Patent GB-947952-A (GB)
Title: Hypotensive compositions comprising ª -alkyl phenylalanine derivatives and aldosterone antagonists
IPC: C07J21/00
Filed: 1961-12-22
Abstract: Halospiroxenone derivatives (having aldosterone antagonist activity) of the general formula: <FORM:0947952/C2/1> in which each of Z1 and Z11 is a hydrogen atom or a methyl radical, Z is an alkyl radical, X0 is a hydrogen or halogen atom, Y is a hydrogen atom or a hydroxyl or keto group and X1 is a halogen atom may be prepared by the following reaction sequences.  (I) 20-spirox-4-ene-3, 21-dione is reacted with butanone dioxolane in the presence of p-toluenesulphonic acid monohydrate to give 3-ethylene-dioxy-20-spirox-5-ene-21-one which is reacted with dimethyl oxalate to give 3-ethylenedioxy-22-(methoxalyl)-20-spirox-5-ene-21-one. This compound, when treated with perchloryl fluoride in the presence of sodium ethoxide gives 3-ethylene-dioxy-22-fluoro-20-spirox-5-ene-21-one which, on treatment with p-toluensulphonic acid in acetone, gives 22-fluoro-20-spirox-4-ene-3, 21-dione. Treatment of this compound with chloranil in tert.-butanol gives 22-fluoro-20-spirox-4, 6-diene-3, 21-dione which is reacted with thioacetic acid to give 7a -acetylthio-22-fluoro-20-spirox-4-one-3, 21-dione having the formula: <FORM:0947952/C2/2> (II) 22-fluoro-20-spirox-4-ene-3, 21-dione is treated with sodium methylate and diethyl oxalate, the product is treated with methyl iodide in the presence of anhydrous potassium carbonate and the ethyl acetate extract of the reaction product is treated with sodium methoxide in absolute alcohol to give 2a -methyl-22-fluoro-20-spirox-4-ene-3, 21-dione which, on oxidation with SeO2 yields 2-methyl-22-fluoro-20-spirox-1, 4-diene-3, 21-dione which may be used in place of the previously mentioned 22-fluoro-20-spirox-4-ene-3, 21-dione to give the corresponding 7-acetylthio-D  6-compound.  The corresponding 11-keto- and 11-hydroxy-9a -fluorocompounds may be prepared in the same way starting from a 20-spirox-4, 9(11)-diene-3, 21-dione and introducing the 22-halogen in the above manner followed by treatment with N-bromo-succinimide and perchloric acid to give the 9a -bromo-11-hydroxy compounds, reaction with potassium acetate to give 9, 11-epoxy compounds and reaction of these compounds with HF to give 9a -fluoro-11-hydroxy compounds which may be oxidised in known manner to the 11-ketocompounds. These, when thus prepared may be treated as above to introduce the 7-acetylthio substituent. The corresponding 7a -alkanylthio-20-spirox-4-ene-3-ones having the general formula <FORM:0947952/C2/3> in which Z1 is a hydrogen atom or a methyl radical, Z is an alkyl radical, X0 is a hydrogen or halogen atom and Y is a hydrogen atom or a hydroxyl or keto group and the same pharmacological activity may be prepared by the following reaction sequence:  20-Spirox-4-ene-3, 21-dione is reacted with butanone dioxolane and p-toluenesulphonic acid monohydrate to give 3-ethylenedioxy-20-spirox-5-ene-21-one which, on treatment with LiAlH4, yields 3-ethylenedioxy-17a -(31-hydroxypropyl) -5-androstene-17b -ol which is treated with p-toluenesulphonyl chloride chloride in pyridine to give 3-ethylenedioxy-20-spirox-5-ene which, when treated with p-toluenesulphonic acid monohydrate, gives 20-spirox-4-ene-3-one. The 7-acetylthio substituent may be introduced into this compound by the procedures described above and the other structural characteristics may be introduced as previously described or by standard reactions. The 19-normethyl compounds corresponding to the above-mentioned aldesterone antagonists may be prepared by the following reaction sequence. 3-methoxy-17a -(31-hydroxypropyl)-1, 3, 5 (10)-estatriene-17b -ol is treated with p-toluenesulphonyl chloride to yield 3-methoxy-19-nor-20-spirox-1, 3, 5 (10)-triene which is reacted with lithium in anyhures ammonia/tetrahydrofuran at -80 DEG C. to give 3-methoxy-19-nor-20-spirox-2, 5 (10)-diene which is reacted with oxalic acid in ethanol to give 19-nor-20-spirox-5 (10)-ene-3-one which is reacted with sodium methylate in methanol to yield 19-nor-20-spirox-4-ene-3-one into which the 7-acetylthio substituent may be introduced by the previously indicated procedures. Spiroenone enol ethers which are also aldosterone antagonists may be prepared by treating the above 19-nor-20-spirox-4-ene-3-one with ethylorthoformate (acid catalyst) to give 3-ethoxy-19-nor-20-spiro -3, 5-diene.  