FI57583B - FRAMEWORK FOR THERAPEUTIC TREATMENT OF THERAPEUTIC EQUIPMENT NYA 15-SUBSTITUTES-OMEGA-PENTANORPROSTAGLANDINER - Google Patents

Description

· Λ Γβ, / 44. ANNOUNCEMENT rnrfi7 [Β] (11) UTLÄGGNINGSSKRIFT ο f bo 5 ^ ^ (51) Kv.lk?/fnt.CI.3 c 07 C 177/00 // C 07 D 307/54, 333/24 ENGLISH I - Fl N LAN D (21) P «t # nttll» k «mu * - PttM« tam6knlng 2162/73 (22) HakamltpUvi - An * 6knlnpd »f 05.07.73 (23) AlkupUvft - GUtlfhaudag 05.07.73 (41) Translators JulklMluI - Bllvlt off «mllg lU.01 7I +

Patent · And registration germination · (44) Date of issue of the notice of issue. -

Patent- och ragistarstyralaan Amttkuutk «d ochutUkriftwipuMicend 30.05.80 (32) (33) (31) PrrJetty« toiksu * —Begird prtorltet 13.07.72 USA (US) 271220 Proof-Styrkt (71) Pfizer Inc., 235 East l + 2nd Street, New York, NY, USA - (72) Michael Ross Johnson, Gales Perry, Conn., Hans-Jurgen Ernst Hess,

Old Lyme, Conn., Thomas Ken Schaaf, Old Lyme, Conn., Jasjit Singh Bindra, Groton, Conn., USA (US) (7 ^) Oy Kolster Ab (5 * 0 Method for Therapeutically Applicable, New 15-Substituted-u This invention relates to a process for the preparation of certain novel naturally occurring compounds corresponding to prostaglandins, and in particular to the preparation of novel 15-substituted prostaglandins, and to the preparation of certain 15-substituted prostaglandins.

Prostaglandins are C-20 unsaturated fatty acids with various physiological effects. For example, E- and A-series prostaglandins are potent vasodilators (Bergstrom, et al., Acta Physiol. Scand. 61+: 332-33, 1965, and Bergstrom, et al., Life Sci. 6: 1 * 1 + 9-1 + 55, 1967) and lower arterial-vascular blood pressure (vascular paralysis) when administered by intravenous injection (Weeks and King, Federation Proc. 23: 327, 1961 + *, Bergstrom, et al. 1965, op. Cit. *, Carlson, et al., Acta Med. Scand. 183: ^ 23- ^ 30, 1968j and Carlson, et al., Acta Physiol. Scand. 75: 161-169, 1969). Another well - known physiological form of action of PGE 1 and PGE 3 is their function as bronchodilators (Cuthbert, Brit.

J. 1+: 723-726, 1969).

One major physiological form of action of natural prostaglandins is associated with the reproductive cycle. PGEg + is known to have the ability to induce 2,57583 labor (Karim, et al., J. Obstet. Gynaec. Brit. Cwlth. 77: 200-210, 1970), to induce therapeutic miscarriage (Bygdeman, et al., Contraception, U, 293 ( 1971) and useful in fertility control (Karim, Contraception, 3 »173 (1971) · Several E and F series prostaglandins have been patented as inducers of childbirth (Belgian patent 75 ^ 158 and West German patent 2 03 ^ 6M), and PGE 1, Fgr and F 2 to control the reproductive cycle (South African Patent 69/6089) It has been shown that administration of PGE 2 can result in luteolysis, Nature 230, 528 (1971) and due to prostaglandins, it is useful in controlling fertility by a method in which smooth muscle stimulation is not necessary.

Still other known physiological forms of action of PGE2 are e.g. inhibitory effect on gastric acid secretion (Shaw and Ramwell, in: Worcester Symp. on Prostaglandins, New York, Wiley, 1968, pp. 55-6M and also antiplatelet effect (Emmons, et al., Brit. Med. J. 2: U68 -U72, 1967).

It is known that such physiological effects occur in vivo only shortly after prostaglandin administration. The bulk of the evidence indicates that the reason for this rapid cessation of activity is that natural prostaglandins are rapidly and efficiently inactivated by metabolism upon oxidation of the carboxylic acid side chain position and the 15 °° hydroxyl group. (Anggard, et al., Acta Physiol. Scand., 81, 396 (1971) and references cited therein). It has been shown that the placement of a 15-alkyl group in prostaglandins results in a prolongation of the action time, possibly due to the inhibition of oxidation of the C15 hydroxyl group by Föankee and Bundy, JACS 9 ^ 3665 (1972) 7, Kirton and Forbes, Prostaglandins, 1, 319 (1972). ).

