DE2130281A1 - D-homoimide derivatives with a sterane structure and process for the preparation thereof - Google Patents

Description

DH. STEPHAN G. BESZEDES PATENT ADVOCATE

DACHAU at MÖNCHEN

BOX 1168

AM HEIDFWEG 2

TELEPHONE: DACHAU 43 Postal checking account Munich 1368 Bank account no. 90 637 at Kreis- und St «« · Sparkasse Dachau-Indersdorf

P 559

description

for patent application

JUDGE GEDEON VEGYESZETI GYAR R.T,

Budapest, Hungary

concerning

D-homoimide derivatives with a star skeleton and process for the preparation thereof

The invention relates to D-homoimide derivatives with a sterane structure of the general formulas

2 -

109885/1839

fc e s i e hun g s w is e

E stands for a xr-eie or, in particular in the form of ketal derivatives, masked oxy group or hydrogen and a free or, in particular in WoTEi of ester or ether derivatives, masked hydroxy group and

Ep denotes a, preferably lower, alkoxy radical.

1Ö9885 / 1839

ORIGINAL INSPECTED

The new compounds according to the invention of the general Formulas I and Ia are used as starting substances for production of therapeutically valuable bactericidal and bacteriostatic compounds, for example 3ß-hydroxy -17-aza-20-oxo-21-chloro-5c (-pregnane or 3> 21-Di-

usable.

There are only a few such connections from the literature with a sterane structure, which have a homoimide structure in the D-ring, are known. For example, by Regan and co-workers 3 ^ ~ Acetoxy-16,17-secoandrost-5-en-16,17-dicaΓboximide by reacting 16,17-dioxo-3ß-acetoxyandrost-5-en-16- -oxime produced with thionyl chloride (J. Am. Chem. Soc. 78 » 639 £ 19563) · The manufacture of the 3-hydroxy derivative of this Compound was described by Hassner and Pomeranz, according to which 3ß-acetoxy-15 »17-seco-D-norandrost-5-en-15-carbamoyl- -17-carboxylic acid methyl ester and this compound in a solvent at 130 to 150 ° C with potassium bisulfate or sodium borohydride was reacted (J. Org. Chem. 27, 1 {/ 1962J). The derivative of this compound with a saturated B-ring, namely 3ß-Hydroxy-16,17-seco ~ 5f <-androstane ~ 16,17-dicarboximide, was made by R.D. H. Heard and co-workers from 16,17-dioxo-3ß-hydroxy-5o (-androstane-16-oxime by heating prepared to boiling in the presence of a solvent mixture consisting of acetic anhydride and pyridine (J. Org. Chen. 24, 172 [1959J). The synthesis of 16,17-seco- -5o (-androstane-16,17-dicarboximide was developed by Jones et al reported in a publication (J. Chen. Soc. 1 957 [1969J).

The invention also relates to the production of the components according to the invention D-Horaoii ^ idderivate or differently expressed 16,17-Seco-16,17-dicarbcnsäureiraide of the general formulas I and Ia.

109885/1839

BATH ORIGINAL

Thus, according to an advantageous embodiment of the invention, there is a method for producing the invention Compounds, which is characterized in that a compound of the general formulas

N-OH

respectively

■ N - OH

109885/1839

wherein R and Rp are as defined above, is subjected to rearrangement associated with ring expansion in an acidic medium. The following procedure can be used: a 16-oxime derivative of the general formulas II or Ha (US Pat. No. 5,135,772; German Pat. No. 875,650) is dissolved in glacial acetic acid at temperatures below the boiling point of this solvent and becomes a homogeneous solution a mineral acid, expediently sulfuric acid, is added. The reaction mixture is kept for several hours depending on the temperature sensitivity of the corresponding oxime derivative to temperatures of 20 to 100 ⁰ C and then the solution of the resulting D-Homoimides is cooled to room temperature in glacial acetic acid and this water is added dropwise. The deposited product is filtered off, washed, dried and, if necessary, recrystallized. In this reaction, oxo groups masked in the form of ketal derivatives and hydroxyl groups masked in the form of ester or ether derivatives can be completely or partially converted into the free oxo or hydroxyl groups.

