DE2006635B - 16alpha, 17alpha (propen 2 yhden dioxy) 9 fluorine 11 beta, 21 dihydroxy delta high 1.4 pregnadienes or their 21 esters, process for their production and pharmaceutical agents containing them as the sole active ingredient - Google Patents

Description

1. A mineral acid such as hydrochloric acid is used as the catalyst or perchloric acid is used. It is in a regarding the reaction mixture

inert organic solvents such as benzene, toluene, xylene, dioxane or tetrahydrofuran, worked The reaction takes place with stirring at room temperature and over a Duration from 3 to 24 hours; the start-up time is usually the one during the redemption of the 9 - fluorine - 11 / 1.16 «, 17.21 - tetrahydroxypregnadiene in suspension at the beginning of the reaction - (1,4) - dione - (3,20) elapses. After the reaction is complete, the catalyst resulting acid by treating the reaction mixture with an aqueous alkali solution, like an aqueous sodium bicarbonate solution, neutralized and the 9-fluoro-11 / J, 21 -dihydroxy-16 «, 17 - (propene - (2) - ylidendioxy) - pregnadiene - (1,4) - dione - (3i, 2O) by usual means such as extraction with a solvent, isolated and then purified and optionally recrystallized.

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2. For the esterification that may take place, the 9-fluoro-l l ^ l-dihydroxy-16a, 17- (propene - (2) - ylidendioxy) - pregnadiene - (1,4> -dione- (3,20) to a solution of the anhydride in pyramid, if the anhydride - based on the stoichiometrically necessary amount - is used in large excess; the reaction takes 10 to 40 hours at room temperature

"accomplished. After the esterification has ended, the reaction mixture is treated with a 10 71η? ίλιμ aqueous acid solution and isolate the ^ζιυζ " ^{ζ <} * V >> precipitate formed by filtration.

3. The salt formation which may take place takes place with the preferred use of alkali metal or ammonium bicarbonate, carbonate or hydroxide. For example, the stoichiometrically necessary amount of an alkali metal bicarbonate dissolved in water can be reacted with the pregnane derivative of the formula (1) having a free carboxyl group (^ COOH) present in a hydroorganic solution, such as an aqueous acetone solution. After the reaction has ended, the desired salt is obtained by separating off the solvent
Vacuum insulated.

Table 1

2102-18 (a) 2102-26 (a) 2102-25 (c). TAA

Percentage regression of the thymus gland depending on the administered doses (mg / kg; 2 x daily)

10

72 75 80 79 75

79 72 88 77 76

<U

73 74 77 73 42

0.01

21 60 25 31 6

OJOOl

(a, solution or suspension in peanut oil..

(b) Directly when used with the help of NaHCO, in water brought into solution.

(c) Aqueous solution.

in the

The products of the formula (1) according to the invention have pharmacological properties that of are of great importance; they are in particular with a very strong t'yoiolytic and glycogenic Effectiveness endowed and excellent anti-inflammatory agents.

The products of the formula (1) in which R is a hydrogen atom (hereinafter referred to as product no. 2102-18 and described in more detail in Example 1) or the CH ₁ —CO radical (this product becomes hereinafter referred to as 2102-26 and described in Example 2) or the

HOOC-CH ₂ -CH ₂ -CO-ReSt

(hereinafter referred to as 2104-24 and in example 3 described) or the

2. The effect of the products on hepatic glycogenesis was tested according to the method of Venn i η g et al. (Endocrinology, 1946, 38, 79). For this purpose, groups of rats were administered subcutaneously a total dose of 2, 4 and 8 μg per animal 5 days after the suprarenalectomy, using the product to be tested dissolved in 1.4 ml of an aqueous solution containing either 5% glucose and 10% ethyl alcohol ( 2102-18 and 2102-26) or 5% glucose (2102-25) alone. This 1.4 ml volume of solution was administered subcutaneously in seven consecutive injections at 45 minute intervals. A group of control animals was given the solvent alone under the same conditions. The mean glycogen content of the liver, based on 100 g of the organ, is ^; n

Table 2 given. In the comparison stitches was found a value of practically 0.

Table 2

40 Tested connection

NaOOC-CH ₂ -CH ₂ -CO-ReSt

(hereinafter referred to as 2102-25 and described in Example 4).

