Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Patent
1990-01-22
1991-08-06
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
568322, 568319, 568337, A61K 3112
Patent
active
050378546
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a substituted phenone and to methods for the preparation thereof. More specifically, the invention relates to substituted phenones of which the substituents are selected from hydroxyl and methoxy groups and halogen atoms.
The present invention is concerned with a group of compounds which is related to a naturally occurring class of substances of hitherto unknown composition and structure. This is a group of biologically active substances which participates in the differentiation of cells, the degree of biological activity varying with the various substituent groups and isomers of the substituted phenone. The existence of one or more "differentiation inducing factors" (DIF) has been reported in the literature but the the composition and structure is unknown. Reference is made to the following which describe the discovery, isolation, purification and the biological role of DIF: possible morphogen controlling differentiation in Dictyostelium"; Jermyn, "Purification of stalk-cell-inducing morphogens from Dictyostelium discoideum"; R. Kay, "Cell differentiation without morphogenesis in Dictyostelium discoideum"; and, Brookman and R. R. Kay, "Dictyostelium mutants lacking DIF, a putative morphogen".
The composition and structure of DIF has now been identified, by the inventors, as lying within the group of compounds which is the subject of the present invention.
According to the present invention there is provided a compound of the general formula I; ##STR1## in which R.sub.1 is a straight or branched chain alkyl or alkenyl group having from 3 to 8 carbon atoms;
The group R.sub.1 has from 3 to 8 carbon atoms, examples of such being methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, n-pentyl, isopentyl, hexyl, heptyl, octyl and octenyl.
Preferably, the group R.sub.2 is a methoxy group, and either or both of R.sub.3 and R.sub.4 are halogen, most preferably chlorine, atoms.
The present invention also provides the compounds 2,6-dihydroxy-3,5-dichloro-4-methoxy valerophenone; 2,6-dihydroxy-3,5-dichloro-4-methoxy butyrophenone; and 2,6-dihydroxy-3-chloro-4-methoxy valerophenone. [The IUPAC nomenclature for these compounds is 1-[3,5-di-chloro-2,6-dihydroxy-4-methoxy)phenyl]-hexan-1-one; 1-[(3,5-dichloro-2,6-dihydroxy-4-methoxy)phenyl]-pentan-1-one; and, 1-[(3-chloro-2,6-dihydroxy-4-methoxy)phenyl]-hexan-1-one, respectively.]
The present invention also provides a first method of preparing the above-defined compound of general formula I, comprising reacting together a compound of general formula II, ##STR2## in which R.sub.2 is as defined above with an alkanoyl chloride of formula R.sub.1.CO. Cl wherein R.sub.1 is as defined above, to give a product having the general formula III; ##STR3## in which R.sub.1 and R.sub.2 are as defined above, and subjecting the compound of formula III to a Fries Rearrangement reaction in the presence of aluminium trichloride thereby to form a compound having the general formula IV; ##STR4## in which R.sub.1 and R.sub.2 are as defined above, followed by halogenation to give a compound having the general formula I defined above.
The reaction between the compound of formula II and the alkanoyl chloride is preferably carried out in pyridine solvent. The Fries Rearrangement may be effected at lower temperature (20.degree.-30.degree. C.) to favour formation of one isomer or at higher temperature (90.degree.-100.degree. C.) to favour formation of another isomer. For example, the reaction of 3,5-dihydroxy anisole with an alkanoyl chloride produces the compound defined by formula III above in which R.sub.2 is methoxy and R.sub.1 is an alkanoyl group. This may then be subjected to Fries Rearrangement at 25.degree. C. to give the para-methoxy isomer or at 100.degree. C. to favour the ortho-methoxy isomer (not included in this invention). The desired isomer can then be subjected to halogenation.
This reaction scheme is shown in FIG. 2 herewith, using 3,5-dihydroxyanisole and pentanoyl chloride for illustration. The halogenation step is exemplified in Example 2 below.
The
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Kay Robert R.
Masento Mark S.
Morris Howard R.
Taylor Graham W.
3i Research Exploitation Limited
Reamer James H.
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