It was, of course, desirable to be able to create products similar to prostaglandins that have the same physiological effects as natural compounds, but with a better selective duration of action and retention of activity. Improved selectivity of action was expected to alleviate severe side effects, particularly side effects in the gastrointestinal tract, which have often been observed after continuous addition of natural prostaglandins to the body (Lancet, 536, 1971).

These shortcomings can be overcome by using the novel 15-substituted W-pentanorprostaglandins prepared in accordance with this invention.

The present invention relates to a process for the preparation of novel prostaglandin E and F series compounds for therapeutic use, having the formula

M

/ - (CH a) n -Ar 1 H </ rXh wherein Ar is o- or β-furyl, oi- or β-thienyl, oi- or β-naphthyl, biphenyl or phenyl; n is an integer from 0 to 2, provided that when Ar is phenyl, biphenyl or naphthyl, then n is 0 or 1; R is hydrogen or methyl; W is a single bond or a cis double bond; and Z is a single bond or a trans double bond, provided that when Ar is phenyl, then W is a cis double bond and Z is a single bond, M is oxo or;

'' OH

and their C 1-4 acetoxy esters and pharmaceutically acceptable salts thereof.

The process of the invention is characterized in that (a) a compound of formula

M

C00H

7 (CH0) „- Ar II

/

THP0 h ^ ÖTHP

wherein Ar, n, M, R, W and Z are as defined above and THP is 2-tetrahydropyranyl, is reacted with a suitable acid; or (b) a compound of formula I wherein Ar, R, n and M are as defined above, W is a single bond or a cis double bond when Z is a trans double bond, and Z is a single bond when W is cis - a double bond, catalytically hydrogenated to give a compound of formula I wherein Ar, n, R and M are as defined above and W and Z are single bonds; or 57583 1 * (c) a compound of formula 0o-c-ch3

S

XNy / COOR 'J- ^ Z_ ^, (CH0) “Ar / 2 n

H0 / X

° H

wherein W is a single bond, Ar, n, R and Z are as defined above, and R 'is hydrogen or lower alkyl, is reacted with a suitable acid to produce a compound of formula I wherein M is yH,

'V) H

and, if desired, preparing a 9α-acetoxy ester by reacting the resulting 9α-hydroxy compound with a suitable acetylating agent, and, if desired, preparing a pharmaceutically acceptable salt of a compound of formula I.

It will be apparent to one skilled in the art that there is no stereochemistry at the lactol carbon in the molecular structures of the hemiacetals.

It is further understood that as used herein, the term "zero series prostaglandin", for example PGE 2, refers to prostaglandins in which the 5-6 and 13-1 ^ double bonds are saturated; e.g., PGEq is 5-6, 13-1 ^, tetrahydro PGEg. In addition, as used herein, the terms "zero series", "one series" or "two series" refer to the degree of unsaturation of the side chains, e.g.

PGEg and PGFβ are "two-set" prostaglandins, while PGE2 and PGFβ are "one-set" prostaglandins. In addition, as used herein, the term "lower alkyl" refers to alkyl groups having 1-U carbon atoms.

In numerous in vivo and in vitro experiments, we have shown that the new prostaglandin analogs have physical effects comparable to those of natural prostaglandins (see above). These experiments include, but are not limited to, inhibitory effect on guinea pig uterine, guinea pig ileum, and rat uterine smooth muscle, inhibitory effect on guinea pig histamine-induced bronchospasm, canine hypertension, inhibitory effect on ADP- or collagen-induced platelet aggregation.

5 57583 The physiological reactions observed in these experiments are useful in determining the utility of a test substance in the treatment of a variety of natural and pathological conditions. Such defined beneficial effects include: antihypertensive effect, bronchodilator effect, vasodilator effect, antiplatelet effect, anti-pulse irregularity effect, cardiac stimulating effect, anti-ulcer effect, smooth muscle effect (useful for muscle function) as a labor inducer and a discontinuing drug), and an inhibitory effect on fertility through a mechanism that does not affect smooth muscle, such as the luteolytic mechanism.

The novel compounds of this invention have highly selective activity properties compared to those of the corresponding naturally occurring prostaglandins and, in many cases, have a longer duration of action. The best example of the therapeutic significance of these prostaglandin analogs is the efficacy of 13,1-dihydro-16-phenyl-ω-tetranorprostaglandin E1, a compound whose antihypertensive effect is much better in efficacy and duration than PGE2 itself. The concomitant smooth muscle stimulating effect is significantly less than that of PGEg.