The examinations carried out and the educational results can be summarized as follows will:

1. The thymolytic activity was determined in the rat by the method of Stephenson (J. Pharro. Pharmacol, 1960, 12, 411 to 415). The products were injected subcutaneously daily for 3 days in two doses in the morning and in the evening. The animals were sacrificed on the fourth day. The thymus glands were removed, weighed and their weight in milligrams. 1 expressed per 100 g of body weight. It was with groups of comparison animals and animals, the different doses of the to be tested Compounds (as shown in Table 1) obtained worked. In Table 1 the percentage Regression of the thymus gland in the treated animals, based on the mean value of the thymus weight of comparison animals. Incidentally, for comparison purposes, Table 1 contains values that under the same conditions with the well-known triarncinolone acetonide (hereinafter abbreviated as »TAA«! were achieved.

2102-18 2102-26 2102-25 TAA Glykngen content of the liver in grams

per 100 g Orgfin depending on

the administered dose in fR

3.29
2.66
1.81
1.60

1.89 1.45 0.30 1.53

0.32 0.15 0.03 0

3. The anti-inflammatory activity of the compounds on the carrageenin abscess was based on a variant of the method of B e η i t ζ and Hall (Arch, intei. pharmacodyn. Therap., '963, 144, 185 to 195) below - compliance with the following conditions tested: Male rats of about 50 g were divided into groups of five animals. At the The animals received oral or intraperitoneal injection for the first few days either the compounds to be investigated or the carrier used alone. The daily dose was divided into two half-doses administered in the morning and in the evening. On the second day this treatment was repeated and all received immediately after the first administration Animals subcutaneously in the dorsolumbar region 0.5 ml of a 2% carrageenin suspension in physiological solution. On the third day, the animals were inhaled 24 hours after the carrageenin injection Chloroform killed. Then the dorsolumbar

area freed from hair and the abscess removed. Exudate and gelatinous substance were weighed immediately after isolation.

The effectiveness of the compounds is expressed in terms of percentage abscess inhibition. This The percentage is the difference between those in the control animals and the treated animals The abscess weights found are determined, which are then related to the abscess widths in the comparison animals would. The results obtained are shown in Table 3 summarized:

Table 3

Dermatoses, asthma and viral liver inflammation

Tested Verbtadung

2102-18 (a)
2102-26 (a)
2102-25 (b)

TAA

Appointment

roe

art

PnnmtuafeAbsprozessgewiriits- inhibitJon as a function of , ₅ <tai veialiigmlil * Mi I ^ ot ^ q

p.o.

p.o.

p.o.

i.p.

p.o.

inmg / kg / day

lox »

17th

00 JL 1 o, ij 63 48 38 26th 51 43 33 56 35 39 42 51 24 34 51 48 16.5 20th

(?) Solution or suspension in an aqueous solution of

Gum arabic,
(b) Aqueous solution.

4. The anti-inflammatory activity of the compounds was also against the Carrage- \ o ninöuem by the method of Winteru.a. (Proc. Soc. Exp. BioL Me <-, 1962, 111, 544 to 547). The connections ora! administered in aqueous solution (2102-25) or suspended in gum arabic solution (2102-18) at such a concentration that the volume absorbed was 2.5 ml / kg body weight. 1 hour after the administration, the thickness of the right hind paw was measured and then 0.05 ml of a 1% carrageenin solution in physiological solution was injected into the sole cushion. 3 hours later, the thickness of the treated paw was measured again. The difference between the two measurements is a measure of the strength of the edema caused by carrageenin. Its inhibition in the animals treated with compounds according to the invention was durci. Comparison with parallel measurements in comparison animals determined that had only been treated with the vehicle used. Table 4 shows the results:

Table 4

Tested connection

2102-18
2102-25
TAA ..

Percentage of edema inhibition
depending on the
administered doses in mg / kg 10 1 : oo 33 21 54 38 21 50 45 T) 48

In view of their remarkable pharmacological properties, the products of the formula (1) according to the invention form medicaments and in particular medicaments with anti-inflammatory effects which are very useful in therapy. You can, for example, in humans with acute or chronic rheumatic complaints, with inflammatory Die you the complaints to be treated, the product used, the subject of treatment and the type of administration depending on the usual dose in humans, for example, 1 to 100 mg per day for oral administration.

