a broad hydroxyl absorption (3200-3650 cm -1), strong carbonyl absorptions at 1740 cm (ketone) and 1710 cm (acid), and a medium absorption at

970 cm for the trans double bond.

EXAMPLE 22

9-oxo-11-deoxy-15a-hydroxy-16-phenyl- -tetranorprostanic acid ( 18b).

A heterogeneous mixture of 800 mg of 9-oxo-11-deoxy-15α-hyd-

• roxy-16-phenyl-cis-5-trans-13-w-tetranorprostanic acid ( 13b) and

100 mg of 10% palladium-on-charcoal 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 is concentrated. Purification of the crude product by silica gel chromatography using chloroform as eluent gives the desired 9-oxo-11-deoxy-15a-hydroxy-16-phenyl-u>-tetranorprostanic acid (18b).

EXAMPLE 23

9a,15a-dihydroxy-16-phenyl-w-tetranorprostanic acid (18b) and 93,15a-dihydroxy-16-phenyl-u-tetranorprostanic acid ( 18b)..

To a solution of 100 mg of 9-oxo-15a-hydroxy-16-phenyl-oj-tetranorprostanic acid (18b) in 30 ml of methanol, cooled to 0°C, was added a solution of 500 mg of sodium borohydride in 50 ml of methanol of cooled to 0°. The reaction mixture was stirred at 0° for 20 minutes and then for 1.0 hour at room temperature. The reaction mixture was then diluted with 6 mL of water and concentrated. The concentrated solution was covered with ethyl acetate and then acidified to pH 3 with 10% hydrochloric acid. The ethyl acetate layer was washed with water (2x10 mL) and brine (10 mL), dried (sodium sulfate) and concentrated. The crude residue was purified by silica gel column chromatography using mixtures of chloroform-methanol as eluents to give first 9α,15α-dihydroxy-16-phenyl-to-tetranorprostanic acid ( 18b ) as a viscous oil weighing 16 mg , 58 mg of a mixture of C y epimers, and finally 93,15a-dihydroxy-16-phenyl-w-tetranorprostanic acid ( 18b ) as a viscous oil weighing 10 mg.

EXAMPLE 24

9-oxo-153~ (tetrahydropyran-2-yloxy)-16-(m-tolyl)-13-trans-to-tetranorprostenic acid ( 17c).

A solution of 200 mg (0.445 mmol) of 9-oxo-153~(tetrahydro-pyran-2-yloxy)-16-(m-tolyl)-5-cis, 13-trans-prostadioic acid ( 16c)

in 20 ml of ethyl acetate containing 30 mg of 10% Pd/C was stirred in 1 atmosphere of hydrogen at 0-5° for 1 hour. At this point, hydrogen uptake had ceased. The mixture was filtered and evaporated

to give 200 mg of 9-oxo-153-(tetrahydropyran-2-yloxy)-16-(m-tolyl)-13-trans-w-tetranorprostenic acid (17c) as a colorless oil.

EXAMPLE 25

9-oxo-153_hydroxy-16-(m-tolyl)-13-trans-oj-tetranorprostenic acid (17c)

A solution of 200 mg (0.445 mmol) of 9-oxo-153~(tetra-hydropyran-2-yloxy)-16-(m-tolyl)-13-trans-α-tetranorprostenic acid (17c) in 10 ml of a 65: 35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 18 hours and then concentrated by rotary evaporation. The resulting 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-1β3-hydroxy-16-(m-tolyl)-13-trans-u-tetranorprostenic acid (17c), 50 mg, was collected. The infrared spectrum (CHC1-.) showed a broad hydroxy absorption at (3650-3200 cm -1), strong carbonyl absorption at 1740 cm and 1710 cm for the ketone and acid respectively, and absorption at 970 cm 1 for the trans double bond.

EXAMPLE 26

9,15-dioxo-16-(m-tolyl)-5-cis, 13-trans-w-tetranorprostadic acid (26c).