Similarly, other 13β-dihydro-16-Ar-substituted PGEg analogs, 16-Ar-substituted PGEq (tetrahydro-PGEg), and 16-Ar-substituted PGEg-prostaglandins, and in particular 16-ot-thienyl preparations, prepared in accordance with this invention. ω-tetranor PGE2 and 16- [β-naphthyl-β-tetranor PGE2 have the desired antihypertensive effect. In addition, E-series 16-Ar-substituted prostaglandins are very effective in inhibiting gastric acid secretion. When administered orally, they are useful in the treatment of indigestion or excessive gastric activity. It should be noted that the 15-substituted-13,1H-dihydro-oj-pentanorprostaglandins prepared in accordance with this invention are particularly useful due to their increased selectivity. For example, 16-Ar-substituted-N-tetranor-13,1β-dihydro PGE2 has a highly selective antihypertensive effect while 17-Ar-substituted-U> -tris-nor-13,1β-dihydro has highly selective effect on smooth muscle. Furthermore, the 15-Ar-substituted-O-Penta-nor-13,1β-dihydro-E2-prostaglandins prepared according to the present invention have a highly selective bronchodilator effect.

Similarly, 17-furyl-W-trisnorprostaglandin F1 and E2 have an excellent smooth muscle stimulating effect that can be used to control fertility, miscarriage, and induction of labor, while the compounds simultaneously have antihypertensive effects. Other novel 17-substituted w-trisnor-6 57583 in the E and F series of this invention

With prostaglandins, i.e. the 17-Ar-substituted Prostaglandins of the E and F series prepared in accordance with this invention have a desired smooth muscle stimulating effect. Novel F-series 15-Ar-substituted ω-pentanorprostaglandins also have utility in induction of labor and abortion, and in fertility control, with F-series 16-Ar-substituted UJ-tetranorprostaglandins being useful in controlling fertility. affect smooth muscle.

Furthermore, 16-thienyl-β-tetranorprostaglandin Emilia and 16-β-diphenyl-β-tetranorprostaglandin Aeg have a potent bronchodilator effect and a minor non-vascular smooth muscle effect. Similarly, other 16-Ar-substituted? -Tetranorprostaglandin E1 and Eg analogs prepared in accordance with this invention have the desired bronchodilator effect.

All prostaglandins prepared according to this invention can also be used as salts of pharmaceutically acceptable cations. In addition, C 1-4 acetoxyesters are as useful as the prostaglandins from which they are derived. In some cases, the use of these esters is less likely to cause undesirable side effects than the corresponding unesterified prostaglandins. These esters are readily prepared by standard methods well known to those skilled in the art.

Prostaglandin analogs with beta-hydroxyl on the C15 carbon have a similar effect as their epimers. In some cases, however, the selectivity of these compounds is greater than that of epimeric compounds.

The novel compounds of this invention can be used in a variety of pharmaceutical preparations containing the compound or a pharmaceutically acceptable salt thereof, and can be administered as well as natural prostaglandins by various routes such as, inter alia, intravenous and infra-amniotic, oral and topical injection, including aerosols. , intravaginally and intranasally.

For the induction of abortion, E- or F-series 17-substituted β-trisnorprostaglandin may be administered as an aqueous suspension or tablets orally in doses of about 1 to 20 mg and administered every 1 to 7 days. For intravaginal administration, suitable dosage forms would be lactose tablets containing the same substance or an impregnated tampon. Suitable doses for such treatment are considered to be a dose of about 1-20 mg in the case of a 17-ot furyl PGFβ derivative or a dose of about 10-200 mg in the case of a 17-ot furyl PGEg derivative used in 1 -7 servings.

Alternatively, for abortion, 17-substituted-UJ-trisnorprostaglanins can be administered intra-amniotic at doses of 5- ^ 0 mg, 1-5 times 7 5 7 S 8 3 per day, or by intravenous injection at doses of 5-500 g / ml. min. in about 1-2¾ hours.

Alternatively, for abortion, 17-substituted-1β-trisnorprostaglanins may be administered extra-amniotically at doses of 0.5 to 50 μg / min. Within 1-2¾ hours.

Another suitable use of 17-Ar-substituted prostaglandin analogs prepared in accordance with this invention is their use as pathogens. For this purpose, an ethanol-saline solution of a 17-substituted -β-trisnor or PGE2 derivative can be used as an intravenous injection at a dose of about 0.05 to 50 [mu] g / min. for about 1 to 10 hours or as capsules, tablets, solutions or suspensions for oral administration in doses of 0.005 to 5 mg used for 1 to 7 days.

