Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1990-01-16
1992-07-21
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514179, 552519, 552623, 552646, C07J 100, C07J 4100, A61K 31565
Patent
active
051322994
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the subject matter characterized in the Patent Claims, i.e. new 11.beta.-phenyl-4,9,15-estratrienes, methods for their production and pharmaceutical preparations containing these compounds.
The compounds in accordance with the invention are characterized by the general formula I ##STR3## where
X implies an oxygen atom or a hydroxyimino grouping N.about.OH,
R.sup.1 stands for a hydrogen atom or a methyl group,
R.sup.2 implies a hydrogen atom, an alkyl radical or an acyl radical with in each case 1 to 10 carbon atoms,
R.sup.3 stands for a hydrogen atom, a cyanomethyl group, --(CH.sub.2).sub.n CH.sub.2 Z where n implies the numbers 0, 1, 2, 3, 4 or 5, Z=--H or --OR.sup.5 with R.sup.5 having the significance of a hydrogen atom or an alkyl or acyl group with in each case 1 to 10 carbon atoms, or for --(CH.sub.2).sub.m --C.tbd.C--Y where m=0-2 and Y implies a hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group with in each case 1 to 10 carbon atoms,
R.sup.4 represents a straight-chain, saturated aliphatic (C.sub.1 -C.sub.4)-acyl residue.
The alkyl and acyl contained in R.sup.2, or the alkyl, acyl or alkoxy groups contained in R.sup.5 and Y should in each case have 1- carbon atoms, preference being given to the methyl, ethyl, propyl, formyl, acetyl, propionyl, butyryl, benzoyl, methoxy and ethoxy groups.
The acyl residue R.sup.4 can exhibit up to 4 carbon atoms. Examples that can be cited are the formyl, acetyl, propionyl or butyryl residue. R.sup.4 is preferably located in the 3- or 4-position of the phenyl ring.
Preferred compounds of the general formula I are: ne en-3-one en-3-one atrien-3-one 5-estratrien-3-one 5-estratrien-3-one e atrien-3-one trien-3-one trien-3-one -3-one
The new 11.beta.-phenyl-4,9,15-estratrienes of general formula I are produced in accordance with the invention by the method described in claim 3.
Production of the educts of general formula II starts from 17-keto steroids of general formula III ##STR4## (European Patent Application 86101548.5, Publication-No. 190759) where K implies an acidic hydrolysable keto protection group and R.sup.4' has the same significance as R.sup.4 but contains a ##STR5## grouping instead of ##STR6## where K.sup.1 stands for K or for a hydrogen atom and a protected hydroxyl group jointly. In particular K represents a keto group blocked in the form of the ketal, thioketal, oxime or methyl oxime.
By e.g. modified Saegusa oxidation [Tetrahedron 42 (1986) 2971] of the corresponding enol compounds of the 17-ketone, the C-15 double bond is introduced into the D-ring. The trimethylsilyl enol ether required for example can be produced by converting the 17-ketone with lithium diisopropylamide in tetrahydrofurane into the corresponding enolate and blocking by trimethylchlorosilane. (Synthesis 1983, 1).
Compounds of general formula II, obtained after conversion of the C-17 keto group into the C-17 substitution pattern, in the significance of R.sup.2 and R.sup.3 ultimately desired in the final product of general formula I ##STR7## where R.sup.1, R.sup.4' and K have the above-described meaning, R.sup.2' and R.sup.3' have the same meaning as R.sup.2 and R.sup.3 and any existing hydroxyl and/or acyl and/or alkyne groups being if necessary protected, are subsequently treated with acid or an acidic ion exchanger to selectively split off water with subsequent production of the 4(5) double bond and at the same time to remove any existing protective groups. This acidic treatment takes place in a manner which is in fact conventional by dissolving the compound of formula II in a solvent miscible with water such as aqueous methanol, ethanol or acetone and allowing catalytic quantities of mineral or sulphonic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, perchloric acid or p-toluene sulphonic acid or an organic acid such as acetic acid to act on the solution long enough for the water to be split off and the protective groups to be removed. The reaction which takes place at tempera
REFERENCES:
patent: 2530817 (1950-11-01), Ehrensten
patent: 2940968 (1960-06-01), Sletzinger et al.
patent: 4536401 (1985-08-01), Neef et al.
patent: 4609651 (1986-09-01), Rohde et al.
Grant and Hackh's Chemical Dictionary (1987, New York, McGraw-Hill Book) p. 14.
Beier Sybille
Chwalisz Krzysztof
Elger Walter
Hofmeister Helmut
Neef Guenter
Bond Robert T.
Schering Aktiengesellschaft
Ward E. C.
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