DE2555210A1 - NEW ANALOGA OF NATURALLY OCCURRING PROSTAGLANDINS - Google Patents

Description

Our no. 20 280 P / La Pr / br

Pfizer Inc. New York, N.Y., V.St.A.

New analogues of naturally occurring prostaglandins

The present invention relates to certain new analogs of naturally occurring prostaglandins, particularly new ones ll-deoxy-15-substitut.-tf-pentanorprostaglandins and valuable Intermediate products for their manufacture.

As is well known, the prostaglandins are unsaturated C _2Q fatty acids, which show various physiological effects. For example, the prostaglandins of series E and A are effective vasodilatbrene (cf. Acta Physiol. Scand., Vol. 64, pages 332 to 333 (1965) and Life Sci., Vol. 6, pages 4 * 19 to ^ 55 (1967) ] and lower case of intravenous administration the systemic arterial blood pressure (vasodepression) CVGL. Federation Proc, Vol. 23 _S page 327 (196 * 1), Acta Med. Scand., Vol. I83, pages 423 to 430 (1968)

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and Acta Physiol. Scand., Vol. 75, pp. 16-169 (1969)]. Another well-known physiological effect of PGE ₁ and PGE "is that of a bronchodilator [cf. Brit. Med. J., Vol. 4, pages 723-726 (1969) 3. Another important physiological role played by the natural prostaglandins is related to the port plant cycle. PGEp is known to have the ability to induce labor Cvgl. J. Obstet. Gynaec. Brit. Cwlth., Vol. 77, pp. 200-210 (1970) 3, to induce a therapeutic abortion. Contraception, Vol. 4, page 293 (1971) 3 and fertility control Cvgl. Contraception, Vol. 3, page 173 (1971) 3. On various prostaglandins of series E and F as active ingredients for inducing labor in mammals Cvgl. BE-PS 75-4 and DT-PS 2 03 * »6413 as well as on PGE ₁ , PGF ₃ and PGF ₃ as active ingredients for controlling the reproductive cycle. ZA-PS 69 / 6O893 patents have been granted. It has been shown that luteolysis can occur as a result of administration of PGFpa tvgl. Nature, vol. 230, page (1971) 3) and consequently prostaglandins are used to control fertility after a process in which smooth muscle stimulation is not required.

Other known physiological _{activities of PGE 1} are in the inhibition of gastric acid secretion Cvgl. Shaw and Ramwell, Worchester Symp. On Prostaglandins, New York, Wiley, 1968, pages 55 to 643 and in platelet aggregation Cvgl. Brit. Med. J ₀ Vol. 2, pages 468 to 472 (1967) 3.

Recently, it has been known that such physiological effects in vivo only for a short period of time after administration of a prostaglandin. Research suggests that the reason for this

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A rapid decrease in effectiveness is to be sought in that the natural prostaglandins are quickly and effectively deactivated by the metabolism, namely by β-oxidation of the carboxylic acid side chain and by oxidation of the 15α-hydroxyl group [cf. Acta. Physiol. Scand., Vol. 81, p. 396 (1971) and the references cited therein]. It has been proven that the introduction of a 15-alkyl group into the prostaglandins causes an increased duration of action, which is possibly due to a protection of the C 9H , p. 365I (1972) and Prostaglandins, Vol. 1, p. 319 (1972) 3.

There was therefore a need to provide analogs of the prostaglandins which had physiological activities comparable to the natural prostaglandins but which, however, show an increased selectivity and duration of activity. It was to be expected that, due to an increased selectivity of the effect, the considerable side effects, in particular the gastrointestinal side effects frequently observed after systemic administration of the natural prostaglandins [cf. Lancet, 536 (I97I) I ₁ would be reduced, "

These needs are met by the new 11-deoxy - ^ - pentanorprostaglandins and their C _{1 (} - epimers > polygons in the 15-position have a hydroxyl or keto group and a substituent of the following general formula:

R Ar-CH-

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wherein Ar is an α- or β-thienyl; 5-phenyl-α- or -thienyl-; 5-lower-alkyl-α- or -β ~ thienyl-; α- or β-naphthyl-; Tropyl-, phenyl-; 3, ^ - dimethoxyphenyl-; 3,4-methylenedioxyphenyl-; 3,4-dichlorophenyl-; 3 »5-dimethylphenyl-; or a monosubstituted phenyl radical, the substituent being a bromine, chlorine or Fluorine atom, the trifluoromethyl, phenyl or a lower one Is alkyl or lower alkoxy group; and wherein R represents a hydrogen atom or the methyl group, as well as the pharmaceutically acceptable salts of these compounds.

Preferred compounds according to the invention are the 15-substitut.-II-deoxy - &> - pentanor_prostaglandins of the series E and P, their Cc epimers and C _lt - "" ^K e ^fc or derivatives and their esters in which the esterifying group is a C ^ ~ to CjQ-alkyl group; C "- to Cg-aralkyl group; the α- or ß-naphthyl group; is the phenyl or a substituted phenyl group, the substituent being a lower alkyl, lower alkoxy or the phenyl group or a chlorine, bromine or fluorine atom.

Such preferred compounds have the general formula

wherein Ar is the α- or β-thienyl; 5-phenyl-α- or -β-thienyl-; 5-lower-alkyl-α- or -β-thienyl-; α- or β-naphthyl-; Tropyl-, phenyl-; 3,5-dimethylphenyl-; 3,4-dimethoxyphenyl-; 3, ^ - methylenedioxyphenyl-; 3, ⁱ f-dichlorophenyl or a monosubstituted phenyl group in which the substituent is a bromine, chlorine or fluorine atom or the trifluoromethyl,

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Denotes phenyl, lower alkyl or lower alkoxy group; R represents a hydrogen atom or the methyl group; M and N one of the groups

0 H ^ - OH, and i) ^

W is a single bond or a cis double bond; Z is a single bond or a trans double bond, and R ^{f is} a hydrogen atom, a C.- to C _1Q -alkyl-; C "- to C _q - aralkyl-; the α- or ß-naphthyl-; Phenyl or a substituted phenyl group in which the substituent is a lower alkyl, lower alkoxy or phenyl group or a chlorine, bromine or fluorine atom.

A particularly preferred group of the new compounds are those of the general formula I OH

COOR ¹

and their C _{1 (} - epimers, - in addition to the 11-deoxyprostaglandins, in which the 11-deoxyprostaglandin is 11-deoxy-PGEp, -PGE ₁ , -PGF _2a , PGF _2β , -PGF ^, -PGF ^, -PGE ^ -PGF ^, -PGF ^,

, -13, lU-dihydro-PGF _{2 (X} , and -13,1 ^

dihydro-PGF-o is _} their esters at carbon atom 1, in which the esterifying group is a C ₁ -. to C _1Q -alkyl group; Cj to Cg aralkyl group; the α- or β-napithyl group; the phenyl or a substituted phenyl group, the substituent of which is a lower alkyl, lower alkoxy or the phenyl group or a chlorine, bromine or fluorine atom, as well as their C _{1 (} - epinate and C 1 - keto derivatives rich in the 15-position a hydroxyl or keto group and a

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Have substituents of the following formula;

R Ar-CH-

wherein Ar is the α- or β-thienyl; 5-phenyl-α- or -ßthienyl-, 5 "lower-alkyl-α- or -β-thienyl-; α- or β-naphthyl-; Tropyl-, phenyl-; 3,5-dimethylphenyl-; 3 »^ - Dimethoxyphenyl-; Ss ^ -Methylenedioxyphenyl-; 3,4-dichlorophenyl or a monosubstituted phenyl group in which the substituent is a bromine, chlorine or fluorine atom or denotes trifluoromethyl, phenyl, a lower alkyl, or lower alkoxy group, and in which R is a hydrogen atom or represents the methyl group.

Another preferred group of the new compounds has the general formula

COOR «

and includes their C 1-4 epimers. . while another preferred linking group has the general formula

/ ^^^ COOR ¹

Ar

and comprises the C ", - epimers.

Ip

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In the above general formulas, W, R ¹ , R and Z have the meanings given above.

The compounds of the following 3 general formulas are also particularly preferred;

COOR ¹

^^ Y ^ ^CE ^ At

In these formulas, W, Z, R and R ^{T have} the meanings given above.

Particularly preferred compounds are:

II-deoxy-16-phenyl-W-tetranor-PGE ₀ 11-deoxy-16-phenyl-üJ-t et ranor-PGE «,

rae.-II-deoxy-16- (β-naphthyl) -w-tetranor-PGE ₂ , H-deoxy-16- (5-phenyl-a-thienyl) -üJ-tetranor-PGE ₂ , II-deoxy-15 - ((-) - 1-phenyl-1-ethyl) - «7-pentanor ~ PGE ₂ , ll-deoxy-16- (m-tolyl) -i *? - tetranor-PGE ₂ , 15-Epi-ll- deoxy-l6- (m-tolyl) -iJ-tetranor-PGE ₂ , ll-deoxy-15-keto-l6- (m-tolyl) - ^ - tetranor-PGE ₂ , ll-deoxy-13, l ⁱ l- dihydro-l6-phenyl - ^ - tetranor-PGE ₂ , IS-Epi-ll-deoxy-lö-phenyl-W-tetranor-PGEp, ll-deoxy-15 - ((+) - l-pnenyl-l-ethyl) -tf-pentanor-PGE ₂ ,

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15-Epi-11-deoxy-15 ((+) - l-phenyl-l-ethyl) - ^ - pentanor-PGE ₂ , rac.-ll-Deoxy-lö-Cp-chlorphenyD-W-tetranor-PGE ^, rac.-II-Deoxy-IS-keto-Lö-Cß-naphthyD-W-tetranor-PGE- and IS-Epi-II-deoxy-Lö-Cp-chlorophenyD-W-tetranor-PGE-.

The invention also relates to valuable intermediates for the production of these prostaglandins, namely:

Compounds of the general formula

I f. ■

and their C _{1 (} - epimers>

wherein R _{1 is} 2-tetrahydropyranyl- or dimethyl-tert-butyl

id *

silylrest'ifnd M, W, Z, Ar, R ¹ and R have the meanings given above;

Compounds of the general formula

■ A

H ^ -OR *

ι !

and their C. ^ epimers,

OH
where Q = 0 or ^, and

R is the 2-tetrahydropyranyl or dimethyl tert-butylsilyl radical or represent a hydrogen atom;

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Compounds of the general formula

in which R, Z and Ar have the meanings given above; and

Compounds of the general formula

Il

, 2

2 3 ^ ^H0

wherein R and R are each C ₁ - to C «-alky! groups, phenylalkyl groups with up to 9 carbon atoms, the phenyl, toly1, α- or β-naphthyl or p-biphenyl group, where R can also be a hydrogen atom .

To prepare the new compounds according to the general formula Kwobei Ar, R, N, Z, MjW and R ^{1 have} the meanings mentioned above in connection with the formula I) and their pharmaceutically acceptable salts, a prostaglandin blocked in the 15-position of the general formula
in the

00R ¹

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wherein R is the 2-tetrahydropyranyl or dimethyl-tert-butylsilyl radical means hydrolyzed so that N represents the group

or <f

means, where if in the hydrolysis product M is a keto group is to group this

HI H. · OH or

is reduced, or, if N in formula I is to be a keto group, the hydrolysis product is oxidized, M being protected during the oxidation in the preparation of the end products in which M contains an OH group, and v / if R ^{1 is} an ester is, the product R ^f = H is esterified, and optionally in the case of the products in which R ¹ = H, the pharmaceutically acceptable salts are prepared.

