NO146280B - BIS-TETRAHYDROPYRANYLETERS FOR USE AS INTERMEDIATE FOR PREPARING A PHYSIOLOGY ACTIVE P-BIFENYLESTER OF A PROSTAGLANDIN ANALOGUE OF THE E OR F SERIES - Google Patents

Description

The present invention relates to new intermediate products

suitable for the preparation of certain novel analogs of naturally occurring prostaglandins, particularly the novel 15-substituted-oj-pentanor prostaglandins described in Patent No. 145,437.

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 (Bergstrom et al., Acta Physiol. Scand. 64:332-33 1965 and Bergstrom et al., Life

Pollock. 6:449-455, 1967) and lowers systemic arterial blood pressure (vasodepression) by intravenous administration (Weeks and King, Federation Proe. 23:327, 1964; Bergstrom, et al., 1965 op. eit.; Carlson, et al. , Acta Physiol. Scand. 75:161-169, 1969). Another well-known physiological action of PGE 2 and PGE 2 is bronchodilation (Cuthbert, Brit. Med. J. 4:723-726, 1969).

A further important physiological role for the natural prostaglandins is in connection with the reproductive cycle.

PGE2 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 is useful in regulating fertility (Karim, Contraception 3, 173 (1971). Patents have been obtained for a number of prostaglandins of the E and F series for inducing labor in mammals (Belgian patent 754 158 and West German Patent 2 034 641) and regarding the use of PGF^ F2 and F3 for regulation of the fertility cycle (South African Patent 69/6089) It has been shown that luteolysis can occur as a result of the administration of PGF2a [Labhsetwar, Nature 230 528 (1971)] and prostaglandins can thus be used for fertility regulation by means of a method where smooth muscle stimulation is not necessary.

Additional known physiological effects for PGE^ are

by the inhibition of gastric acid secretion (Shaw and Ramwell, in: Worcester Symp. on Prostaglandins, New York, Wiley, 1968, pp. 55-64) and also by the platelet agglomeration (Emmons, et al., Brit. Med. J. 2:468 -472, 1967).

It is now known that such physiological effects can only be produced in vivo for short periods after the administration of a prostaglandin. A large body of evidence indicates 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 15o-hydroxyl group (Anggard, et al., Acta. Physiol. Scand. ,

81, 396 (1971) and references cited therein). It has been shown that the introduction of a 15-alkyl group into the prostaglandin has the effect of increasing the duration of action probably by preventing the oxidation of the C15-hydroxyl [Yankee and Bundy, JACS 94, 3651 (1972), Kirton and Forbes, Prostaglandins, 1,

319 (1972)].

It is of course considered desirable to produce analogues of prostaglandins which would have physiological effects which were equivalent to 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 observed after systemic administration of natural prostaglandins (Lancet, 536, 1971).

It is also considered necessary to produce compounds

which can be easily crystallized since the isolation and purification of non-crystalline products requires a long time and is inefficient.

These requirements are met by the new physiologically active para-biphenyl esters of prostaglandin analogues of the E or F series with the formula

where

A 0 etr il Ar2, (Cm H2 „e) r n - et elhleer lt -t(aCHll 2 -.) m fr-a OR 21 , thivl or 4, n R e_r is et ahlkeylt l mtaed ll fr<f>a <ra>

1 to 3 carbon atoms, Ar is α-furyl, Ø-furyl, α-thienyl, |3-thienyl, α-naphthyl, &-naphthyl, phenyl or monosubstituted phenyl where the substituent is methoxy, methyl or phenyl,

R is para-biphenyl,

R is hydrogen or methyl,

W is a single bond or cis-double bond,

Z is a single bond or trans-double bond, and

M is oxo. In one of the methods for producing the new compounds of formula I above, new intermediates are used, and according to the invention, intermediates of the formula are provided where A, R, R1, M, W and Z are as stated above, and THP is 2-tetrahydropyranyl.

Preferred intermediates are 1) a compound of the formula: and 2) a compound of the formula:

where A, R, Z, W, THP and R"'' are as indicated above.

