DK146202B - TRANS-DELTA2 PROSTAGLANDIN ANALOGUE AND MATERIALS CONTAINING THESE FOR USE AS ANTIFERTILITY AGENTS AND OTHER NON-MEDICAL PURPOSES - Google Patents

Description

in 146202 o

The present invention relates to novel 2 trans-Δ-prostaglandin analogs and materials containing them for use as antifertility agents and other non-medicinal purposes selected from contraception, regulation of rupture and induction of abortion and fevers in female mammals and a material for use therewith. .

In the specification of British Patent No. 1,416,410, disclosed trans-A-prostaglandin analogues of the formula

in 7 5 3 COOH

/ VW

Li

OH

Wherein A is a group of formula

OH

4 <tf - 4

OH OH

25 II III Γ7 X is ethylene, ie. -CHgCHg- or trans-vinyl, i.e. trans- -CH = CH-, R 1 is a straight or branched alkyl group of 1-10 carbon atoms or a straight or branched alkyl group of 1-6 carbon atoms having a phenyl substituent or a cycloalkyl substituent of 5-7 carbon atoms, 2 R is a hydrogen atom or a straight or branched alkyl group having 1-4 carbon atoms, the curved line ww means, of the hydroxy group attached to the carbon atom in the α or 35 β configuration, as well as alkyl esters thereof having 1-10 carbon atoms in a straight or branched chain and cyclodextrin clays of such acids or esters and non-toxic salts of such acids, except trans-Δ-PGE In the above patent specification it is mentioned that the compounds possess known valuable pharmacological properties which are typical of prostaglandins, but in a selective manner, including in particular hypotensive action, inhibitory effect on platelet aggregation, inhibitory effect on gastric acid secretion and formation. of gastric ulcer, as well as bronchodilating effect, and that they are valuable in the treatment of hypertension, in the treatment of peripheral circulatory disorders, in the prevention and treatment of cerebral thrombosis and myocardial infarction, in the treatment of gastric ulcer and in the treatment of asthma.

It has now been found in further research and experiments that trans-Δ-prostaglandin analogs of formula I wherein A is a group of formula <jc

OH

X is trans-vinylene, is the 1,1-dimethylpentyl group, i.e.

CH is -c- (ch 2) 3-ch 3, 6h 3 2 2 and R is a hydrogen atom, i. 16,16-dimethyl-trans-A-PGE 2 and the methyl ester thereof, the cyclodextrin clathrates of such an acid or ester, and non-toxic salts of such acid, which compounds are not specifically described in the above-mentioned British patent, are unexpectedly in possession. excellent biological properties.

35 2 3 146202

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The invention relates to these trans-Δ-prostaglandin analogs, which are characterized in that they have the general formula 0

Il and COOR

5 / SvWN? / VI

Xa sr v chT VI

<1 ° J U 16 ^ 3 08 20 T ^

OH OH

10 wherein R represents a hydrogen atom or a methyl group and the wavelength / WM / denotes the hydroxy group's association in β or preferably α configuration, or cyclodextrin clathrates thereof or, if R is hydrogen, its non-toxic salts with bases, f. eg. sodium salt.

The present invention relates to all such for compounds in the "natural" form as depicted.

The material of the invention is characterized in that it comprises a prostaglandin analogue of the general formula set forth in claim 1 or a cyclodextrin clathrate thereof or, when R is hydrogen, a non-toxic salt thereof with a base attached to a pharmacologically acceptable carrier or coating. suitable for administration of such agents to animals.

The compounds of formula VI, as will be appreciated by those skilled in the art, have four chirality centers located at the carbon atoms of the alicyclic ring designated 8, 11 and 12, and at the C-15 carbon atom to which a hydroxy group is attached. The presence of chirality, as you know, leads to the occurrence of isomerism. All isomers 30 of formula VI and mixtures thereof are within the scope of the invention.

The prostaglandin analogues of formula VI and, when R is hydrogen, their non-toxic salts have been found to have exceptionally good abortifacient and stimulating effect on the contraction of the uterus, which 4

ISLAND

146202 effects are not disclosed in British Patent Specification No. 1,416,410 for specifically mentioned compounds of Formula I. These compounds are therefore valuable for use as anti-fertility agents and for other non-medical purposes selected from contraception and induction of abortion. or of mothers of pregnant mammals and to regulate the mammalian rut and menstrual cycle.

The prostaglandin compounds of the invention have relatively weak force in the development of diarrhea as compared to their valuable biological properties as mentioned above and can therefore be used for the stated purposes in appropriate dose sizes that do not cause diarrhea as an undesirable side effect.

