SUBSTITUTED PHENONE

Abstract: A compound which has the biological action of inducing cell differentiation has general chemical formula (I), in which R1 is a straight or branched chain or cyclic alkyl or alkenyl group; R2 is an alkoxy or hydroxy group; R3 is a hydrogen or halogen atom; and, R4 is a halogen atom. Preferred values for the groups are R1 = C3 to C8 alkyl; R2 = methoxy; and, either or both of R3 and R4 = chlorine. The compounds: 1) 2,6-dihydroxy-3,5-dichloro-4-methoxy valerophenone; 2) 2,6-dihydroxy-3,5-dichloro-4-methoxy butyrophenone; and, 3) 2,6-dihydroxy-3-chloro-4-methoxy valerophenone are of particular interest.

Description: SUBSTITUTED PHENOHE This invention relates to a substituted phenone a to methods for the preparation thereof. More specifically, the invention relates to substituted pheno of which the substituents are selected from hydrox 1 and methoxy groups and halogen atoms. The present invention is concerned with a group of compounds which is related to a naturally occurring clas 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 th various substituent groups and isomers of the substitute 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: Nature,, vol. 303, No. 5914, pp 242-244 (1983): R.R. Kay & K.A. Jermyn, "A possible morphogen controlli differentiation in Dictyostelium" ; Eur. J. Biochem., 136, pp 51-56 (1983): R.R. Kay, Dhokia & K.A. Jermyn, "Purification of stalk-cell- inducing morphogens from Dictyostelium discoideum"; Nature, vol. 252, No. 5570, pp 717-719 (1976): CD. Town, J.D. Gross & R.R. Kay, "Cell differentiation without morphogenesis in Dictyostelium discoideum"; and, Cell, vol. 33, 397-403 (1983): . Kopachik, A. Oohata, B. Dhokia, J.J. 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; in which R, is a straight or branched chain or cyclic alkyl or alkenyl group; R_ is an alkoxy or hydroxy group; R-. is a hydrogen or halogen atom; and, R. is a halogen atom. The group R. may have from 1 to 10 carbon atoms, examples of such being methyl, ethyl, n-propyl, iso- propyl, n-butyl, isobutyl, n-pentyl, isopentyl, hexyl, heptyl, octyl and octenyl. It is preferred that in the compound of general ffoorrmmuullaa II,, RR,, is an alkyl or alkenyl group of from 3 to 8 carbon atoms Preferably, the group R~ is a methoxy group, and ' either or both of 3 and R. 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 l-[(3,5- di- chloro-2,6-dihydroxy-4-methoxy)phenyl]-hexan-1-one; 1- [(3,5-dichloro-2,6-dihydroxy-4-methoxy) henyl]-butan-1-o and, l-[(3,5-di-chloro-2,6-dihydroxy-4-methoxy) henyl]- hexan-1-one, respectively.] The present invention also provides a first method o preparing the above-defined compound of general formula I, comprising reacting together a compound of general formula II, in which R-. and R. are as defined above with an alkanoyl chloride of formula R..CO. Cl wherein R, is as defined above, to give a product having the general formula III; R 3 in which R, to R. 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 the 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 (20-30°C) to favour formation of one iso er or at higher temperature (90-100 C) to favour formation of another isomer, an example being the reaction of 3,5-dihydroxy anisole with an alkanoyl chloride produces the compound defined by formula III above in which the methoxy group lies in an ortho position and which may be subjected to Fries Rearrangement at 25 C to give the para-isomer or at 100°C to favour the ortho-isomer (not included in this invention) . This reaction scheme is shown in Fig. 1 herewith, using 3,5-dihydroxyanisole and pentanoyl chloride for illustration. The invention also provides a second method of preparing the compound of general formula I defined above, comprising reacting an iminochloride of formula R,.C (=NH) . Cl in which R χ is as defined above,with a phenol having the general formula IV in which R 2 , R, and R. are as defined above, to form a ketimine hydrochloride having the formula V; (V) in which R1, to R4. are as defined above, and hydrolysing the said ketimine to form the