JPS6117840B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to new derivatives of the pregnane series, which have already been described in the prior art literature and which can be extremely valuable starting materials for the production of useful products. Not only does it provide a means to obtain derivatives which are nitrogenated at position 18, but they also have pharmacological properties themselves.

The methods known to date for producing the above-mentioned 18-position nitrogenated derivatives of the pregnane series are generally extremely difficult to carry out;
In particular, it is known that such methods are difficult because they involve degradation reactions of very complex molecules (natural molecules or synthetically produced molecules); Both require numerous manipulations and lead to extremely low yields.

For example, a French patent for a method for producing pregnane derivatives having an amino functional group at position 18
Methods with long and difficult reaction routes are known, such as the method described in No. 1265442. in this way,
The first step requires the preparation of a starting compound with an 18-20 amino ring system, and then the introduction of the amino function involves conversion of the starting compound into the corresponding acylamino compound and hydrolysis of the 18-acylamino compound. Two steps are required: generation of an amino compound. It has also been pointed out that the purification of this 18-acylamino compound takes a long time because it requires multiple recrystallizations.

Furthermore, it can be seen from the description in West German Patent No. 61543 that it is particularly difficult to introduce a nitrogen atom into the 18th position of a pregnane compound. This patent also states that the reduction of azide groups is very difficult and that using aluminum-lithium hydride as a reducing agent has the drawback of decomposition of other functional groups such as ester or epoxy groups. There is. Furthermore, this patent relies on the use of sodium borohydride to avoid such drawbacks, but suggests that the reaction cannot be carried out effectively in the absence of a cobalt complex catalyst. ing.

In contrast to such prior art, the present invention does not require the production of an 18-20 amino ring system;
A method has been discovered that allows a pregnane compound having an azide group that is easily reduced to an amino group to be easily and rapidly produced in a single step. Furthermore, the present invention allows the reduction of this azide function to an amino group to effectively convert aluminum-lithium hydride without damaging the ester or ether function used to protect the 20-hydroxy group. A method has been found that can be used.

It is therefore an object of the present invention to overcome the disadvantages of the prior art mentioned above and in particular to shorten the reaction route to the nitrogenated derivatives known in the art and to provide new stable nitrogenated products.

Another object of the invention is to provide products having pharmacological properties and useful in the pharmaceutical field.

A further object of the present invention is to provide a new method for the production of these new products,
The process according to the invention is distinguished by its high yield.

The novel derivatives according to the invention have an azide group in position 18 and either a hydroxy function or a protecting group for the hydroxy function such as an ester, ether or tetrahydropyranyloxy group, or a ketone function in the 20 position. It is characterized by having.

The new derivatives according to the invention can be represented by the following general formula: [In the formula, R ₁ represents a hydrogen atom, CH ₃ COO, or a hydroxy group, and R ₂ represents a tetrahydropyranyloxy group, an oxygen atom, a hydroxy group, or OCOCH ₃ present at _the 20th position; When R 2 is an atom, it indicates the presence of a double bond, and when R ₂ is other than an oxygen atom, it indicates the presence of a single bond]. The azide group at position 18 is easily reduced to an amino group.

In the case of the above-mentioned compounds in which either one of R ₁ or R ₂ is an ester group, the ester group is preferably an acetate group.

It is also advantageous if R ₁ or R ₂ is a tetrahydropyranyloxy group.

The method for producing a pregnane derivative having an azido group _N3 at the 18-position according to the present invention is to prepare a pregnane derivative having an iodo group at the 18-position and a hydroxy functional group at the 20-position in a dipolar aprotic solvent ( aprotic dipolar golvent), in which the hydroxyl function at position 20 is prefixed to prevent the iodinated derivative from cyclizing to form the corresponding 18-20 epoxy derivative. and protect it.

The dipolar aprotic solvent used is a nucleophilic bimolecular substance.
substitutions) are preferred.

Any conventional technique may be used to preprotect the hydroxyl function at position 20. Preferably, the hydroxy functionality is combined with an organic acid, such as formic acid,
Esterification with acetic acid or propionic acid or with functional derivatives of the acids mentioned, such as acid chlorides or acid anhydrides.