As can be seen from the following scheme, the 1st stage (1 »2) consists of a condensation between the known Aldehyde 1 (cf. Tetrahedron Lett., 1971, page 4753) and a corresponding 3-ketophosphonate, the enone is formed. The ketophosphonate is usually by condensation of the corresponding carboxylic acid ester with a Dialkyl methyl phosphonate produced. Typically, the desired methyl ester is made with dimethyl methyl phosphonate condensed.

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Enone 2 is then reduced to enol 3 with zinc borohydride or a sterically hindered alkyl borohydride, such as lithium triethyl borohydride or potassium tri-sec.-butyl borohydride. This reduction leads to a mixture of epimers, both of which can be used as substrates for the further reactions. Compound 3 is used to prepare prostaglandin analogs with an α-hydroxyl group on the C. The epimer of compound 3 is used to produce prostaglandin analogs with a ß-hydroxyl group at the C _lt - used. Furthermore, the mixture of the C _lc epimers can be used for the preparation of the 15-ketoprostaglandin analogs. The epimers obtained in the reduction with the hydride can be separated by column chromatography, preparative thin-layer or preparative liquid high-pressure chromatography. In the reduction, ethers, such as tetrahydrofuran or 1,2-dimethoxyethane, or acetonitrile are generally used as solvents.

The enone 2 can catalytically form the ketone 6 with hydrogen be reduced, which is a suitable starting material for the preparation of the 13,1 ^ -dihydroprostaglandin analogues according to of the invention. This reduction can either be done with a homogeneous catalyst such as tris-tri-phenylphosphine rhodium chloride, or with a heterogeneous catalyst system such as platinum, palladium or rhodium be performed. The stage at which the reduction is carried out is not critical, as below will be shown,

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SCHEME A

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255521Q

The enone 2 can also be used to produce the borohydride ion of the alcohol 7 can be reduced in a single step, or the enol 3 can also be used to produce the alcohol 7 can be catalytically reduced using the conditions described above.

The reaction stage 3 * ■ 4 includes the protection of the free

Hydroxyl group with the help of an acid-sensitive protective group. Any protective group sufficiently sensitive to acid is satisfactory, but the most common protective groups are the tetrahydropyranyl or dimethyl-tert-butylsilyl group, which can be introduced into the molecule by combining the compound to be protected with dihydropyran and a acidic catalyst, usually p-toluenesulfonic acid, in an anhydrous medium or with dimethyl tert-butylsilyl chloride and imidazole treated.

The step *} - ^ - 5 is a reduction of the lactone H to the halbacetal 5 using a suitable reducing agent, such as, for example, diisobutylaluminum hydride, in an inert solvent. Lower reaction temperatures are preferred, with -60 to -80 C being usual. However, if the reduction does not start, higher temperatures can also be used. Compound 5 is then purified, if desired by column chromatography. As indicated in Scheme A, compounds H and 5 can be catalytically reduced to compounds 8 and 9, respectively, by the method set out above.

The transfer from 6— ^ 9 takes place in the for the transfer 2 - ^ - 5 outlined way.

The remainder of the synthesis of the prostaglandin analogs according to the invention belonging to the Z series is shown in Scheme B.

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- lit -

Stage 5-> 10 is a Wittig condensation in which the hemiacetal 5 is reacted with ^ - (carboxy) -butyltriphenylphosphonium bromide (22) in dimethyl sulfoxide in the presence of sodium methyl sulfinyl methide. The connection 10 is then cleaned as set out above. The conversion from 10 -> 11 is an acid-catalyzed hydrolysis of the protective group. Any acid which does not cause destruction of the molecule in the course of deprotection can be used; however, 65 % aqueous acetic acid is most commonly used. The dimethyl-tert-butylsilyl protective group can, however, also be removed by the action of tetraalkylammonium fluoride in a solvent such as, for example, tetrahydrofuran. The product is then as shown above; cleaned. Compound 11 is a II-deoxy-15-substitute-W-pentanorprostagland in the series F-. ^ ^e prostaglandin analogs of the series E _? According to the invention (13) are produced from the intermediate product 10, which can be oxidized by any reagent which is capable of oxidizing hydroxyl groups but which does not attack double bonds. However, Jones reagent is generally preferred. The product is purified in the manner outlined above to give intermediate 12. The latter can be converted into the prostaglandin analogs according to the invention of the series E _? (13) in the manner shown for the conversion of 10 → 11 and its C _Q epimers, which can be separated from one another by column, preparative thin-layer or preparative liquid high-pressure chromatography, and which are converted into the prostaglandin analogs according to the invention of the series P_ and Pp _ß according to the for the conversion of 10 - * 11 However, compound 13 can also be reduced with sodium borohydride, whereby

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the prostaglandin analogs according to the invention of the P series _? and Pp_ can be obtained directly. As described above for compound 15, this Eρimereηlösung can be separated, pure PGF "" and PGF_ _{O being} obtained.

dQ there

SCHEME B

2ä 609825/1008

The various reduced prostaglandin analogs according to the invention, ie the prostaglandins of series 1 and O and 13> l ¹ i-dihydro-2, are prepared according to scheme C. The intermediate product 6 can be converted into the compound 19 according to the process steps which have already been discussed for the conversion of 2 -? - 10, the latter can then be converted into the compound 20 according to the above for the conversion of 10 - ^ - 15 Process stages are transferred. The compound 20 can be catalytically reduced to the compound 18 (R = THP or (CH, ^ SiC (CH, K)) according to the process steps set out above, which are the precursors for the prostaglandin analogs of the series 0 according to the invention.

16-> 17 is a selective catalytic hydrogenation of the 5,6-cis double bond at low temperature using catalysts as described above. The use of palladium-on-carbon as a catalyst and a reaction temperature of -20 ° C. is particularly preferred for this reduction. The compound 17 (R = THP or (CH,) pSi C (CH,),) is not only a precursor of the prostaglandin analogues according to the invention of series 1, but also of series 0, since they are produced using the for the stage M - > ■ 8 described methods for compound 18 can be reduced. Similarly, compound 16 can be reduced to compound 18 by the same procedure. The protective groups are removed as described above, and in this way the compounds 17, 18, 19 and 20, where R = THP or (CH ^) ₂ SiC (CH,), for the preparation of the prostaglandins according to the invention of series 1, 0 and 13,1 ^ -dihydro-2 are freed from the protective group. The production of the prostaglandins of the series E and P, the prostaglandin being one of the series 0 or 1, or the series 13,14-dihydro-2 from the compounds 16, 17, 18, 19 and 20 is carried out on the previous steps for the transfer of connection 10 in the manner described in connections 11, 12, 13 »i4 and 15.

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SCHEME C

οοπ

Ar

COOH

COOK

COOH

Ar

18th

R ₁ -H, THP or (0113) 2 SI 0 (0113) 3

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Furthermore, the 15-substitut. -G7-Pentanorprostaglandinanäloga of the series E., P. _ß and F * _a can be obtained directly from the corresponding prostaglandin analogs of the series 2 by first protecting the hydroxyl group by introducing dimethylisopropylsilyl groups, selectively reducing the cis double bond and removing the protecting group.

As a rule, the reduction is set out above for stage 16—> 17. carried out; the removal of the protecting group takes place by touching the reduced protected Compound with a mixture of acetic acid and water in the ratio 3: 1 for 10 minutes or until the Implementation is practically complete.

The ll-deoxy-15-substitut .- &? - pentanorprostaglandin analogs of the series 1 according to the invention can be prepared according to the alternative synthesis shown in Scheme D. In the first stage this. Production process the hemiacetal, namely 2- [5a-hydroxy-2ß-benzyloxymethylcyclopent-la-yl] -acetaldehyde-y-hemiacetal; with the disodium salt of H- (carboxy) -butyltriphenylphosphonium bromide (22), as before for step 5 - ^ 10 shown implemented. This intermediate product can be processed further, as described in detail in the examples below.

As shown in Scheme D, hemiacetal 21 is reacted with reagent 22 to form compound 23.

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SCHEME D

or.

0-CH ₂

21

0PCh ₂ CH ₂ CH ₂ CH ₂ -COOH

Na +

OH

he

^ COOH

^ CHO

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The conversion of 23 to 2k involves the esterification of the carboxyl group with diazomethane to form the methyl ester as an intermediate. Other blocking groups can also be used provided that the group is stable to hydrogenation and mildly acidic hydrolysis and is removable by mildly basic hydrolysis. Examples of such groups are C ₁ - to Cg-alkyl groups, phenylalkyl groups with up to 9 carbon atoms, the phenyl, tolyl, p-biphenyl or α- or ß-naphthyl group. Acylation of the methyl ester intermediate with acetic anhydride and pyridine leads to the acetate intermediate. Other blocking groups can be used provided that the group is resistant to hydrogenation and mild acidic hydrolysis. Examples of such groups are Cp- to Cq-alkanoyl groups, phenalkanoyl groups with up to 10 carbon atoms, the benzoyl, toloyl, p-phenylbenzoyl or α- or β-naphthoxy groups. The protected benzyl ether ensures after reduction with hydrogen and palladium-on-charcoal in a suitable solvent with a content of a suitable acidic catalyst, with ethanol and acetic acid or ethyl acetate and hydrochloric acid being particularly preferred - _} the formation of a hydroxyl compound, the oxidation of which with Collins Reagent leads to the aldehyde 2 ¹ ».

Process stage 2H -> 17 comprises the treatment of compound 2k with the sodium salt of the corresponding 3-ketophosphonate under conditions which have been described above for stage 1 - »- 2, an enone being formed, which is reduced with a sterically hindered alkyl borohydride such as lithium triethyl borohydride or potassium trisec.-butyl borohydride; or zinc borohydride, leads to an enol. The hydroxyl group is then protected by treatment with dihydropyran to form a tetrahydropyranyl ether. Other protecting groups can also be used provided that they are stable to mildly basic hydrolysis and easily removed by mildly acidic hydrolysis

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can be. Examples of such groups are the tetrahydrofury1 and dimethyl-tert-butylsilyl groups. These Protected compound is then brought into contact with aqueous sodium hydroxide solution to form compound 17. The conversion of the compound 17 into the II-deoxy-15-substitut.-fca-pentanorprostaglandins row 1 according to the invention is carried out according to the method set out above.

SCHEME E

0OH

COOH

Ar

25th

COOH-

27

COOH

0OH

Ar

29

30th

Θ09825 / 1 OÖfi

M-

OOH

HO ^ H

The ll-deoxy-15-keto-15-substitut .- & - pentanorprostaglandins E according to the invention can be prepared as summarized in Scheme E. Step 25-26 comprises the oxidation of the C 1-4 alcohol radical of compound 25. Any reagents which can oxidize hydroxyl groups but which do not attack double bonds can be used for this purpose; however, it is preferred to use Jones reagent. The 15-keto-prostaglandin-E analogs according to the invention of series 13, l ^ -dihydro-2, -1 and -0 can be prepared from compounds 27, 29 and 31, as was done for step 25-26 above was set out.