To a solution, cooled to -10° under nitrogen, av

130 mg (0.35 mmol) of 9-oxo-15α-hydroxy-16-(m-tolyl)-5-cis, 13-, trans-^-tetranorprostadic acid ( 25c ) in 20 ml of reagent grade acetone was added 0.14 ml Jones' reagent. After 3 minutes at 0°, 5 drops of 2-propanol were added, and the reaction mixture was stirred for a further 5 minutes, then diluted with 50 ml of ethyl acetate, washed with water (2x20 ml), brine (1x20 ml), dried (Na2S04) and concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Brinkmann). After elution of less polar impurities, the desired 9,15-dioxo-16-(m-tolyl)-5-cis,13-trans-w-tetranorprostadic acid (26c), 100 mg, was collected. The infrared spectrum (CHC13) showed strong carbonyl absorption at 1740 cm"<1> for the ketone, 1710 cm<1> for the acid and at 1660 cm<-1> and 1610 cm"<1> for the enone.

EXAMPLE 27

9α-acetoxy-15α-(tetrahydropoyran-2-yloxy)-16-(m-tolyl)-5-cis, 13-trans-co-tetranorprostadic acid.

A mixture of 300 mg (0.625 mmol) of 9α-hydroxy-15cx-(tetra-hydropyran-2-yloxy)-16-(m-tolyl)-5-cis,13-trans-to-tetranorprostadic acid (33c), 1.88 ml of pyridine and 0.28 ml of acetic anhydride were stirred under N at 50° for 5 hours and then poured into ice water and extracted with ethyl acetate. The ethyl acetate extract was washed with water (1 x 20 mL) and brine (1 x 20 mL), dried (Na 2 SO 4 ) and concentrated to give 306 mg of 9α-acetoxy-15α-(tetrahydropyran-2-yloxy)-16-(m-tolyl ) -5-cis, 13-trans-co-tetranorprostadic acid.

EXAMPLE 28

9α-acetoxy-15α-hydroxy-16-(m-tolyl)-5-cis-13-trans-co-tetranorprostadic acid.

A solution of 306 mg of 9α-acetoxy-15α-(tetrahydropyran-2-yloxy)-16-(m-tolyl)-5-cis-13-trans-co-tetranorprostadic acid in 10 ml of a 65:35 mixture of glacial acetic acid: water was stirred under nitrogen at 25° for 18 hours and then concentrated by rotary evaporation. The resulting 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 9g-acetoxy-15a-hydroxy-16-(m-tolyl)-5-cis-13-trans-co-tetranorprostadic acid, 85 mg, was collected. The infrared spectrum (CHC1-J showed carbonyl absorption at 1730 cm ^ and broad hydroxyl absorption at 3650-3200 cm

EXAMPLE 29

9α-acetoxy-15-oxo-16-(m-tolyl)-5-cis-13-trans-co-tetranorprostadic acid.

To a solution cooled to -10° under N2 of 85 mg (0.19 mmol) of 9ct-acetoxy-15α-hydroxy-16-(m-tolyl)-5-cis-13-trans-co-tetranorprostadic acid in 10 ml of acetone of reagent quality was set 0.07 ml Jones' reagent. After 3 minutes at 0°, 5 drops of 2-propanol were added, and the reaction mixture was stirred for a further 5 minutes and was then diluted with 50 ml of ethyl acetate, washed with water (2x20 ml), with brine (1x20 ml), dried (Na2SO4 ) and concentrated to give 80 mg of 9α-acetoxy-15-oxo-16-(m-tolyl)-5-cis-13-trans-to-tetranorprostadic acid.

EXAMPLE 30

9α-Hydroxy-15-oxo-16-(m-tolyl)-5-cis, 13-trans-ω-tetranorprostadic acid (34c).

A mixture of 80 mg (0.18 mmol) 9α-acetoxy-15-oxo-16-(m-tolyl)-5-cis-13-trans-to-tetranorprostadic acid, 0.5 ml 1.0 N aqueous sodium hydroxide, 2 ml of tetrahydrofuran and 1.5 ml of methanol were stirred at 27° for 12 hours. The reaction mixture was concentrated by rotary evaporation, and the crude product was purified by chromatography on silica gel (Mallincrodt CC-7) eluting with methylene chloride and ethyl acetate. After elution of the less polar impurities, 9α-hydroxy-15-oxo-16-(m-tolyl)-5-cis-13-trans-co-tetranorprostadic acid (34c), 18 mg, was collected. The infrared spectrum showed strong carbonyl absorption at 1660 cm ^ •and 1610 cm for the enone and broad hydroxy absorption at 3650-3200 -1

cm

EXAMPLE 31

2-[5α-hydroxy-23-(3-oxo-4-(m-tolyl)but-1-yl)cyclopent-la-yl]-acetic acid, Y-lactone ( 6c ).