Etherification of the hydroxy functionality with alcohols, especially aliphatic alcohols such as methanol, ethanol, propanyl alcohol or butyl alcohol, is also available.

The above protection method can also be carried out satisfactorily by reacting the starting iodo-hydroxy derivative with dihydropyran.

If the protection of the hydroxy function is carried out by esterification, it is advantageous to carry out the acylation with an acid anhydride which can simultaneously act as a solvent for both the iodized derivative and the product obtained. Excellent results are obtained with acetic anhydride, for example in the presence of tosylic acid (p-toluenesulfonic acid) or pyridine.

The ester derivatives thus obtained are stable in acid media.

Excellent results are also obtained by reacting the iodinated derivative of the starting material with dihydropyran under known conditions. This reaction is advantageously carried out at room temperature by stirring in an excess of dihydropyran, which at the same time acts as a solvent, in the presence of p-toluenesulfonic acid, which acts as a catalyst.

This etherified derivative as well as the derivative having a tetrahydropyranyloxy group in the 20-position are stable in alkaline media.

The ester or ether derivative obtained when such etherification or esterification is carried out is then treated with an alkali nitride, Preferably, it is reacted with sodium nitride (NaN ₃ ).

This 20-position hydroxy function is then converted into a hydroxy function by saponification if previously esterified or by acid hydrolysis (e.g. with an acetic acid-water mixture) if previously etherified. to play.

If the starting iodo-hydroxy derivative initially has a hydroxyl group (R ₁ =OH) at the 3-position, this hydroxyl group at the 3-position is removed during the esterification or etherification of the hydroxyl group at the 20-position (this reaction), esterification or etherification. This 3-position hydroxy group is also regenerated in the step of regenerating the 20-position hydroxy group under the conditions described above.

Derivatives with a ketone function in position 20 start from pregnane derivatives with an azide function in position 18 and a hydroxyl function in position 20, and this hydroxyl function can be removed using, for example, the Kilianil reagent.
reagent) (chromium oxidation).

However, in some cases the protection of the functionality present in the 3-position of the starting iodized derivative may require the selection of special reagents, in particular the esterification or etherification step of the 20-position hydroxy function. may require the selection of special reagents. This special precaution is not necessary when R ₁ is hydrogen.

If R ₁ is originally an acetate group (OCOCH ₃ ), it is necessary to form an ether or tetrahydropyranyloxy group to protect the hydroxy function at position 20. After forming the azide, this 20-position hydroxy function is regenerated by acid hydrolysis (eg under the conditions described above) (this hydrolysis does not act on the 3-position acetate group). If the corresponding ketone derivative is desired, the product obtained can then be sent to a final oxidation step.

Conversely, if R ₁ is an ether group, for example a tetrahydropyranyloxy group, protection of this 20-position hydroxy function can be by acylation. This 20-position hydroxyl group is regenerated by saponifying it after azide formation, and this saponification has no effect on the tetrahydropyranyloxy group. If desired, this 20
The corresponding ketone derivatives can finally be obtained by oxidizing the hydroxy function in position.

All reactions contemplated above (esterification, etherification, formation of the 18-position azide group) are carried out in approximately stoichiometric yields.

This azide derivative provides easy and quick access to pregnane derivatives having a nitrogen functionality (other than azide) in the 18-position.

For example, the corresponding amine products can reduce these azides with reducing agents (e.g. aluminum-
lithium hydride, sodium borohydride)
It can be produced by reduction by the action of or by catalytic hydrogenation.

Starting from an azide ester, a first
amine-alcohols can be produced directly.

This reaction route is of the type shown by the following formula.

The iodinated derivatives of the starting materials are described in French Patent Application No. 71-18479 (filed May 21, 1971) and in the additional French Patent Application No.
No. 72-06172 (filed February 23, 1972). Other pregnane derivatives having an iodo group in position 18 of the pregnane structure, which are advantageously prepared according to the methods described in these French patent applications, can also be used.