The preferred compound for abortion-inducing activity and stimulating effect on uterine contraction is 16,16-dimethyl-trans-Δ-PGE 3 -methyl ester.

2 Ex. (i) 16,16-dimethyl-trans-Δ - PGE 3 methyl ester stimulates uterine contraction when administered intravenously to a pregnant rat on the 20th day of gestation at a dose of 0.5 pg / kg body weight , (ii) induce a decrease in blood pressure when administered intravenously to an allobarbital anesthetized dog at a dose of 1 µg / kg body weight, and (iii) induce diarrhea at a dose of 25 1200 µg / kg body weight by oral administration. at 50%, they treat mice, as determined by standard laboratory tests.

2

Of the effects of 16,16-dimethyl trans-Δ - PGE 2 methyl ester, (i) the uterine contracting activity is the valuable effect, and (ii) the hypotensive and (iii) the diarrhea-inducing effect is considered as undesirable effects. The biological effects on rats of 16,16-2-dime thyl-trans-Δ-PGE 2 -methyl ester and of prostaglandin analogues already known from British Patent Specification no.

1,416,410, e.g. 16 (R) -methyl-trans-Δ-PGE, 16 (i ^) -phenyl-2-35 -ω-trinor-trans-Δ-PGE ^, and 15 (1β) -methyl-trans-Δ-PGE ^, 5 0 146202 is compared in the following table which also contains data for 16,16-dimethyl-trans-A-PGE ^. Thus, in the table, the two lower compounds are compounds of the invention, while the top three are known comparative compounds which represent the closest technique.

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X CM d Ρ Φ CM -P Φ CM ^ -p / ι φ-ρ -p <fl ε / itn s y \

φ N x in Q) N-hNq) η N

gi ftp gi ti I H ti I

i ιη 10 I in ι ιη> ι i tn - c ^ d h d vodx cod

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m -P iø -P ft m-P vo-Pg ιο -P

Hl Hil HI Hil Hl y

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146202 7

As will be seen from the table, 16,16-dimethyl-trans-A-PGE 2 and its methyl ester produce a strongly desired effect (contraction of the uterus) that is at least 10 times more potent than that of the known compounds. In addition, the selectivity index (separation of desired activity from side effects), ie. the ratio (ii) / (i) or (iii) / (i) of 2 16,16-dimethyl trans-Δ. -PGE ^ and its methyl ester far higher than that of the known compounds. These data show that 16,16-dimethyl-trans-A-PGE 2, and its methyl ester, have a highly contracting effect on the uterus, which is the superior activity of the known tested compounds. Therefore, the compounds of the invention are better and safer for use as antifertility agents and other non-medical purposes such as at termination of pregnancy, without medical indication, ie. for the induction of labor or miscarriage in pregnant mammals, for contraception for regulation of the breast and for menstrual regulation in female mammals, than the known tested compounds, which are otherwise the best in this regard in the art.

The trans-Δ prostaglandins of formula VI can be prepared as further described in the parent application (patent application no. 25/77).

By the term "non-toxic salt" is meant a salt whose cation is relatively harmless to the animal organism when used at the desired dose and where beneficial biological properties of the compound of formula VI are not destroyed by side effects resulting from the cation . The salts are preferably water soluble. Suitable salts include the alkali metals, e.g. sodium and potassium, and ammonium salts and pharmaceutically acceptable, i. non-toxic, amine salts.

Amines suitable for the formation of such salts with carboxylic acids are known and include e.g. amines which are theoretically derived from the substitution of one or more hydrogen atoms in ammonia by groups which may be the same or different when more than one hydrogen atom is replaced, e.g. alkyl groups having 1-6 carbon atoms and hydroxyalkyl groups having 1-3 carbon atoms.

The non-toxic salts can be prepared from an acid of formula VI e.g. by reacting stoichiometric amounts of an acid of formula VI (R is H) and a corresponding base, e.g. an alkali metal hydroxide or carbonate, ammonium hydroxide, ammonia or an amine in a solvent. The salts can be isolated by lyophilizing the solution or, if sufficiently insoluble in the reaction medium, by filtration, if necessary after removal of a portion of the solvent.

2

The trans-A-prostaglandin analogues of formula VI may optionally be converted to cyclodextrin clathrates. The clathrates can be prepared by dissolving the cyclodextrin in water 15 and / or an water-miscible organic solvent, and adding to the solution the prostaglandin compound in a water-miscible organic solvent. The mixture is then heated and the desired cyclodextrin clathrate product is isolated by evaporation of the mixture under reduced pressure or by cooling and separation of the product by filtration or decantation. The ratio of organic solvent to water can be varied according to the solubility of the starting materials and products. Preferably, the temperature should not exceed 70 ° C during the preparation of the cyclodextrin clathrates. α-, (3- or γ-cyclodextrins or mixtures thereof can be used in the preparation of the cyclodextrin clathrates. The conversion to cyclodextrin clathrates serves to increase the stability of the prostaglandin compounds.