Scheme P comprises the preparation of the 11-deoxy-15-keto-15-substitut.-itf-pentanorprostaglandin; ~ Fp and -FpQ analogs together. Step 33-34 involves the acylation of compound 33 with acetic anhydride and pyridine to form an intermediate acetate. Other blocking groups can also be used provided that the group is resistant to mild acidic hydrolysis. Examples of such groups are the Cp to C _q -Alkanoy groups!, Phenalkanoylgruppen having up to 10 carbon atoms, benzoyl, tolyl, p-phenylbenzoyl, or a- or ß-naphthoyl. Then the protecting group is on

as described above, to give a second intermediate product. The next level includes the

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Oxidation of the C., Alcohol residue, a third intermediate product being obtained. Any reagent which can oxidize hydroxyl groups but which does not attack double bonds can be used; however, Jones reagent is typically used. The last stage of this reaction sequence comprises the transesterification of the protecting group on the C Q.

SCHEME P

Ar

0OH

COOK

Ar

33

35

COOH

Ar

COOH

COOH

Ar

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SCHEME ^w (ff.)

COOH

Ar

39

OOH

Ar

= THP OR

M =

HO., H

^{si C} ( ^CH 3) 3

.-OH

The transesterification is usually carried out by making the compound with anhydrous potassium carbonate in an alcoholic solvent, such as, for example, methanol, the lüJ-keto-F- or _-F 2ß-analogs according to the invention being obtained. The analogs according to the invention of the 15-keto-prostaglandins P_ or P ₀ of series 13, 14-dihydro-2, -1 and -0

«Λ Yes

can be made from compounds 35, 37 and 39 in the manner described for 33 and 34. It will noted that for the preparation of all 15-keto compounds according to the invention the stereochemistry of the hydroxyl group at C., - is unimportant; both 15β »15Λ or a mixture of epimers leads to the same 15-keto analog. If purification by column chromatography is desired in the methods described above, suitable ones will be used chromatographic carriers such as neutral clay and silica gel, used, with silica gel with a mesh size of 0.248 to 0.074 now being generally preferred will. The chromatography is expediently, as is shown below in the examples, in reaction-inert Solvents such as ether, ethyl acetate, benzene, chloroform, ethylene chloride, cyclohexane or η-hexane.

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by
If the purification / high-pressure liquid chromatography is carried out, suitable carriers are, for example, "Corasil", "Porasil" and "Lichrosorb", using inert solvents such as ether, chloroform, methylene chloride, cyclohexane or η-hexane.

The formulas presented above show optically active compounds. It should be noted, however, that the formulas have both optical antipodes, e.g. 8,12-nat and 8,12-ent, should include, which are also claimed. The two optical antipodes can use the same methods can be easily prepared using only the corresponding optically active aldehyde as a precursor. It should be noted that the corresponding racemates, thanks to their content of the aforementioned biologically active optical isomers also have valuable biological activity, and that such Racemates are also to be encompassed and claimed by the formulas presented above. The racemic mixtures are prepared by the same methods as those used for the synthesis of the optically active compounds, where the corresponding racemic precursors are merely used instead of the optically active starting materials. It can also be seen that the formulas presented above include an optically active center at the C.g, when R is the methyl group. As a result, the above formulas are intended to have both optical antipodes at the C ^ g (e.g. of configuration R and S), which are also claimed. The two optical antipodes on the C.g are easily prepared by the same process, using only the corresponding optically active phosphonate used as a forerunner.

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It has been proven by numerous studies in vivo and in vitro that the new prostaglandin analogs Have physiological effects which are comparable to those of natural prostaglandins, the new connections, however, are much more tissue-selective and in their effects are longer lasting. These tests include a test for the effect on the isolated smooth muscle of the uterus of guinea pigs, the ileum of guinea pigs and the uterus of rats, a test regarding the inhibitory effect of histamine-induced bronchospasm in guinea pigs, a test for the effect on blood pressure in dogs, a test for the inhibitory effect of stress elicited ulceration in the rat; a test for elicitation of diarrhea in the mouse and a test for the inhibition of stimulated gastric acid secretion in the rat and the dog.

The physiological responses observed in these tests are to determine the usefulness of the compounds tested are useful for the treatment of various natural and pathological conditions. Examples for such determined usabilities are the following:

Afc ft *

Activity as a vasodilator, antihypertensive agent, bronchodilator, anti-arrhythmic and cardiac stimulating effectiveness, as well as effectiveness as an anti-fertility and anti-ulcer agent. An advantage that generally benefits the 11-deoxyprostaglandins of the series E ^ is their increased stability compared to those like PGEp. Also own the II-deoxy-15-substitut.-c ^ -pentanorprostaglandins according to the invention a highly selective efficacy profile compared to the corresponding naturally occurring prostaglandins and they show a longer duration of action in many cases. The prostaglandin analogs according to the invention have a valuable vasodilatory effectiveness. A first example

809825 / 1ÖÖ6

for the therapeutic importance of these prostaglandin analogs is the effectiveness of ll-deoxy-16-phenyl - ^ - tetranorprostaglandin-E and 15-epi-ll-deoxy-16- (m-tolyl) - ^ - tetranorprostaglandin-E, which compared to PGE- themselves have a very increased hypertensive effectiveness and duration of action. Compared to PGE _? At the same time, the stimulating effect on the smooth muscles is considerably reduced. Other E and F _R analogs of the invention show a similar desirable hypotensive effect.

Furthermore, the II-deoxy-16- (m-tolyl) - ^ - tetranorprostaglandin-E ₂ and II-deoxy-16- (5-phenyl-oc-thienyl) -t ^ -tetranorprostaglandin-Ep show a strong bronchiodilator activity with decreased non-vascular smooth muscle effectiveness. In a similar manner, other analogs of the invention of II-deoxy-15-substitute.-UX- pentanorprostaglandin-E show. and -Ep desirable efficacy as bronchodilators.

Another excellent example of the therapeutic importance of these prostaglandin analogs is the strong selective antiulcer and anti-secretory activity of II-deoxy-16- (ß-naphthyl) -tf-tetranor-PGE ₂ and II-deoxy-15-keto-lö-Cß- naphthyD - ^ - tetranor-PGEp. Other PGE and 15-keto analogs of the invention show similar desirable gastrointestinal activities.

The C ^ phenyl esters of the prostaglandin analogs according to the invention are prepared from the appropriate acids by mixing them with the desired phenol in the presence of dicyclohexylcarbodiimide in an inert reaction solvent. The Cj alkyl or phenyl alkyl esters the prostaglandin analogs of the invention are from the

609825 / $ 100

corresponding acids prepared by reacting them with the corresponding diazo compound in the presence of a reaction-inert Reacts solvent. Such esters have the activity of the acid from which they are derived. the Esters of the prostaglandin analogs according to the invention which are acylated at Cq and / or C. are easily obtained from the corresponding parent compounds prepared by acylation, usually using the carboxylic acid anhydride or chloride is made as acylating agent. Such acyl groups are lower alkanoyl groups, the benzoyl group and substituted benzoyl groups in which the substituent is a halogen atom, the trifluoromethyl group, is a lower alkoxy or the phenyl or formyl group. Such esters have the effectiveness of Erostaglandin analogue from which they are derived.

The prostaglandin analogs which the C. "a ß-hydroxyl group and the C ₁ - group have a lower alky, have their epimers similar effect. In some cases, however, the selectivity exhibited by these compounds exceeds that of the epimeric compounds, as is the case with the 15-epi-16-m-tolyl-PGE ₂ analog for hypotensive potency. Pharmacologically useful salts which can be used for the purposes mentioned above are those with pharmacologically useful metal cations, ammonium, amine or quaternary ammonium cations.

Particularly preferred metal cations are those derived from alkali metals such as lithium, sodium and Potassium, and derived from alkaline earth metals such as magnesium and calcium, although also cationic forms of other metals such as aluminum, zinc and iron fall under the term "pharmacologically acceptable salts".

609825/1006

Pharmacologically useful amine cations are those which are 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, a-phenylethylamine, ß-phenylethylamine, Ethylenediamine, diethylenetriamine and similar aliphatic, cycloaliphatic and araliphatic amines with up to 18 carbon atoms including as well as heterocyclic amines such as piperidine, morpholine, pyrrolidine, Piperazine and its lower alkyl derivatives, such as 1-methyl pyrrolidine, !, it-dimethylpiperazine, 2-methylpiperidine and "the like, as well as amines containing water-solubilizing or hydrophilic groups, such as mono-, di- and Triethanolamine, ethyl diethanolamine, n-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, Tris (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (p-tert-amy! Phenyl) -diethanolamine, Galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, Phenylephrine, epinephrine, procaine and the like.

Examples of suitable pharmacologically useful quaternary;?!. Ammonium cations are the tetramethylammonium, tetraethylammonium, BenzyItrimethylammonium and phenyltriethylammonium cations.

m The inventive compounds may / be a variety of pharmaceutical preparations used containing the compounds or the pharmaceutically acceptable salt; they can be administered in the same manner as natural prostaglandins by a variety of routes of administration, such as intravenous, oral and topical routes, including intravaginal and intra-

609825/1006

³⁰ "2565210

nasal route, as well as administration as an aerosol.

For bronchodilation or to increase the nasal effectiveness, a suitable dosage form is an aqueous-ethanolic solution of II-deoxy-16-Ar-substitute, - & ^r -tetranor-PGE ₁ or -PGEp, which is made using a quantity of fluorocarbons as propellant from about 3 to 500 yug / dose is used as an aerosol.

The l6-Ar-substitut invention. ITF tetranorprostaglandinanaloga the series E ", and E_ 13, l ^l-dihydro-i E_, or -F.

ά U C. JD

are effective antihypertensive agents. For the treatment of hypertension, these medicaments can expediently be used as intravenous injection, in doses of about 0.5 to 10 µg / kg, or preferably in the form of capsules or tablets in doses of 0.005 to 0.5 mg / kg / day.

The 15-keto-16-Ar-substitute-47-tetranorprostaglandin analogs according to the invention or Lö-Ar-substitute .- ^ - tetranorprostaglandin-E analogs are valuable remedies against incantation. These can be used to treat peptic ulcers Medicines in the form of capsules or tablets are administered in doses of 0.005-0.5 mg / kg / day.

For the manufacture of one of the aforementioned dosage forms or another of the numerous other possible forms, various reaction-inert diluents, Excipients or carriers are used. Examples of such substances are water, ethanol, gelatins, Lactose, starches, magnesium stearate, talc, vegetable oils, Benzyl alcohol, gums, polyalkylene glycols, petrolatum, Cholesterol and other known drug carriers.

609825/1008

25B5210

Optionally, these pharmaceutical compositions Auxiliaries, such as preservatives, wetting agents or Contain stabilizers or other therapeutic agents such as antibiotics.

The following examples serve to explain the invention in more detail. The temperatures are given in ⁰ C and the melting and boiling points are uncorrected.