The method described in this French patent application consists of reacting the corresponding terminally iodized pregnane derivative with iodine in a solvent such as cyclohexane, and then reacting under reduced pressure for 60 min.
By distilling off the solvent at a temperature below 0.degree. C. and then crystallizing the residue in a solvent such as acetone to produce a substantially pure corresponding pregnane derivative having an iodo group at the 18-position.

In the method according to the present invention, the only positions involved in the reaction are the 18th and 20th positions of the molecule, so even if other groups in the molecule are protected according to conventional methods if necessary, the 18th position is Replacement of is possible.

Azide products such as the product are useful starting compounds for the synthesis of pregnane derivatives having a nitrogen-containing group at the 18-position thereof. These allow the facile preparation of compounds with known useful therapeutic activity and new pregnane derivatives bearing a substituent in the 18-position.

This azide derivative is particularly valuable in that it is itself stable. For example, the azide derivatives can undergo rearrangements in the structure of their respective nuclei, and substitutions can be made at various positions of these nuclei without danger to the azide group, e.g. in position 18, and these The azide group chemically and generally exhibits the same functionality as in known derivatives having an azide group at a position other than the 18-position.

For example, starting from an azide derivative of the formula (R ₁ and R ₂ represent acetate groups), in a first step this azide derivative can be converted to aluminum, e.g.
3-hydroxyconanine or 3,3-dimethoxyconanine can be produced by a method in which the corresponding amine derivative is produced by reduction under the action of lithium hydride.

example The general route for the reaction is as follows.

Starting from an iodo-18-hydroxy-20 derivative, the hydroxy function is protected by stoichiometric esterification.

This esterification is carried out at room temperature using one of the following reagents:
It can be carried out with the same yield using: - acetic anhydride/tosylic acid or - acetic anhydride/pyridine. (HMPT)] to obtain an azide group at the 18th position. It is optional to carry out this operation in a nitrogen atmosphere.

Example 1 Preparation of 18-azido derivatives from 18-iodo-hydroxy-20β,5α-pregnane (a) Protection of the hydroxyl function (first method) 100 mg of the compound of formula were dissolved in 3.5 ml of acetic anhydride. A few crystals of tosylic acid were added to this and the mixture was stirred at room temperature for 24 hours. A small amount of water was added to the solution and the solution was extracted with methylene chloride to neutralize the organic phase. This was dried and evaporated under reduced pressure. Crude product ()
107 mg was obtained.

(Second method) 120 mg of the compound of formula were stirred in 2 ml of an equal mixture of acetic anhydride and pyridine at room temperature for 24 hours. The solution was diluted with water and then extracted with methylene chloride. The organic phase was acidified with 3 drops of hydrochloric acid, washed with water and then made alkaline with ammonia. This was dried and evaporated under reduced pressure.
135 mg of crude product was obtained.

The products of these two batches showed the same analytical characteristics (RMN, IR, thin layer chromatography). These were collected together and crystallized with acetone until a constant melting point was obtained.

The product of this formula had the following properties.

Melting point: 121°C [α] _D : +2° (in chloroform) IR spectrum: Ester bands at 1740 cm ^-1 and 1240 cm ^-1 (b) Substitution of iodo group by azide group 70 mg of the compound of the formula was added to HMPT (5 ml). Dissolved. Add 140mg of sodium nitride to this,
The mixture was stirred at 90° C. for 3 hours under nitrogen atmosphere. Cool this solution, dilute with water,
Acidified with hydrochloric acid and then extracted with a benzene-ether mixture. This organic phase was washed with water until the washings became neutral. This was dried over sodium sulphate and evaporated under reduced pressure. After two crystallizations, a product with a constant melting point ()32
I got mg.

The product of this formula had the following properties.

Melting point: 180℃ IR spectrum: Azide band at 2000cm ^-1 , 1740cm ^-1
and an ester band at 1250 cm ^-1 .