A suitable dosage form for inducing bronchodilation would be an aqueous-ethanolic solution of 16-Ar-substituted-tetranor-PGE 3 or -PGE 1, which is used in the form of an aerosol with the fluids being fluorinated hydrocarbons in an amount of about / dose up to 16 doses per day. To enhance the efficacy of a nasal dose, a suitable dosage form would be a 16-Ar-substituted aqueous solution of tetranor-PGE 4 or -PGE 4 used as nasal drops at 1-100 μg / dose, as needed.

The E2- and 13,1β-dihydro Eg series 16-Ar-substituted-β-tetranor-prostaglandins are useful antiulcer agents. For the treatment of indigestion, these dosages are preferably administered orally in the form of aqueous suspensions, solutions or, preferably, capsules or tablets at doses of 0.001 to 0.10 mg / kg, up to a maximum of 12 doses per day.

All of the novel compounds prepared in accordance with this invention are also useful as their C 1-4 acetoxy esters. These specific esters are valuable because they are very easily crystallized, so that they can be recovered in very pure form and in remarkably good yields, with the crystallization of prostaglandins usually producing considerable difficulties.

The 16-Ar-substituted β-tetranor prostaglandins of the EJ, Eg, EQ, and 13,1-dehydro-E2 series are useful antihypertensive agents (as are the E-series 15-Ar-substituted-U) pentanorprostaglandins. ). In the treatment of hypertension, these drugs may be suitably administered by intravenous injection at doses of about 0.5 to 10 μg / kg, or most preferably in capsules or tablets, at doses of 0.005 to 0.5 mg / kg / day.

Various reaction-neutral diluents, excipients or carriers may be used in the preparation of any of the above dosage forms or any possible many other dosage forms. Such substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, 8,57583 talc, vegetable oils, benzyl alcohols, natural resins, polyalkylene glycols, petrolatum, cholesterol and other known carriers used in pharmaceutical products. If desired, these compositions may contain adjuvants such as preservatives, wetting agents, stabilizers or other drugs such as antibiotics.

The following examples are presented to illustrate the invention. In these examples, all temperatures are reported in degrees Celsius, all melting and boiling points are uncorrected, and all biological test values are expressed as percent activity of PGEg activity or given in the same amounts (i.e., PGE2 = 100) unless otherwise noted. The biological values shown below were obtained using the following test methods:

Histamine - induced bronchoconstriction - guinea pigs.

The bronchodilator effect in conscious Reed-Willet guinea pigs (200–250 g) starved overnight was evaluated by the method of Van Arman’s Miller and O’Malley (1). After pre-challenge or aerosol administration of water or a mixture of test drug and water at pre-selected intervals, a histamine aerosol was applied to each animal as follows: A 0% aqueous solution of histamine was placed in a Vaponephrine Standard Nebulizer (Vaponephrine Company, Edison). , New Jersey) and the solution was sprayed with compressed air (6 lb / in) for 1 minute into a sealed 8x8x12 inch clear plastic container. The guinea pigs were placed in the tank immediately after this. The respiratory status of the guinea pig (bronchial fracture reflection) for one minute after being in the reservoir was assessed by the following numbers: 0, normal respiration; 1, breathing become a little more laborious; 2, breathing become more laborious; 3, breathing has become alarmingly laborious and fumbling; coma. The estimated values for the control group and the experimental group (8 animals per group) were added together, compared, and the difference was expressed as a percentage of protective capacity (1) 1. Van Arman, C, G., Miller, L.M. and O'Malley, M.P .: 10.0U9: a catecholamine bronchodilator and hyperglycemic agent, J. Pharmacol. Exp. Ther. 133 90-97, 1961.

Dog blood pressure

Mongrel dogs were anesthetized with sodium pentobarbitol, 30 mg / kg / i.v.

Femoral artery blood pressure was measured with a mercury manometer and reproduced on smoke paper and the heart rate was determined from the electrocardiogram obtained using subcutaneous electrodes. The drugs were administered by cannula into the femoral vein.

Isolated gastrointestinal and reproductive tissue

All measurements were performed in a 2 ml tissue bath using a Phipps-Bird Linear Motion Transducer Model ST-2. The tissues were allowed to remain in the bath until a permanent maximum was reached, at which time they were washed and allowed to return to their baseline condition. All assay results are the averages of at least three separate tissues for each reported dose of 9,57583. The values of the analogous compounds were compared with the dose response obtained with the natural PG compound in said tissue. To compare efficacies, a standard dose of natural PG was selected and all reaction effects were calculated as a percentage of its reaction effect. Addition values were reported as the minimum effective dose (MED) and the consistently effective dose (CED) to determine the sensitivity of the compound to each tissue. The standard equivalent dose (SED) was determined. This value was defined as the amount of compound (ng / ml) that elicited a response corresponding to the response of a given standard dose of PG in tissue.