609825/1008

example 1

2- [2ß-Benzyloxymethyl-5ot-hydroxycyclopent-la-yl] -acet aldehyde-y-hemiacetal (21)

A stirred, cooled to -78 ⁰ C solution of 10.0 g (40.0 mmol) of 2-benzyloxymethyl-L2ß-5a-hydroxycyclopentla.-yij-acetic acid-v-lactone in 100 mL of toluene was treated dropwise with 55.5 ml a 20 jSigen solution of diisobutylaluminum hydride in hexane was added. The solution was stirred in the cold under nitrogen for 40 minutes and then methanol was added dropwise until the evolution of gas ceased. The mixture was then warmed to room temperature and concentrated. The resulting oil was slurried in hot methanol, filtered and the piltrate was concentrated. Purification of the crude product by silica gel chromatography using mixtures of benzene and ethyl acetate as eluent resulted in the desired γ-hemiacetal (21); Yield: 8.91 g (86 Jf).

Example 2

7- [2β-Benzyloxymethyl-50-hydroxycyclopent-11-yl3-cis-5- heptenoic acid (23) , '

A solution of 4.96 g (11.2 mmol) 4- (carbohydroxy-n-butyl) -triphenylphosphonium bromide (22) in 8.85 ml of dimethyl sulfoxide was added dropwise with 9> 73 ml (21.2 mmol) of a 2.18 m Solution of sodium methylsulfinyl methide in dimethyl sulfoxide are added. The resulting red ylide solution was with a Solution of 1.12 g (4.50 mmol) 2- [2ß-Benzyloxymethyl-5 <* - hydroxycyclopent-ia-ylj-acetaldehyde-y-hemiacetal (2) in 11 ml of dimethyl sulfoxide are added. After another 45 minutes

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While stirring, the reaction mixture was poured into ice water. The basic aqueous solution was extracted with a mixture of ethyl acetate and ether in a ratio of 2: 1, covered with ethyl acetate and acidified to pH 3 with 1.0 η hydrochloric acid. The aqueous layer was extracted further with ethyl acetate, the combined ethyl acetate extracts were washed with water, over anhydrous Magnesium sulfate dried and concentrated. Purification of the crude product was carried out by silica gel chromatography to the desired 7- [2β-benzyloxymethyl-5 * -hydroxycyclopentla-yll-cis-5-heptenoic acid (23).

Example 3

Methyl-7? -C2ß-benzyloxymethyl-5 ^a -hydroxycyclopent la yl3- cis-5-heptenote

A solution of 1.41 g (4.06 mmol) of 7- [2 [beta] -benzyloxymethyl-5ci-hydroxycyclopent-la-yl3-cis-5-heptenoic acid (23) in 17 »5 nil anhydrous ether was treated at room temperature with a ethereal diazomethane solution rubbed until the yellow color lasted 5 minutes. The reaction mixture was through Dropwise addition of glacial acetic acid decolorized. The ether solution was then saturated with sodium bicarbonate and saturated Washed brine, dried over anhydrous magnesium sulfate and concentrated to give the desired Connection has been obtained.

Example fr

Methyl 7- [2β-benzyloxymethyl-5ot-acetoxycyclopent-la-yi] - cis-5-heptenoate

A mixture of 1.28 g (3.5 ² J mmol) of methyl 7- [2β-benzyloxymethyl-5tt-hydroxycyclopent-la-yl] -is-5-heptenoic acid, prepared

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prepared according to Example 3, 5.0 ml of pyridine and 0.736 ml (7.78 mmol) of acetic anhydride was stirred under nitrogen at 50 ⁰ C overnight. The mixture was then cooled to room temperature and diluted with 75 ml of ether. The ethereal solution was washed once with water and three times with saturated copper (II) sulfate solution, dried over anhydrous magnesium sulfate and concentrated to give the desired compound.

Example 5

Methyl 7- [2β-hydroxymethyl-5tt-acetoxycyclopent-la.-yi] heptenoate

A heterogeneous mixture of 1.27 g (3.14 mmol) of methyl 7 ~ £ 2ß-benzyloxymethyl-5 ^c <'- acetoxycyclopent - l <x-yl] -cis-5-heptenoate, prepared according to Example 4, 305 mg of 10 % palladium-on-charcoal and 13 ml of a mixture of absolute ethanol and glacial acetic acid in a ratio of 20: 1 were stirred at room temperature under a hydrogen atmosphere for 20 hours. The mixture was then filtered through Celite 545 and the piltrate was concentrated to give the desired compound.

Example 6 Methyl 7-L2ß-formyl-5tt-acetoxycyclopent-la-ylj-heptanoate (24)

A mechanically stirred solution of 3.37 ml (41.7 mmol) Pyridine in 50 ml of methylene chloride, which had been cooled to 10 to 15 ° C., was added in portions under nitrogen 1.89 g (18.9 mmol) of chromium trioxide were added over a period of 30 minutes. The deep burgundy solution was then allowed to return to room temperature

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allowed to warm and then cooled to OC. The cold one Solution was made with a solution of 7 ^ 7 mg (2.37 mmol) Methyl 7-t2ß-hydroxymethyl-5 ^ -acetoxycyclopent-lit-yl] -heptanoate, prepared according to Example 5, mixed with 70 ml of methylene chloride, a dense black precipitate being formed made at the same time. The suspension was stirred in the cold for 15 minutes after which 7.21 g (52.2 mmol) of finely ground sodium bisulfate monohydrate was added. After stirring for a further 10 minutes, 6.25 g (52.2 mmol) anhydrous magnesium sulfate added. After stirring for an additional 5 minutes, the dark suspension became filtered through a pad of celite, washed with methylene chloride and then concentrated by rotary evaporation, wherein the crude methyl 7- £ 2ß-formyl-5a-acetoxycyclppent-layl] heptanoate (2 * 1) was obtained, which without further Cleaning was continued.

Example 7

Methyl 9a-acetoxy-15-oxo-16- (p-chlorophenyl) -13-trans- ^ norproetenoate

A suspension of Ho mg (2.61 mmol) of a 57% strength dispersion of sodium hydride in mineral oil in 20 ml of tetrahydrofuran was 7 ^ 0 mg (2.61 mmol) of dimethyl-2-oxo-3- (p-chlorophenyl) propylphosphonate offset. The mixture was then stirred for 1 hour under nitrogen at room temperature. To this mixture was added a solution of 7 ^ mg (2.37 mmol) of the crude methyl 7- [2 [beta] -formyl-5oc-acetoxycyclopent-la-yl3-heptanoate (24) in ² J ml of tetrahydrofuran. The resulting reaction mixture was stirred under nitrogen at room temperature for 2 hours. It was then adjusted to a pH of about 7 with glacial acetic acid and rotary evaporation

609825/1006

constricted. The crude product was purified by chromatography on silica gel, the desired methyl-9 <* -
acetoxy-15-oxo-16- (p-chlorophenyl) -13-trans - ^ "- tetranor-; prostenoate was obtained.

Example 8 . ^

Methyl 9a-acetoxy-15QL-hydroxy-16- (p-chlorophenyl) -13-transtv-tetranorprostenoate and methyl-ga-acetoxy-15QL-hydroxy- 16- (p-chlorophenyl) -13-trans-tv'-tetranorprostenoate

A cooled to -78 ⁰ C, located under nitrogen. Solution of 900 mg (2.0 mmol) of methyl ga-acetoxy-IS-oxo-lo- (p-chlorophenyl) -13-trans- ^t v ^ -tetranorprostenoate, prepared according to Example I ₉ in 30 ml of tetrahydrofuran was mixed with 2 , 0 ml of a 1.0 M solution of lithium triethylborohydride in tetrahydrofuran are added. The reaction mixture was stirred in the cold for 30 minutes and then 1 ml of a mixture of water and acetic acid in a ratio of 9: 1 was added. The resulting reaction mixture was allowed to warm to room temperature; then it was concentrated. The product obtained was diluted with ethyl acetate; the organic layer was extracted with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. Purification of the product by Silxkagelchromatögraphie obtained led to the methyl 9 ^a ~ acetoxy-15SS-hydroxy-L6 (p-chlorophenyl) -13-trans - ^ - tetranorprostenoat and methyl-ga-acetoxy-lso-hydroxy-LOE-Cp -chlorophenyl) -13-trans-k ^ tetranorprostenoate. The 15β product of this example can be converted into the inventive IS-epi-II-deoxy-Lö-pchlorphenyl-W-tetranorprostaglandin E., P _la and F.

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leads to be. Example 9

9 £ x _J l5a-dihydroxy-l6- (p-chlorophenyl) -13-trans- ^l v ¹ tetranor prostenic acid (17a)

A mixture of 100 mg of methyl 9 ^a -acetoxy-15 ^a -hydroxyl6- (p-chlorophenyl) -13-trans-i ^ ^: -tetranorprostenoate, prepared according to Example 8, 1.0 ml of a 1.0 η aqueous sodium hydroxide solution, 1.0 ml of tetrahydrofuran and 1.0 ml of absolute methanol were stirred at room temperature for 1.5 hours under nitrogen. The solution was then acidified by adding 1.0 ml of 1.0 η aqueous hydrochloric acid (the pH of the acidified solution was about 5). The acidified solution was then extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate and concentrated. The purification of the crude product led to 9 ^a , 15 ^a -dihydroxy-16- (p-chlorophenyl) -13-trans-1 ^ -tetranorprostenäure (17a).

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Example 10

Methy l ^ a-acetoxy-15α- (tetrahydropyrane-2-yloxy) -16- (pchlorophenyl) -13-trans-iu-tetranorprostenoate

A mixture of 453 mg (1.0 mmol) of that prepared according to Example 8 Methyl 9a-acetoxy-15a-hydroxy-16- (p-chlorophenyl) -13-trans-uj-tetranorprostenoats, 0.14 ml (1.53 mmol) dihydropyran, 4.2 ml methylene chloride and 1 crystal of p-toluenesulfonic acid monohydrate was stirred at room temperature under nitrogen for 20 minutes. The reaction mixture was then diluted with ether, washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated to give the title compound.

Example 11

9a-Hydroxy-15a- (tetrahydropyran-2-yloxy) -16- (p -chlorophenyl) -13-trans-oj-tetranoroprostic acid (17a)

A homogeneous solution of 537 mg (1.0 mmol) of the methyl 9a-acetoxy-15a- (tetrahydropyran-2-yloxy) -16- (p-chlorophenyl) -13-trans-ω-tetranorprostenoate prepared in Example 10, 3.0 ml (3.0 mmol) of a 1.0N aqueous sodium hydroxide solution, 3.0 ml of methanol and 3.0 ml of tetrahydrofuran were added under nitrogen stirred overnight. The reaction was then carried out by adding 3.0 ml (3.0 mmol) of a 1.0N aqueous solution of hydrochloric acid deterred. The quenched solution was diluted with ethyl acetate. The organic layer became over anhydrous

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-39- 25552T0

Dried magnesium sulfate and concentrated. The raw product was purified by silica gel chromatography to give the desired title compound.