It will be understood that the term "prostaglandin of the "zero" series", e.g. PGE^, refers to prostaglandin where the 5-6 and 13-14 double bonds are saturated; i.e. PGEQ is 5-6, 13-14-tetrahydro-PGE2. In addition, the designations "one-series" or "two-series" refer to the degree of unsaturation in the side chain, e.g. PGE2 and PGF2q are prostaglandins of the "two series" while PGE^ and PGF^a are prostaglandins of the "one series". The term prostaglandin should be understood to include both epimers at C^. In addition, the term "lower alkyl group" is used for alkyl groups containing from 1 to 3 carbon atoms. The invention will be more easily understood by reference to the following reaction schemes which, together with the description, illustrate the production of the new intermediates according to the invention and their use in the synthesis of co-pentanor prostaglandins.

As shown in Scheme A, the first step (1-»■ 2) is the condensation of a suitable ester with a dialkylmethylphosphonate, giving oxophosphonate 2. The desired methylester is usually condensed with dimethylmethylphosphonate.

12+3 the oxophosphonate 2 is reacted with the known [Corey

et al., J. Am. Chem. Soc. , 93 , 1491 (1971] aldehyde H to prepare the enone 3^.

After chromatography or crystallization, the enone 3_ is transferred to a mixture of tertiary alcohols _13 and IA by reacting the suitable lithium alkyl and the isomers 13 and 14 are separated by column chromatography. The enone 3_ is reduced with zinc borohydride to a mixture of alcohols, 4_ and _5, which can be separated as indicated above. The isomer separation in this step is not absolutely necessary and the epimeric mixture can be passed through the following steps to the resulting prostaglandin analogues which can then be separated. In this reaction, ethers such as tetrahydrofuran or 1,2-dimethoxyethane are usually used as solvents, although methanol is sometimes preferred to ensure specific reduction. Further transfers of £ are shown in Scheme B: 4 + 6 is a base-catalysed hydrolysis where the p-biphenyl-carbonyl protecting group is removed. This is conveniently carried out with potassium carbonate in methanol or methanol-tetrahydrofuran solvent. 6^ ■+ 1_ comprises the protection of the two free hydroxyl groups with the acid-labile protecting group, 2-tetrahydropyranyl, which is introduced into the molecule by treatment with dihydropyran and an acid catalyst in an anhydrous medium. The catalyst is usually p-toluenesulfonic acid.

7 8 is a reduction of the lactone 1_ to the hemiacetal 8^

by using diisobutylaluminum hydride in an inert solvent. Low reaction temperatures are preferred and -60°

to -70°C is common. However, higher temperatures can be used if overreduction does not take place. 8 is purified if desired by column chromatography. 8 + 9 is a Wittig condensation where the hemiacetal f5 is reacted with (4-carbohydroxy-n-butyl)-triphenylphosphonium bromide in dimethylsulfoxide, in the presence of sodium methylsulfinyl methide.

9 is cleaned as indicated above.

9 + 10 is an oxidation of the secondary alcohol £ to the ketone 10_. This can be done by using oxidizing agents that do not attack the double bonds; however, it is preferred to use Jones reagent. The product is cleaned as indicated above.

Optionally, the compounds of formula 5_, 1J3 and 1£ in scheme A can be used instead of 4_ in scheme B to form corresponding intermediates analogous to compounds 9 and 10.

Scheme C illustrates the synthesis of the precursors of 13,14-dihydro-15-substituted-w-pentanorprostaglandins. 1 3.."*" il in 19<<> the enone 3^ is reduced to the tetrahydro compound by using complex metal hydrides as reducing agents, LiAlH4, NaBH4, KBH^, LiBH^ and Zn(BH4)2. Particularly preferred is NaBH4. The products 19. °<3 19.'» are separated from each other by column chromatograph i.

