HU191216B - Process for the synthesis of stable 4,4-dioxo-4-thia-prostacycline derivatives - Google Patents

Abstract

Optically active or racemic 4,4-dioxo-4-tia-prostacyclin derivs. of formula (I) are obtd. by condensing a cpd. of formula (III) with a cpd. of formula (IV), heating the resulting cpd. of formula (II) and opt. removing the protective gps. from the hydroxyl and/or hydrolysing the ester gp. and/or forming a salt from the free acid.

Description

The present invention relates to novel optically active or racemic 4,4-dioxo-4-thia-prostacyclin derivatives having pharmaceutically acceptable biological activity and to pharmaceutical compositions containing them as active ingredients.

In the formula I, the substituents have the following meanings:

Q is a group -CO ¹ R ¹ , wherein

R ^{1 is} hydrogen, C 1-4 alkyl,

The cis or trans vinylene group,

R ^{2 is a} straight or branched C 3 -C 7 alkyl group,

R ^{3 is} hydrogen or C 1-4 alkanoyl,

B chemical bond.

The compounds of the formula I according to the invention are physiologically very important metabolites of arachidonic acid in mammals. are considered effective analogues of prostacyclin (PGL).

Prostacyclin (PGI ₂ ), discovered in 1976, is one of the most prominent representatives of natural prostanoids with very significant biological activity. (Prostacyclin ed. JR., Vane and S. Bergström, Raven Press New York 1979). The pharmacologically most interesting properties of PGI ₂ are related to inhibition of platelet aggregation and vasodilatory effects. In addition, other biological effects are known (e.g., it reduces gastric acid secretion, dilates the airways, so-called cytoprotective effects are also known).

The major problem with using PGI _{2 as a} drug is the extreme instability of the substance and its non-selective biological effect. The reason for the instability of PGI _{2 is} the highly reactive enolether moiety, which reacts with both an external and an intracellular proton source to degrade the molecule to 6-oxo-PGEaifg. One way to chemically stabilize the enolether moiety is by electron withdrawing groups located near the enolether functional group. By this principle, the 4,4-dioxo-4-thia-PGI ₂ derivatives of the present invention are stabilized. The sulfonyl group incorporated into the molecule reduces the electron density of the enol ether of the molecule, thereby reducing its reactivity and increasing its stability. Thus, in contrast to PGI _2, the materials of the present invention exhibit surprising stability: they can be maintained for several hours in 1N hydrochloric acid and acetic acid media without significant degradation. The half-life of PGI _{2 at} physiological pH η = (7.4) is only 3-4 minutes, and the rate of degradation in an acidic medium is even higher (J.Chem.Soc., Chem. Cornmun., 1979, 129).

The compounds of formula (I) exhibit substantially the same activity spectrum as prostadlin. For example, they inhibit platelet aggregation induced by ADP, arachidonic acid or collagen at concentrations of 1 to 1000 gamma / ml. However, some of their representatives, like

4,4-Dioxo-4-thia-PGI ₂ methyl ester exhibits significant pharmacological selectivity over PGI ₂ . The compound induces selective, vasodilatory vasodilation at doses ranging from 0.05 to 1.0 mg / kg in cats, while its systemic antihypertensive and antiaggregatory activity at this concentration is negligible.

Thus, the compounds of formula (I) of the present invention are novel porstacyclin (PGI ₂ ) derivatives which exhibit unexpected selectivity over PGI ₂ and are substantially more stable.

According to the present invention, compounds of formula (I) are prepared by reacting a compound of formula (III) wherein A, B, R ² and R ³ are as defined above with a compound of formula (IV) wherein R ⁴ is aryl, or a substituted aryl group and Q is as defined above, then the resulting compound of formula II, wherein R ¹ , R ² , R ³ , R ⁴ , Q, A and B are as defined above, is heated.

Substituents hereinafter have the meanings given above.

