DK144730B - ANALOGY PROCEDURE FOR PREPARING 2-DESCARBOXY-2-TETRAZOLYL (5) -PROSTAGLANDINE2 COMPOUNDS - Google Patents

Description

(19) DENMARK

6 (12) PUBLICATION WRITING (11) 1W30B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 4307/72 (51) | nt.ci.3 C 07 D 257/04 (22) Filing Day 51 · & ug. 1972 (24) Running day 31- Aug. 1972 (41) Aim. available March 2 1973 (44) Submitted May 24, 1982 (86) International Application no.

(86) International filing day (85) Continuation day (62) Stock application no.

(30) Priority 1. S ep. 1971, 177102, US

(71) Applicant PFIZER INC., New York, US.

(72) Inventor Hans-Jurgen Ernst Hess, US: Thomas Ken Schaaf, US: Leonard Joseph Czuba, US.

(74) Associate Engineer Hofman-Bang & Boutard.

(54) Analogous process for preparing 2-descarboxy-2-tetrazolyl (5) -prostaglandin E2 compounds.

The invention relates to an analogous process for the preparation of certain novel analogs to the naturally occurring prostaglandins, namely, novel 2-descarboxy-2-tetrazolyl (5) -prostaglandin-E 2 compounds of the general formula I as set forth in the preamble, which method is peculiar to that stated in the characterizing part of the claim.

D The prostaglandins are unsaturated fatty acids with 20 carbon atoms, such as [. exhibits various physiological effects. Eg. the prostaglandins of the E and A rows are potent vasodilators (Bergstrom et al.,

Acta Physiol. Scand. 64,332-339, 1965 and Bergstrom et al., Life Scl.

- 6,449-455, 1967). This relaxant effect on small blood vessels is probably responsible for the decrease in systemic arterial blood pressure (vasodepression) observed by intravenous injection of PGE-1 and PGA-2 (Weeks and King, Federation Proc. 23,327 »1964; Bergstrom et al. I965, op. Cit. Carlson et al., Acta Med. Scand. 193, 423-430, 1968; and Carlson et al., Acta Physiol. Scand. 75, 161-169 (1969).

Another well-known physiological effect for PGE 2 and PGE 2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4,723-726, 1969).

Another important physiological role for the natural prostaglandins is in the propagation cycle. PGE2 is known to have the ability to induce labor (Karim et al., J. Obstet Gynaec. Brit. Cwlth. 77,200t210, I97O) and also to induce therapeutic abortion (Karim et al., Brit. Med. J. in print). Patents have been obtained on several prostaglandins of the E and F rows as mammalian carcinogens (Belgian Patent No. 754 158 and Patent Specification No. 2 034 641) and on PGF1, F2 and F propagation cycle (South African Patent Publication No. 69/6089).

Still other known physiological activities for PGE1 are to inhibit gastric acid secretion (Shaw and Ramwell, "Worcester Symp. On Prostaglandins" New York, Wiley, 1968, pp. 55-64) and also platelet aggregation (Emmons et al., Brit. J. Med., 2,468-472, 1967).

It is also known that such physiological effects in vivo will only be induced for a short time after the administration of a prostaglandin. A considerable amount of testimony indicates that the reason for the rapid cessation of activity is that the natural prostaglandins are rapidly and effectively deactivated metabolically by the oxidation of the carboxylic acid side chain and by the oxidation of the 15o Scand., 81, 396 (1971) and references therein).

Of course, there was a strong desire to produce analogues to the prostaglandins, which would have physiological activities similar to the natural compounds, but in which the selectivity of the action and duration of activity were increased.

This is also achieved with new compounds prepared by the process of the invention. These 2-descarboxy-2-tetrazolyl (5) -E2-prostaglandins, wherein the carboxylic acid moiety is replaced by the tetra-zole ring and wherein the 15β hydrogen may, if desired, be replaced by a 15β-methyl group, uniquely satisfies the above requirements , ie that they have Activity profiles comparable to those of the original prostaglandins and exhibit a longer duration of action than the original prostaglandins.

The process of the invention and preparation of intermediates can be illustrated by the following reaction scheme:

Scheme

OH

in N "- N

. N * -N

THPO

III

Jones' reagent Ψ

0 N - N

N-N

THPo '^

IV

Acetic acid PGE2 ~ tetrazolyl I (R1- #) 4

As shown in the reaction scheme, the starting compound III, the tetrazolyl analog of the bis-THP ether of PGF2 (X, first with Jones * reagent to form the bis-THP ether of PGE2-tetrazolyl (IV)), is then hydrolyzed by the process of the invention. with acetic acid to give the desired PGE 2 -tetrazolyl (I, R 2 = H), which is concentrated and purified by column chromatography.

For the preparation of 15β-methyl derivatives of the above-mentioned prostaglandin E2-tetrazolyl compound, only the base compound III with a methyl group in the 15β position is used, and proceed as indicated above to prepare the desired compound.