The compounds 4^ and 5 in scheme A can also be reduced catalytically with hydrogen to _19 and 19/ . The step at which the double bond is reduced is not critical, and the hydrogenation of J5 or 1_ in Scheme B will also provide useful intermediates for the subsequent preparation of 13,14-dihydroprostaglandin analogues. This reduction can be achieved either with a homogeneous catalyst such as tris-(triphenylphosphine)chlororhodium I or with a heterogeneous catalyst such as platinum, palladium or rhodium. In a similar manner, the precursors of 15-lower alkyl-15-substituted-cj-pentanorprostaglandins are synthesized by replacing _13 and 14 with 4^ and _5 in the synthesis just described. The transfer of 1_9, 19', 20' and 20_ follows the pathway shown in scheme B when 4_ is replaced by lj), _19' , 20' and 20 and one obtains the relevant 13,14-dihydro-intermediates according to the invention containing hydrogen or lower alkyl group at carbon 15.

Scheme D illustrates the preparation of various reduced 15-substituted-u)-pentanorprostaglandin precursors:

19 -*■ 2_2 is performed as illustrated in form B for 4_ -»• 9_. 2_2

can be used both as a precursor to a 13,14-dihydro-15-substituted-cQ-pentanorprostaglandin of the "2-series" or as an intermediate to 2J3, a precursor to a 13,14-dihydro-15-substituted- 03-pentanorprostaglandin of the "1 series". 22_ •* 23_ is carried out by catalytic hydrogenation using the catalyst described for the reduction of 4 ■> 19 in scheme C. The intermediates of the type _21 are prepared by selective hydrogenation of the 5,6-cis double bond at low temperature using catalyst as such as those described for 4_ ■+ 1_9. For this hydrogenation, it is particularly preferred to use palladium on carbon as a catalyst and a reaction temperature of -20°. The intermediates of type 21 are not only precursors of 15-substituted-w-pentanorprostaglandins of the "1 series", but are also precursors of the compound of type 2_3 via the pathway discussed for 22 -> 2j3.

The C-^-epimers of 21, 2/ 2 and 2_3 can be used as precursors to the 15-epi series of the prostaglandin derivatives as described above, and 15-lower-alkyl-15-substituted-ou-pentanorprostaglandins which are reduced in 5,6 and/or the 13,14 position and their C 1 -epimers can be prepared from the appropriate substituted analogues of 9 1 and 1 9 ; the syntheses of these follow schemes A and B.

13,14-dihydro-15-lower-alkyl-15-substituted-io-pentanorprostaglandins are available from the appropriate substituted precursors via Scheme D.

The synthesis of the natural prostaglandins has been carried out

by Prof. E. J. Corey et al. (Corey, et al., J. Amer. Chem. Soc. , 92_, 2586 (1970); and references therein), and prostaglandins prepared by this reaction sequence, as well as by other reaction schemes or isolated from natural materials are suitable for use as precursors to the compounds according to the present invention.

The introduction of the p-biphenyl group to produce the new p-biphenyl ester intermediates according to the present invention is shown in Scheme E which also illustrates the conversion of the intermediates to the final prostaglandin p-biphenyl esters

("PBE").

The p-biphenyl group is introduced by means of an esterification reaction which can suitably be carried out by bringing the suitable precursor acid into contact with 1-10 mol of p-phenylphenol in the presence of 1-2

moles of dicyclohexylcarbodiimide in a reaction-inert solvent, usually methylene chloride. As indicated in Scheme E, 9_ can be transferred to 9 PBE by the esterification reaction as indicated above and 9 PBE can be transferred to 10 PBE by the same methods indicated for the transfer of 9_ to 1_0 as previously indicated.

The compounds 10 PBE and 9 PBE can be converted into 11 PBE and 12 PBE respectively by acid hydrolysis of the tetrahydropyranyl groups. Any acid that does not cause breakdown of the molecule while the protecting group is removed can be used, but usually 65% aqueous acetic acid is used. The product is purified by column chromatography as described above.

p-biphenyl esters such as 9 PBE, 10 PBE, 11 PBE and 12 PBE can be used as substrates for various hydrogenation schemes previously described for the preparation of the prostaglandin analogues of the "one" and "zero" series to prepare the corresponding p- the biphenyl esters of the "one" and "zero" series.

If, by the previous procedures, you want to

purify by chromatography, suitable chromatographic supports are neutral alumina and silica gel, and 60-200 mesh silica gel is usually preferred. Chromatography is suitably carried out in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane or n-hexane.