The preparation of compounds of formula (IV) can be carried out by analogy to the literature (Tetrahedron, 33, 2019 (1977)).

Compounds of formula (III) are also known or may be prepared by literature analogies (EJ. Corey et al., JACS 93, 1491 (1971)).

The condensation of the compounds of formula (III) and (IV) is carried out in the presence of a base. Alkali metal hydroxides include organic lithium compounds such as butyllithium or lithium diisopropylamide or metal hydrides such as sodium hybrid. The reaction may comprise from 1.0 to 10 equivalents of base relative to the compound of formula (III). When alkali metal hydroxides are used, protic solvents such as water alcohols or solvent mixtures such as aqueous tetrahydrofuran. aqueous alcohols - used. While other bases are used aprotic solvents such as diethyl ether tetrahydrofuran or dipolar aprotic solvents such as diethyl ether tetrahydrofuran or dipolar aprotic solvents such as hexamethylphosphonic acid triamide, dimethylsulfoxide. The condensation is carried out at a temperature of -80 ° C to 100 ° C.

It is particularly preferred to conduct the condensation with sodium hydroxide in a methanol-water solvent mixture at 20-35 ° C.

The compounds of formula (II) are heated at a temperature of from 50 to 200 ° C. Suitable solvents are aromatic solvents such as benzene, toluene, halogenated solvents such as chloroform or dipolar aprotic solvents such as dimethylformamide. It is particularly preferred that the heating be carried out in dimethylformamide at a temperature of 110 to 130 ° C.

Heating may also be carried out under solvent-free conditions.

The hydroxyl groups of the compounds of formula (I) prepared as above may optionally be deprotected.

The compounds of the present invention may be used as active ingredients in pharmaceutical compositions because of their biological effects. Of course, in such cases, only the pharmacologically acceptable salts can be taken into consideration. These compositions can be used to prevent or cure diseases such as peripheral vascular disease (artherosclerosis obliterans, Burger's disease, diabetic angiopathy), limb circulation improvement, myocardial infarction size and death rate.

They are suitable for reducing the number and severity of seizures in many types of angina, and for treating various types of other circulatory diseases such as pulmonary hypertension and heart failure. They can be valuable in preventing cerebral ischaemia

-2191 216 and healing. They can also be used in the treatment of asthma, ulcers and other diseases of the gastrointestinal tract, in patients with liver and pancreas. In acute hepatic injury to rats with carbon tetrachloride (1.6 mg / kg p.O.), serum glutainate-oxalacetate transaminase (SGOT) activity was reduced as follows:

5 (Z) -4,4-dioxo-4-thia-PGI ₂ methyl ester: 100 µg / kg

i.p., 40%

5 (E) -4,4-dioxo-4-thia-PGI ₂ methyl ester: 100 µg / kg

i.p., 20%

It is also useful in preventing extracorporeal circulation (renal hemodialysis, cardiac pacemaker) to prevent loss of troncocyte, either alone or in combination with heparin. Another use is in the inhibition of metastasis in patients with tumors. The medical treatment with the compositions has the advantage that they can be administered intravenously, subcutaneously, intramuscularly and orally (gastrointestinal). The required amount is 0.0001-10 mg / kg. The exact dosage depends on the condition to be treated, the severity of the disease, the rate of drug delivery, the individual sensitivity of the patient and the organ being treated, and the ability to respond. Dosages as well as the most convenient route of administration can be readily determined by one skilled in the art.

Commonly used in the preparation of pharmaceutical compositions, such as filler, diluent, taste and odor, formulation, pH and osmotic pressure adjustment, stabilization, absorption, etc., are commonly used in the preparation of such compositions. additives are used. The formulations are solid (tablets, capsules, dragees, powders, pellets, etc.), liquid (solutions for infusion, inhalation or injection, lotions, drops, drops, etc.) or liquid (creams, ointments, balms, suppositories, etc.). ).

The materials described herein can be used as the sole agent or in combination with another agent.