Numerous tests in vivo have shown that the tetrazolyl-prostaglandin analogs prepared by the process according to the invention have similar physiological activities as those exhibited by the natural prostaglandins. These tests include: a test for effect on isolated rabbit aortic and guinea pig smooth muscle, a test for inhibition of norepinephrine-induced lipolysis in isolated rat fat cells, a test for effect on histamine-induced bronchospasm in guinea pigs, a test for effects on canine blood pressure, and a test for effects on rat blood pressure.

When tested for isolated smooth muscle from the rabbit aorta, the threshold dose for spasmogenic effect was found to be 250 ng / ml for PGE2 and 500 ng / ml for PGE2 tetrazolyl. At the same test using guinea pigs, values of 20 ng / ml and 100 ng / ml were obtained for the same two compounds.

In the test for protection of 100 µg / ml of the test compound against histamine-inducing guinea pig bronchospasm, values of 65-75% were obtained for PGE2 and PGE2-tetrazolyl.

In testing for effects on canine blood pressure, both PGE2 and PGE2 tetrazolyl were found to be depressants, and values of 0.16 µg and 0.8 µg / ml of the two compounds were obtained as the threshold dose for this effect. In the case of rat blood pressure, the compounds were also depressors and the threshold dose for PGE2 and for PGE2 tetrazolyl was 10.0 / ug / ml.

144730 5

That the duration of action of the 15 β-methyl-tetrazolyl analog is increased over the original prostaglandin is clearly illustrated by the data set out in Table 1 below. This experiment shows that a comparable drop in blood pressure was achieved in anesthetized dogs with a comparable intravenously administered dose of the natural prostaglandin PGE2 and of its tetrazolyl analog. In the case of the 15β-methyl-PGE2-tetrazolyl analog, it was found that although the size of the dose must be increased to achieve an equally large drop in blood pressure, the time period during which this reduced pressure is maintained is greatly increased.

6 1Λ Λ 7 3 O

TABLE · 1 1 2

Dog Applied Dose Pre Post mmHg Return No compound mg / ml IV turnaround min.

1 PffBg 4 158 110 28 25 PGE2-tetrazolyl 4 158 110 28 31 15-methyl-PGE2 50 155 108 27 57 tetrazolyl 2 PGE2 2 150 92 58 4 PGEg-tetrazolyl 2 125 95 50 6 15-methyl-PGE 2 - 50 128 95 55 26 tetrazolyl 3 PGE2 2 115 92 23 6 PGE2-tetrazolyl 2 114 90 24 10 15-methyl-PGE2 50 114 90 24 120 tetrazolyl 4. PGE2 2 130 100 30 6 PGE2-tetrazolyl 2 132 110 22 6 15 -methyl-PGE2- 50 136 103 55 50 tetrazolyl 5 PGE2 2 115 82 55 5 PGE2-tetrazolyl 2 110 90 30 8 15-methyl-PGE2- 50 120 92 28 40 tetrazolyl 1 Blood pressure before administration of the agent 2 Blood pressure after administration of the agent 7 1U730

The novel compounds prepared by the process of the invention can be used in a wide variety of pharmaceutical compositions containing the compound or a salt thereof, and may be administered by a variety of routes, such as intravenously, orally and topically, including e.g. . aerosol, intravaginal and intranasal salt.

The natural prostaglandins are well known means of inducing abortion, and it can reasonably be predicted that the tetrazolyl-pros-taglandins will share this ability. For such treatment, an aqueous suspension of PGE2-tetrazolyl may conveniently be administered in an amount of 0.2-5.0 mg / dose at 1-7 oral doses per day. day.

If intravaginal abortion therapy is desired, a suitable agent could be a sterile ethanolic solution of this tetrazolyl-prostaglandin or lactose tablets with this compound. In such treatments, a suitable dosage could be 15-200 mg / dose with 1 or 2 doses daily.

In cases where a mid-pregnancy miscarriage is necessary, an effective agent could be an ethanol-dextrose solution of PGE 2 -tetrazolyl administered as an intravenous infusion. A suitable dosage could be 5-500 yug / min. administered for a period of from about 1 to about 24 hours.

Another suggested use for the tetrazolyl prostaglandins is as a web remover. For this purpose, an ethanol saline solution of PGE 2 -tetrazolyl could be used as an intravenous infusion in an amount of 3-100 ng / kg / min. in from about 1 to about 10 hours.

For the preparation of any of the above dosage forms, or any of the numerous other possible forms, various reaction-inert diluents, excipients or carriers may be used. Such substances include e.g. water, ethanol, gelatins, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, rubbers, polyalkylene glycols, petroleum vaseline, cholesterol and other known carriers for medications. If desired, these pharmaceutical compositions may contain adjuvants such as preservatives, wetting agents, stabilizers or other therapeutic agents such as antibiotics.

The following examples serve to further illustrate the process of the invention.