compound of general formula I defined above. It is preferable, but not essential, that the reaction between the iminochloride and the phenol be carried out in the presence of anhydrous zinc chloride, ferric chloride or aluminium trichloride as a catalyst. The second method is illustrated by the reaction scheme laid out in Fig. 2. The invention will now be described, by way of illustration, by the following Examples. EXAMPLE 1 One equivalent of 3,5-dihydroxyanisole was reacted with one equivalent of isovaleroyl chloride in pyridine as solvent for a period of one hour by the reaction scheme shown in Fig.l. The solvent pyridine was remov from the reaction mixture to give 3-hydroxy-5-methoxy- phenyl isobutyrate (the monoester) and 5-methoxyphenyl- 1,3-diisobutyrate (the diester) in approximately equal amounts. The isolated monoester intermediate (or in some experiments the crude mixture) was subjected to a Fries Rearrangement reaction in the presence of aluminium trichloride, as shown in Fig.l, in dichlormethane (2 vols) by adding the ester over one hour and reacting at eeiitthheerr 2255 oorr 110000°°CC ffoorr ffoouurr hhoours followed by standing overnight at room temperature. The mixture of ketones was chlorinated as described in Example 2 below (where appropriate) and the product isolated by HPLC using C, „ Microbondapak (Trade Mark) . The column was eluted isocratically in 65% of 5% acetic acid and 35% n-propanol. EXAMPLE 2 Isohexanonitrile was reacted with 3 ,5-dihydroxy- anisole by the reaction scheme shown in Fig. 2 herewith for a period of 72 hours to produce the ketimine chlorid shown. The ketimine chloride was dissolved in 20% (v/v) methanol in water. The products of hydrolysis were (1) an orange coloured oil (containing the ketone) which was retained on filtering and solidified on cooling, (2) a feathery off-white precipitate which developed as the filtrate cooled and (3) a yellow liquor. The ketone, in chloroform, were halogenated (as appropriate) using a solution of the halogen in water at room temperature for five minutes with shaking. The process was repeated with fresh halogen water as appropriate to form the mono- or di-halo derivatives. Using the methods described in Example 1 or Example 2, and appropriate starting materials, the compounds listed below have been prepared. 1 C 3 H 7 Cl OMe H 2 C 3 H 7 - Cl OMe Cl 3 C 4 H 9 Cl OMe H 4 C 4 H 9 Cl OMe Cl 5 i"C 4 H 9 H OMe H . 6 i-c Λ Cl OMe H 7 - i"C 4 H 9 Cl OMe Cl TABLE I (continued) No . R. 8 C 5 H 11 Cl OMe H 9 C 5 H 11 Cl OMe Cl 19 Br C 5 H 11 OMe H 11 C 5 H 11 Br OMe Br 12 C 5 H 11 I OMe H 13 i-C 5 H 1]L Cl OMe H 14 i-c 5Hll Cl OMe Cl 15 C 6 H 13 Cl OMe H 16 C 6 H 13 Cl OMe Cl 17 C 7 H 15 Cl OMe H 18 C 7 H 15 Cl OMe Cl 19 C 8 H 15 Cl OMe H 20 C 8 H 15 Cl OMe - Cl EXAMPLE 3 Test for Differentiation Inducing Activity The compounds were tested for differntiation inducin activity by the procedure described in Euro. J. Biochem. , 136, pp 51-56, (1983): R.R. Kay, B. Dhokia & K.A. Jermyn, "Purification of stalk-cell-inducing morphogens from Dictyostelium discoideum" The following selection from Table I, given as Table II below, lists the most preferred compounds, being those which have been found to possess differentiation inducing activity. TABLE II NO . R . R. 2 C 3 H 7 Cl OMe 3 C 4 H 9 Cl . OMe H 4 C 4 H 9 Cl OMe Cl 6 i-C 4 H g Cl OMe H 7 i-C 4 H g Cl OMe Cl 8 C 5 H 11 Cl OMe H 9 C 5 H 11 Cl OMe Cl 10 C 5 H 11 Br OMe H 11 C 5 H 11 Br OMe Br 13 i-C 5 H Cl OMe H 14 i-c 5H]L1 Cl OMe Cl 15 C 6 H 13 Cl OMe H 16 C 6 H 13 Cl OMe Cl 18 C 7 H 15 Cl OMe Cl 20 C 8 H 15 Cl OMe Cl EXAMPLE 4 (For Comparison) In order to investigate the effects of altering the positions and identity of the various substituents in the phenyl ring, a very large number of isomers and analogues of the compounds found to be active were prepared. The activities of these related compounds were determined and compared with the most closely related cof the active compounds. The results are given in Table III below. The active compounds bear the reference number assigned i Table I above, the related but