Guinea pig ileum: The ileum was excised from male guinea pigs weighing 200-300 g, which had been killed by twisting the neck. The tissue was suspended in 2 ml of 37 ° C llyrode solution (2). PGEg (30 ng / ml) and / or PGF20 (30 ng / ml) were used to detect tissue activity.

^ Guinea pig uterus (3): Unborn females (300-1 * 00 g) without mating time were killed by twisting the neck. Separated uteri were germinated at 37 ° C in 2 ml of modified Krebs solution (12). Uterine activity was determined using PGE2 (1.0 ng / ml) and / or PGFβ2. Hale, L.J. ed. Biol. Lah. Date pp. 92, 1958.

3. Clegg, P.C., P. Hopkinson, and V.R. Pickles, J. Physiol. 167: 1, 1963-1. W. S. Umbreit, R.H. Burris and J.F. Stauffer, Monometric Techniques 11 + 8, 1957.

The following table compares the novel compounds of the invention with the known compound 16-phenyl-PGE2.

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ft ro * - O O O II H 3 · Η> P

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HP HPt 0 0 0 * -h W-HPP> P

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Example 1 9-Oxo-1H-15,15- (N-dihydroxy-16-phenyl-cis-β-6J-tetranor-prostenoic acid A solution of 772 mg of 9-oxo-11β, 15β-bis- (tetrahydropyran-2-yloxy) -6-phenyl-cis-5-cd-tetranor-prostenoic acid in 7.0 ml of a glacial acetic acid / water mixture (65:35) was stirred under nitrogen at 25 ° for 20 hours, then The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-U 100-200 mesh) eluting with ethyl acetate, and after less eluting the polar impurities, 361 mg of oily 9-oxo-11-oxy was collected. -6-phenyl-cis-5-W-tetranor-prostenic acid The IR spectrum (CHCl 3) -1 J had carbonyl absorbances at 1710 and 1735 cm

Biological activity: guinea pig uterus 1j guinea pig histamine aerosol test 0j canine blood pressure 1 + 00 (long-term effect).

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Example 2 9-Oxo-11ol-15 ° (-dihydroxy-16-p-diphenyl-6o-tetranorprostanoic acid

A heterogeneous solution of 9-oxo-11β, 15αHydroxy-16-p-di-phenyl-cis-5-trans-13- (O-tetranorprostadienoic acid and 5% palladium-on-carbon catalyst in absolute methanol was hydrogenated (1 atm ) At 25 ° for 2 hours The reaction mixture was filtered and evaporated to dryness to give 9-oxo-11β, 15 ° <3'-dihydroxy-16-p-diphenyl-6β-tetranorprostanoic acid, mp 120-123 °. the spectrum (KBr,) showed carbonyl adsorptions at 1715 cm-1 and -1.

1735 cm, wide OH region and no trans double bond adsorption.

Example 3 9-Oxo-11β-dihydroxy-16- (2-thienyl) -cis-5-trans-13β-tetranoradadienoic acid

A solution of 760 mg (1.39 mmol) of 9-oxo-11β, 15β-bis- (tetrahydropyran-2-yloxy) 16- (2-thienyl) -cis-5-trans-13 -W-tetranor-prostadienoic acid in 3.0 ml of a mixture of glacial acetic acid and water (65i35) was stirred under nitrogen at 25 ° for 18 hours, after which it was concentrated on a rotary evaporator.

The resulting crude oil was purified by column chromatography using silica gel (Mallinckrodt CC-h, 100-200 mesh) and ethyl acetate as eluent.

After elution of the less polar impurities, 369 mg of 9-oxo-11α, 15β-dihydroxy-16-2-tieeoyl-cis-5-trans-13-U) -tetranorostadienoic acid were collected as a semi-solid.

The IR spectrum showed carbonyl adsorptions at 1730 and 1705 cm 1, and at 972 cm 1 weak adsorption corresponding to the 13.1 trans double bond.

The product of this example can be converted to the 16- (2-thienyl) -CJ-tetranorprostaglandins of the Eq and E 1 series by the methods of Examples 6 and 7. In a similar manner, the corresponding N-thienyl compounds were prepared.

IR-17H IR: 1715, 17 ^ -0.99 cm-1 15? -OH IR: 1715, 17 ^, 0.970 cm-1

Example k 9d (.11 g <.15α-trihydroxy-16- (2-thienyl) -cis-5-trans-13-cl-tetranorprostadienoic acid

A mixture of 0.76 g of 9 ° (.-Hydroxy-11β, 15β-bis- (tetrahydropyran-2-yl) -16- (2-thienyl) -cis-5-trans-13-6 Tetranorprostadienoic acid in 5 ml of a mixture of acetic acid and water (65:35) is stirred under nitrogen at room temperature overnight, then concentrated in vacuo to a viscous oil The crude product is purified by column chromatography on Mallinckrodt CC-U silica gel using ethyl acetate as eluent.

