CS201030B2 - Method of producing prostaglandins analogues - Google Patents

Description

The invention relates to a process for the preparation of novel 16-substituted omega-tetranorprostaglandins.

Prostaglandins are unsaturated fatty acids with 20 carbon atoms, showing various physiological effects.

The present invention provides a process for the preparation of prostaglandin analogs of formula (I)

in which

Ar represents a phenyl or biphenyl group,

W is a single bond and

Z represents a single bond or a trans-double bond, their acetyl, formyl or benzoyl esters at any of the free hydroxyl groups in the C 1 and C 1 position, and their pharmaceutically acceptable salts, characterized in that the compound corresponding to the above general formula of formula I, wherein Ar is as defined above and W and Z are double bonds, selectively catalytically hydrogenates to form a compound of formula I wherein W is a single bond and Z is a trans-double bond, or wherein W and Z are double bonds, or a compound of formula I wherein W is a single bond and Z is a trans double bond, or a compound of formula I wherein Z is a single bond and W is a cis double bond, catalytically hydrogenated to form a compound of formula (I) wherein both W and Z are single bonds and are optionally obtained the product is converted into any of the above-mentioned free hydroxyl groups by treatment with an appropriate acylating agent to the 11 alpha- and / or 15α-acetyl-, form- or benzoyl ester, and the resulting compounds are optionally converted to pharmaceutically acceptable salts.

The preparation of prostaglandin analogs which are used as starting materials in the above process is described in the description of the invention to U.S. Pat. No. 201,027.

The hydrogenation according to the invention can be carried out either using a homogeneous catalyst, such as tristriphenylphosphine rhodium chloride, or using a heterogeneous catalyst, such as platinum, palladium or rhodium.

For the selective hydrogenation of the 5,6-cis-double bond, palladium on carbon is particularly preferably used as a catalyst and is operated at -20 ° C.

The 16-substituted omega-tetranorprostaglandins of the E series can be obtained directly from the corresponding Group 2 prostaglandin analogues by first protecting the hydroxyl group by introducing a dimethylisopropylsilyl residue, selective hydrogenation of the cis double bond and cleaving the protecting group.

The deprotection is generally carried out by treating the prostaglandin analog with dimethylisopropylchlorosilane and triethylamine. The hydrogenation is carried out as described above and the deprotection is effected by contacting the resulting protected compound with acetic acid / water 3: 1 for 10 minutes or until the reaction is substantially complete.

If chromatographic purification is desired or desirable in the above-described processes, generally suitable chromatographic supports, including neutral alumina and silica gel, preferably silica gel with a particle size of 60 to 200 mesh, are preferably used for this purpose. The chromatography is conveniently carried out in inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane.

Numerous in vivo and in vitro tests have shown that the new prostaglandin analogues exhibit physiological effects comparable to those of natural prostaglandins (see US Patent No. 201,027). These tests include, but are not limited to, an effect test on isolated smooth muscle from guinea pig uterus, guinea pig uterus and rat uterus, inhibition of norepinephrine-induced lipolysis in isolated adipose cells of rats, inhibition of histamine-induced bromchospasm in guinea pigs. , inhibiting pentagastrin-induced hydrochloric acid secretion in rats and dogs, and inhibiting ADP or collagen-induced platelet aggregation.

The physiological responses observed in these assays are useful in determining the utility of test compounds for the treatment of various natural and pathological conditions. Based on the above tests, it has been found that the types of activity exhibited by the compounds of the invention include antihypertensive activity, bronchodilator activity, vasodilator activity, antithrombogenic activity, antiarrhythmic activity, heart stimulating activity, antiulcerative activity, smooth muscle activity (due to which are described compounds useful as antifertility agents, delivery or abortion inducing agents) and antifertility activity by a mechanism not affecting smooth muscle, for example by a luteolytic mechanism.

The novel compounds of the invention exhibit highly selective potencies compared to the corresponding natural prostaglandins. Thus, 15-Ar-substituted prostaglandin ET (tetrahydroprostaglandin ET) has the desired hypotensive activity. In addition, the 16-Ar-substituted prostaglandins of E series are particularly effective in inhibiting gastric acid secretion (after oral administration) and as a result are useful in the treatment of peptic ulcers or gastric hyperactivity.

Furthermore, the 16-Ar-substituted omega-tetranorprostaglandins E according to the invention have the desired bronchodilator activity.

All prostaglandins of the invention can also be used in the form of salts and pharmaceutically acceptable cations. The same uses as the prostaglandins from which they are derived also have esters at _C11 and C1-4 in which the acyl group is an acetyl, formyl or benzoyl residue. In some cases, the use of these esters is associated with a lower incidence of adverse side effects compared to the corresponding non-esterified prostaglandins. Said esters are readily prepared by standard methods well known in the art.

The novel compounds of the invention may be used in the form of various pharmaceutical preparations comprising a compound of the invention or a pharmaceutically acceptable salt thereof. and which, as in the case of natural prostaglandins, can be administered by a variety of routes, such as intravenously, extra- and intraamniotically, orally or topically, including, for example, aerosol administration, intravaginal and intranasal administration.