A heterogeneous . mixture of 6.8 g of 2-[5α-hydroxy-2(3-(3-oxo-4-(m-tolyl)-trans-buten-1-yl)cyclopent-la-yl]acetic acid, Y-lactone ( 2c) and 670 mg of 10% palladium-on-charcoal in 55 ml of ethyl acetate were shaken in a Parr shaker for 30 minutes. The mixture was then filtered through a pad of "Celite" and concentrated. Purification of the crude residues by silica gel chromatography using 10% ethyl acetate in benzene as eluent gave the desired 2-[5α-hydroxy-23-(3-oxo-4-(m-tolyl)but-1-yl)cyclopent-la-yl]-acetic acid, Y -lactone (6c) as a solid with a melting point of 60.5-62.5° and with a weight of 2.9 g.

The product according to this example (6c_) can be converted into the new 13,14-dihydro-prostaglandin-two-series analogues by the methods according to examples 16-21, 23, 26-30 and 34-35.

EXAMPLE 32

2-[5α-Hydroxy-2(3-(3α-(tetrahydropyran-2-yloxy)-4-phenylbut-1-yl)-cyclopent-la-yl]acetic acid, γ-lactone (8b).

A heterogeneous mixture of 500 mg of 2-[5α-hydroxy-2[3-(3α-(tetrahydropyran-2-yloxy-4-phenyl-trans-buten-1-yl)cyclopent-la-yl]acetic acid, (4b) and 50 mg of 5% rhodium-on-alumina in 5 ml of ethyl acetate are stirred under 1 atmosphere of hydrogen for 2 hours. The mixture is then filtered through a pad of "Celite" and concentrated. Purification of the crude residue by silica gel chromatography affords the desired product 2- [5α-hydroxy-2(3-(3α-(tetrahydropyran-2-yloxy)-4-phenylbut-1-yl)cyclopent-la-yl]acetic acid, γ-lactone (8b)..

The product according to this example (8b) can be converted into de

novel 13,14-dihydroprostaglandin two-series analogs by the methods of Examples 28-21, 23, 26-30 and 34-35.

EXAMPLE 33

2-[5α-hydroxy-23-(3α-dimethyl-tert-butylsilyloxy-4-(3,5-dimethylphenyl)-trans-butenyl-lyl)cyclopent-la-yl]acetic acid, γ-lactone (4d) .

A solution of 1.47 g (4.95 mmol) of 2-[5a-hydroxy-23-(3a-hydroxy-4-(3,5-dimethylphenyl)-trans-buten-1-y1)cyclopent-la-yl ] acetic acid, γ-lactone (3d), 945 mg (6.3 mmol) of dimethyl tert-butylsilyl chloride and 910 mg (13.4 mmol) of imidazole in 2.5 ml of dimethylformamide were 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 (3 times), dried (anhydrous magnesium sulfate), and concentrated. Purification of the crude residue by silica gel chromatography using chloroform as eluent gave the desired product 2-[5α-hydroxy-23-(3α-dimethyl-tert-butylsilyloxy-4-(3,5-dimethylphenyl)-trans-buten-1-yl)cyclopent-la-yl]acetic acid, y - lactone (4d) as a viscous oil weighing 1.67 g.

The product according to this example (4d) can be converted into the corresponding new 11-deoxy-prostaglandins by the method according to examples 18-30, 32 and 34-35.

EXAMPLE 34

p-biphenyl (ent)-9-oxo-11-deoxy-15α-hydroxy-16-phenyl-cis-5-trans-13-co-tetranorprostadienoate.

To a solution of 365 mg (1.02 mmol)(ent)-9-oxo-11-deoxy-15α-hydroxy-16-phenyl-cis-5-trans-13-oj-tetranorprostadic acid in 40 ml of methylene chloride 11.7 ml of a 0.1 M solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in methylene chloride was added. The solution was stirred under nitrogen for 18 hours and then concentrated. The residue was purified by silica gel chromatography using mixtures of benzene:chloroform as eluents to give the desired p-biferiyl (ent)-9-oxo-11-deoxy-15tx-hydroxy-16-phenyl-cis-5-trans-13 -to-tetranorprostadienoate as a white substance with a melting point of 68-70° and a weight of 200 mg.

EXAMPLE 35

n-decyl (rac)-9-oxo-11-deoxy-15α-hydroxy-16-phenyl-cis-5-trans-w-tetranorprostadienoate.