It will be seen that the formulas indicate optically active compounds. However, it is clear that the corresponding racemates are also useful for forming final prostaglandin racemates which have valuable biological action due to the content of the biologically active optical isomer, and such racemates are also covered by the preceding formulas and by the claims. The racemate mixtures are easily prepared by the same methods used to synthesize the optically active compounds by simply using the corresponding racemic precursors instead of the optically active starting materials.

The following examples are given to illustrate the invention. In the examples, all temperatures are given in °C, and all melting points are uncorrected.

Example 1

p-biphenyl-9-oxol-lla, 15o- bis-(tetrahydropyran-2- yloxy)-16- phenyl-cis- 5- trans- 13- 6o- tetranorprostadienoate

A solution of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-(D-tetranorprostadic acid (10a) (1 equivalent), p-phenylphenol (10 equivalents) and dicyclohexylcarbodiimide (1.25 equivalents) in methylene chloride are stirred overnight, concentrated (in vacuo) and purified by column chromatography to give p-biphenyl-9-oxo-lla-15a-bis-(tetrahydropyran-2-yloxy) -16-phenyl-cis-5-trans-13-u)-tetranor-prostadienoate.

Without separation, the product is hydrolyzed with 65% aqueous acetic acid to form p-biphenyl-9-oxo-lla,15a-dihydroxy-16-phenyl-cis-5-trans-13-w-tetranorprostadienoate, m.p. 120-121°C (ether-pentane), IR spectra, mass spectra and UV spectra were consistent with the structure.

By applying the above procedure, the other 15-substituted-o)-pentanorprostaglandin-p-biphenyl esters of the E series according to the present invention can be obtained in a similar manner by replacing compound 10a in the above example with the appropriate 11,15-bis-(tetrahydropyran -2-yloxy)-15-substituted-ui-pentanor-prostaglandin.

Example 2

p- biphenyl- 9a- hydroxy- lla, 15a- bis-(tetrahydropyran-2- yloxy)-16- phenyl- cis- 5- trans- 13- 0)- tetranorprostad ierioate

A solution of 9a-hydroxy-lla, 15tx-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-to-tetranorprostadic acid (9a) (1 equivalent), p-phenylphenol (10 equivalents) and dicyclohexylcarbodiimide (1.25 equivalents) in methylene chloride are stirred overnight, concentrated (in vacuo) and purified by column chromatography to give p-biphenyl-9a-hydroxy-lla, 15ci-bis-(tetrahydropyran- 2-yloxy)-16-phenyl-cis-5-trans-13-u)-tetranor-prostadienoate.

By using the above methods, other 15-substituted-a)-pentanorprostaglandin-p-biphenyl esters according to the present invention can be obtained in a similar way by replacing compound 9a in the example above with the suitable 11,15-bis-(tetrahydropyran-2-yloxy )-15-substituted-(D-pentanorprostaglandin.

Without separation, the product is hydrolyzed with 65% aqueous acetic acid to form p-biphenyl-9a,11a,15a-trihydroxy-16-phenyl-cis-5-trans-1 3-cj-tetranorprostadienoate, m.p. 117-119°C.

Claims (1)

Bis-tetrahydropyranyl ether for use as an intermediate for the preparation of a physiologically active para-biphenyl ester of a prostaglandin analogue of the E or F series with the formula: where A is Ar(CH-) - or - (CH„) -OR2, where n is an integer from 2 n 2 m 2 0 to 2, m is an integer from 1 to -4, R is alkyl with from 1 to 3 carbon atoms, Ar is α-furyl, 3-furyl, α-thienyl, 13-thienyl, α-naphthyl, |3-naphthyl, phenyl or monos ubsti tue rt phenyl where the substituent is methoxy, methyl or phenyl, R" <*>" is para-biphenyl, R is hydrogen or methyl, W is a single bond or cis-double bond, Z is a single bond or trans double bond, and M is oxo, characterized in that it has the formula: where A, R, R, M, W and Z are as above, and THP is 2-tetrahydropyranyl.