Example 1

5-phenyl-sulfinyl-4,4-dioxo-4-thia-PGI methyl ester

1.091 g (4.44 mmol) of the compound of formula IV (wherein Q is CO ₂ R ¹ , R ^{1 is} hydrogen, R ⁴ = phenyl) and 1.2 g (4.03 mmol) of general formula III To a solution of the compound of formula (wherein R ² is nC ₅ H _t i, R ³ = hydrogen, B = chemical bond, A is trans-vinylene) is added 15 ml (15 mmol) of 1 N sodium hydroxide solution at room temperature. . The reaction is complete within 2 hours. The methanol was then evaporated in vacuo, the residue acidified to pH 2-3 with sodium hydrogen sulfate and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with 2x20 L saturated brine and dried over magnesium sulfate. After the desiccant was removed, the ethyl acetate solution was esterified with a solution of diazomethane in ether at 0 ° C. The solvent was removed and chromatographed on ethyl acetate (150 g) of silica gel adsorbent to isolate the title compound (840 mg).

Rf 0.33 (ethyl acetate-acetone 3: 1)

UV (EtOH): _.lambda.max = 245 nm, e = 4.000 lg

Example 2

5 (ZJ- and 5 (E) -4,4-dioxo-4-thia-PGJ _2- methyl ester

529 mg (1.0 mmol) of the compound of formula II (wherein Q is CO ₂ R ¹ ; R ¹ = methyl, A = trans vinylene; R ² = nC ₅ H, j; R ³ = hydrogen. B = Chemical bond (solution of phenyl (R ⁴ ) in 10 ml of dimethylformamide) is stirred at 120 ° C for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL). Extract with ethyl acetate (3 x 50 mL). The combined organic phases were washed with water (2 x 40 mL), brine (2 x 20 mL), dried over magnesium sulfate, removed under reduced pressure, and purified by short column chromatography. Chromatography on 60 g of silica gel 60 adsorbent. ethyl acetate-acetone 6: 1 as eluent.

There were thus obtained 281 mg of 5 (E) -4,4-dioxo-4-thia-PGI _; methyl ester, 131 mg of 5 (Z) -4,4-dioxo-4-thia-PGI, methyl ester and 166 mg of a mixture of the above isomers.

5 (E) -4,4-dioxo-4-thia-PGI ₂ methyl ester

R f = 0.31 (3: 1 ethyl acetate-acetone) 1 H NMR (CDCl ₃ , δ, ppm): 5.7 (1H, s)

5.5-5.65 (2 H, m)

4.9 (1H, m)

3.67 (3H, s)

5 (Z) -4,4-dioxo-4-thia-PGI ₂ methyl ester R _f = 0.24 (ethyl acetate-acetone 3: 1) 1 H NMR (CDCl 3, δ, ppm): 5.5- 5.65 (1H, m)

5.22 (1H, s)

5.22 (1H, m)

3.64 (3H, s).

Example 3

5-Phenyl :: zulfmyl-4,4-dioxo-4-ua-PC, ₁₁ -methyl ester-11,15-diacetate

529 mg (1 µmol) of 5-phenylsulfinyl-4,4-dioxo-4-thiaPGI, methyl ester are dissolved in 20 ml of dichloromethane, 404 mg (4 mmol) of triethylamine, 25 mg (0.2 mmol) of 4-dimethylamine are added. aminopyridine and 310 mg (3 mmol) of acetic anhydride. The reaction mixture was stirred at room temperature for 20 minutes and then methanol (1 ml) was added. After stirring for another 10 min, the reaction mixture was diluted with 100 mL of ether, 10 mL of 1M sodium hydrogen sulfate solution, 10 mL of water, 10 mL of saturated sodium hydrogen sulfate solution, 10 mL of water, 10 mL of saturated sodium bicarbonate solution. The reaction mixture was washed with water (2 x 10 mL), brine (2 x 10 mL), dried over magnesium sulfate and the solvent was distilled off in vacuo. This gave 650 mg (99%) of the title compound as a colorless oil.

Rf: 0.31 (3: 1 hexane-acetone)

IR: (film): 3400, 1740, 1325, 1150, 1100, 1070

UV (ethanol): A _max 245 nm, log: 3.93 ¹H NMR (CDC1 _3, δ, ppm): 7.4-7.8 (6H, m)

5.5 (2H, m)

4.95.5.1 (2 H, m)

4.05 (1H, m)

3.75 (3H, s)

2.02.2.11 (6H, s) 2.75-3.0 (4H, m).

Example 4

5 (E, Z) -4,4-Dioxo-4-thia-PGI _2- methyl ester-11,15-diacetate

5-Phenylsulfinyl-4,4-dioxo-4-thia-PGI, methyl ester-11,15-diacetate (605 mg, 0.99 mmol) was dissolved in dimethylformamide (6 mL). In the following, the procedure of Example 2 is followed. The crude product was chromatographed with hexane-acetone (3: 1).

Thus, from the title compound

-3191 216

284 mg (58%) of the 5 (E) isomer,

132 g (27%) of the 5 (Z) isomer are obtained as a colorless oil.

5 (E) -4,4-dioxo-4-thia-PGI _2- methyl ester-11,15-diacetate:

Rp 0.38 (hexane-acetone 3: 1) ¹ H NMR (CDCl ₃ , δ, ppm): 5.7 (1H, s)

5.55 - 5.65 (2H, m)

5.1-4.87 (2 H, m)

4.11 (1H, m)

3.65 (3H, s)

2.04, 2.17 (6H, s)

5 (Z) -4,4-dioxo-4-thia-PGI _2- methyl ester-11,15-diacetate Rp 0.26 (hexane-acetone 3: 1) ¹ H NMR (CDCl 3, δ, ppm): 5 5-5.65 (2 H, m)

5.05-4.85 (2H, ni) 15 5.22 (1H, s)

4.05 (2H, m)

3.64 (3H, s)

2.17.2.05 (6H, s)

Claims (5)

A process for the preparation of novel optically active or racemic 4,4-dioxo-4-thia-PGI ₂ analogs of the formula I wherein Q is CO ₂ R ^: wherein R ¹ is hydrogen or C 1-4 alkyl. . A is cis or transvinylene, R ² is a straight or branched C 3 -C 7 alkyl group, R ³ is hydrogen or C 1-4 alkanoyl, B is a chemical bond for the preparation of a compound of formula III wherein R ² , R ³ , A and B are as defined above with a compound of formula IV wherein R ⁴ is aryl or substituted aryl, Q 5 is as above condensed, the resulting compound of formula II where R ¹ , R ² , R ³ , R ⁴ , Q, A and B are as defined above is heated and optionally deprotected on the hydroxy groups. 2. The process of claim 1 wherein the compound of formula (III) wherein R ² , R ³ , A and B are as defined above is a compound of formula (IV) wherein R ⁴ , ^R1 and Q are as defined above - is condensed in the presence of a base at temperatures between -80 ° C and 100 ° C. 3. The process of claim 2, wherein the base is selected from the group consisting of alkali metal hydroxides, lithium compounds, and metal hydrides. The process of claim 1 wherein the compound of formula II wherein R ¹ , R ² , R ³ , R ⁴ , Q, A and B are as defined above, in a solvent or solvent-free conditions It is heated at 50-200 ° C. 5. A process for the manufacture of a medicament for use in inhibiting anticoagulant and selective hypotension, characterized in that at least one of claims 1 to 4 is administered. A compound of formula (I) as claimed in any one of claims ¹ to ³ , wherein R ¹ , R ² , R ³ , A, B and Q are as defined above, as a filler, diluent, taste and odor, formulation, pH, and formulation into a pharmaceutical composition using osmotic pressure-adjusting or stabilizing, absorption-promoting and / or formulation auxiliaries.