For administration as an antifertility agent or for the aforementioned other non-medicinal purposes, prostaglandin analogs of formula VI or a cyclodextrin clathrate thereof or, when R is hydrogen, a non-toxic salt thereof with a base are generally attached to a pharmaceutical carrier or coating. In practice, these compounds are usually administered orally, vaginally, rectally or parenterally.

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166202 9

Solid compositions for oral administration include beaten tablets, pills, dispersible powders and granules. The compositions for oral administration also include capsules of absorbable material such as gelatin containing one or more of the active substances with or without the addition of diluents or excipients.

Solid vaginal administration compositions comprise pessaries prepared in a manner known per se and containing one or more of the active compounds.

Solid rectal administration compositions comprise suppositories composed in a manner known per se and containing one or more of the active compounds.

Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions.

The percentage content of active substance in such preparations may be varied, such that it should be such that a suitable dosage is obtained taking into account the desired biological effect. It is to be understood that several dosage forms 20 may be administered at about the same time. As a rule, the compositions usually contain at least 0.025 wt.% Of active ingredient when used for injection; for oral administration, the compositions usually contain at least 0.1% by weight of active substance. The dose used depends on the desired biological effect, route of administration and duration of treatment.

The dose is usually between 1 and 1000 µg by oral, intravaginal, intravenous or extraamniotic administration for the purpose of contraception (contraception) and regulation of menstruation in women and to induce 30 abortions or labor in pregnant women (not on medical indication).

For female animals such as cows, mares, sows, female sheep and bitches, the dose is usually between 0.001 and 50 mg / animal by intramuscular, subcutaneous, intrauterine, intravaginal and intravenous administration for the synchronization of rupture, in the treatment of decreased fertility and to induce abortion and initiation of farrowing.

The following examples illustrate the preparation of the novel prostaglandin analogs of this invention. Herein, "IR", "NMR" and "TLC" denote "infrared absorption spectrum", "nuclear magnetic resonance spectrum" and "thin layer chromatography" respectively. Where solvent ratios are indicated by chromatographic separation, these ratios are by volume.

10

Example 1 2 16,16-Dimethyl-trans-A-PGE 2 - [9-oxo-11α, 15α-dihydroxy-16,16-dimethylprosta-trans-2-trans-13-diacetic acid] 2.35 g of 9- oxo-11α, 15α-bis- (2-tetrahydropyranyloxy) -15 -16,16-dimethylprosta-trans-2, trans-13-diacetic acid (readily prepared as described in Example 2 of Patent Application No. 25/77) is dissolved in 6 of tetrahydrofuran and 60 ml of a 65% (v / v) aqueous acetic acid solution and the solution is stirred at 60-70 ° C for 20 minutes. The reaction mixture is then extracted with ethyl acetate and the organic layer is washed with water, dried and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using ethyl acetate / cyclohexane (2: 3) as the eluent to give 270 mg of the title compound.

25 TLC (developing solvent tetrahydrofuran / chloroform / acetic acid = 2: 10: 1): Rf = 0.30.

NMR (CDCl3 solution): 6.99 (1H, dt), 5.78 (1H, d), 5.90 (3H, broad s), 5.70-5.40 (2H, m), 4 , 40-3.78 (2H, m), 2.95-2.55 (1H, dd).

30

Example 2

Methyl 9-oxo-11α, 15α-dihydroxy-16,16-dimethyl-prosta-trans-2 -2, trans-13-dienoate (or 16,16-dimethyl-trans-Δ-PGE₂-methyl ester) Dissolve 50.8 mg of 16,16-dimethyl-trans-A the reaction mixture turns yellow. The reaction mixture is evaporated under reduced pressure at low temperature and the residue is purified by column chromatography on silica gel, using ethyl acetate / cyclohexane (1: 3) as the eluent to give 40 mg of the title compound.

TLC (developing solvent chloroform) -tetrahydrofuran / acetic acid = (10: 2: 1): Rf = 0.51.