T5 57583 After elution of less polar impurities, the desired 9β, 11β, 1β-trihydroxy-16- (2-thienyl) -cis-5-trans-13β-tetranorprostadienoic acid is obtained in the form of a viscous, colorless oil weighing 51 mg.

The product obtained above can be converted to the F? Series 16- (2-thienyl) -ϋ-tetranor-prostaglandin by the method of Example 7. It can also be converted to the Fg 2 series 16- (2-thienyl) -β-tetranorprostaglandin by the method of Example 6.

Example 5 9-Oxo-1M, 15 ° C-dihydroxy-16- (2-thienyl) -cis-5'-tetranorprocenoic acid

A solution of 800 mg of 9-oxo-11β, 15β-bis- (tetrahydropyran-2-yloxy) -16- (2-thienyl) -cis-5-CJ-tetranorprocenoic acid in 7.0 ml of glacial acetic acid and water the mixture (65:35) is stirred under nitrogen at 25 ° for 20 hours and then concentrated on a rotary evaporator. The crude oil obtained is purified by chromatography on a column using silica gel (Mallinckrodt CC-U 100-200 mesh) and ethyl acetate as eluent. After elution of less polar impurities, oily 9-oxo-11β-β5-dihydroxy-16- (2-thienyl) -cis-5-β-tetranorprostenoic acid is collected *

Example 6 9-Oxo-1 lot, 15 (<c-dihydroxy-16- (2-thienyl) -m-tetranorprostanoic acid

Heterogeneous solution of 37 mg (0.089 mmol) of 9-oxo-11 ° C, 15 ° (-dihydroxy-16- (2-thienyl) -cis-5-trans-13-β-tetranorprostadienoic acid and 13 mg of 5% palladium-on-carbon The catalyst in 3 ml of absolute methanol is hydrogenated (1 atm) at 0 [deg.] C. for 2 hours, and the reaction mixture is filtered and evaporated to dryness to give 9-oxo-11β-dihydroxy-16- (2-thienyl) - [? - tetranor - prostanoic acid.

Example 7 "9-Oxo-11α, 15α-α-dihydroxy-16- (2-thienyl) -trans-13β-tetranorprostenoic acid

A solution of 50 mg of 9-oxo-11et, 15β-dihydroxy-16- (2-thienyl) -cis-5 'trans-13- (4-tetranorprostadienoic acid in 5 ml of dry ether) is treated with 1 + 1 + 8 mg dimethylisopropylchlorosilane and 360 mg (3.6 mmol) of triethylamine at 25 ° for 1 + 8 hours, cool the reaction mixture to 0 °, add methanol and wash the resulting solution with water (3 x 2 ml), dried (MgSO 4) and evaporated to dryness The crude residue is dissolved in 6 ml of methanol containing 30 mg of 50% Pd / C catalyst and the resulting slurry is hydrogenated for 1+ hour at -22 ° (CCl 4 / dry ice). After filtration through a fine filter and concentration, the hydrogenated product is hydrolysed for 10 minutes in 2 ml of acetic acid / water (3: 1), diluted with water (20 ml) and extracted with ethyl acetate (1+ x 15 ml) and the combined organic extracts are washed with water (2 x 10 ml). ), 6 57583 is dried (MgSO 4) and evaporated to dryness to give 9-oxo-11α, 15β-dihydroxy-16- (2-thienyl) trans -13 - ^ - tetranorprostenoic acid.

Example 8

Methyl 9β-acetoxy-11 (A, 15/3 -dihydroxy-trans-13-16- (3-thienyl) -tetranorprostenoate and methyl 9α-acetoxy-11α, 15β-dihydroxy-trans -13-16- (3-thienyl-N-AJ-tetranorprostenoate

A solution of 1.60 g (2.16 mmol) of crude methyl-9 ° -acetoxy-11β- (tetrahydropyran-2-yloxy) -1,5-hydroxy-trans-13-16- (3-thienyl) - <w-tetra-norprostenoate in 10.7 ml of a mixture of acetic acid and water (65:35) is stirred at 1 + 0 - 2 ° under nitrogen for 2.5 hours. The reaction mixture is then concentrated to give a crude epimeric diol mixture. The crude product is purified by column chromatography on silica gel to give the desired methyl 9 ° -acetoxy-11 ° C, 15β-dihydroxy-trans-13-16- (3-thienyl) -? O-tetranorprostenoate and the epimeric methyl-PCR acetoxy-11β, 15β-dihydroxy-trans-13-16- (3-thienyl) -6J-tetranorprostenoate.