According to a further advantageous embodiment of the invention is a method for producing the invention Compounds, which is characterized in that a compound of the general formulas

109885/1839

ORIGINAL INSPECTED

III

relational white

IHa,

wherein R and Ep are as defined above and X and Y are carbamoyl and carbalkoxy groups, but with the further proviso that in one and the same compound the substituents X and Y are different and preferably one of the two is a carbamoyl group, is subjected to an addition reaction , intended. As Garbalkoxygruppeη are lower carbalkoxy _ä particular carbomethoxy and Carbäthoxygruppen preferred. The following procedure can be used: One of the D-Seco-5 «i-androstan-

109885/1839

ORIGINAL INSPECTED

or D-Seco ^ oc-östra-i, 3 »5 (1O) -triene derivatives of all common formulas III or purple, which can be prepared by known processes (J. Chem. Soc. 1,957 [19693; J. Eed. Chem. 12, 192 [1969]; US patent 3,317,557) »in a polar, expediently alcohol associated, solvent and then dissolved in an alkaline medium in the presence of alkali or alkaline earth metal alcoholates or alkali or alkaline earth metal hydroxides made a ring closure. After evaporation of the solvent, the residue is triturated with Y / ater and the pH of the suspension is adjusted with vigorous stirring and cooling set to 7. The product obtained in this way is filtered off, dried and, if necessary, recrystallized.

Through the above 2 embodiments of the invention, the new 16 * 17-Seco-16, ^ - dicarboximide with a sterane structure of the general formulas I and Ia can be prepared in good yield and in a simple manner.

The process according to the invention is explained in more detail with reference to the following examples, which are not to be interpreted as limiting.

109885/1839

example 1

16,17-Secoöstra-i, 3,5CiO) -triene-16,17-dicarboximide-3-methyl ether

There were 51 g of 16,17-Dioxoöstra-1,3,5 (10) -triene-16-oxime-

-3-methyl ether dissolved in 1,460 cnr glacial acetic acid. After that the-

o 3

this solution at 60 C continuously a mixture of 97 cnr

concentrated sulfuric acid and 245 cnr water were added and the reaction mixture was kept for 1 hour in a stream of nitrogen at temperatures of 85 "to 95 ° C. and then cooled to room temperature and with vigorous stirring it was added dropwise 15 l of ice water. The suspension was stirred for 30 minutes filtered and the precipitate was washed free of acid with ψ water and dried under vacuum at temperatures of at most 60 ⁰ g. Thus 45 g (88% of theory) of 16,17-Secoöstra-i, 3.5 (io) ~ trien-16 , -methyläther obtained 17-dicarboximide-3; melting point: 218 to 221 ⁰ C (recrystallized from methanol).

Elemental analysis:

calculated: C = 72 , 82%, H. = 7 , 40%, N = 4 Λ7% \ found: G = 72 , 70%, H. = 7 , 35%, N = 4 , 60%. example 2

3ß-acetoxy-16,17-seco-5T (-androstane-16,17- <3-carboxylic acid imide and 3ß-hydroxy-16,17-seco-5o (-androstan- -16,17-dicarboximide

200 g of 3.beta.-hydroxy-16,17-dioxo-5oi-androstan-16- oxime of glacial acetic acid at 80 ⁰ C in a nitrogen atmosphere at 5 ^J 800 cm. Thereafter, the homogeneous solution was continuously a mixture of sulfuric acid and 384 cnr 960 cnr ⁵ Water

_ 9 _ 109885/1839

added and the reaction mixture was kept at temperatures of 80 to 90 ° C. for 1 hour and, after cooling to room temperature, 40 l of ice water were added dropwise. The suspension was filtered after stirring for 30 minutes, and the precipitate was washed with water until acid free and dried under vacuum at temperatures of at most 60 ⁰ C. The product obtained (177 g) was a mixture of 3ß-acetoxy-16,17-seco-5a'-androstane-16,17-dicarboximide and 3ß-

Melting point: 180 to 190 ° C (with decomposition). This mixture could be acetylated or hydrolyzed in a known manner

a) 3β-Acetoxy-16,17-seco-5i < ^r -androstane-16,17- -dicarboximide

177 g of the mixture of 3β-acetoxy-16,17-seco- -5 <j <-androstane-16,17-dicarboximide and 3β-hydroxy-16,17- -seco-5i {-androstane-16,17 -dicarboximide dissolved in 1770 cnr pyridine and then 708 cnr acetic anhydride were added. The reaction mixture was left to stand for 16 hours at room temperature in a nitrogen atmosphere, after which about 30 liters of ice water was added dropwise with vigorous stirring. The deposited 3.beta.-acetoxy-seco-5o -16.17 (androstane-16,17 - '<iicarbonsäureimid was filtered, washed until reaching neutral reaction and dried under vacuum at 50 ⁰ G dried to give 290 g (84th % of theory); the compound recrystallized from methanol, which crystallized with 1 mol of methanol, melted at 213 to

Elemental analysis:

calculated: C. = 67.14%, H - 8th , 97%, N = 3 , 56%; found: G «67.17%, H " 8th , 96%, N « 3 , 72%.

