DE1518002B2 - Isoflavans and isoflavens and processes for their preparation and pharmaceuticals containing them - Google Patents

Description

The invention relates to isoflavans and isoflavens of the general formulas Ia and Ib

CH, 0

OCH ₂ CH ₂ NR ¹ R ²

(Ia)

CH ₃ O

(Ib)

OCH ₂ CH ₂ NR ¹ R ²

in which R ¹ and R ^{2 are} either an ethyl group or, together with the nitrogen atom, the pyrrolidine ring and their physiologically acceptable salts with acids.

In addition to a low estrogenic effect, these compounds have a good contraceptive effect.

This is how their contraceptive effect (anti-fertility effect) is described, based on the experimental method used by Martin und'Mitarbeitern in J. of Reproduction and Fertility, Vol. 5, p. 239 (1963), and by Emmens and Martin, ibid., Vol. 9, p. 269 (1965), comparable to that of the known compound 2- [p- (3,4-dihydro-6 - methoxy - 2 - phenyl -1 - naphthyl) - phenoxy] - ethylpyrrolidine hydrochloride (D) (see Duncan et al. In Proceedings of the Society for Experimental Biology and Medicine, Vol. 112, pp. 439 to 442 (1963), as can be seen from the following experiments:

The compounds to be tested are administered orally in various dosages to groups of five administered to female rats on the 1st to 3rd and 4th to 6th day after conception; the day on the spermatocytes can be detected in the vaginal swab (taken in the morning) is considered to be first day. The animals are observed up to the 15th day, then killed and checked for any (dead resorbed or live) fetuses are examined.

The following compounds according to the invention were used in the comparative experiments:

4- [p- (2-pyrrolidinoethoxy) phenyl] -

7-methoxy-3-isoflavene (P),
4-hydroxy-4- [p- (2-pyrrolidinoethoxy) phenyl] -

7-methoxy-isoflavan (A),

4- [p- (2-diethylaminoethoxy) phenyl] -

7-methoxy-3-isoflavane (B) and 4-hydroxy-4- [p- (2-diethylaminoethoxy) phenyl] -7-methoxy-isoflavane (C).

The following contraceptive efficacy was determined (it is indicated in the table next to the Dosage the number of examined animals in percent in which no pregnancies were found):

Daily dosage P. A. B. C. D. (mg / 100 g) 1 100 100 100 100 0.1 90 84.5 40 70 100 0.01 64 31 ; - 50

Taking into account the variance, the preparations were therefore about equally effective in contraceptive terms.

The estrogenic effect was determined for compounds P and B in comparison to D in the classic Allen-Doisy test determined on rats (the table indicates the number of investigated in addition to the dosage Percent of animals in which oestrus was detected; the substances were administered orally):

■ j ₀ dosage P. B. D. _L. ■ (mg / 100 g) : 10 13th 80 3 0 - ³⁵ 1 0 83 75 0.3 0 .— 0.1 -. 25th

While D showed a strong estrogenic effect, P showed only a slight or none and B a lower estrogenic effect.

The acute toxicity of the compound P was determined when administered orally to male and female rats; the LD ₅₀ after 24 hours of observation was> 320 mg / kg. The known compound D (cf. Duncan, Lc.) has an LD ₅₀ of 302 mg / kg.

It is advantageous that the compounds according to the invention have a low estrogenic effect, there are complications in the administration of contraceptive agents with strong estrogenic effects, such as Bleeding, may occur.

The isoflavans and isoflavens of the general formulas Ia and Ib given above and their physiological properties Compatible salts with acids are prepared by being known per se Way an isoflavanone of the general formula II

CH, O

(H)

with an organometallic compound of the general

my formula III

(Ill)

CH ₇ CH ₇ -NR ¹ R

lt> 2

in which R ¹ and R ^{2 have} the meaning given above and M denotes the MgCl, MgBr or MgI group or a lithium atom, or that an isoflavane or isoflavane of the general formulas IVa or IVb is used

_HO

(IVa)

0-CH ₂ CH ₂ NR ¹ R ²

HO

(IVb)

0-CH ₇ CH ₂ NR ¹ R ²

in which R ¹ and R ^{2 have} the meaning given above, are reacted in a manner known per se with a methylating agent or an isoflavane or isoflavane of the general formulas Va or Vb