The same procedure using a 7a -lower alkanoylthio-19-nor-20-spirox-4-ene-3-one yields the corresponding 3-ethoxy-7a -lower alkanoylthio-19-nor-20 spirox -3, 5-dienes. Other alkyl orthoformates yield other ethers.ALSO:Pharmaceutical hypotensive preparations comprise about 125 to 2000 parts by weight of the L-form of an a -alkyl phenylalanine compound having the L or DL absolute spacial configuration of the general formula <FORM:0947952/A5-A6/1> in which R1 is a C1-5 alkyl radical, R11 is a hydrogen atom or an alkyl radical, each of R1 and R is a hydrogen atom or a C1-6 alkanoyl radical, X is a hydrogen or halogen atom or an alkyl or trifluoromethyl radical and is in the para position to the amino acid side chain if other than hydrogen and n is 1, 2 or 3 or a salt thereof and 100 to 800 parts by weight of a 20-spiroxane aldosterone antagonist.  Optionally, there may also be present a sulphamoyl-substituted benzothiadiazine - or 3,4 - dihydrobenzothiadiazine - 1,1 - dioxide diuretic.  Specified aldosterone antagonists are those of the following types: (1) 20-spirox-4-ene-3,21-diones of the general formula <FORM:0947952/A5-A6/2> wherein R* is a hydrogen atom or methyl radical, W1 and W11 are each a hydrogen atom or an -S-alkanoyl radical the D 1 and/or D 6 double bonds being present when W11 and/or W1 are hydrogen atoms; (ii) 7a -alkanoyl-thio-16a  (or b ) - methyl - 20 - spirox - 4 - ene (or 1,4- diene)-3,21-diones of the general formul  <FORM:0947952/A5-A6/3> <FORM:0947952/A5-A6/4> <FORM:0947952/A5-A6/5> wherein Y is a hydrogen atom, or a b -hydroxy radical or a keto-oxygen, X0 is a hydrogen or halogen atom, Z is an alkyl radical and the dotted line indicates an optional D 1(2) double bond; 16a (orb )-methyl-19-nor-20-spirox-4-ene-3,21-ones of the general formula <FORM:0947952/A5-A6/6> 21a (or b ) - halo - 7a  - alkanoylthio - 20 - spirox-4-one (or 1,4-diene)-3,21-diones of general formula <FORM:0947952/A5-A6/7> wherein Z is an alkyl radical, each of Z1 and Z11 is a hydrogen atom or a methyl radical, X0 is a hydrogen or halogen atom, X11 is an a - or b -halogen atom, Y is a hydrogen atom, a b -hydroxyl group or a keto oxygen atom and the dotted lines indicate optical D 1(2) and D 6(7) double bonds; 7a  - alkanoylthio - 19 - nor - 20-spirox - 4 - ene - 3 - one compounds of the general formul  <FORM:0947952/A5-A6/8> <FORM:0947952/A5-A6/9> wherein Z is an alkyl radical, R111 is an alkyl, cycloalkyl or aralkyl radical; 20-spirox-4-ene (or 1,4 or 4,6-diene)-3-ones of the general formula <FORM:0947952/A5-A6/100> wherein Z1 is a hydrogen atom or a methyl radical, X0 is a hydrogen or halogen atom, Y is a hydrogen atom, a b -hydroxyl group or a keto oxygen, W1 is a hydrogen atom or an -S-CO-Z group in which Z is an alkyl radical and the dotted lines indicate optional D 1(2) and D 6(7) double bonds the latter being a single bond when W1 is other than a hydrogen atom. The benzothiadiazine diuretic may have the structural formula <FORM:0947952/A5-A6/111> wherein R is a hydrogen or halogen atom or a trifluoromethyl radical, a C1-5 alkyl or alkoxy radical or a nitro or amino radical; R1 is a hydrogen atom or a C1-5 alkyl radical; R2 is a hydrogen atom, an alkyl radical, a phenyl, a trihalomethyl-substituted phenyl or a halophenyl radical, or a benzyl, a trihalomethyl-substituted benzyl or a halobenzyl radical; R3 is a hydrogen atom or a C1-5 alkyl radical and either unsubstituted or halogen-substituted or trichloromethyl-substituted, or R2 and R3 are alkyl groups joined together to form with the carbon atom to which they are attached a cycloaliphatic ring; each of R4 and R5 is a hydrogen atom or a C1-5 alkyl radical and optionally halogen-substituted, trihalomethyl-substituted or hydroxy-substituted.  Other compounds of this type which may be used are those of the general formul  <FORM:0947952/A5-A6/122> <FORM:0947952/A5-A6/133> wherein R is a hydrogen or halogen atom or a trifluoromethyl radical, or a C1-5 alkyl or C1-5 alkoxy radical or a nitro or amino radical; R1 is a hydrogen atom or a C1-5 alkyl radical; and R2 is a hydrogen atom or a C1-5 alkyl, phenyl, benzyl or styryl radical.  The compositions may be in forms suitable for oral administration, e.g. tablets and capsules and for injection. Specifications 826,921, 928,923 and 936,074 are referred to.