- 10 -

109885/1839

b) 3ß-hydroxy-16,17-seco-5K-androstane-16,17- -dicarboximide

There were 150 g of the mixture of 3.beta.-acetoxy-16 _r 17-seco-5 {-? -Androstane-16,17-dicarboxylic acid imide and 3.beta.-hydroxy-16,17 - seco-androstane-16,17 -5E { -dicarboximide dissolved in a mixture of 3 180 cnr methanol and 360 cn ^ 15% sodium methylate solution. The reaction mixture was allowed to stand for 4 hours at room temperature, after which the pH of the solution was adjusted to 7 with hydrochloric alcohol. The solvent was evaporated in vacuo and the residue was triturated with water, filtered off and washed with water. The product was dried at temperatures not exceeding 60 ° C. 130 g (90% of theory) of 3β-hydroxy-16 _t 17-seco-5 "'- -androstan-iös ^ -dicarboxylic acid imide were obtained; Melting point: 226 to 227 ° G «

Elemental analysis:

calculated: G = $ 71.4-8, H = 9.08%, II = 4.38%; found: G = 71.28%, H = 9.18%, H = 4.50%.

Example 3

3-Ozo-16,17-seco-5oi-androstane-16 _s 17-dicarboxylic acid e is id

22.6 g of 3-ethylenedioxy-16 _s 17-lioxo-5c <-androstan- -16-oxime were dissolved in 580 cm of glacial acetic acid at 80 ° C. Thereafter, this solution was continuously added in a nitrogen atmosphere

3 ⁵ p

a mixture of 38.4 cur sulfuric acid and 100 enr water added and the reaction mixture was left on for 1 hour Maintained temperatures of 80 Ms 90 ° C and after cooling to room temperature it was added dropwise 4 l of ice water. Of the deposited precipitate became after about 50 minutes

- 11 -

09885/1839

Stir, filtered off, washed with water and dried under vacuum. In this way 17 g (86% of theory) 3-0xo-16,17-seco-5i / -androstane-16,17-dicarboximide were obtained; Melting point: 240 to 242 ^° C

Elemental analysis:

calculated: G = 71.89%, H = 8.57%, N = 4.41%; found: C = 71.81%, H = 8.62%, N = 4.61%.

Example 4

3-ethylenedioxy-16,17-seco-5 ^ -androstane-16,17- -dicarboximide

8.9 S 3 ~ £ 'fchylenedioxy-15,17-seco-5Y-D-norandrostan- -i ^ -carbamoyl - ^ - carboxylic acid methyl ester dissolved in 100 cmr of methanol and then 10 cnr of a 16% sodium methylate solution were added. After a few minutes the The pH of the reaction mixture was adjusted to 7 with acetic acid. The solvent was then evaporated, the residue was triturated with water and the precipitated 3-Xthylenedioxy-16,17- -seco-5c \ '- androstane-16,17-dicarboximide filtered off, with Water washed well and dried. Yield: 7.9 g (97% of theory); Melting point: 242 to 244 ° C (recrystallized from methanol) .

Elemental analysis:

Calculated: C = 69.77%, H = 8.6556, N = 3.88%; found: C = 69.7%, H = 8.75%, H = 3.98%.

- 12 -

109885/1839

Example 5

3ß-tetrahydropyranyloxy- * 16.17 ~ seco-5 * <- androstan- -16,17-dicarboximide

12.4 g of 3β-tetrahydropyranyloxy-15,17-seco-5oi-D- -norandrostane-15-carbamoyl-17-carboxylic acid methyl ester were dissolved in 250 ml of methanol and then 10 cm ^ of a 16% strength sodium methylate solution were added. After about 3 minutes, the pH of the reaction mixture was adjusted to 7 with acetic acid. After the solvent had evaporated, the residue was triturated with water, filtered off, washed and dried to constant weight under vacuum at temperatures of at most 60 ° C. 10.5 g (95% of theory) of 3β-tetrahydro- f pyranyloxy-16,17-seco-5c-androstane-16,17-dicarlon acid imide were obtained; Melting point: 225 "to 226 ⁰ C (recrystallized from Ithylacetat).