RMN spectrum: methyl-19-singlet at 0.77ppm, methyl-19-singlet at 1.16 (j=6)
21 doublet 2.02 and acetyl-20 singlet CH ₂ -18AB A=3.10 B
= 3.55 (j = 13) H-20 m Centered example 2 at 4.80 18-iodo-hydroxy-3β, 20β-5α-
Preparation of 18-azido derivatives from pregnane-acetyl-3 (a) Protection of the hydroxyl function 1100 g of the mixture of formulas were stirred at room temperature in 20 ml of an equal mixture of acetic anhydride/pyridine. After 24 hours, the solution was diluted with water and extracted with ethylene chloride. The organic phase was acidified with a few drops of hydrochloric acid, washed with water and then made alkaline with ammonia. This was dried over sodium sulphate and evaporated under reduced pressure. 1185 g of crude product was obtained. Product crystallized from hexane and has a constant melting point
880 mg of compound () was obtained.

This product () had the following physical and chemical properties: Melting point: 131.5°C Empirical formula: C ₂₅ H ₃₉ O ₄ I = 530.5 [α] _D : -2° IR spectrum: Ester band 1730 cm ^-1 , 1240 cm ^-1 RMN spectrum: singlet CH ₃ -19, 0.82 ppm CH ₃ -21, 1.16 ppm (j=
6) Double acetyl-3,20,
Singlet CH ₂ -18 at 2.0ppm, AB A=2.95,
B=3.23 (j=11) H-3,20 m Centered at 4.80 (b) Substitution of iodo group by azido group 760 mg of the compound of formula () was dissolved in 15 ml of HMPT. 1.4 g of sodium nitride was added to this solution, and the mixture was stirred at 90° C. under nitrogen pressure. 3 hours later
This solution was cooled. Water acidified with hydrochloric acid was added to this solution and the solution was extracted with a benzene-ether mixture. The organic layer was washed with water until PH was neutral, dried over sodium sulphate and evaporated under reduced pressure. After two crystallizations with 500 mg of methanol, a constant melting point product was obtained (compound XI).

The properties of this product (XI) were as follows: Empirical formula: C ₂₅ H ₃₉ O ₄ N ₃ = 445.5 Melting point: 132°C (methanol) [α] _D : +20° IR spectrum: 2100 cm ^-1 Azide band 1725 cm ^-1 and ester band 1250 cm ^-1 RMN spectrum: Methyl-19, 0.85 ppm singlet CH ₃ -21, 1.16 ppm (j =
6) double let OCOCH ₃ -3,20,
Singlet CH ₂ -18 at 2.0ppm, AB A=3.07,
B=3.52 (j=13) H-3, 20, m Centered at 4.80.

(c) Production of a derivative aminated at position 18 (primary amine) from the compound of formula XI 100 mg of the compound of formula Stir down. This mixture was refluxed for 3 hours. After cooling the solution, it was diluted with ethyl ether. Excess aluminum-lithium hydride was destroyed with a saturated solution of sodium sulfate. The organic solution was dried with purified dry sodium sulfate. This was filtered through sintered glass and evaporated under reduced pressure. 75 mg of crude product was obtained. This was crystallized from absolute ethanol. This product, empirical formula
Amino- ₁₈ -hydroxy-3β,20β _- pregnane-5α (XII) with _C21H37O2N =335.5 exhibited the following properties.

Melting point: 240℃ IR spectrum: Alcohol and amine bands from 3200 to 3500 cm ^-1 RMN spectrum: [in heavy methanol (CD ₃ OD)]: CH ₃ -19, singlet at 0.85 ppm CH ₃ -21, 1.12 ppm (J =
6) Double let CH ₂ -18, AB A=
2.42ppm, B=2.85ppm
(j=13) H-3,20,m 3.55ppm
Centered (d) Amino-18-hydroxy-3β,20β-5α
-N-dimethylconane-5α- from pregnane
Preparation of en-20-(N)-one-3() derivative 160 mg of the compound of formula (XII) was dissolved in 5 ml of acetic acid. To this solution was added portionwise 110 mg of chromic acid dissolved in 0.5 ml of water. After 12 hours, the solution was diluted with ethanol to destroy excess chromic acid. Water was added to this and the mixture was made alkaline with ammonia. This was extracted with ether and the organic phase was evaporated under reduced pressure. 132 mg of crude product () was obtained. The physical constants of this product are given in the literature (Bull.Soc.Chim.1964,
P.1566, JANOT, LUSINCHI &
GOUTAREL).