inactive compounds being referenced from number 100. TABLE III No . R . R. R_ B 2 C 3 H 7 OH Cl OMe Cl OH 100 C 3 H 7 OMe H OH H OH 101 C 3 H 7 OH H OMe H OH 102 C 3 H ? OMe Cl OH Cl OH 9 C 5 H 11 OH Cl OMe Cl OH 103 C 5 H 11 OMe H OH H OH 104 C 5 H 11 OMe Cl OH H OH 105 C 5 H 11 OMe Cl OH Cl OH 106 C 5 H 11 OH H OMe H OH 18 C 7 H 15 OH Cl OMe Cl OH 107 C 7 H 15 OMe Cl OH Cl OH These are but examples of the a large number of comparative tests which have been carried out and which demonstrate that cell differentiation activity is depend upon there being an alkoxy group in the para-position to the ketone group, a halogen atom in either or both of th meta- positions with both ortho-positions occupied by hydroxyl groups. The identity of the group R, has been shown to be, by and large, irrelevant and may be selected on the basi of availability or convenience. A certain amount of biological evidence has been published that alkenyl chai may have activity in respect other than in cell differentiation and it is therefore indicated that value may be obtainable in inserting an alkenyl group as R.. No alteration of the preparative procedure is required, merely selection of an appropriate starting material whi contains an alkenyl rather than an alkyl group as exemplified hereinabove.

Claims: CLAIMS A derivative of a phenone, having the general chemical formula I: in which R. is a straight or branched chain or cyclic alkyl or alkenyl group; R 2 is an alkoxy or hydroxy group; R, is a hydrogen or halogen atom; and, R. is a halogen atom. A derivative as claimed in claim 1, in which R. is an alkyl group having from one to ten carbon at A derivative as claimed in claim 1 or claim 2, which R 2 is an alkoxy group. A derivative as claimed in claim 3, in which R„ is a methoxy group. 5. A derivative as claimed in any of the preceding claims, in which R_ and R 4 are both halogen atoms. 6. A derivative as claimed in claim 5 in which the halogen is chlorine or bromine or iodine. 7. The compound 2,6-dihydroxy-3,5-dichloro-4-metho valerophenone. The compound 2,6-dihydroxy-3,5-dichloro-4-metho butyrophenone. 9. The compound 2,6-dihydroxy-3-chloro-4-methoxy valerophenone. 10. A method of preparing a compound of general formula I defined in claim 1, comprising reacting together a compound of general formula II, in which R_ and R 4 are as defined above with an alkanoyl chloride of formula; R- ^ .CO. Cl wherein - ^ is as def ined above , to give a produc having the general formula III ; in which R. to R. are as defined above, and subjecting the compound of formula III to a Fries Rearrangement reaction in the presence of alumini trichloride thereby to form the compound having t general formula I defined above. 11. A method as claimed in claim 10 in which the reaction between the compound of formula II and t alkanoyl chloride is carried out in pyridine solv 12. A method as claimed in claim 11, in which the Fries Rearrangement is carried out at a temperatu of around 25°C. 13. A method of preparing the compound of general formula I defined in claim 1, comprising reacting iminochloride of formula: R 1 .C (=NH) Cl in which R. is as defined above,with a phenol having the general formula IV in which R 2 , R 3 and R. are as defined above, to form a ketimine hydrochloride having the formula V; in which R, to R. are as defined above, and hydrolysing the said ketimine to form the compound general formula I defined above. 14. A method as claimed in claim 13, in which the reaction between the iminochloride and the phenol i carried out in the presence of anhydrous zinc chloride, ferric chloride or aluminium trichloride a catalyst. 15. A biologically active preparation containing, as active principle, a compound having the general formula I claimed in claim 1.

Inventors: KAY ROBERT ROGER, MASENTO MARK STEVEN, MORRIS HOWARD REDFERN, TAYLOR GRAHAM WALTER, KAY, ROBERT, ROGER, MASENTO, MARK, STEVEN, MORRIS, HOWARD, REDFERN, TAYLOR, GRAHAM, WALTER
Applicants: RESEARCH CORP, RESEARCH CORPORATION LIMITED
Application year: 1988
Main classification: C07C49
IPC codes: C07C45, C07C49