Example 9 9 <*, 11 <* .15ox, -trihydroxy-trans-13-16- (3-thienyl) -6J-tetranorprostenoic acid

A mixture of 65 mg (0.15 mmol) of the chromatographed diol prepared in Example 8, 0.1 + 5 ml (0.1 + 5 mmol) of 1.0 N aqueous sodium hydroxide solution, 0.1 + 5 ml of tetrahydrofuran and 0 , 1 + 5 ml of absolute methanol, stirred under nitrogen at room temperature for 1.5 hours. The solution is then acidified by adding 0.1 + 5 ml of 1.0 N aqueous hydrochloric acid (the pH of the acidified solution was about 5). · The acidified solution is extracted with ethyl acetate (1+ x 2 ml). The combined extracts are dried (anhydrous magnesium sulfate) and concentrated to give the desired 90 ° C. , 11c ^. 15 «^ - trihydroxy-trans-13-L6- (3-thienyl) -Fc -.'- tetranorprostenoic acid.

Example 10 9-Oxo-11 ° C.15-dihydroxy-13-trans-16- (3-thienyl) -6J-tetranorprostenoic acid

A homogeneous solution of 0.179 g (0.328 mmol) of crude 9-oxo-11β, 15β-bis- (tetrahydropyran-2-yloxy) -trans-13-16- (3-thienyl-N-tetranor- prostenic acid in 2 ml of a mixture of acetic acid and water (65:35) is stirred under nitrogen at 1 + 0 to 2 ° for 5 hours, the reaction mixture is concentrated on a rotary evaporator and then using an oil pump, and the crude product is purified by column chromatography on silica gel (Mallinckrodt CC). 7) to give the desired 9-oxo-11 ° -15 ° C-dihydroxy-13-trans-16- (3-thienyl) -α-tetranorprostenoic acid.

IT 5 7583

Example 11 9-Oxo-11d, 15o (-dihydroxy-17- (2-thienyl) -cis-5-trans-13-bJ-trisnor-prostadienoic acid

A solution of 2b0 mg (0.33 + + mmol) of 9-oxo-11c *, 15 (bis-tetrahydro-pyran-2-yloxy) -17- (2-thienyl) -cis-5-trans W-trisnor-prostadienoic acid in 3.0 ml of a mixture of glacial acetic acid and water (65:35) was stirred under nitrogen at 25 ° for 18 hours and then concentrated on a rotary evaporator.

The resulting crude oil was purified by column chromatography using silica gel (Mallinckrodt CC-b 100-200 mesh) and ethyl acetate as eluent. After elution of less polar impurities, 100 mg of oily 9-oxo-11β-, 15β-dihydroxy-17- (2-thienyl) -cis-5'-trans-13- (O-trisnor-prostadienoic acid) was collected.

The product of this example can be converted to the 17- (2-thienyl) - (>) -? Trisnor prostaglandins of the Eq and E ^ series by the methods of Examples 6 and 7.

Example 12 9-Oxo-11β-, 5'-dihydroxy-17- (2-thienyl) -cis-5-trans-13-trans-tris-propionic acid

A solution of 500 mg (0.893 mmol) of 9-oxo-110β, 15β-bis-tetrahydro-pyran-2-yloxy) -17- (2-thienyl) -cis-5-trans-13- and N-tris-nor- prostadienoic acid (10'b) in 7.0 ml of a mixture of glacial acetic acid and water (65:35) was stirred under nitrogen at 25 ° for 18 hours and then concentrated on a rotary evaporator. The resulting crude oil was purified by column chromatography using silica gel (Mallinckrodt CC-1 + 100-200 mesh) and ethyl acetate as eluent. After elution of less polar impurities, 215 mg of semi-solid 9-oxo-11β, 15β-dihydroxy-17- (2-thienyl) -cis-5-trans-13-W-trifluorostadienic acid were collected.

Example 13 9-Oxo-11β-dihydroxy-17- (2-furyl) -cis-5-trans-13-60-trisnor-propionic acid

A solution of b23 mg (0.702 mmol) of 9-oxo-11,15-bis-tetrahydropyran-2-yloxy) -17- (2-furyl) -cis-5'-trans-13-e- trisnor-prostadienoic acid in 3.0 ml of a mixture of glacial acetic acid and water (65:35) was stirred under nitrogen at 25 ° for 18 hours, after which it was concentrated on a rotary evaporator.