Example 3 Azido-18-hydroxy-(20R)-pregnane-5α and acido-18-5α-pregnane-
Manufacture of 20.

The reaction route is as follows: (i) Azido-18-hydroxy-(20R)-pregnane-5α 1,250 mg of the azide-ester of formula () was dissolved in 10 ml of methylene chloride. Ethanolic potassium hydroxide N was added to the solution and the mixture was mechanically stirred overnight. The reaction mixture was subjected to alkaline hydrolysis by heating at 65° C. for 30 min (control of the reaction was carried out by thin layer chromatography in neutral medium, CH ₂ Cl ₂ /MeOH (49:1)). ). This mixture was then extracted with methylene chloride and 1.1
g of residue was obtained. This residue was recrystallized from acetone to give 880 mg of the product of formula. The physical and chemical properties of this product were as follows.

Melting point: 136°C [α] _D : +48° IR spectrum: (OH) band at 3,550 cm ^-1 Azide band at 2,100 cm ^-1 RMN spectrum: Singlet at CH ₃ -19, 0.81 CH ₃ -21, 1.12 (j=6)
Double let CH ₂ −18, AB3.23 and
3.61 (j=12) H-20, centered on m3.55 Mass spectroscopy: m/e345=M ⁺ m/e317=M-28 (0.5%) m/e302=M-28-15 (2.5%) m /e299=M-28-18 (2%) m/e289=M-56 (0.5%) m/e271=M-56-18 (3%) Analysis value: C ₂₁ H ₃₅ ON ₃ = 345.51 (ii) Azido-18-5α-pregnane-20 Azido-hydroxy derivative of formula ()868
0.9 ml of Kiliani reagent was added within 5 minutes to a solution of .mg in 25 ml of acetone. The reaction mixture was cooled in an ice-water bath and mechanically stirred for 30 minutes. The mixture was diluted with water and the mixture was extracted with benzene to obtain 815 ml of residue. This residue was crystallized in acetone and
660 ml of a compound of formula were obtained. The physical and chemical properties of the product of this formula are as follows: Melting point: 136°C [α] _D : +88° RMN spectrum: CH ₃ -19, singlet at 0.79 CH ₃ -21, singlet at 2.18 CH ₂ −18, AB3.09, 3.52
(j = 12.5) Analysis value: C ₂₁ : H ₃₃ : ON ₃ = 343.50 Circular dichroism: λ _nax = 293 nm △ε = 3.43 (c = 0.11 g/; dioxane) Example 4 Azide-18- Acetate-3-tetrahydropyranyloxy-20-pregnane-5α (
), Azido-18-acetate-3-hydroxy-20-pregnane-5α (XI) and Azido-18-acetate-3-5α-pregnane-
Manufacture of 20(XII).

According to the above reaction route, the reaction was carried out as follows.

500 mg of a compound of formula were dissolved in a mixture of 6 ml dioxane and 0.5 ml dihydropyran. To this was added 40 mg of tosylic acid and the mixture was stirred at room temperature for 15 minutes. The product of formula was collected by adding ammonia-methanol solution to this mixture and then extracting with methylene chloride. product of formula
Obtained 270 mg. The melting point after crystallization with ether is
The temperature is 155-156°C.

The product of this formula was then converted to HMPT under conditions substantially similar to the description of the corresponding step in Example 1 above.
It reacted with the sodium nitride placed inside. Formula XI
The physical and chemical properties of this product were as follows: Melting point: 132-133°C [after crystallization with acetone-hexane mixture (4:6 volume ratio)] IR Spectrum: Azide band at 2100 cm ^-1 and ester band at 1735, 1250 and 1030 cm ^-1 The product of formula XI (1.6 g) was mixed with ethanol
Dissolved in 16 ml of water-acetic acid mixture (3:1:2 by volume) and heated the solution to 100° C. for 15 minutes. The solution was cooled and the product was removed, washed with water-ammonia solution and dried.