Example 12-

9-0xo-15a- (tetrahydropyran-2-yloxy) -16- (p -chlorophenyl) -13-trans -to-tetranorprostenic acid (17a)

A cooled under nitrogen to -15 to -20 ⁰ C solution of 199 mg (0.371 mmol) of 9a-hydroxy-15ct- (tetrahydropyran-2-yloxy) -l6- (p-chlorophenyl) -13-trans-u) -tetranorprostensäure (17a) in 4.0 ml of acetone was added dropwise 0.163 ml (0.408 mmol) of Jones reagent. The reaction was stirred in the cold for 15 minutes and then quenched by the addition of 0.19 * 1 ml isopropanol. The quenched reaction was stirred in the cold for 5 minutes and then diluted with ethyl acetate. The organic solution was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated to give the title compound, which was used without purification.

Example 13

norprostenic acid (17a)

A homogeneous solution of 175 mg (0.328 mmol) 9-oxo-15a- (tetrahydropyran-2-yloxy ) -16- (p-chlorophenyl) -13-trans-uretranorprostenic acid (17a) in 5 ml of a 65:35 mixture of acetic acid to water was added for 20 minutes under nitrogen

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touched. The reaction was concentrated by rotary evaporation followed by the use of an oil pump. The crude product was purified by silica gel chromatography to give the title compound. The product of this example (17a) can _; can be reduced as described in Example 23 and gives the corresponding PGP ₂ and PGF _{? ft} analogs.

Example 14

Dimethyl 2-oxo-3-phenylpropylphosphonate

A solution of 6.2 g (50 mmol) of dimethyl methyl phosphonate (Aldrich) in 125 ml of dry tetrahydrofuran was cooled to -78 ° C. in a dry nitrogen atmosphere. The cooled phosphonate solution was mixed with 21 ml 2,37M n-butyl lithium in hexane (Alfa Inorganics, Inc.) was added dropwise within 18 minutes at such a rate that the reaction temperature never rose above -65 ⁰ C. After further stirring for 5 minutes at -78 ⁰ C 7.5 g (50.0 mmol) of methyl phenylacetate was added dropwise at a rate that the reaction temperature below -70 ⁰ C held minutes). After 3.5 hours at -78 ⁰ C the reaction was allowed to warm to ambient temperature, neutralized with 6 ml of acetic acid and subjecting it to rotary evaporation to give a white gel was formed. The gelatinous material was taken up in 75 ^m l of water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts washed (50 cm HPO), dried (MgSO ₂ J) and using a water jet pump to a crude residue concentrated and distilled, boiling point 13 * 1 to 135 ° C (<0.1 mm) _/ and gave 3.5 g (29%) of dimethyl 2-oxo-3-phenylpropylphosphonate (2).

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The NMR spectrum (CDCl-,) showed a centered at 3.76

* O

Düblet (J = 11.5 cPs, 6H) for (CH ₃ O) -P-, a at 3.37 zen

trated triplet (2H) for -CH ₃ -O-CH ₂ -CH, a singlet at 3.286 (3H) for CH ₃ -O-CH ₂ , a dblet centered at 3.146

O O

(J = 23 cPs, 2H) -C-CH ₀ -P-, a singlet at 3.96 (2H) O ^ά

for -CH ₂ -C- and a broad singlet at 7.26 (6H) for ^C 6 ^H 5-

Example 15

(nat.) - 2- / 5a-Hydroxy-2ß- (3-oxo-4-phenyl-trans-l-buten-l-yl) cyclopent-la-yl-acetic acid-y-lactone (2b)

6.93 g (28.6 mmoles) of dimethyl ^ -oxo ^ -phenylpropylphosphonate in 420 ml of anhydrous THP were treated with 1.21 g (28.6 mmoles) of 572 sodium hydride in a dry nitrogen atmosphere at room temperature. After stirring for 60 minutes, 2 - / _ 5a-Hydroxy-2ß-formylcyclopentan-la-yl7acetic acid-γ-lactone (1) in 50 ml of anhydrous THP was added. After 95 minutes the reaction mixture was quenched with 4.2 ml of glacial acetic acid, filtered, evaporated and combined with 250 ml of ethyl acetate and successively with 100 ml of saturated sodium carbonate solution (2x), 150 ml of water (Ix), 150 ml of saturated saline solution (Ix) , dried (Na _? SO ^) and evaporated to give 2.51 g of the title compound as a pesticide after column chromatography (silica gel, Baker with a mesh size of 0.074 to 0.250 mm); Melting point 52 to 56 ⁰ C, ΓαJ ^ = + 35.0 ° (C = 0.8, CHCl ₃ ).

+) washed

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The NMR spectrum (CDCI,) showed a doublet of 6.806
centered doublets (IH, J = 7.16 cPs) and a doublet centered at 6.276 (IH, J = 16 cPs) for the ο olefinic protons, a broad singlet at 7.266 (5H) for C ₆ H-CH ₂ -C Singlet at 3.826 (2H) for C ₆ H-CH ₂ -C- and multiplets at 4.78-5.186 (IH) and 1.2-2.86 (8H) for the
remaining protons.

Example 16

(nat.) 2- ^ 5a-Hydroxy-2ß- (3 <z-hydroxy-4-phenyl-trans-1-butenl-yli-cyclopent-la-yl-acetic acid-v-lactone (3b)

A solution of 2.5 g (9.25 mmol) (nat.) 2- / 5cc-hydroxy-2β- (3-oxo-4-phenyl-trans-1-buten-1-yl) cyclopent-la-yl7acetic acid -Y-lactone (3) ml of dry in 30 THP was added dropwise in a dry nitrogen atmosphere at -78 ⁰ C with 9.25 ml of a 1, OM Lithiumtriäthylborhydridlösung added. After stirring for 30 minutes at -78 ⁰ C 20 ml of acetic acid / water (40:60) was added. After the reaction reached room temperature, 40 ml v / ater was added and the reaction was extracted with methylene chloride (3 x 50 ml), washed with brine (2 x 5 ml), dried (Na ₂ SO 4) and concentrated with the aid of a water aspirator . The resulting oil was purified by column chromatography on silica gel.

nigt (Baker "analyzed reagent with a mesh size of 0.074 to 0.250 mm) using cyclohexane and ether as an eluant. After eluting the less polar impurities, a fraction was obtained which contained 365 mg of the title compound, a 578 mg precession

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- Ä3-

of mixed 3b and Epi-3b and finally a fraction (489 mg) of (nat.) 2- / 5α-Hydroxy-2β- (3β-hydroxy-4-phenyltrans-1-buten-1-yl / cyclopent-la-yl-acetic acid-γ-lactone Epi-3b.

The (nat.) 3b possessed / δ_7 £ ⁵ = + 6.623 ° (G = 1.0 CHCl ₃ ) and (nat.) Epi-3b possessed / δ_7p ⁵ = + 2 * 1.305 ° (C = 1.69, CHCl ).

The 15-epi product of this example (Epi-3b) can be used according to the Procedure of Examples 17-30 and 32-35 in the 15-Epi-II-deshydroxyprostaglandins according to the invention converted will.

The products of this example (3b and Epi-3b) can be prepared by the procedure of Examples 32, 18 to 21, 23, 26, 27 to 3 ^1, and J to 35 in the 13.4-dihydro-ll-deoxy-prostaglandin analogs Two rows being transformed.

Example 17

(nat.) - 2- ^ 5a-Hydroxy-2ß- (3a ~ (tetrahydropyran-2-yloxy) -4 phenyl-trans-l-buten-l-yDcyclopent-la-yl-acetic acid-Y-lactone {lib)

A solution of 805 mg (2.96 mmol) (nat.5-2- ^ Sa-Hydroxy-2ß- (3a-hydroxy-4-pheny1-trans-1-b uten-1-yl7cy clopent-la-yl7-acetic acid-Y-lactone (3b) in 20 ml of anhydrous methylene chloride and 0.735 ml of 2,3-dihydropyran was at 0 ° C in a dry Nitrogen atmosphere with 35.3 mg of p-toluenesulfonic acid monohydrate offset. After stirring for 35 minutes, the reaction mixture was combined with 150 ml of ether, the ethereal solution with

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-U.N

saturated sodium bicarbonate (2 100 ml) and then with saturated brine (1 χ 100 ml), dried (Na ₂ SO.) and concentrated to give 1.2 g (> 100 %) of the crude title compound.

The IR spectrum (CHCl,) had a medium absorption

- 1
at 975 cm for the trans double bond and a strong one

Absorption at 1770 cm "for the lactone carbonyl.
Example 18

(nat.) - 2- / 5 (X - Rydroxy-2ß- (3a- (te trahydropyran-2-yloxy) -diphenyl-trajis-1-buten-1-yljcyclopent-la-yl / acetaldehyde-hemiacetal (5b)

A solution of 1.1 g (2.96 mmol) 2 - / ^ 5a-Hydroxy-2ß- (3a- (tetrahydropyran-2-yloxy) -4-phenyl-trans-l-buten-l-yl) cyclopent- Ia-yl7essigsäure-y-lactone (4b) in 15 ml dry toluene was cooled to -78 ⁰ C in a nitrogen atmosphere. This cold solution was added dropwise 4.05 ml of 20% diisobutylaluminum hydride in η-hexane (Alfa Inorganics) at such a rate that the internal temperature never rose above -65 ⁰ C (15 minutes). After further stirring for 30 minutes at -78 ⁰ C, anhydrous methanol was added until gas evolution ceased ^ and allowed the reaction mixture to warm to room temperature. The reaction mixture was combined with 150 ml of ether, washed with 50 # sodium potassium tartrate solution (2 × 50 ml) and brine (1 × 75 ml), dried (Na ₂ SO ^) and concentrated to give 883 mg of the title compound after column chromatography.

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-H ₅ -

Example 19

9a-Hydroxy-15a- (tetrahydropyran-2-yloxy) -16-phenyl-cis-5-trans-13-tetranorprostadienoic acid (10b)

A solution of 3> 83 g (4-carbohydroxy-n-butyl) triphenylphosphonium bromide (23) was treated in a dry nitrogen atmosphere in 10 ml of dry dimethyl sulfoxide with 11.9 ml of a 2, 1M solution of sodium methylsulfinyl methoxide in dimethyl sulfoxide. This red ylide solution was added dropwise with a solution of 1.2 g (3.3 mmol) of 2- / 5a-hydroxy-2β- (3a- (tetrahydropyran-2-yloxy) -4-phenyl-trans-1-butene-1 -yl) -eyclopent-la-yl-acetaldehyde-Y-hemiacetal (5b) in 15.0 ml of dry dimethyl sulfoxide was added within 20 minutes. After stirring for an additional 20 minutes at room temperature, the reaction mixture was poured into ice water, 10 ^ HCl (60 ml) and ethyl acetate (100 ml). The acidified solution was extracted with ethyl acetate (2 × 100 ml) and the combined organic extracts washed with water (1 × 100 ml) and brine (100 ml), dried (MgSO ₂ ,) and evaporated to a residue. The residue was purified by column chromatography on silica gel (Baker "Analyzed s' reagent with a mesh size of 0.074 to 0.250 mm) using chloroform and ethyl acetate as eluants. Removal of the high R" impurities gave 2.0 g of the title compound.