To a solution of 30 mg of (rac)-9-oxo-11-deoxy-15a-hydroxy-16-phenyl-cis-5-trans-u-tetranorprostadic acid in 25 ml of ether was added a solution of diazodecane in ether (the reaction was followed by thin-layer chromatography using 10% methanol in methylene chloride as eluent: Rf for starting material 0.33, Rf for product 0.82). The solution was then concentrated and the crude product was purified by column chromatography to give the desired n-decyl (rac)-9-oxo-11-desoxy-15ct-hydroxy-16-phenyl-cis-5-trans-co-tetranorprostadienoate as a viscous oil weighing 5 mg.

Claims (4)

1. Process for the preparation of an 11-deoxy-u-penta norprostaglandin with the formula where Ar is α- or 3-thienyl, 5-phenyl-α- or -3-thienyl, 5-lower-alkyl-α- or -3-thienyl, α- or 3-naphthyl, tropyl, phenyl, 3,4 -dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4-dichlorophenyl, 3,5-dimethylphenyl and monosubstituted phenyl where the substituent is bromine, chlorine, fluorine, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; R is hydrogen or methyl; and R' is hydrogen, alkyl with from 1 to 10 carbon atoms, aralkyl with from 7 to 9 carbon atoms, α- or 3-naphthyl, phenyl or substituted phenyl where the substituent is lower alkyl, lower alkoxy, chlorine, bromine, fluorine or phenyl; and W is a single bond or cis-double bond; • Z is a single bond or trans-double bond; and N and M are each keto, or and the pharmaceutically acceptable salts thereof, characterized in that a 15-blocked prostaglandin of the formula where R <1> , M, W, Z, R and Ar are as indicated above, and R1 is 2-tetrahydropyranyl or dimethyl-tert-butylsilyl, is hydrolyzed to give a compound where N is ord< that if a connection is desired where M is and when M in the hydrolysis product is keb and if N in the compound of formula I is to be keto, ■ the hydrolysis product is oxidized while M is kept protected during the oxidation when M in the end products is to contain OH, and when it is desired that R' is an ester group, the product is esterified where R' is H, and optionally when R' is H, the pharmaceutically acceptable salts are prepared. 2. Enone which is an intermediate for the production of prostaglandins, characterized by .that it has the formula and the C^-epimers and C^-e<p> imeric mixtures thereof, where Ar is α- or 3-thienyl, 5-phenyl-α- or -3-thienyl, 5-lower-alkyl-α- or -3-thienyl, α- or 3-naphthyl, tropyl, phenyl, 3,4 -dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4-dichlorophenyl, 3,5-dimethylphenyl and monosubstituted phenyl where the substituent is bromine, chlorine, fluorine, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; R is hydrogen or methyl; N is keto or and where' R<1> is hydrogen, 2-tetrahydropyranyl or dimethyl-tert-butylsilyl, and Z is a single bond or trans-double bond, and Q is =0 or 3. 15-prostaglandin which is an intermediate for the production of prostaglandins, characterized in that it has. the formula and the C^^ -epimers and C^-epimeric mixtures thereof, wherein R 1 is 2-tetrahydropyranyl or dimethyl-tert-butylsilyl; M is 0, or and Ar is α- or 3-thienyl, 5-phenyl-α- or -3-thienyl, 5-lower alkyl-α- or -3-thienyl, α- or 3-naphthyl, tropyl, phenyl, 3.4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4-dichlorophenyl, 3.5-dimethylphenyl and monosubstituted phenyl where the substituent is bromine, chlorine, fluorine, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; R is hydrogen or methyl; and R <1> is hydrogen, alkyl with from 1 to 10 carbon atoms, aralkyl with from 7 to 9 carbon atoms, α- or 3-naphthyl, phenyl or substituted phenyl where the substituent is lower alkyl, lower alkoxy, chlorine, bromine, fluorine or phenyl ; and W is a single bond or cis-double bond; and Z is a single bond or trans double bond. 4. Substituted pentane which is an intermediate for the production of prostaglandins, characterized in that it has the formula where R' and R 2 are each alkyl of 1 to 10 carbon atoms, aralkyl of 7 to 9 carbon atoms, α- or 3-naphthyl, phenyl or substituted phenyl where the substituent is lower alkyl, lower alkoxy, chlorine, bromine, fluorine or phenyl, and R' can also be hydrogen.