CH, O

OH

(Va)

CH ₃ O

(Vb)

OH

in a manner known per se with a compound of the general formula VI

Q - CH ₂ CH ₂ NR ¹ R ² (VI)

in which R ¹ and R ^{2 have} the meaning given above and Q is a hydroxyl group or a chlorine, bromine or iodine atom, and that the 4-hydroxy-isoflavane obtained is then optionally treated in a manner known per se with a dehydrating agent and / or the isoflavane or isoflavane obtained is converted into a physiologically acceptable acid addition salt by treatment with an acid.
As organometallic compounds of the general formula III, there are above all those which are derived from p-chlorophenyl (2-diethylaminoethyl) ether, ρ - bromophenyl (2 - diethylaminoethyl) ether, ρ - chlorophenyl - (2 - pyrrolidinoethyl) - ether or ρ - bromophenyl - (2 - pyrrolidino - ethyl) - ether.

The reaction of an isoflavanone of the formula II with an organometallic compound of the general formula III is expediently carried out in an inert solvent such as ether, anisole, dibenzyl ether, dioxane, benzene, toluene, methylene chloride or, preferably, tetrahydrofuran or in mixtures of these solvents. In some cases, the addition of a Lewis acid suitable for complex formation, such as magnesium bromide, is advantageous. In, r a rule, the ketone in solution or in solid form -H to a solution of the organometallic conjunction ί in one of the solvents mentioned zugege- j ben. The implementation is mostly exothermic; the reaction temperature is generally between -20 and +70 C, but preferably at room temperature. To complete the reaction, the reaction mixture can be heated for some time until the solvent used has boiled. After the reaction has ended, the reaction product is hydrolyzed, if appropriate after evaporation and recovery of the solvent.

If the hydrolysis is carried out with water or under acidic conditions, e.g. B. with hooves of watery Ammonium chloride solution or dilute hydrochloric acid in the cold, then, as a rule, there is no water split off, and the carbinols of the general formula Ia are obtained.

If you want to get the contrast dehydration products of general formula Ib (Isoflavene), so "you can see the carbinols obtained the general- -. _R _ Formula Ia dehydrate This can be done by acid (treatment under mild conditions For example, you can see the carbinols.. treat with dilute mineral acid such as aqueous sulfuric acid or aqueous hydrochloric acid in the warm or longer time in the cold. Other common dehydration methods can also be used, for example treatment with formic acid, perchloric acid, p-toluenesulfonic acid, acetic acid, acetic anhydride, p-toluenesulfonic acid chloride or with thionyl chloride, Phosphorus oxychloride, methanesulfonic acid chloride or methylchlorosulfite in pyridine. It is also possible to dispense with isolation of the carbinols (Ia). For example, one arrives directly at the isoflavens of the general formula Ib if the work-up of the Grignard reaction with dilute mineral acids is carried out in the Warmth.

It is also possible to have free hydroxyl groups in an isoflavane or isoflavane of the general formulas To methylate IVa or IVb in a manner known per se.

The methylation can be carried out, for example, by reaction with appropriate methyl halides or sulfates or lower methyl esters in the presence of

1 Ö1ö UUZ

Alkali such as sodium or potassium hydroxide or carbonate. take place, with one of the usual inert solvents such as acetone or methyl ethyl ketone may be present.

For the reaction of a compound of the general formula Va or Vb or Vb with a compound of the general formula VI, a corresponding chloride, bromide or iodide is used. The etherifications of compounds of the formulas Va or Vb take place, for example, according to the principle a Williamson synthesis, whereby one of the corresponding alkali phenolates (sodium or potassium phenolates) goes out. But it is also possible to combine the free phenolic compound with the corresponding Amino alcohol in the presence of acidic catalysts such as sulfuric acid, phosphoric acid, p-toluenesulfonic acid, to implement.