IR (liquid film): 3400, 2940, 2850, 1750, 1730, 1660, 1440 and 1280 cm

Example 3 16,16-Dimethyl-trans-A--PGE ^ 2.35 g of 9-oxo-11α, 15α-bis- (2-tetrahydropyranyloxy) -16,16-dimethyl-prosta-trans-2, trans -13-diacetic acid (prepared as described in Example 6 of Patent Application No. 25/77) is dissolved in a mixture of 1.8 ml of tetrahydrofuran and 18 ml of 65% (v / v) aqueous acetic acid and the solution is stirred at 60-70 °. C for 20 minutes. The reaction mixture is extracted with ethyl acetate and the organic layer is washed with water, dried and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using ethyl acetate / cyclohexane (2: 3) as eluent to give 270 mg of the title compound having the following physical data: IR (liquid film): 3400, 2930, 1740, 1695 , 1650, 980, 870 and 850 cm NMR (CDCl 3 solution): 7.2-6.8 (1H, m), 6.6-5.37 (6H, m), 5.03-4.7 (IH, m).

TLC (developing solvent tetrahydrofuran / chloroform / acetic acid = 2: 10: 1): Rf = 0.30.

12 166202 0

Example 4 "2 16.16- Dimethyl trans-A-PGE-, methyl ester * · 2 50.8 mg of 16,16-dimethyl-trans-A-PGE ^ (prepared as described in Example 3) is dissolved in 3 ml of diethyl ether, and 5 to this solution are added freshly prepared ethereal solution of diazomethane so that the reaction mixture turns yellow The reaction mixture is evaporated under reduced pressure at low temperature and the residue is purified by column chromatography on silica gel using ethyl acetate / cyclohexane (1: 3) as eluent, to give 30 mg of the title compound having the following physical data: IR (liquid film): 3400, 2940, 2850, 1740, 1730, 1660, 1440 and 1280 cm -1.

TLC (developing solvent chloroform / tetrahydrofuran / acetic acid: 10: 2: 1): Rf = 0.51.

NMR (CDCl 3 solution: 7.10-6.75 (1H, m), 5.95-5.40 (3H, m) '3.71 (3H, s), 4.20-3.60 (2H , m), 2.75 (1H, dd), 1.00-0.75 (9H / m).

Example 5 2 16.16- Dimethyl trans - / - -PGE 2 -methyl ester

To a solution of 745 mg of methyl 9a-hydroxy-11a, 15a-bis- (2-tetrahydropyranyloxy) -16,16-dimethylprosta-trans-2, trans-13-dienoate (prepared as described in Example 9 in Patent Application No. 25/77) in 22 ml of diethyl ether is added a chromic acid solution prepared from 0.94 g of chromium trioxide, 4.55 g of manganese sulfate and 1.06 ml of sulfuric acid in 22 ml of water and the mixture is stirred at 0 ° C for one hour. The reaction mixture is then extracted with diethyl ether and the extract washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure to give 732 mg of methyl-9-oxo-1α, 15 α-bis- (2-tetrahydropyranyloxy) - 16,16-dimethylprosta-trans-2, trans-13-dienoate having the following physical data: 35 TLC (benzene / ethyl acetate developing solvent = 2: 1): Rf = 0.74.

13 146202 0

To a solution of 732 mg of the above 9-oxo compound in 1.9 ml of tetrahydrofuran is added 19 ml of a 65% (v / v) aqueous solution of acetic acid and the mixture is stirred at 55-65 ° C for one hour. .

Then the reaction mixture is extracted with ethyl acetate and the extract washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure to give 119 mg of the title compound having the following physical data: 10 TLC (developing solvent) chloroform / tetrahydrofuran / acetic acid = 10: 2: 1): Rf = 0.51.

IR (liquid film): 3400, 2940, 2850, 1750, 1730, 1660, 1440 and 1280 cm -1 NMR (CDCl 2 solution): 7.10-6.75 (1H, m), 5.95-15 -5, 40 (3H, m), 31.71 (3H, s), 4.20-3.60 (2H, m) '2.75 (1H, dd), 1.00-0.75 (9H, m) .

The following example describes the material of the invention for use in an antifertility agent.

Antifertility agent o 2 mg of 16,16-dimethyl trans-Δ-PGE 3 methyl ester (prepared in Example 4 or 5 above) is dissolved in 10 ml of ethanol, mixed with 18.5 g of mannitol, sieved through a 30 mesh sieve. , dried at 30 ° C for 90 minutes and sieved through a 25 mesh screen. 200 mg of Aerosil® (microfine silica) is added and the resulting powder is machine-loaded into 100 No. 2 hard gelatin capsules, each capsule containing 20 µg of 16,16-dimethyl-trans-A-PGE 2 methyl ester. which, after the capsule has been lowered, is released into the stomach for use 30 as an antifertility agent which needs to be taken only a few times a month, especially just before regular bleeding occurs.