The resulting crude oil was purified by column chromatography using silica gel (Mallinckrodt CC-100-200 mesh) and ethyl acetate as eluent. After elution of less polar impurities, 20 U mg of crystalline 9-oxo-11 ° C, 15 c * -dihydroxy-17- (2-furyl) -cis-5-trans-13-CJ-trisnor-prostadienoic acid were collected, m.p. was 98-99 ° · 18 5 7583 The product of this example can be converted to the 17 (2-furyl) -O> trisnorprostaglandins of the Eq and E ^ series by the methods of Examples 6 and 7.

Example 1U

9β-Trihydroxy-17α- (2-furyl) -cis-5-trans-13β-trisnor-prostadienoic acid

A solution of 700 mg (0.33 μmol) of 9c * -hydroxy-1-ol, 15o (-bis-tetrahydropyran-2-yloxy) -17- (2-furyl) -cis-5-trans-13 - W-trisnorprostadienoic acid in 5 ml of a mixture of glacial acetic acid and water (65:35) was stirred under nitrogen at 25 ° for 20 hours, after which it was concentrated on a rotary evaporator.

The resulting crude oil was purified by column chromatography using silica gel (Mallinckrodt CC-1 + 100-200 mesh) and ethyl acetate as eluent. w After elution of less polar impurities, 108 mg of oily 9?, 11o (, 15e <-trihydroxy-17- (2-furyl) -cis-5-trans-13-6> -trisnor-prostadienoic acid were collected.

The IR spectrum (CHCl 3) showed carbonyl adsorption at 1710 cm 1 and trans double bond adsorption at 965 cm The product of this example can be converted to the 17 '(2-furyl) -W-trisnorprostaglandins of the series and sequences according to Examples 5 and 6. methods.

Claims (2)

19 57583 Patents: Process for the preparation of therapeutically useful novel prostaglandin E and F series compounds of formula M JL W / \ COOH / -jp ^ / (CH2) n-Ar 1 H ° # ^ OH -m * wherein Ar is o- or β-furyl, oi- or β-thienyl, β- or β-naphthyl, biphenyl or phenyl; n is an integer from 0 to 2, provided that when Ar is phenyl, biphenyl or naphthyl, then n is 0 or 1; R is hydrogen; W is a single bond or a cis double bond; and Z is a single bond or a trans double bond, provided that when Ar is phenyl, then W is a cis double bond and Z is a single bond; M is oxo or; and their C 1-4 acetoxy esters and their pharmaceutically acceptable salts, characterized in that (a) a compound of formula MJ) * V Ne-is / \ C00H f NK / 11 *! 1. · * 11 THPO H wherein Ar, n, M, R, W and Z are as defined above and THP is 2-tetrahydropyranyl, is reacted with a suitable acid; or (b) a compound of formula I wherein Ar, R, n and M are as defined above, ¥ is a single bond or a cis double bond when Z is a trans double bond, and Z is a single bond when W is a cis double bond , is catalytically hydrogenated to give a compound of formula I wherein Ar, n, R and M are as defined above and W and Z are single bonds; or (c) a compound of formula 57583 0 ff O-C-CH 3 J - w / V, / ^ ^ COOR 'wherein W is a single bond, Ar, n, R and Z are as defined above, and R' is hydrogen or lower alkyl, is reacted with a suitable acid of the formula To prepare a compound of formula I wherein M is and, if desired, ®.0C, a 9® C-acetoxy ester is prepared by reacting the resulting 9c-hydroxy compound with a suitable acetylating agent, and if desired, a pharmaceutically acceptable salt of a compound of formula I is prepared. 57583 21 For the preparation of therapeutic therapies for the treatment of prostaglandic substances E and F series, in which the form M Il ^ v / \ / ^ COOH _I Z (CH2) n-Ar I H0 '# ί {ί ^> ^ 0ΤΙ color Ar är <*, - or β-furyl, or β-thienyl, oL- or β-naphthyl, biphenyl or phenyl; n is ett heltal 0-2, förutsatt att dä Ar är phenyl, biphenyl eller naphtyl, sa är n 0 eller 1; R e statement; W en enindindning eller en cis-dubbelbindning; och Z is en-publication or trans-duplication, for which there is phenyl, s II and W is cis-duplication; M är oxso eller; The VOH and the C 1-4 ethoxy esters and the pharmaceutical esters are selected from the group consisting of (a) in the formulation of Formula I (AcV \ C00H) -11711150 R ^ n_0THP color Ar, n, M, R, W and Z are obtained from each other, and THP is 2-tetrahydro-pyranyl; or (b) in the case of formula I, color Ar, R, n and M in the same column as in W, and in the case of cis-duplication, and in the case of trans-duplication, and in the case of W en cis-dubbelbindning,