Elemental analysis:

calculated: C = 71.4-3%, H = 9.24%, N = 3.47% j found: C = 71.23%, H = 9.30%, IT = 3.67%.

Claims 109885/1839

Claims (1)

Claims D-homoimide derivatives with a sterane structure of the general Formulas N-H ■ respectively N-H 109885/1839 wherein R stands for a free or, in particular in the form of ketal derivatives, masked oxo group or hydrogen and a free or, especially in the form of ester or Ether derivatives, masked hydroxyl group and R ~ denotes a, preferably lower, alkoxy radical. 2.) D-Homo imide derivatives radiAif ^ Ruh 1, characterized in that the masked oxo group, for which R can stand through Alkoxy radicals with 1 to 4, preferential prices 1 or 2, carbon atoms is masked. 3.) D-homoimide derivatives according to claim 1, characterized in that the masked hydroxyl group, which R may have, is masked by aliphatic ester or ether radicals with 1 to 4 _r, preferably 1 or 2 carbon atoms. 4.) D-homoimide derivatives according to claim 1, characterized in that that the masked hydroxyl group which R may have, by heterocyclic ether radicals, preferably those with 4 or 5 carbon atoms, is masked. 5) D-homoimide derivatives according to claim 1 or 4, characterized in that that the masked hydroxyl group that R may have, by heterocyclic ether radicals, the Oxygen as a heteroatom on iron, is masked. 6.) D-homoimide derivatives according to claim 1, characterized in that the alkoxy radical, for which R _{2 can} stand, has 1 to 4, preferably 1 or 2, carbon atoms. - 15 109885/1839 7 ·) Process for the preparation of the compounds according to claim to 6, characterized in that one a) a combination of the general formulas N-OH respectively N-OH 109885/1839 wherein R and R ~ are as defined in claims 1 to 6, in an acidic medium one subject to rearrangement associated with ring expansion or b) a combination of the general formulas III respectively HIa, -M- 109885/18 39 where R and Rp as in claims 1 to are set and X and Y Qarbamoyl- and Carbalkoxy groups mean, but with the further proviso that the substituents X and Y are different in one and the same compound are and preferably one of the two is a carbamoyl group, a ring closure reaction subject. 8.) The method according to claim 7a »characterized in that that the ring-widening reaction in glacial acetic acid at the boiling point of this solvent or at lower Temperatures. 9.) Method according to claim 7a or 8, characterized in that that the ring-widening reaction in the presence of a mineral acid, advantageously sulfuric acid , performs. 10.) Method according to claim 7b> characterized in that the ring closure reaction is carried out in an alkaline medium performs. 11.) Method according to claim 7 *> or 10, characterized in that the ring closure reaction is carried out in a polar Solvent, advantageously in an alcohol, performed. 12.) The method according to claim 7b »10 or 11, characterized in that that the ring closure reaction in the presence of alkali or alkaline earth metal hydroxides, respectively Performs alkali or alkaline earth metal alcoholates. 15 ·) Method according to claim 7a, 8 or 9 »characterized in that that 16,17-Dioxoöatra- -1,3,5 ("10) -triene-16-oxime-5-methyl ether, 3ß-hydroxy- - 18 109885/1839 -16j 17-dioxo-5 <\ - androstane-16-oxime respectively 3-Ethylenedioxy-16,17-dioxo-5 ^ -androstane-16-oxime used. 14.) Method according to claim 7b, 10, 11 or 12, characterized in that that 3-ethylenedioxy-15,17-seco-5o (-D-norandrostan-15-carbanioyl-17- methyl carboxylate (3-ethylenedioxy-16,17-seco-5 »{- -androstan-16-airiid-17-carbonsäureme thy! ester) or Jß-tetrahydropyranyloxy-15,17-seco-5 ^ -D- -norandrostane-15-carbamoyl-17-carboxylic acid methyl ester (3ß-Tetrahydropyranyloxy-16,17-seco-5ci-androstane-16- -amid-17-carboxylic acid ethyl ester) is used. 109885/1839