DE1468925C - Process for the production of 17-hydroxy-oestra-1,3,5 (10) -trien- square brackets on 17,16-c square brackets zudihydropyrazoles, as well as some compounds produced in this way - Google Patents

Description

wherein the dashed lines represent one or the other of the two positions which make up the double bond of the dihydropyrazole ring, and which of the two possible tautomeric Forms of these compounds correspond, and St represents an Östra-1,3,5 (10) -triene radical which is attached to the Rings A, B and C by halogen atoms or by hydroxyl, lower alkyl, lower alkoxy, lower acyloxy, ketal, thioketal, enol ether, enolic thioether or lower enol acylate groups may be substituted, the steroid nucleus also having a double bond in the 9 (11) position may have, characterized that one has a corresponding 16-hydroxymethylene-17-oxo-oestra-1,3,5 (10) -triene condensed with hydrazine or its hydrate, being in the range of room temperature and in an organic Solvent works.

2. 3-Methoxy-17-hydroxy-oestra-1,3,5 (10) -trieno- [16c-17] -dihydropyrazole.

3. 3-chloro-17-hydroxy-estra -1,3,5 (10) -trieno- [16c-17] -dihydropyrazole.

4. · 2-methyl-3-methoxy-17-hydroxy-estra-1, 3,5 (10) -trieno- [16c-17] -dihydropyrazole.

5. 2-Fluoro-3,17-dihydroxy-estra-1,3,5 (10) -trieno- [16c-l 7] -dihydropyrazole.

45

The present invention relates to a process for the preparation of 17-hydroxy-estra-1,3,5 (10) -triene- [17,16-c] -dihydropyrazoles the general formula

StJ

OH

NH

wherein the dashed lines represent one or the other of the two positions which make up the double bond of the dihydropyrazole ring, and which of the two possible tautomeric forms of these compounds correspond, and St represents an estra-1,3,5 (10) -triene residue which passes through rings A, B and C. Halogen atoms or by hydroxyl, lower alkyl, lower alkoxy, lower acyloxy, ketal, thioketal, Enol ether, enolic thioether or lower enol acylate groups can be substituted, the Steroid core can also have a double bond in the ίο 9 (11) position.

We know of numerous works on pyrazolosteroids, the heterocycle of which on carbon atoms 16 and 17 of ring D is bound. The majority of authors use to make these compounds Hydrazine hydrochloride, which leads to the non-hydroxylated pyrazole derivatives.

Certain authors also have the use of hydrazine hydrate or hydrazine itself as a starting material described. Among the latter one can see M. J. Michelson, PhD thesis 1962, Univ. Mic, 63, 2003 (1963) with the title "Synthesis and stereochemistry of 2-pyrazolines" and P. R u g g i e r i and Staff, Gazz. Chim. Ital., 93, 269 (1963). There These authors, however, work in the heat, under reflux of the solvent, have not succeeded to isolate the hydroxylated derivatives that form intermediates when hydrazine is mixed with a dicarbonyl steroid lets react.

It has now been found that it is possible to hydrazine or its hydrate with estra-1,3,5 (10) -trieno-16-hydroxymethylene-17-keto derivatives to condense in the cold, and so to be hydroxylated in the 17-position Pyrazolo-oestra-1,3,5 (10) -trienes arrives, which have valuable physiological properties.

The present invention also relates to
3 - methoxy -17 - hydroxy - oestra -1,3,5 (10) - trieno- [16c-17] -dihydropyrazole,

3 - chlorine -17 - hydroxy - estra - 1,3,5 (10) - trieno- [16c-17] -dihydropyrazole,

2 - methyl - 3 - methoxy - 17 - hydroxy - oestra-1,3,5 (10) -trieno- [16c-17] -dihydropyrazole and
2-fluoro-3.17-dihydroxy-estra -1,3,5 (10) -trieno- [16c-17] -dihydropyrazole.

These products according to the invention have valuable pharmacodynamic properties. they show have a significant anticholesterolemic effect and have little or no estrogenic effect.

The process according to the invention for the preparation of the new compounds of the formula given is characterized in that a corresponding 16-hydroxymethylene-17-oxo-estral, 3,5 (10) -triene is condensed with hydrazine or its hydrate, in the range of Room temperature and works in an organic solvent. Lower alcohols, ethers or benzene are expediently used as the organic solvent.
The reaction is advantageously carried out in a lower alcohol, such as ethanol, in an interval from 0 to 30 ^° C.

Depending on the reaction temperature and the type of With starting steroids, the reaction proceeds more or less rapidly. In certain cases, a few will suffice Minutes.

The following steroids can be named as starting products:

3 4

3 - methoxy -16 - hydroxymethylene -17 - oxo - östra- production of S-chloro-lo-hydroxymethylene-

1,3,5 (10) -triene, 17-oxo-estra-1,3,5 (10) -triene
2-methyl-3-methoxy-16-hydroxymethylene-17-oxo-

östra-l, 3,5 (10) -triene, stage A: Production of 3-chloro-17-oxo-östra-

3 - chlorine -16 - hydroxymethylene -17 - oxo - estra- 5 13 5 (10) -estratriene

l, 3,5 (10) -triene, '.

3-methoxy-16-hydroxymethylene-17-oxo-estra- Dissolve 5 g of 3 - chlorine - Π β - hydroxy - estra-

1,3,5 (10), 9 (II) -tetraene, 1,3,5 (10) -triene (described in the U.S. Patent

S-Methoxy-II / S-hydroxy-n-oxo-lo-hydroxyme- 3 117140) in 100 ecm acetone, gives 8 ecm one

ethylene-oestra-l, 3,5 (10) -triene and io Sn-chromosulfuric acid solution, stir for a few minutes

2-FluoΓ-3-hydroxy-16-hydroxymethylene-17-oxoten at room temperature and then mixed with 5 ecm

östra-1,3,5 (10) -trien. Methanol. After leaving to stand for a short time, it is diluted

the reaction mixture with 100 ecm of water, sucks the

The reactive groups, such as the keto groups in the precipitate formed, washes with water up to positions other than the 17-position of the molecule 15 neutrality, dries and then dissolves the raw material obtained from the starting steroid, which increases the risk of secondary product (4.970 g) in Chloroform, treats the mineral reactions in the condensation with hydrazine with tene solution with animal charcoal, filtered, concentrates the filtrate, bring yourself, methanol can be added beforehand by customary methods, while still distilling, sucking the protection. crystallized product and dries. This gives ~~ - ao 4.360 g of product, which is purified by successive Example 1 pasting in ethanol and ethyl acetate. Man ". ",,. _Λ ,,,, ... isolates 4.1 g of pure product from F = 252 ° C, 1, Ä I " ¹¹ ^ Methoxy-n-hydroxy-ostra- _{[] f} _ _{+ 15QO ± 15 (= 0 η $ η chloroform)} .
l, 3,5 (10) -trieno- [16c-17] -dihydrop _y razol The product is soluble in chloroform, ethyl acetate in Man g of 3-methoxy-25 is poorly soluble under nitrogen atmosphere for 2, very slightly soluble in alcohols and in 16-hydroxy-methylen-17-0x0-oestra-1,3,5 (10) -triene insoluble in water,
(described by Bardhan, Journal of the Chemical Society, 1848 [1936]) in 20 ecm of ethanol, adds analysis: C ₁₈ H ₂₁ OCl = 288.805;
2.44 ecm hydrazine hydrate and stir the reaction- calculated C 74.85, H 7.33, Cl 12.28%,
mixture found for 10 minutes at a temperature of 30 74 8 7 5 121 ° /
from 30 C.

It is cooled on ice, filtered off with suction, washed with ice-cold. The compound has not yet been used in the literature and is dried. The residue obtained is described
gives after recrystallization from acetone under reflux 1.17 g of 3-methoxy-17-hydroxy-oestra-1,3,5 (10) -tri- 35 Stage B: S-chloro-lo-hydroxymethylene-n-oxoeno- [16c -17] -dihydropyrazole from F = 174-176 ° C, oestr-1,3,5 (10) -triene
[<*] *> = + 163.5 ° (C = 1 ° / ₀ chloroform).

This compound results in the form of a colorless one is 3 g of 3-chloro-17-oxo-oestra-1,3,5 (10) -triene in Crystals that dissolve in water, propylene glycol and acetyl 300 ecm anhydrous benzene and then sets 30 ecm amine insoluble, in alcohol, ether and benzene a little anhydrous ethyl formate, 3 g 50% sodium hydride are soluble and soluble in acetone and chloroform. and 1.8 ecm of methanol and heated for 2 hours The product has not yet been refluxed in the literature, writing under nitrogen. , atmosphere is stirring.

The starting compound was prepared according to the method described in J. Chem. It is then allowed to cool and poured into water. Man

Soc. 1936, p. 1848, described method prepared. 45 washes the aqueous phase with ether, chases that away

Solvent by bubbling nitrogen through, filtered and acidified by adding hydrochloric acid

B ice ρ ie 1 2 f _au pH - _at \. It sucks off, washed with water until

Production of S-Chlor-H-hydroxy-östra- ^: ™ ^r the washing water dries and maintains neutrality

!, ^ (lOHrieno- ^ e-ni-dihydropyrazole - £ | ₍ ^ or-16- ^ agm ^ na »- ^

The mixture is stirred under nitrogen at room temperature (c = 1 ° / ₀ dimethylformamide).

a mixture of 1.56 g of S-chloro-lo-hydroxymethylene- The product is colorless and in alcohol and chloro-

17-oxo-oestra-l, 3,5 (10) -triene, 15 ecm ethanol and 1 ecm form slightly soluble.

Hydrazine hydrate. After stirring for 10 minutes, the 55th

Dissolution complete. This is followed by an analysis: C ₁₈ H ₂₁ O ₂ Cl = 316.815;
Reprecipitation. The mixture is stirred for a further 10 minutes, calculated C 72.02, H 6.68, Cl 11.2%,
sets with 15 ecm of ice-cold water and sucks off. found 71.5, 6.6, 11.1%.
The precipitate is washed with ice-cold ethanol and dried. The 3-chloro-60 is obtained. dihydro- described. ■.
~ pyrazole in the form of colorless crystals that appear in

melt around 120 ° C. LR. - Bands at 3600 cm " ¹ , example 3

3380cm- ¹ , 1590cm- ¹ and 1485cm- ¹ . . " _T "".,,,,,, _,,

This connection has not yet yon 6 _5! Production in the literature ^ methyl-S-methoxy-n-hydroxy

described ostra-1,3,5 (10) -tneno- [16c-17] -dihydropyrazole

The starting material was prepared according to the following: Stirring under nitrogen at room temperature

method described. a mixture of 1.1 g of 2-methyl-3-methoxy-16-hy-

5 6

droxymethylene-17-oxo-oestra-1,3,5 (10) -triene, 11 ecm Analysis: C ₂₀ H ₂₆ O ₂ = 298.41;
Ethanol and 1.2 ecm hydrazine hydrate. After 15minuti- u ^^ ru ^^ t rsnio Η «?« »/

according to agitation almost complete dissolution takes place and aphmnen 8Π S 8 7 "/

subsequent reprecipitation. One cools to 0 ⁰ C, S ^ unaen öu, o, ö, / / _o .

The precipitate is filtered off with suction, washed with ice-cold 5. The compound has not been ethanol in the literature and dries. The 2-methyl-described is obtained in this way.
3 - methoxy - 17 - hydroxy - oestra - 1,3,5 (10) - trieno-

[loc-ni-dihydropyrazole. IR bands at 3600 cm ",? Ϊ́ ^ ^0: " Position of 2-methy-3-methoxy-

and 3400 cm "and in the range of 1600 cm" and 16-hydroxy-methylene-17-oxo-ostra-1,3,5 (10) -ton

1500 cm ", which is on the substituted aromatic io Man gives 3 g of 2-methyl-3-methoxy-17-oxo-estra-

Core. l, 3,5 (10) -triene in 300 ecm anhydrous benzene and adds

The product is insoluble in water, in alcohol then 30 ecm anhydrous ethyl formate, 3 g 50%

fairly sparingly soluble and soluble in chloroform. Sodium hydride and 1.8 ecm of methanol. One brings

In the literature, the compound was not yet taking the reaction mixture for about 2 hours

described. 15 Stir and reflux nitrogen atmosphere.

The starting product was then allowed to cool and then poured into water. Man

method described. if the aqueous phase washes with ether, it drives away

Solvent by passing nitrogen through it, filtered and acidified to pH 1 by adding hydrogen chloride to produce 2-methyl-3-methoxy-16-hydroxy- _{20 acid.} It sucks the low-methylene-17-oxo-estra-l formed, 3,5 (10) -triene _sc HLAG off, washed with water until neutral,

dries and receives 2.5 g of crude product, which you can directly

Stage A: Production of 2-methyl-3-methoxy- ^{for the} production of 2-methyl-3-methoxy-17-hy-

17jS-hydroxy-oestra-1,3,5 (10) -trienedroxy-oestra-1,3,5 (10) -trieno- [16c-17] -dihydropyrazole

25 used.

15.9 g of 2-methylestradiol are added to 80 ecm of acetone. The compound has not yet been found in the literature

and adds 43 ecm of a ln sodium hydroxide solution and 16 ecm described.
Add water and reflux. 8.8 ecm Example 4 is given

Methyl sulfate and holds for about 30 minutes _TT "". ,,, "". ,

under reflux. Then cool to room temperature- 30 Λ% ^^ \ Τ, nf '} ^ Ii ^T f ^y \

door, pour the reaction mixture into water, sucks l, 3.5 (10), 9 (II) -tetraeno- [16c-17] -dihydropyrazole

the precipitate formed is washed with water and the same procedure as in Example 3 is used.

dries in vacuum. Starting from hydrazine hydrate and 3-methoxy

The crude product obtained is 16-hydroxymethylene-17-oxo-oestra-l, 3.5 (10), 9 (ll) -te- from isopropyl ether

recrystallized. 14.65 g of pure product are obtained, 3-methoxy-17-hydroxy-estra-

from F = 142 ° C. 1,3.5 (10), 9 (II) - tetraeno - [16c-17] - dihydropyrazole in

The product is in water, diluted aqueous form of colorless crystals. I.R. bands at

Insoluble acids and alkalis. 3600 cm "and 3400 cm".

The connection has not yet been made in the literature

Analysis: C ₂₀ H ₂₈ O ₂ = 300.42; ₄₀ described.

calculated C 79.97, H 9.39, O 10.64 ° /, The starting compound is according to the subsequently

found 79 ^ 85 '9 ^ 45 * 10/7%.' method described.

The starting product is in the USA patent specification production of S-methoxy-lo-hydroxymethylene

3166 577 described. 45 17-oxo-ostra-1,3,5 (10), 9 (II) -tetraene

A solution of 7.7 g is stirred under nitrogen

Stage B: Preparation of 2-methyl-3-methoxy-3-methoxy-17-oxo-oestra-1,3,5 (10), 9 (II) -tetraene in

17-oxo-oestra-l, 3,5 (10) -triene 300 ecm benzene and 23 ecm ethyl formate and then gives

•. 10 g of 50% sodium hydride. You hold the reaction

Under nitrogen and with cooling, 5 g of 50 ionic mixture are added with stirring for about 5 hours in 50 ecm of pyridine, 5 g are added at room temperature and the mixture of 2-methyl-3-methoxy-17 /? - hydroxy-oestra-1 is then heated , 3.5 (10) -triene, with stirring for 45 minutes under reflux, dissolved in 25 ecm pyridine, stirred for about. The mixture is cooled and 300 ecm water is added. The reaction mixture is poured out for 25 hours at room temperature, the aqueous phase is separated off, the benzene phase is extracted into water and the organic phase is separated off with water, the various combined aqueous phases are washed off, which are mixed in several portions with methylene phases Ether extracted with hydrochloric acid chloride. The methylene chloride is washed, the precipitate formed is filtered off with suction, the solution is successively with 1N hydrochloric acid, one is washed with water, dried and recrystallized from saturated sodium bicarbonate solution and with water to methyl ethyl ketone. 7.2 g of pure Prozur neutrality are recovered and dried over sodium sulfate. 60 duct from F = 162 ° C, [<x] l ° = +215 ± 1 ° (c = 1% The solution is treated with animal charcoal, suctioned off and dimethylformamide).

narrows to dryness. By recrystallization from the product is dissolved in chloroform and dilute aqueous

Methanol are obtained 4 g of pure product from the ring alkalis and soluble in alcohols and acetone F = 153 ° C, ^[(x]! S = + 161.4 ° (c = 0.5% methanol). Sparingly soluble.