The product of this example (10b) can be converted by the method of example 21 to gctjlSa-dihydroxy-lo-phenyl-cis-S-trans-13-tetranorprostadienoic acid (lib) are hydrolyzed. That

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Product of this example (10b) may also, following the procedure of Examples 2H and 25 in the 9oc, 15a-dihydroxy-l6-phenyl-trans-13-UEU tetranorprostensäure (17b), by the
Process of Examples 22 and 21 into 9 <x, 15a-dihydroxyl6-phenyl-u-tetranorprostanoic acid (18b) or according to the process of Examples 21 and 26 into 9,15-dioxo-16-phenylcis-5-trans-13 -tü-tetranorprostadienoic acid (3 ^ b) can be converted.

Example 20

9-Oxo-15a- (tetrahydropyran-2-yloxy) -16-phenyl-cis-5-trans-13-to-tetranorprostadienoic acid (12b)

A solution cooled to -10 ° C under nitrogen of 1.33 S (2.9 mmol) 9a-hydroxy-11-deoxy-15a- (tetrahydropyran-2-yloxy) ■ 16-phenyl-5-trans-13-u > -tetranorprostadienoic acid (10b) in 30 ml of reagent-grade acetone was added dropwise with 1.6 ml of Jones reagent. After 5 minutes at -10 ⁰ C 1.0 ml of 2-propanol were zugesetzt.und the reaction mixture was stirred for a further 5 minutes, after which it combined with 100 ml of ethyl acetate, (3 x 50 ml) with water and brine (1 50 ml χ Washed, dried (MgSO ₁ ^) and concentrated to give 1.3 g of the title compound.

The product of this example (12b) can be converted to the corresponding II-deoxyprostaglandin Pp and Fp ^ analogs of the invention by the procedures of Examples 23 and 21. The product of this example (12b) can
also according to the method of Examples 22 and 21 into g-Oxo-lSa-h'ydroxy-Lö-phenyl-tu-tetranorprostanoic acid (18b)
being transformed.

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Example 21

9-Oxo-15a-hydroxy-16-phenyl-cis-5-trans-13-keto-tetranorprostadienoic acid (13b)

A solution of 1.3 g of 9-oxo-15a- (tetrahydropyran-2-yloxy) -16-phenyl-cis ~ 5-trans-13-prostadienoic acid (12b) in 20 ml of a 65:35 mixture of glacial acetic acid to water was added under nitrogen stirred at 25 ° C for 18 hours and then concentrated by rotary evaporation. The resulting crude oil was by column chromatography on silica gel (Mallinckrodt CC-7) using chloroform and ethyl acetate as Eluent purified. After eluting the less polar impurities were ^ 50 mg of the desired Title compound won. The IR spectrum (CHCl) showed

- 1 a broad hydroxyl absorption (3200 to 3650 cm), strong

- 1 -

Carbonyläbsorptionen at 17 ¹ IO cm (ketone) and 1710 cm (acid) and a medium absorption at 970 cm "for the trans-Doppe bond!.

Example 22

9-Oxo-II-deoxy-15a-hydroxy-16-phenyl-o) -tetranorprostanoic acid (I8b)

A heterogeneous mixture of 800 mg of g-hydroxy-16-phenyl- "cis-5-trans-13-ü) -tetranorprostanoic acid (13b) and 100 mg of 10% palladium-on-charcoal in 50 ml of methanol was stirred under an atmosphere of hydrogen for 2 hours. The mixture was then filtered through a pad of celite and the piltrate constricted. Purification of the crude product by silica gel chromatography using chloroform as an eluant, gave the desired title compound.

609825/1005

Example 23

9a * 15a-dihydroxy-16-phenyl-u) -tetranorprostanoic acid (18b) and 9β, 15a-dihydroxy-16-phenyl-u) -tetranorprostanoic acid (18b)

A solution of 100 mg of 9 ~ oxo-15a-hydroxy-16-phenyl-oj-te tranorprostanoic acid (18b) in 30 ml of methanol, cooled to ⁰ ° C., was cooled with a solution of 500 mg of sodium borohydride in 50 ml of methanol to O ⁰ C, offset. The reaction was stirred for 20 minutes at 0 ^° C. and then for 1 hour at room temperature. The reaction mixture was then diluted with 6 ml of water and concentrated. The concentrated solution was covered with a layer of ethyl acetate and then acidified to pH 3 with iO ^ iger hydrochloric acid. The ethyl acetate layer was washed with water (2 × 10 ml) and saturated brine (10 ml), dried (sodium sulfate) and concentrated. The crude residue was purified by silica gel column chromatography using chloroform / methanol mixtures as the eluent, first adding 9ä, 15a-dihydroxy-16-phenyl-o) -tetranorprostanoic acid (18b) as a viscous oil, 58 mg of a mixture of C 8 epimers and finally 10 mg of 9β, 15a-dihydroxy-16-phenyl-ü) -tetranorprostanoic acid (18b) was obtained as a viscous oil.

Example 24

9-Oxo-15β- (tetrahydropyran-2-yloxy) -16- (m-tolyl) -13-transu) -tetranorprostenic acid (17c)

A solution of 200 mg (0.445 mmol) of 9-oxo-15β- (tetrahydropyran-2-yloxy) -16- (m-tolyl) -5-cis-13-trans-prostadic acid (16c) in 20 m! Ethyl acetate containing 30 mg of 10% Pd / C, was in an atmosphere of hydrogen for one hour

609825/1001

0 to 5 ⁰ C stirred. At this point the hydrogen uptake had ceased. The mixture was filtered and evaporated to give 200 mg of the title compound as a colorless oil.

Example 25

9-oxo-15β-hydroxy-16- (m-tolyl) -13-trans-u) -tetranorprostenic acid (17c)

A solution of 200 mg (0.445 mmol) of 9-oxo-15β- (tetrahydropyran-2-yloxy) -16- (m-tolyl) -13-trans-u) -tetranorprostenic acid (17c) in 10 ml of a 65:35 mixture of glacial acetic acid and water was stirred under nitrogen at 25 ° C for 18 hours and then concentrated by rotary evaporation. That included Resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC- * 7) using methylene chloride and ether purified as an eluant. After eluting the less polar impurities, one recovered 50 mg of the title compound. The IR spectrum (CHCl3) showed

- 1 wide hydroxy absorption at 3650 to 3200 cm,

- 1 - 1

strong Carbony! absorption at 1740 cm and 1710 cm for the ketone or the acid and an absorption at 970 cm for the transdouble bond.

Example 26

9,15-Dioxo-16- (m-tolyl) -5-cis, -13-trans-m-tetranorprostadxenoic acid (26c)

A solution, cooled to -10 ° C under nitrogen, of 130 mg (Θ, 35 mmol) 9-oxo-15a-hydroxy-16- (m-tolyl) -5-cis, 13-trans-u) -tetranorprostadienoic acid (25c) in 20 ml of reagent grade acetone

609825/1 006

0.14 ml of Jones reagent was added. After 3 minutes at 0 C, 5 drops of 2-propanol were added and the reaction mixture was stirred for a further 5 minutes, after which it was diluted with 50 ml of ethyl acetate, washed with water (2 × 20 ml) and brine (1 × 20 ml), dried ( Na ₃ SO ₁ J and concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Brinkman). After eluting the less polar impurities, 100 mg of the desired title compound were obtained. The IR spectrum (CHCl 3) showed strong carbonony ! absorption at 17 ^ 0 cm " ¹ for the ketone, 1710 cm" ¹ for the acid, and at 1660 cm and 1610 cm for the enone.

Example 27

9ä-acetoxy-15a- (tetrahydropyran-2-yloxy) -16- (m-tolyl) -5-cis, 13-trans-tutranorprostadienoic acid

A mixture of 300 mg (0.625 mmol) 9a-hydroxy-15cc- (tetrahydropyran-2-yloxy) -16- (m-tolyl-5-cis, 13-trans-ketranorprostadienäure (33c) ', 1.88 ml pyridine and 0.28 ml of acetic anhydride was stirred under N at 50 ° C. for 5 hours, then poured onto ice water and extracted with ethyl acetate The ethyl acetate extracts were washed with water (1 χ ml) and brine (1 20 ml), dried (Na ₃ SO ^) and concentrated to give 306 mg of the title compound.

Example 28

norprostadienäure

A solution of 3-6 mg of 9a-ethoxy-15®- (tetrahydropyran-2-yloxy) -16- (m-tolyl) -5-cis-13-trans-iM-tetranorprostadienoic acid

609825/1006

in 10 ml of a 65:35 mixture glacial acetic acid / water was under Stirred nitrogen at 25 ° C for 18 hours and then concentrated by rotary evaporation. The resulting crude oil was determined by column chromatography on silica gel (Baker) using ethyl acetate and methylene chloride as Eluent purified. After eluting the less polar impurities obtained 85 mg of the desired Title compound. The IR spectrum (CHCl,) showed carbonyl

- ■■■■■ _- < j

absorption at 1730 cm and broad hydroxyl absorption at 3650 to 3200 cm " ¹ .

Example 29

9 <x -etoxy-15-oxo-16- (m-tolyl) -5-cis-13-trans-eotranorprostadienäure

A solution cooled to -10 ° C. under N ₂ , of 85 mg (0.19 mmol) of 9a-acetoxy-15a-hydroxy-16- (ra-tolyl) -5-cis-13-trans-totetranorprostadienoic acid in 10 ml of reagent-grade acetone was mixed with 0.07 ml of Jones Reagent added. After 3 minutes at 0 ° C., 5 drops of 2-propanol were added and the reaction mixture was stirred for a further 5 minutes, after which it was diluted with 50 ml of xyl acetate, washed with water (2 × 20 ml) and brine (1 × 20 ml), dried (Na ₂ SO ^) and concentrated to give 80 mg of the title compound.

Example 30

9a-Hydroxy-15-oxo-16- (m-tolyl) -5-cis, 13-trans-u) -tetranor-

postadienoic acid

A mixture of 80 mg (0.18 mmol) ga (m-tolyl) -5-cis-13-trans- (δ-tetranorprostadienoic acid, 0.5 ml

609825/1005

1 ON aqueous sodium hydroxide, 2 ml of tetrahydrofuran and 1.5 ml of methanol was stirred at 27 ⁰ C for 12 hours. The reaction was concentrated by rotary evaporation and the crude product purified by chromatography on silica gel (Mallinckrodt CC-7) using methylene chloride and ethyl acetate as the eluent. After the less polar impurities had been eluted, 18 mg of the title compound were obtained. The IR spectrum showed strong carbonyl absorption at 1660 cm and 1610 cm for the enone and broad hydroxy1 absorption at 3650 to 3200 cm " ¹ .

Example 31

2- _J / 5et-hydroxy-2ß- (3-οχο-ή- (m-tolyl) but-l-yl) cyclopent-ia-yl7-acetic acid-Y-lactone (6c)

A heterogeneous mixture of 6.8 g 2- / 5 <x-hydroxy-2ß- (3-0x0-il-Cm-tolyD-trans-buten-1-yDcyclopent-la-yl-acetic acid-Y-lactone (2c) and 67Ο 10 mg palladium on carbon in 55 ml ethyl acetate was shaken in a Parr shaker for 30 minutes, the mixture was then filtered through a pad of celite and concentrated. Purification of the crude residue by silica gel chromatography using 10% ethyl acetate in benzene as eluant gave 2.9 g of the desired Tite! compound as Peststoff having a melting point from 60.5 to 62.5 ⁰ C.