For salt formation, those acids come into consideration that provide physiologically harmless salts. Organic and inorganic acids such as corresponding aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic or sulfonic acids, e.g. B. formic acid, Acetic acid, propionic acid, pivalic acid, diethyl acetic acid, oxalic acid, malonic acid, succinic acid, Pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, Sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid, Ascorbic acid, isonicotinic acid, methanesulphonic acid, ethane disulphonic acid, / 9-hydroxyethanesulphonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, Sulfuric acid, nitric acid, hydrohalic acids, or phosphoric acids, such as Orthophosphoric acid can be used.

The new compounds can be mixed with conventional drug carriers in the human or Veterinary medicine can be used. The carrier substances used are organic or inorganic Substances in question that are suitable for parenteral, enteral or topical application and that contain the new compounds do not react, such as water, vegetable oils, polyethylene glycols, Gelatine, milk sugar, starch, magnesium stearate, talc, petroleum jelly, cholesterol. To the parenteral administration are used in particular solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants. Tablets can also be used for enteral administration or coated tablets, for topical application ointments or creams, which may or may not be sterilized or with Auxiliaries such as preservatives, stabilizers or wetting agents or salts for influencing the otonic Pressure or mixed with buffer substances are to be applied.

The dosage of the substances according to the invention is preferably 1 to 500 mg.

example 1

2.2 g of 4-p-hydroxyphenyl-7-methoxy-3-isoflavene are dissolved in 50 ml of absolute acetone and treated with 2.5 g of anhydrous potassium carbonate and an ethereal solution of 2-pyrrolidinoethyl chloride (obtained from 7 g of 2-chloroethylpyrrolidinium chloride) . The mixture is refluxed with stirring for 24 hours, then concentrated, water and ether are added, the ether layer is separated off, dried over potassium hydroxide, evaporated and the residue is chromatographed on 50 g of basic aluminum oxide, the 4-p - (2-Pyrrolidinoethoxy) -phenyl-7-methoxy-3-isoflavene eluted with chloroform. Then it is recrystallized from ether. The compound melts at 92 to 93 ° C. '..'',','. .....

Similarly prepared: 4-p- _(2-i · piäthylaminoäth- oxy) phenyl-7-methoxy-3-isoflavene, F. 72-73 ⁰ C; ,,,;.

The 4-p-hydroxyphenyl-7-methoxy-3-isoflavene used as the starting material above is as follows

ίο have been produced:

0.76 g of 7-methoxy-isoflavanone, dissolved in 30 ml of absolute benzene, are added dropwise to an ethereal Grignard solution of 0.23 g of magnesium and 3.1 g of bromophenylbenzyl ether. The ether is distilled off and the mixture is boiled for 16 hours. It is cooled, the reaction product is decomposed with 100 ml of 10% strength hydrochloric acid, the benzene layer is separated off, washed successively with water, 10% strength sodium hydroxide solution and again with water, dried over sodium sulfate and the solvent is removed. The residue consists of 4-p-Benzyloxyphenyl-7-methoxy-3-isoflaven from F. 109 to Hl ⁰ C. ^

3.9 g of the 4-p-benzyloxyphenyl-7-meth ^ - ~ oxy-isofiavens obtained are catalytically hydrogenated in 100 ml of ethyl acetate with 3 g of 5% palladium carbon. After absorption of 226 ml of hydrogen to break the Hydrogenation and filtered off the catalyst, the filtrate was distilled to dryness and chromatographed f the \ crude product on silica gel amorphous 4-p-hy- 'droxyphenyl-7-methoxy-3-isoflavene with a mp of 118 ° C.

B e i s ρ i e 1 2

a) 18.6 g of pure N- (p-bromophenoxy-ethyl) pyrrolidinium chloride are dissolved in 240 ml of ethanol and 480 ml dissolved in absolute tetrahydrofuran. The solution is filtered clear and gaseous ammonia is passed in for 30 minutes a. After filtering again, the solvents are removed under reduced pressure.

The residue is taken up in 100 ml of absolute tetrahydrofuran and the ammonium chloride is filtered off and removed the solvent under reduced pressure. The same is now done with 50 ml absolute Tetrahydrofuran repeated.

A solution of the above N- (p-Brompherioxy- ■> ethyl) pyrrolidine in 40 ml of absolute tetrahydrofuran is then with the exclusion of moisture to a boiling suspension of 1.5 g of magnesium in 20 ml of absolute tetrahydrofuran was added dropwise, whereby the The reaction starts by adding a little iodine and a little ethyl bromide. You still heat the whole thing 15 minutes to the boil, then allowed to cool and a solution of 3.1 g of 7-methoxyisofiavanone is added dropwise in 30 ml of absolute tetrahydrofuran, after which corn is boiled for another 15 minutes. Then the obtained Product in the cold by adding 100 ml of saturated aqueous ammonium chloride solution decomposed, the whole thing extracted three times with 100 ml of ether each time, the extract successively with 100 ml Water, 100 ml of 1N sodium hydroxide solution and washed three times with 50 ml of water each time, then with sodium sulfate dried, filtered and evaporated to dryness. The crude product is based on 250 g of basic aluminum oxide chromatographed, using benzene and benzene / chloroform mixtures is eluted. With benzene / chloroform 4: 1, 3 g of 4-p- (2-pyrrolidinoethoxy) are obtained - phenyl - 4 - hydroxy - 7 - methoxy - isoflavan from the column, which is then from ether / petroleum ether (1: 2)

409 515/451

1 O 1 O UUZ

9 10

is recrystallized: mp 148 to 149 ° C; λ _ιηαχ 276 and b) By boiling the according to a) for half an hour

286 nm, E}? _m 99 and 79, no UV maximum above ten bases with 35 times the amount of 5% ethanol

300 nm. Lischer hydrochloric acid and the usual work-up is the

In an analogous manner one obtains: with p- (2-diethyl- 4 - ρ - (2 - pyrrolidinoethoxy) - phenyl - 7 - methoxy-

aminojithoxy) -phenylmagnesiumbromiddas4-p- (2-Di- 5 3-isofiaven (M.p. 92 to 93 ° C) and 4-p- (2-diethylamino-

äthylaminoäthoxy) - phenyl -A- hydroxy - 7 - methoxy- ethoxy) -phenyl-7-methoxy-3-isoflavene (m.p. 72 to 73 ° C)

isoflavane with a temperature of 55 ° C (from ether / petroleum ether [1: 2]). obtain.

Claims (4)

Patent claims: 1. Isoflavans and isoflavens of the general formulas Ia and Ib CH ₃ O OCK ₇ CK ₇ -NR ¹ R ² (Ia) CH, O (Ib) OCH ₂ CH ₂ -NR ¹ R ² in which R ¹ and R ² each represent either an ethyl group or, together with the nitrogen atom, the pyrrolidine ring and their physiologically acceptable salts with acids. 2. 4 - [p - (2 - pyrrolidinoethoxy) phenyl] -7-methoxy-4-isoflavene. 3. A process for the preparation of isoflavans (Ia) or isoflavens (Ib) as specified in claim 1 general formulas Ia or Ib, characterized in that one known per se Way an isoflavanone of the general formula II CH.O (H) with an organometallic compound of the general formula III (ΙΠ) 0-CH ₇ CH ₇ -NR ¹ R id 2 in which R ¹ and R ² have the meaning given in the claim and M denotes the MgCl, MgBr or MgJ group or a lithium atom, converts or that one isoflavane or isoflavans of the general formulas IVa or IVb HO (IVa) HO CH ₇ CH ₇ NR ¹ R ² (IVb) 0-CH ₂ CH ₂ NR ¹ R ² in which R ¹ and R ^{2 have} the meaning given in claim 1 is reacted in a manner known per se with a methylating agent or an isoflavane or isoflavane of the general formulas Va or Vb CH, O (Va) CH, O (Vb) in a manner known per se with a compound of the general formula VI Q - CH ₂ CH ₂ NR ¹ R ² (VI) in which R ¹ and R ^{2 have} the meaning given in claim 1 and Q is a hydroxyl group or a chlorine, bromine or iodine atom, and that optionally the 4-hydroxy-isoflavane obtained is then reacted in a manner known per se with a dehydrating agent Treated agent and / or the isoflavane or isoflavene obtained is converted into a physiologically acceptable acid addition salt by treatment with an acid. 1 01b UUZ 4. Medicament containing a compound of the general formula given in claim 1 Ia or Ib or a physiologically acceptable salt thereof in addition to customary inert carriers and Additives.