The product is in methanol which is refluxed 65 _

boils, soluble, sparingly soluble in isopropyl ether and in analysis: C ₂₀ H ₂₂ U ₃ - JlU, JS;
Water and dilute aqueous acids and alkalis calculated C 77.39, H 7.14%,

insoluble. found 77.4, 7.1%.

7 8

The compound has not yet been established in the literature. In an analogous manner, starting from

described. 3 /? - methoxy - Ιΐβ - hydroxy - 16 - hydroxymethylene

The starting product was according to the in J. Chem. 17-oxo-östra-l, 3,5 (10) -triene, a new compound,

Soc. (1963), p. 5086. which in turn starting from 3-methoxy-II / J-hydroxy-

5 17-oxo-estra-1,3,5 (10) -triene (described in the USA.

Example 5 patent specification 2 874 173) is obtained, the 3-methoxy-

",,,"., ""., J .. Ilj3- ₎ 17-dihydroxy-oestra-1,3,5 (10) -trieno- [16c-17] -di

1 ^st , S ^V ° - ⁿ 2-FJ ^u otu3 "-dAydroxy-ostia. Hydropyrazole, a new compound, produced. F = 157 ° C,

l, 3.5 (10) -tneno- [16c-17] -dihydropyrazole _[a] " _{= +136} o _± 40 _{(c = χ} ο _{/ ο} chloroform)

The procedure is the same as in Example 3. 10

Based on hydrazine hydrate and 2-fluoro-3-hy UV spectrum (ethanol)

droxy-16-hydroxy-methylene-17-oxo-oestra-1, 3.5 (10) - 1,970 _m " _r - ow

triene one obtains 2 - fluorine - 3.17 - dihydroxy - estra- ^max '* ^μ '

1,3,5 (10) - trieno - [16c-17] -dihydropyrazole. The 25b ηιμ,

binding has not yet been described in the literature. 15 222 ΐημ.

The starting compound was prepared according to the method described below. As mentioned above, have the inventiveness _TT "■ _", H ^ t, products obtainable according to interesting pharma production by J.-fluoro-S-hydroxy-lo-hydroxy illogical properties. In particular, they show a methylene-1 ^ oxo-ostni.l, 3,5 (10) -taen _{20 strong} hypocholesterolemic effect.

1.6 g of 2-fluoro-estrone are suspended in 140 cm. Thus 3-methoxy-17-hydroxy-oestra-benzene, 18 ecm of ethyl formate and 0.8 g of sodium 1,3,5 (10) -trieno- [ 16c-17] -dihydropyrazole for the treatment hydride and then slowly 0.8 ecm of methanol. Man treatment of hypercholesterolemia and therefore as Bring IV2 hours to reflux, cools, dilutes diffractive or remedies for arterial diseases, with water and decanted the alkaline phase by 35 cerebral arteritis, aortitis, coronaritis, angina pecman with a mixture of benzene and Ether washes. toris and atheromatosis can be used.
It is filtered, degassed under nitrogen and acidified for a long time. You can add hydrochloric acid to buccal, perlingual, transsamous. Suck is administered by the cutaneous or rectal route,
formed precipitate and dries it. It can be in the form of injectable solutions or holds 1.57 g of 2-fluoro-3-hydroxy-16-hydroxymethylene 30 suspensions, which are in ampoules or bottles for 17-oxo-oestra-l, 3.5 (10 ) -trien are bottled in the form of a solid colored one-time use, as tablets, loose product, which are soluble in dilute aqueous alkalis, dragees, sublingual tablets, capsules or suppository alcohol, benzene and chloroform and are prepared in water torien.

and dilute aqueous acids is insoluble. The applied dosage ranges between

F = 250 ⁰ C. 35 1 and 50 mg per day in adults depending on the species

The compound has not yet been administered in the literature,

described. The pharmaceutical forms, such as injectable

The starting product was after the in Biochem. Solutions or suspensions, tablets, coated tablets,

Z. 1963, pp. 628, 338, the method described sublingual tablets, capsules and suppositories are

represents. 40 manufactured by conventional methods.

Claims (1)

Patent claims: 1. Process for the preparation of 17-Hydroxyöstra-1,3,5 (10) -triene- [17,16-c] -dihydropyrazolender general formula OH St. NH