Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-03-19
1994-08-30
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D22102, C07J 7300
Patent
active
053429486
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the preparation of 17.beta.-substituted-4-aza-5.alpha.-androstan-3-one derivatives.
17.beta.-substituted-4-aza-5.alpha.-androstan-3-one derivatives bearing an acylureidic side chain at the 17.beta. position are described in our copending application PCT/EP 91/00228. In this patent application the derivatives are synthesised by a process which involves introducing the acylureidic chain as the last step.
It has now surprisingly been found that the 17.beta.-acylureidic group has an unexpected stability and a low reactivity. This means that reactions may be performed on the A-ring moiety of a steroid already bearing an acylureidic group without there being any adverse effect on the latter.
According to the present invention, there is provided a process for the preparation of a compound of formula (I) ##STR2## wherein X is oxygen or sulphur;
R.sub.1 is hydrogen or C.sub.1 -C.sub.6 alkyl;
each of R.sub.2 and R.sub.3 is, independently, hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.6 cycloalkyl, C.sub.6 -C.sub.9 cycloalkylalkyl, R.sub.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.6 cycloalkyl, C.sub.6 -C.sub.9 cycloalkylalkyl or aryl; and the symbol represents a single or a double bond, the process comprising:
a) oxidizing a compound of formula (II) ##STR3## wherein X, R.sub.2, R.sub.3 and R.sub.4 are as defined above, to obtain a compound of formula (III) ##STR4## wherein X, R.sub.2, R.sub.3 and R.sub.4 are as defined above;
b) reacting a compound of formula (III), as defined above, with a compound of formula (IV) ##STR5## wherein X, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above;
c) reducing a compound of formula (V), as defined above, to obtain a compound of formula (I) wherein is a single bond, and X, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above;
d) optionally dehydrogenating a compound of formula (I) wherein is a single bond and X, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above to obtain a compound of formula (I) wherein is a double bond and X, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above; and/or, if desired,
e) optionally separating a mixture of isomers into the individual isomers.
An advantage of the process of the invention is that the presence of the acylureidic side chain in the precursors (intermediates) makes these more readily purifiable by crystallization. This enables any trace of unreacted intermediate in the final product to be avoided. Another remarkable advantage is that, by reducing the 5,6-double bond of a compound which already contains the .beta.-acylureidic side chain, in accordance with the process of the invention, no 5.beta.-reduced side-product is obtained.
In the formulae of this specification the dotted line ( ) indicates a substituent in the .alpha. configuration, i.e. below the plane of the ring, and the wedged line ( ) indicates a substituent in the .beta. configuration, i.e. above the plane of the ring.
In this specification the alkyl groups and the aliphatic portions of the arylalkyl and cycloalkylalkyl groups may be straight or branched chain.
R.sub.1 is preferably hydrogen or a methyl or ethyl group.
Each of R.sub.2 and R.sub.3 is preferably hydrogen, methyl, ethyl, isopropyl, tert-butyl, tert-butylmethyl, cyclohexyl or cyclohexylmethyl. R.sub.4 is preferably hydrogen, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, tert-butylmethyl, cyclohexyl, cyclohexylmethyl, phenyl or 2,6-dichlorophenyl; most preferably R.sub.4 represents a hydrogen atom.
Examples of preferred compounds obtained by the process of the invention are:
1) 1-[4-methyl-3-oxo-4-aza-5.alpha.-androstane-17.beta.-carbonyl]1,3-diisopro pylurea;
2) 1-[3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carbonyl]-1,3-diisopropylur ea;
3) 1-[3-oxo-4-aza-5.alpha.-androstane-17.beta.-carbonyl]-1,3-diisopropylurea;
4) 1-[4-methyl-3-oxo-4-aza-5.alpha.-androstane-17.beta.-carbonyl]-1,3-diisopr opylthiourea;
5) 1-[3-oxo-4-aza-5.alpha.-androstane-17.beta.-carbonyl]-1,3-diisopropylthiou rea;
6) 1-[4-methyl-3-oxo-4-aza-5.alpha.-andro
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Steroids, vol. 46, No. 1 July 1985, San Francisco, US, pp. 655-676, G. Rapi, et al, "Reaction of Some Antiinflammatory 17-.beta.(2-aminooxazol-4-yl) Steriods with Hydrogen Peroxide". Synthesis of Steriod-17-spiro-5-oxazolidine-2, 4-dione'.
Ceriani Lucio
Griggi Pierluigi
Nesi Marcella
Panzeri Achille
Daus Donald G.
Farmitalia Carlo Erba S.r.l.
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