EXAMPLE 1

Output Connector

To a stirred solution of 400 mg (0.731 millimoles) of 3β- [3α- (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl] -2- [6- (tetrazol-5-yl) - cis-2-Hexen-i-yi] -4a- (tetrahydropyran-2-yloxy) -ia-hydroxycyclopentane in 12.3 ml of acetone at -10 ° C was added dropwise over five minutes..0.29 Jones reagent , prepared in advance from 2.67 g of chromium trioxide and 2.3 ml of concentrated sulfuric acid diluted to 10 ml with water. The resulting mixture was stored for 15 minutes at -10 ° C and then treated with 0.46 ml of isopropyl alcohol. The mixture was stirred for a further 5 minutes at -10 ° C and partitioned between ethyl acetate (30 ml) and water (30 ml). The ethyl acetate layer was separated and combined with an ethyl acetate extract and the aqueous layer. The combined solutions were washed with three 15 ml portions of water, dried over magnesium sulfate and concentrated (water jet pump, about 40-50 ° C) to give 358 mg of 4α (tetrahydropyran-2-yloxy) -3β- [3α - (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl) -2α- [6- (tetrazol-5-yl) -cis-2-hexen-1-yl] -cyclopentanone as a viscous oil.

2-decarboxy-2-tetrazolyl (5) -PGEo

The oil prepared above was stirred with 10.7 ml of acetic acid and 5.8 ml of water under nitrogen at 40-45 ° C for 3 hours. The resulting solution was concentrated (water jet pump, about 40-50 ° C) and the residue (275 mg) chromatographed on acidic silica gel (25 g of Mallin-capped Silicar CC-4, mesh size 0.074-0.147 mm) using mixtures of chloroform and methanol as eluents to separate 130 mg of an unidentified mixture and 103 mg (yield 14%) of the desired product, 4a-hydroxy-3β- (3oc-hydroxy-trans-1-octen-1-yl) ) -2- [6- (Tetrazol-5-yl) -cis-2-hexen-1-yl] -cyclopentanone, as a clear, thick, colorless oil. Thin layer chromatography of the product on silica gel glass plates using methylene chloride-methanol (9: 1) or benzene-tetrahydrofuran formic acid (15: 5: 2) as development agents and visualization of the chromatograms by heating with vanillin-phosphoric acid reagent showed a single stain at Rf values of 0.30 and 0.25 respectively on the two systems. The IR spectrum of the product

(CHCl4) showed a strong absorption band at 1730 cm 2 (C = 0) and D

a moderately weak band at 3610 cm- (OH). The UV spectrum of the product (95% ethanol) showed only final absorption. This product was 2-descar-boxy-2-tetrazolyl (5) -PGE2 · Treatment of a small sample of the product with 10% aqueous sodium hydroxide and ethanol for 15 minutes at room temperature gave a single product by thin layer chromatography (R 3, 0.38; silica gel; benzene / tetrahydrofuran / formic acid, 15: 5: 2). The latter product UV spectrum (95% ethanol) exhibited an absorption maximum at 279 nm (19600).

EXAMPLE 2

Output Connector

To a solution, cooled to -15 ° C, of 105 mg (0.187 millimoles) of chromatographed 1-hydroxy-4a- (tetrahydropyran-2-yloxy) -3β- | 3β-methyl-3a- (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl-2- [6- (tetrazole-5-yl) -cis-2-hexene-1-79-cyclopentane in 2.0 ml of acetone was added dropwise 0.1 ml of Jones' reagent. The mixture was stirred for 30 minutes in the cold and then 0.5 ml of 2-propanol was added. The solution was diluted with ethyl acetate, washed 2 times with water and 1 time with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 82 mg (78% yield) of an oily ketone. The crude oil was purified by column chromatography on silica gel ("Baker 'Analyzed'Reagent", mesh size 0.074-0.250 mm) using 10% ethyl acetate in chloroform as eluent to give 56 mg (53.4% yield) of the purified oily ketone, 4α- (tetrahydropyran-2-yloxy) -3β- [3β-methyl-3α- (tetrahydropyran-2-yloxy) -trans-1-octenyl-2β- [6- (tetrazol-5-yl) -cis-2-hexen-1-yl Cyclo-pentanone. Thin layer chromatography of the oily product on silica gel glass plates using 10% methanol in methylene chloride as the eluent showed a single spot with an R

The structure was confirmed by the complete identity of its IR spectrum with the spectrum of the 15-normethyl compound (see Example 1).

2-Desearboxy-2-tetrazolyl (5) -15-methyl-PGEn

A solution of 57 mg (0.10 millimole) of the above-prepared chromatographed bis-THP ether in 0.88 ml of a 65:35 mixture of a, acetic acid and water was stirred at 42 ° for 4.0 hours and then concentrated by rotary evaporation. Chromatography of the crude product, which weighed 48 mg, on silica gel ("Mallinckrodt CC-4") using 2% methanol in chloroform as eluent gave 13 mg (33.4% yield) of the oily diol, 4 (X hydroxy-3β- [3α-hydroxy-3β-methyl-trans-1-octen-1-yl] -2α- [6- (tetrazol-5-yl) cis-2-hexen-1-yl] -cyclopentanone This compound is 2-descarboxy-2-tetrazolyl- (5) -15methyl-PGE 2.

The structure was confirmed by the practical identity of its IR spectrum with the spectrum of the 15-normethyl compound. Treatment of a methanolic solution of the oily product with 40% aqueous potassium hydroxide gave the expected UV absorption at 278 nm (€ 20,000).