Patent GB-1432135-A (GB)
Title: 21-substituted pregnanes
IPC: C07J41/00
Filed: 1972-05-05
Abstract: 1432135 21-Substituted-pregnanes GLAXO LABORATORIES Ltd 4 May 1973 [5 May 1972] 21145/72 Headings C2U and C2C [Also in Division A5] Novel steroids are pregnanes or 19-norpregnanes possessing essentially a 3α-OH group, a 17α-H atom, a 20-oxo group and, at the 21- position, a group of the formula wherein X and Y are independently each O or S; m and p are each independently zero or 1; and R is an aliphatic, cycloaliphatic, araliphatic, aryl or carbon-attached heterocyclic group, or, when m is 1 and p is zero, an optionally substituted amino group, or, when m is zero, a cyano group or H; or are sulphinyl or sulphonyl derivatives of these compounds in which m is zero; and, when the steroids are basic, acid-addition salts thereof. Excluded is the known 21-acetylthio-3α-hydroxy-5#-pregnane-11,20-dione. The novel steroids may possess substituents at other positions of the steroid nucleus, e.g. the 2-, 3#-, 11- and 16- positions, and may be unsaturated, e.g. #<SP>8(9)</SP>, #<SP>1</SP>, #<SP>4</SP>. A hydrogen atom in the 5-position may have α or # configuration. The compounds, other than the sulphinyl and sulphonyl derivatives, are prepared by reacting corresponding steroids containing a readily eliminatable substituent at the 21-position with a sulphur nucleophile. Preferably a 21-halo steroid is reacted with a source of an ionic form of the 21- thio substituent. 21-Substituents in the products may be interconverted, e.g. 21-acylthio hydrolysed to 21-SH, which may be re-acylated; and 21-haloacylthio reacted with an amine to give 21-aminoacylthio. The 21-sulphinyl and 2- sulphonyl compounds are prepared from the 21-thioethers by stepwise oxidation. Other groups and double bonds may subsequently be introduced into the steroid molecule by standard procedures, e.g. as described in Specifications 1,371,175; 1,376,892; and 1,380,248. The novel 3α-ols may also be prepared by stereospecific reduction of the corresponding 3-ones. In any of these processes it may be necessary to protect a 3α-hydroxy or a 20-oxo group, the former for example as a nitrate ester or tetrahydropyranyl ether and the latter as a ketal. 21 - (3 - Chloro - n - propionylthio) - 5α - pregnane-3,11,20-trione is prepared from the corresponding 21-morpholino acetylthio compound by hydrolysis to 21 - mercapto - 5α - pregnane- 3,11,20-trione and acylation of this. 21-Bromo- 3α - hydroxy - 5α - pregn - 1 - ene - 11,20 - dione is prepared from 2# - bromo - 3α - hydroxy- 5α - pregnane - 11,20 - dione via 2#,21 - dibromo - 3α - hydroxy - 5α - pregnane - 11,20- dione and the corresponding 3-tetrahydropyranyl ether. 21 - Bromo - 3α - hydroxy - 19 - nor - 5α - pregnane - 11,20 - dione is prepared by 21- bromination of the corresponding 21-unsubstituted steroid, as are 21-bromo-3α-hydroxy- 3# - methyl - 5α - pregnane - 11,20 - dione; 21- bromo - 3α - hydroxy - 2# - methoxy - 5α - pregnane- 11,20 - dione; 21# - bromo - 2# - ethoxy - 3α- hydroxy - 5α - pregnane - 11,20 - dione; 21- bromo - 3α - hydroxy - 2# - methoxy - 5α - pregnan- 20 - one; and 21 - bromo - 3α - hydroxy - 2#- methyl 5α - pregnane - 11,20 - dione. 11α- Hydroxy - 19 - norpregna - 4,16 - diene - 3,20- dione is prepared from 11α,17α - dihydroxy- 19-norpregn-4-ene-3,20-dione via a semicarbazide and is converted to 3α-hydroxy-19-nor-5α- pregnane-11,20-dione via 3#,11α,20#-trihydroxy- 19 - nor - 5α - pregnane and 19 - nor - 5α - pregnane - 3,11,20 - trione. 2# - Ethoxy - 3α - hydroxy- 5α-pregnane-11,20-dione is prepared from 2α,3α- epoxy - 5α - pregnane - 11,20 - dione and ethanol. 21 - Bromo - 5α - pregnane - 3,11,20 - trione is prepared by oxidation of the 3α-ol. 21-Morpholinoacetylthio - 5α - pregnane - 3,11,20 - trione is prepared from the 21-bromo compound and morpholinothioacetic acid. 4-Morpholinothioacetic acid is prepared from morpholinoacetic acid (isolated via its barium salt), in turn prepared from chloroacetic acid and morpholine. Piperidinothioacetic acid is prepared similarly via piperidinoacetic acid, as are 2 - morpholino - n - thiovaleric acid; 4 - thiamorpholinothioacetic acid (via 4-thiamorpholinoacetic acid); and 1,2,5,6-tetrahydropyridinylthioacetic acid (via 1,2,5,6-tetrahydropyridinylacetic acid). Ortho - iodo - thiobenzoic acid is prepared from o-iodo-benzoyl chloride and hydrogen sulphide. The novel steroids possess anaesthetic activity and may be made up into pharmaceutical compositions with suitable carriers. Preferred are aqueous solutions for parenteral administration containing also a surface-active agent.