1.5 g of product of formula XI were obtained. The physical and chemical properties of this product were as follows: Empirical formula: C ₂₃ H ₃₇ O ₃ N ₃ Molecular weight: 403.55 Melting point: 192°C (after crystallization with acetone) [α] _D : +33 ° (in chloroform) IR spectrum: alcohol band at 3550 cm ^-1 , azide band at 2100 cm ^-1 , ester band at 1740, 1250 and 1030 cm ^-1 RMN spectrum [deuterized chloroform]
(CDCl ₃ )]: Singlet CH ₃ -19: 0.83ppm CH ₃ -21: 1.12ppm (j=6)
Doublelet OCOCH ₃ -3: Singlet CH ₂ -18: AB A=3.20, B= 2.00ppm
3.60 (j=12) 300 mg of this product of formula XII were dissolved in 10 ml of acetone. To this solution was added 1 ml of Chiliani's reagent over 5 minutes. The treatment was then carried out according to the method described in the corresponding step of Example 3 above. 200 mg of the product of formula was obtained. The physical and chemical properties of this product were as follows: Melting point: 179°C (after crystallization with acetone) Empirical formula: C ₂₃ H ₃₅ O ₃ N ₃ Molecular weight: 401.53 IR spectrum: 2100 cm ^- Example ⁵ This example illustrates the use of the azide ^- 18 derivatives according to the invention in the preparation of compounds with known pharmacological activity ^.

(a) 3-Hydroxy-conanine () Starting from a compound of formula (XI), a product of formula (XII) is prepared analogously as above and then (
) to obtain the product.

The product of formula () is reduced with sodium borohydride and treated with formic acid and formol (Eschweiler-Clarke reaction). 3-Hydroxy-conanine was obtained, a compound known to have hypotensive properties.

(b) 3,3-dimethoxy-conanine () Starting from a compound of formula (XI), a compound of formula (ii) is obtained via a compound of formula (XII). The ketone in position 3 of this compound of formula () is converted into an acetal by the action of methanol in an acidic medium, and this product is then treated with formic acid and formol (Eschweiler-Clarke reaction). 3-3-dimethoxyconanine was obtained. This derivative is known to have ganglioplegic action.

Some of the novel substances described so far exhibit hypotensive effects, which can be used therapeutically. It has been found that the product introduced into rabbits at a dose of 5 mg/Kg, injected intravenously in the form of an alcoholic solution, has an effect of reducing arterial tone and reducing central sympathetic colic, and this was evidenced by a drop in hypertension induced by carotid artery occlusion. The observed effects are independent of the solvent; the solvent has no effect in control animals under the same experimental conditions.

At the highest level of the above alcoholic solution that can be administered to rabbits or mice, the product is free of any toxicity. The maximum dose stated is determined by the maximum amount of alcohol that the organism of the test animal can tolerate.

Claims (1)

[Claims] 1 formula (In the formula, R ₁ represents a hydrogen atom, CH ₃ COO, or a hydroxy group, and R ₂ is a tetrahydropyranyloxy group, an oxygen atom, a hydroxy group, or
OCOCH ₃ , 〓 represents the presence of a double bond when R ₂ is an oxygen atom, and represents the presence of a single bond when R ₂ is other than an oxygen atom). A method for producing a pregnane derivative having an azide group that is easily reduced to an amino group, the method comprising: (wherein R ₁ has the same meaning as above), the hydroxy function present at position 20 of the corresponding compound is replaced with an organic acid or a functional derivative thereof, e.g.
18-Iodo-20-
cyclization of the hydroxypregnane derivatives to the corresponding 18-20 epoxy derivatives is prevented; the compound thus obtained with a protected hydroxy group then has the formula MN ₃ where M is an alkali metal, e.g. sodium. with an alkali metal azide in the presence of a dipolar aprotic solvent; optionally by saponification if the hydroxy function is esterified or by saponification if the hydroxy function is etherified. The process consists of regenerating the hydroxyl function by acid hydrolysis and, if necessary, converting this hydroxyl group by further oxidation into a ketone function at position 20.