In the case of the products of the formula (1) with a carbonic acid salt group —COOA, in which A metal iert an alkali , this can, for example, be sodium or

Kalräni sem. ,. ". - - ".

The products of formula (1), m digestive, parenteral or installed locally administrable pharmaceutical compositions. These pharmaceutical agents can, for example, be solid or liquid and be in the pharmaceutical forms customary in human medicine, such as emiachs or sugar-coated tablets. Capsules, granules, solutions, suspensions, syrups, suppositories, various injectable preparations such as solutions, suspensions or sterile powders to be dissolved immediately during treatment. Chips, creams, gels or aerosols. They can be produced by conventional methods. The active ingredient (s) can be used together with customary excipients for pharmaceutical agents, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles. Fats of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers and preservatives.

The following are non-limiting examples of practicing the invention.

example 1

Production of 9-fluoro-II / i, 21-dihydroxy-

16a, 17- (propene) - (2) -ylidenedioxy) -

pregnadiene- (1,4} -dione- (3.20)

A suspension of 1 g of 9-fluoro- 11, 16a, 17.21-tetrahydroxypregnadiene - (1,4) - dione - (3.20) in a mixture of 35 ml of dioxane, 15 ml of acrolein and 0.1 ml of perchloric acid is stirred at ambient temperature for 3 hours. The clear solution obtained is poured into a saturated, aqueous sodium bicarbonate solution. The mixture is extracted twice with benzene and then the benzene extract is concentrated to e ^; n low volume. The crystals formed are suctioned off or spun off, and the 9-fluoro-11 / i, 21 -dihydroxy-16α, 17- (propen (2) - ylidendioxy) - pregnadiene - (1,4) - dione - ( 3.20) in 1 orm of white crystals. Melting point: 200 to 205 ⁰ C in a capillary tube melted shut in a vacuum.

[α] ?: + 82 ° 5 (<t = 1, CHCl ₃ ).
Molecular formula: C ₂₄ H ₂₉ FO ₆ .

Calculated ... C 66.6, H 6.8%;
found .... C 66.1, H 6.7%.

Example 2

Production of 9-fluoro-l 1 / f-hydroxy-

16 «, 17- (propen- (2> -ylidenedioxy) -21 -acetoxy-

pregnadiene- (l, 4) -dione- (3.20)

To a mixture of 1 ml (0.0106 mol) of acetic anhydride and 8 ml of anhydrous pyridine is added

1 g (0.00231 mole) 9-fluoro-1 l / i, 21-dihydroxy-16a, 17- (propene - (2) - ylidendioxy) - pregnadiene - (1,4) - dione- (3.20). The resulting solution is left for 20 hours rest and then add them dropwise to a stirred mixture of 30 g of ice and 10 ml of concentrated Hydrochloric acid. It is stirred for 1 hour, and then sucked or spun the formed Precipitate from which is washed with water until a neutral reaction. After drying for 2 hours at 100 ° C in vacuo one receives 950 mg (87%) 9 - fluorine -1 lfi - hydroxy -16α, 17 - (propen - (2) - ylidendioxy) - 21 - acetoxypregnadiene - (1,4) - dione - (3,20) in the form of white crystals which are fused in the Melt the capillary tube at 220 to 222 ° C.

[«] {?: + 78 ° 4 (c = 1, CHCl ₃ ).
Molecular formula: C ₂₆ H ₃ IFO ₇ .

Calculated ... C 65.8, H 6.6, F 4.0%;
found .... C 66.0, H 6.7, F 4.0%.

Example 3

Production of 9-fluoro-l 10-hydroxy-

16a, 17- (propen- (2) -ylidenedioxy) -21 - (3-carboxy-

propionyloxy) -pregnadiene- (1,4) -d »on- (3.20)

To a solution of 10 g (0.1 mol) of succinic anhydride 10 g (0.0231 mol) of 9-fluoro-l 1 / ί, 21 · κ1ί-hydroxy-l6n.l7 are added fractionally to 42 ml of anhydrous pyridine - (propene - (2) - ylidendioxy) - pregnadiene - (1,4) -dione- (3,20). Leave the resulting solution Rest for 20 hours and then add them dropwise to a stirred mixture of 160 g of ice and 50 ml of concentrated hydrochloric acid. Stirring is continued for 1 hour, and suction or centrifugation is carried out then the precipitate formed, which is washed with 11% water. One brings the precipitate in 11 water again in suspension and stirred for 15 minutes long and then sucks or spins off again. After drying in vacuo at 45 "C for 24 hours 10.4 g (85%) of 9-fluoro-II / hydroxy-16a, 17- (propene - (2) - ylidendioxy) - 21 - (3 - carboxy - propionyloxy) - pregnadiene - (1,4) - dione - (3,20) in the form of white crystals that melt in an open capillary tube at 148 ° C.