A suitable dosage form for inducing bronchodilation is an aqueous ethanolic solution of 16-Ar-substituted tetranorprostaglandins E, used as an aerosol using fluorocarbons as propellants, with a dose ranging from about 5 to 300 pg and administered up to sixteen times a day. Suitably, an aqueous solution of 16-Ar-substituted tetranorprostaglandins E ₁ in the form of nasal drops, applied at dosages of from 1 to 100 µg, is expediently used to increase the effect of nasal administration.

All of the novel compounds of the invention can also be used in the form of their esters at C 1. Examples of suitable esters are those in which the esterifying group is an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 9 carbon atoms, a phenyl or beta-naphthyl group, or a monosubstituted group. phenyl or beta-naphthyl, wherein the substituents in these radicals are selected from the group consisting of halogen atoms, lower alkyl groups, lower alkoxy groups and phenyl groups. Particularly suitable are p-biphenyl esters.

These particular esters are suitable because they crystallize very easily, so that they can advantageously be obtained in a highly pure state and with an excellent yield, while the prostaglandins themselves generally only very difficult to crystallize. The novel β-biphenyl esters have an activity comparable to the corresponding parent compounds and, moreover, have an advantageous flat curve of the activity versus time curve, which is often desirable. They also have a lower effect on the smooth muscle of the gastrointestinal tract, as evidenced by the reduced incidence of side effects such as diarrhea. The novel compounds in the form of p-biphenyl esters are prepared as described above using the appropriate intermediates.

The 16-Ar-substituted omega-tetranorprostaglandins of the invention are useful hypersensitive agents. For the treatment of hypertension, these compounds may conveniently be administered as intravenous injections at doses of about 0.5 to 10 µg / kg or preferably as capsules or tablets at doses of 0.005 to 0.5 mg / kg / day.

Various inert diluents, excipients or carriers can be used to prepare the above and many other possible dosage forms. These include, for example, water, ethanol, gelatin, lactose, starches, magnesium stearate, talc vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petrolatum, cholesterol, and other known materials used to prepare dosage forms. If desired, said pharmaceutical preparations may contain other ingredients, such as preservatives, wetting agents, stabilizers or other therapeutic agents, such as antibiotics.

The invention is illustrated by the following non-limiting examples. In these examples, all temperatures are given in degrees Celsius and the melting points are not corrected.

Example 1

9-oxo-1alpha, 15alpha-dihydroxy-, 6-phenyl-omega-tetranorprostenoic acid

Heterogeneous mixture of 34 mg (0.089 mmol) of 9-oxo-1alpha, 15alpha-dihydroxy-16-phenyl-cis-5-trans-13-omega-tetranorprostadienoic acid and 13 mg of 5% palladium on carbon in 3 ml of absolute methanol for 2 hours Hydrogenation is carried out at 0 [deg.] C. at a pressure of 1 bar. The reaction mixture was filtered and evaporated to give 30 mg of 9-oxo-11,15α-dihydroxy-16-phenyl-omega-tetranorprostanoic acid.

κ -1 -1

The IC spectrum of the product contains carbonyl absorptions at 17 cm and 1735 cm, a wide band for the hydroxyl group and no absorption corresponding to the trans double bond.

Example 2

9-oxo-11 alpha, 15alpha-dihydroxy-16-p-biphenyl-omega-tetranorprostanoic acid

A heterogeneous mixture of 9-oxo-11 alpha, 15alpha-dihydroxy-16-p-biphenyl-cis-5-trans-13-omega-tetranorprostadienoic acid and 5% palladium on carbon in absolute methanol was hydrogenated at 25 ° C for 2 hours at room temperature. pressure 0.1 MPa. Filtration and evaporation of the reaction mixture gave 9-oxo-1alpha, 15α-dihydroxy-16-p-biphenyl-omega-tetranoroprostanoic acid, m.p. 120-123 ° C.

The IR spectrum of the product (KBr-technique) contains carbonyl absorptions at 1715 cm ^-1 and 1735 cm ^-1 , a wide hydroxyl absorption region and no absorption corresponding to the trans double bond.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of prostaglandin analogs of formula (I) wherein: Ar represents a phenyl or biphenyl group, Vi is a single bond and Z represents a single bond or a trans-double bond, their acetyl, formyl or benzoyl esters at any of the free hydroxyl groups at the C, ₁ and C ₁ position, and their pharmaceutically acceptable salts, characterized in that the compound corresponding to the above general formula of formula I, wherein Ar is as defined above and V 1 and Z are double bonds, selectively catalytically hydrogenates to form a compound of formula I wherein V 1 is a single bond and Z is a trans-double bond, or wherein V 1 and Z are double bonds, or a compound of formula I wherein W is a single bond and Z is a trans double bond, or a compound of formula I wherein Z is a single bond and W is a cis double bond, catalytically hydrogenated to form a compound of formula I wherein both W and Z are single bonds and optionally recovered The product is converted to any of the above-mentioned free hydroxyl groups by treatment with an appropriate acylating agent to the .alpha.