The inventive product (6c) may according to the procedures of Examples l6 to 21, 23, 26 to 30, and k ^ of the invention are converted to 35 in the 13,14-Dihydroprostaglandin-Two series analogs.

609825/1008

Example 32

2- / 5a-Hydroxy-2ß- (3α- (tetrahydropyran-2-yloxy) -4-phenylbut-1-yl) -cyclopent-la-yl7acetic acid-Y-lactone (8b)

A heterogeneous set of 500 rag 2- / 5 <x-hydroxy-2ß- (3a- (tetrahydropyran-2-yloxy) -4-phenyl-trans-buten-1-yl) cyclopent-la-yl7acetic acid (4b) and 50 mg of 5% rhodium-on-alumina in 5 ml of ethyl acetate was stirred under 1 atmosphere of hydrogen for 2 hours. The mixture was then filtered through a pad of celite and then concentrated. Purification of the crude residue by silica gel chromatography gave the desired title compound.

The product of this example (8b) can be converted into the 13,14-dihydroprostaglandin two-row analogs of the invention being transformed.

Example 33

2- / 5a-Hydroxy-2ß- (3a-dimethy1-tert-butylsilyloxy-4- (3,5-dimethylphenyl) -trans-buten-1-yl) cyclopent-la-yl7acetic acid-

Y-lactone

A solution of 1.47 g (4.95 mmol) of 2- / 5a-hydroxy-2β- (3ahydroxy-4- (3,5-dimethylphenyl) -trans-buten-1-yl) cyclopentla-yl-acetic acid-γ-lactone (3d), 945 mg (6.3 mmol) of dimethyl tert-butylsilyl chloride and 910 mg (13.4 mmol) imidazole in

609825/1008

2.5 ml of dimethylformamide was under nitrogen at 37 ° C Stirred for 18 hours. The solution was then concentrated. The residue was diluted with methylene chloride and the organic layer washed with water (3 x), dried (anhydrous magnesium sulfate) and concentrated. The cleaning the crude residue on silica gel chromatography using chloroform as the eluent gave 1.67 g the desired title compound as a viscous oil.

The product of this example (4d) can be according to the procedure

of Examples 18 to 30, 32 and 34 to 35 into the corresponding 11-deoxyprostaglandins according to the invention are converted.

Example 34

p-BiphenylCenO-g-oxo-II-deoxy-lSa-hydroxy-Lö-phenyl-cis-5-trans-13-U) -tetranorprostadienoate.

A solution of 365 mg (1.02 mmol) of (ent) -9-0xo-ll-deoxy-15a-hydroxy-l6-phenyl-cis-5-trans-13-iu-tetranorprostadienoic acid in 40 ml of methylene chloride was mixed with 11, 7 ml of an 0.1M solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in methylene chloride are 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 an eluent to give the desired title compound 200 as a white solid mg with a melting point of 68 to 7O ⁰ C received.

609825/1008

Example 35

n-Decyl- (rac) -9-oxo-II-deoxy-15α-hydroxy-16-phenyl-cis-5-trans-eo-tetranorprostadienoate

A solution of 30 rag (rac) -9-oxo-II-deoxy-15a-hyttroxy ~ le-phenylr-cis-S-trans-öj-tetranorprostadienoic acid in 25 ml of ether was treated with a solution of diazodecane in ether. After the reaction, thin-layer chromatography was carried out using 10 % methanol in methylene chloride as the eluent: R1 of the starting material 0.33, R1 of the product 0.82. The solution was then concentrated and the crude product was purified by column chromatography to give 5 mg of the desired title compound as a viscous oil.

609825/1008

Further connections of the structure

Ar, Z * R. mp m-methylphenyl D- H . 8O.5-82.5 o-biphenyl D. H 51-52 ° 5-phenyl-2-thienyl D. H oil £ -naphthyl (rac.) D. H oil p ~ C. chlorophenyl D, H οι.: ρ-t-butylpheny1 D. H oil* phenyl • D (+) Me_ P henyl ■ D (-) Me 55-58 "" Phenyl (ent) D. H 3,5-dimethyl D. H ■ 110-112 ° * Detrans-Dopp'elbiiwlimg; S = simple binding

IRJ data cm " ¹ x rotation 1770, 1680, 1620, 98Ο

177O ₅ 1675, 1620, 980

1775 > 1700, 168O, 1640, 980

1770, 1700, 168O, 1620, 970

1779, 1709, 1672, 1639, 980

1770, 1695, 1675, 1Ö35, 975

I77O / I7IO, 1Ö20, 975 +112.1 (CHCl ₃ ) '1770, 17IO, 1620, 975 -32.79 (CHCl ₃ ) 1765, 16So ₃ 1625, 975 "

6.62, 6.13, 5-88, 10.35 (KBr in / 4)

N3

cn cn

cn

NJ

More connections

Ar R

m-M-ethylphenyl H o -biphenyl H

5-phenyl-2-thienyl H β> -N aphthyl H

JJJ p-Chloropheny-1

p-t-Butylphenyl H Phenyl (+) Me

Phenyl (-) Me

3,4-.PiChIo ^ phenyl H - 3,5rDiaethylphenyl H

• M6thoxy protons
•• β "" * 0

Ar-CH-C-CH ₂ -P- (OMe) ₂

Kp / Fp

rotation

15_8-l62 °. / 0.4mm.

purified by column chromatography Pp 64-65 ° C

p _p? 45-47 °

purified by column chromatography "'

l8o ° - / 0..2 mm.

purified by column chromatography

purified by column chromatography ..

I85-188 ° / 0.2 mm 174 ° / 0.3 mm ■

+205 (CHCl ₃ ) -233 (CHCl ₃ )

KMR (Jcps)

3.75 (II.5) *, 3.02 (22) **

3.74 (11.5) *, 3.O5 (22) **

3.75 (11.5) *, 3.O8 (22) ** 3.73 (11.5) *, 3.10 (22) **

3.76 (II.5) *, 3.I5 (22) **

3.74 (II.5) *, 3.II

3.78 (11.5) *, 3-26

3.7I (11.5) *, 2.93

3.78 (11.5) *, 3.26

3.7I (11.5) *, 2.93

3.77 (11.5) *, 3.I6

3-82 (11.5) *, 3.14

(22) **

22) ** 22) **

22) ** 22) **

ro

cn

cn

cn ho

60982 5/100 6 Ar, R ■ ■ T Further ! links Polarity - Single bond ss (°) • 1 m - Me thy! phenyl H * U0H - - φ .. ...
0— ' γ-
λ7 .r .LP H0 / Et2O ' vn τη-.Me thy! phenyl H / 6-OH 7th 'MP - mahn nnla « IR data, cm "^ · OO o-'βiphenyl H oi-OH _z (a) LP H0 / Et2O 1770, 970, 36ΟΟ I. ο-ßiphenyl H / Sr-OH D. MP 1770, 970, 36ΟΟ 5-phenyl-2-thienyl. H «A-OH D. LP H0 / Et ₂ O 1770, 975, 36ΟΟ 5-phenyl-2-thienyl H / -0H D. MP 1770, 975, 36ΟΟ / 3-waphthyl H c ^ -OH D. LP H0 / Et2O 1770, 975, 360O ^ yö-Afaphthyl H / -0H D. MP 1770, 970, 3600 p ^ chlorine ^ henyl H o ^ -OH D. LP ^- H0 / Et2O 1770, 970, 3598 p-chloro <phenyl H / 5_-0H .D MP 1770, 970, 3598 p-t -sutylphenyl H ⁰ ^ -OH D. J. ^Lp H0 / Et ₂ O 1770, 970, 3598 "o-t-8Utylphenyl H / -0H D- ";" "" MP '■ ·. 1770 970. 3598 Phenyl ■ (+) Me c? <-OH D. LP lO ^ EtoAc / Benz & l> 1770, 970 3598. , Phenyl f +) Me / -OH D. MP ' Il Il 1770, 970 3598 ■ Phenyl (-) Me oL -OH D ' LP 20 ^ Et20 / BenzPl "; 1770, 970, 36ΟΟ Phenyl (-) Me A -OH D. MP Il Il 1770, 970, 36ÖO P «henyl (ent") H oi.-0H D ' . LP Et20 / Qyc lohexam'v 1770, 970, 36ΟΟ Jftienyl (ent) H ' β -OH D. MP ■ 1770, 970, 36ΟΟ 3,5 ^ dimethylphenyl H oi-OH D. LP H0 / EtoAc 1760, 960 36ΟΟ 3 ', 5-methylphenyl H ^ -OH D. LP 1760, 960, 36ΟΟ (a) D = trans double bond; S = D. • 1770, 975, 3550 D. 1770, 975, 3550 D. cn
cn
cn NJ

(c) Solvent system for column chromatography isomer separation

More connections

ιν> cn

m-methylpheny1 m-methylphenyl o-biphenyl o-biphenyl

5-phenyl-2-thienyl

5-phenyl-2-thienyl ß-naphthyl β-naphthyl p-chlorophenyl p-Chlorophenyl p-t-Butylphenyl p-t-butylpheny1 Phenyl

Phenyl

Phenyl phenyl phenyl (ent)

Phenyl (ent) 3,5-dimethylpheny1 3,5-dimethylphenyl

R. Me η ' ^ XAr JP ^ data cirf 970 "τ H Me H Z * 1770, 970. «Ί-ΟΤΗΡ H Me H D. • 1770, 970 yö-OTHP H Me H D. 1770, 970 et-OTHP ' H D. - 1770, 970 ^ -OTHP H D. 1770, 970 oL -OTHP H D. 1770, 970 • / 5-0THP H D. 1770, 970 . α-OTHP H D. 1770, 970 / 3-OTHP H D. . 1770, 970. <λ-0ΤΗΡ H • D 1770, 970 /> -OTHP H D. 1770, 970 Λ-ΟΤΗΡ H D- 1770, 970 / 4-OTHP + D. 1770, 970 Λ-ΟΤΗΡ + D. 1770, 970 / -ΟΤΗΡ
S - OTHP - D. ■ 1770, 970 / ί -OTHP - D. 1770, 960 • β »- ΟΤΗΡ D. '1760, 960 / 6 -OTHP D. 9β5 <* - -ODMTBS D ~ 1700, 1760, 965 / -ODMTBS D. 1760, -_Ρ_

VO

^h D β trans double bond; S «single bond

cn cn cn K)

.Further -

ο
ο
«Η

m- Me thy! phenyl

m- methylphenyl

o-biphenyl

o-biphenyl

5-phenyl-2-thienyl

5-PVienyl-2-thienyl

/ -Naphthyl

ρ -naphthyl

'p-chloro _w phenyl

p-Chlcr ^ phenyl

p-t-butylphenyl

p-t-butylphenyl

Phenyl

P.ienyl.

Phenyl

Phenyl

, Phenyl (ent)

/ henyl (ent)

3,5 * ^D ünethylphenyl '

3,5- ^D ime thy! Phenyl

«I -OTHP · 4-OTH? cA-OTHP ^ -OTKP ol-OTHP

-OTHP -OTHP

/ -OTHP oL -OTHP / -OTHP O ^ -OTHP

y * -OTIEP egg -OTHP ^ -OTHP J- -OTHP j -OTHP cJ> -ODMTBS ß -ODMTBS

H II H. H H H H H K H H H

Me Me Me Me

HHHH Z *

D.
D.
D.
D.
D.
D.
D.
D.
D.

. D.
D.
D.
D.
D.

D._.
D.
D.
D.
D.

IR-Oatencm

970 970 970 970 970 970 970 970 970 970 965 β

-1

975 975 975 975 970 970

$ 9 5,965

* D -.5 trans double bond's = single bond

Ar T

m-ipthylphenyl * £ -0THF m-wethylphenyl, fi> -OTHP o-biphenyl 'ei-OTHP

o-phenyl / 4-0THP

-phenyl-2-thienyl * -OTHP

/ ₇ py
, o'-n'aphthyl
p- \ ChlorvAphenyl
p4chlor ^> phenyl
pt-butylphenyl
Ό-t-butylphenyl
• phenyl
»Phenyl
'phenyl (ent)
phenyl (ent)

/ 6-OTHP J. -OTHP / i -OTHP y- -OTHP A -OTHP

j A -OTHP Ii-OTHP P -OTHP

Other connections W

H D. H D. H D. H D. H D. H D. H D. H D. H D. H D. H D. +) Me , D -) Me D. H D. H D.

ice, double bond '^' ^=: Einfachbindüng trans .Doppelbindung '^ =' Einfachbindüng-

COOH

Ar

-1

D " NMR is correct match D. NMR is correct match D " NMR is correct match D. NMR is correct match D. NMR is correct match D. NxMR is correct match D. ₍ .NMRr true match D- NMR is correct match D,. ■ -NMR is correct match D. 1710, 970 D. .1710, 970 D. 1705, 965 D. 1705, 965 D. 1700, 965 D. 1700, 965

Further_. Links)" O

Ar

Ar

ο » ο co oo

m · Me thy! phenyl

o-biphenyl

o-biphenyl

5-phenyl-2-thienyl

A -, N-phthyl

β jiaphthyl

p ^ py p-t-butylphenyl p-t-bhatylphenyl 'Bhenyl'

Phenyl Phenyl Phenyl (ent) P'henyl (ent) Τ

oi-OTHP

/ S-OTHP '

^ -OTHP

/ Ö-0THP

J.-OTHP

c * · -OTHP

/ 5 -OTHP

Λ-OTHP

/ 5-OTHP

J - OTHP

/ Ö-0THP

J- -OTHF

/ & -OTHP

l, fi -OTHP

V-OTHP

/ 5-OTHP

H * H Me η ' D. D. H Me H D. D. H Me D. D. H D. D. H D. D. H . D. D. H · D. D. H D. D. H ^# D. D. H D. D. '+ D. D. + D. D. - D. D. D. D. D. D. D. D.

* D
** D

Eis double bond ^ = single bond trans double bond S = single bond-

External Connections'
W.

Ar T .R 4- "A-OH H 1 W * Z ** IB data cm match m-, Mb thy! phenyl ^ -OH · H H- / S-OH H D. D '' . NMR is correct match m- «iethylphenyl / -0H H - «Ί.-0Η Η D. D. "NMR is correct • 975 o-biphenyl -Y, ΛΤΤ DD
• ^ -Un n. - ** - 0Η -I D. D. 1735, 1710
NMR is correct match o-'eiphenyl / -0H H I. D. D. 5-phenyl-2-thienyl • i-OH H <* - 0H H. D. D. 1730, 1705 , 9βθ / 5 -, N & phthyl ^ -OH H D. D. 1735, 1710 > 965 fi-Mphthyl / -0H H Me D. D. . 1730, 1710 , 970 ρ A C.hlo E / phenyl ot * -OH H Me • D D. 1730, 1710 , 970 piChlorv ^ phenyl / -0H H Me D. D. 1730, 1715 * 970 ρ-t-Btotylphenyl "A-OH" H Me D. D. 1730, 1715 , 970 £ -tB \ xtylphenyl,
Phenyl / -0H. "H D. D. 1730, 1705 , 970 Phenyl oi-OH "D. D. 1730, 1705 , 970 " Phenyl A-OH D. D. 1730, 1710 , 965 phenyl • ^ -OH D. D. 1730, 1710 , 965 Phenyl (ent) ^ -0H D. D. 1730, 1710 , 960 phenyl (ent) . D. D. ._ 1730, 1710 , 960 Phenyl . D. D. 1735, 1710 3,4 -. $ Ime thoxyphenyl D. S. 1730, 1710 , 965 ο --Me t hylphenyl S. S. 1730, 1715 ■. ■ p. S.

* D = 7 SlS. -Double oil blndups; v_s%, single bond ** ^D = ^- trans , Doppejlb-indungj S = EinfSöh & inüung

ΐ ■ · - ^

he »νχ

K) οτι cn απ ho

Ar

Other connections O

IR data cm

-1

β-naphthyl
Phenyl
Phenyl
o-biphenyl

H D. H D. (+) Me D. H D.

DDDD NMR is consistent.
1735, 1700, 1680, I6g5 .;, 970
1735, 1700, 1670, 1625,975
NMR agrees

⁺ D s cis double bond; S - single weave. ⁺⁺ D s trans double bond; S = single bond.

ro

cn

cn

cn

NJ

Claims (1)

Patent claims: ll-deoxy-tu-pentanorprostaglandins, which are in the 15-position a hydroxyl or keto group and a substituent of the formula R Ar-CH- have, in which Ar α- or ß-thienyl, 5-phenyl-a- or -ß-thienyl, 5-NBderalkyl-a- or -ß-thienyl, a- or ß-naphthyl, tropyl, phenyl, 3,4- Dimethoxyphenyl, 3 _S 4-methylenedioxyphenyl, 3, ¹ i-diehlophenyl, 3 _a 5-dimethylphenyl or monosubstituted phenyl, in which the substituents are bromine, chlorine, fluorine, trifluoromethyl, phenyl, lower alkyl or lower alkoxy, and R is a hydrogen atom or methyl and their C.-esters, in which the esterification group is an alkyl having 1 to 10 carbon atoms, aralkyl having 7 to 9 carbon atoms, α- or β-naphthyl, phenyl or substituted phenyl, in which the substituents are lower alkyl, lower alkoxy, chlorine, bromine , Fluorine or phenyl, or their intermediates in which the 15 OH position is blocked. 2. 11-deoxy-oj-pentanorprostaglandins according to claim 1, the E or F series and have a hydroxyl or keto group in the 15 position or their intermediates, wherein the 15-hydroxy group is blocked. 3. Compound according to claim 1 of the general formula COOR ¹ 60982S / 10ÖS where Ar and R have the preceding meaning and R ^{f is} hydrogen, alkyl having 1 to 10 carbon atoms, aralkyl having 7 to 9 carbon atoms, α- or β-naphthyl, phenyl or substituted phenyl, in which the substituent is lower alkyl, lower alkoxy, chlorine , Is bromine, fluorine or phenyl, W is a single bond or cis double bond, Z is a single bond or trans double bond and and N and M are each keto Tj or <^ and N also mean \ _nn l or OR 1 can mean where R NOH \ H may mean where R is 2-tetrahydropyranol or dimethyl-tert-butylsilyl. 4. A compound according to claim 3 »wherein M H .0H and N H OH and their C ^ epimers. 5. A compound according to claim 3 » in which MH are OH and NH OH and their C _{1 (} - epimers, 6. A compound according to claim 3, wherein M is keto and NH ^x 0H and their C ₁ epimers. 7. A compound according to claim 3 »wherein M II J) H and N are keto. 8. A compound according to claim 3 »wherein M is H OH and N is keto. 9. A compound according to claim 3 ₃ wherein M and N are keto. 60982B / 1ÖOS 10. Intermediate product for the preparation of a compound according to claim 3 of the general formula and their C _1c epimers and C -Epimer mixtures, in which Ar and R have the preceding meaning and R is hydrogen, 2-tetrahydropyranyl or dimethyl-tert-butylsilyl, Z is a single bond or trans double bond and Q = 0 or mean. 11. Intermediate product for the preparation of a compound according to claim 3 of the general formula wherein Ar and R have the preceding meaning and Z is a single bond or trans double bond. 609825 / 1ÖOS 12. 15-substituted compound according to claim 3 ^ of the general formula COOR ¹ and their C _lt - ~ epimers and Cje epimer mixtures, in which Ar and R have the above meaning and R 2-tetrahydro- pyranyl or dimethyl-tert-butylsilyl, M = 0, or <", W is a single bond or a cis double bond and Z a single bond or mean trans double bond. 13 · Intermediate product for the preparation of a compound according to claim 3 of the general formula Il OCR " -CHO ' 60982S / 1ÖÖS wherein R ¹ and R ^{2 are} each alkyl with 1 to IO carbon atoms, aralkyl with 7 to 9 carbon atoms, α- or ß-naphthyl, phenyl or substituted phenyl, in which the substituent is lower alkyl, lower alkoxy, chlorine, bromine, fluorine or Is phenyl. I ⁴ · H-deoxy-16-phenyl-ü) -tetranorprostaglandin E. 15. II-Deoxy-13,14-aihydro-16-phenyl-ü) -tetranorprostaglandin E2.
16 * H-deoxy-16-phenyl-u) -tetranorprostaglandin E ₂ . 17. II-Deoxy-15 - [(-) - 1-phenyleth-1-yl] -ω-pentanorprostaglandin E ₂ . 18. II-Deoxy-15 - [(+) - 1-phenyleth-1-yl] -ω-pentanorprostaglandin E ₂ . 19. ( rac ) -ll-Deoxy-16- (p-chlorophenyl) -ω-tetranor- prostaglandin E ₂ . 20. II-deoxy-16- (m-tolyl) -ω-tetranorprostaglandin E ₂ . 21. 15-epi-II-deoxy-16- (m-tolyl) -ω-tetranorprostaglandin E ₂ . 22. .. l5-epi-ll-deoxy-16- (p-chlo3 ^ j> henyl) -ω-tetranorprostaglandin E ₂ . 23. (rac) -ll-Deoxy-16- (β-naphthyl) -ω-tetranorprostaglandin E ₂ . 60982S / iööß 24. (rac) -ll-deoxy-lS-keto-lo - ($ - naphthyl) -ω-tetranor- prostaglandin E ₂ . 25. II-Deoxy-16- (5-phenyl-a-thienyl) -ω-tetranorprostaglandin E2 « 26. II-Deoxy-IS-keto-16- (m-tolyl) -ω-tetranorprostaglandin E2. . 27. 15-epi-II-deoxy-16-phenyl-ü) -tetranor PGE-. 28. IS-epi-II-deoxy-IS- [(+) -l-phenyl-1-a..thyl] -ω-pentanor PGE ₂ . For: Pfizer Inc. New York, Ν / Υ ·, V.St.A. ¹ A Dr. H. ¹ J. Wo Iff Lawyer 60982 5 / iÖÖ Λ /