[a] '" ⁵ : + 69 ° 8 (c = 1, CHCl ₃ ).
Molecular formula: C ₂₈ H ₃₃ FO ₉ .

Calculated ... C 63.2, H 6.2%;
found .... C 62.8, H 6.4%.

Example 4

Preparation of the sodium salt of 9-fluoro

110-hydroxy-16a, 17- (propen- (2) -ylidendioxy} -

21- (3-carboxy-propionyloxy) -pregnadiene- (1,4) -

dione (3.20)

10 g (0.0188 mol) 9 - fluorine -1 Iß - hydroxy - 16o, 17- (propene - (2) - ylidendioxy - 21 - (3 - carboxy - propionyloxy) - pregnadiene - (1,4) - dione - (3.20) are dissolved in 65 ml of acetone, and then 20 ml of water are added, and a solution of 1.58 g (0.0188 mol) of sodium bicarbonate in 40 ml of water is added dropwise to the resulting solution is stirred for 30 minutes and filtered and the filtrate is then concentrated to dryness in vacuo. The crystalline product obtained is dried in vacuo at 45 ° C. for 24 hours, and 10 g (96%) of the sodium salt of 9-fluoro-11 are obtained /) -hydroxy -16α, 17- (propen - (2) - ylidendioxy) -21- (3 - carboxy - propionyloxy) - pregnadiene - (1,4) -dione- (3,20) in the form of water-soluble white crystals, which decompose in the open capillary tube above 200 ^° C. without melting.

[n] 5 ?: +94 ^u 6 (c = 1, H ₂ O).
Molecular formula: C ₂₈ H _{32 FNaO 9} .

Calculated ... C 60.6, H 5.8, F 3.4%; ίο found .... C 60.6, H 6.1, F 3.4%.

After subcutaneous administration in the rat, the LD ₅₀ is 140 mg / kg (cumulative mortality in 21 days after a single administration of the product).

Example 5

Tablets of the following composition were produced:

9-fluoro-l 10,21-dihydroxy-

16a, l 7- (propen- (2) -ylidenoxy) -

pregnadiene- (1,4) -dione- (3.20) 2 mg

Excipient q.s.p. one tablet of ... 200 mg (ETcipientim single'.lactose, talc, Starch, magnesium stearate).

Example 6

An ointment was made of the following composition:

9-fluoro-l 10,21-dihydroxy-

16a, l7- (propen- (2) -ylidendioxy) -pregnadiene- (l, 4) -dione- (3.20) 0.1 g

Excipient q.s.p 100 g

Example 7

An injectable suspension was prepared with the following formulation:

9-fluoro-1 lp-hydroxy-16a, 17- (propen- {2) -ylidendioxy) -2l-acetoxypregnadiene- <1,4) -dione- {3.20) 40 mg

Aqueous excipient q.s.p 2 ml

Example 8

Manufacture of a preparation for injections with the following formulation

9-fluoro-1 ip-hydroxy-16a, 17- {propen- {2) -ylidendioxy) -21- (3-carboxy-propionyloxy) -pregnadren- (1,4) -dione- (3.20)

Aqueous alkaline excipient ...

20 mg 2ml

Example 9 Production of tablets with the following formulation

Sodium salt of 9-fluoro-l 1 / i-hydroxy-16a, 17- (propen- (2) -ylidendioxy) -21- (3-carböxy-propionyloxy) -pregnadiene- (1,4) -dione- (3, 20) .. 2 mg

Excipient q.s.p. one tablet of 200 mg

(Excipient in detail: lactose, starch, talc, magnesium stearate).

209 550/539

Example 10

Manufacture of a preparation for injections with the following recipe

Sodium salt of 9-fluoro-11 / Mi> jroxy-16a, l 7- {propen- (2) -ylidendioxy) -21- (3-carboxy-propionyloxy) -pregnadiene- (1 AV

dione- (3.20) 20 mg

Aqueous excipient q.s. p. 2 ml

Example 11 Preparation of an ointment with the following composition

Sodium salt of 9-fluoro-11 / ϊ-hydroxy-16a, l 7- (propen- {2) -

(ο

ylidendioxy) -21- (3-carboxy-propionyloxy) -pregnadiene- ( 1.4) -

dione (3.20)

Excipient q.s.p

0.1 g 100 g

Example 12

Production of eye drops with the following formula

Sodium salt of 9-fluoro-11 ^ -hydroxy- 16α, 17- (propen- (2) -ylidendioxy> -21- (3-carboxy-propionyloxy) -pregnadiene- ( 1,4) -dione- (3.20)

10 mg

Isotonic with the tear fluid

Solution q.s.p 10 ml

-S

2757

Claims (3)

Patent claims: I. Pregnane derivatives of the formula CH ₂ OR HO = CH ₂ (D in which R is a hydrogen atom or the acyl radical a linear or branched saturated aliphatic carboxylic acid with 2 to 6 carbon atoms, optionally with a free carboxyl group (—COOH) or its salt (—COOA, where A is an alkali metal or ammonium) is substituted, the carboxyl group being from the —CO group of the acyl radical is separated by at least 2 carbon atoms. 2. Process for the preparation of the pregnane derivatives according to spoke 1, characterized in that D-Fraor-II / Moa.n ^ l-tetrahydroxypregnadiene- (i, 4) -dione- (3.20) with acrolein in the presence of an acidic catalyst Reacts with acetal formation and either the 9 - fluoro - 110.21 - dihydroxy - 16u, 17t - (propen- (2) - ylidendioxy) - pregnadiene - (1,4) - dione - (3,20) formed or this Product esterified with the anhydride of an acid of the formula R '- OH, in which R' is the acyl radical of a linear or branched saturated aliphatic carboxylic acid having 2 to 6 carbon atoms, which is optionally substituted by a free carboxyl group (--COOH) which is substituted by the —CO group of the acyl radical is separated by at least 2 carbon atoms and that the product obtained, if R 'contains a free carboxyl group, optionally converted into the corresponding salt with an alkaline agent. 3. Pharmaceutical agents, characterized by a content of pregnane derivatives according to claim 1 as the sole active ingredient. The invention relates to new pregnane derivatives of the formula CH ₂ OR HO CH - CH = CH ₂ (1) in which R is a hydrogen atom or the aryl radical of a saturated linear or branched aliphatic Carboxylic acid with 2 to 6 carbon atoms, optionally with a free carboxyl group (—COOH) or its salt (—COOA, where A is a Alkali metal or ammonium) is substituted, the carboxyl group from the —CO group of the acyl radical is separated by at least 2 carbon atoms. As is known, the acyl radical is the monovalent radical created by the removal of the hydroxyl group from the carboxyl group of the corresponding carboxylic acid. The invention also relates to the process for the preparation of the pregnane derivatives of the formula (1), which is characterized in that 9-Fiuor- l \ (i, \ 6n, 17,21 - tetrahydroxypregnadiene - (1,4) - dione- (3.20) is reacted with acrolein in the presence of an acidic catalyst to form acetal and that either the 9-fluoro-11 / 2,21-dihydroxy-16 (i, 17 - (propen - (2) - ylidendioxy) - pregnadiene - (1,4) -dione- (3,20) isolated or esterified with the anhydride of an acid of the formula R'-OH, with d <: r R 'the acyl radical of a saturated linear or branched aliphatic carboxylic acid with 2 to 6 Is carbon atoms, which is optionally substituted by a free carboxyl group (—COOH), the latter is separated from the —CO group of the acyl radical by at least 2 carbon atoms and that the product obtained if the radical R 'contains a free carboxyl group, optionally converted into the corresponding salt with an alkaline agent. Finally, the invention relates to the use of the new pregnane derivatives of the formula (1) for drugs, especially for anti-inflammatory effective drugs, as well as pharmaceuticals containing the new pregnane derivatives as active ingredients Compositions. When carrying out the process for the preparation of the derivatives of the formula (1), preference is given to worked as follows: