WO1988004660A2 - Synthesis process and oxygen-containing heterocyclic products thereof - Google Patents

Synthesis process and oxygen-containing heterocyclic products thereof Download PDF

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Publication number
WO1988004660A2
WO1988004660A2 PCT/US1987/003330 US8703330W WO8804660A2 WO 1988004660 A2 WO1988004660 A2 WO 1988004660A2 US 8703330 W US8703330 W US 8703330W WO 8804660 A2 WO8804660 A2 WO 8804660A2
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carbon atom
hydrogen
substituted
alkyls
group
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PCT/US1987/003330
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French (fr)
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WO1988004660A3 (en
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Mitchell A. Avery
Clive Jennings-White
Wesley K. M. Chong
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Sri International
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Priority to GB8818816A priority Critical patent/GB2218088B/en
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Publication of WO1988004660A3 publication Critical patent/WO1988004660A3/en
Priority to SE9000377A priority patent/SE9000377L/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Definitions

  • This invention is in the field of organic chemistry. More particularly it relates to a process for the synthesis of oxygen-containing heterocyclic organic compounds and to materials formed by this process. In one application, this process is used to prepare the antimalarial agent qinghaosu (artemisinin) and a variety of analogs.
  • One key step of the present process is the ozonolysis of a vinylsilane to introduce an oxygen functionality.
  • a reference which involves ozonolysis of a vinylsilane and can lead to an alpha-hydroxyperoxy aldehyde is that of George Buchi, et al., Journal of the American Chemical Society, Vol 100, 294 (1978). This reference illustrates this reaction but in different settings.
  • Another reference is by R. Ireland et al., Journal of the American Chemical Society, Vol 106, 3668 (1984), which relates to silylation.
  • this invention employs unsaturated bicyclic ketones as reactants.
  • references relating to such materials and to methods for forming some of them include W. Clark Still, Synthesis, Number 7, 453-4 (1976); Kazuo Taguchi et al., Journal of the American Chemical Society. Vol. 95, 7313-8 (1973); and E.W. Warnhoff et al., Journal of Organic Synthesis, Vol 32, 2664-69 (1967).
  • the antimalarial qinghaosu has been used in China in the form of crude plant products since at least 168 B.C.
  • the carbons in the artemisinin structure have been numbered as set forth above. When reference is made to a particular location in a compound of this general type, it will, whenever possible, be based on this numbering system. For example, the carbon atoms bridged by the peroxide bridge will always be identified as the "4" and "6" carbons, irrespective of the fact that this invention can involve materials having dif ferent bridge-length structures in which these carbons would properly be otherwise numbered.
  • references to artemisinin and derivatives include the May 31, 1985 review article by Daniel L.
  • the process is directed to the preparation of polyoxa tetracyclic compounds such as artemisinin of the following General Formula I.
  • X is a heteroatom bridge selected from -O-, -S-, and R 1 is an organic bridge which can be a methylene (-CH 2 -) unit or a two or three carbon atom long chain with or without substituents; R 2 is an organic bridge which can be a covalent single bond or a methylene unit through five carbon atom long chain with or without substituents; R 3 is an organic bridge which can be a methylene unit through three carbon chain with or without substituents; R 4 is a hydrogen or an alkyl group, with or without substituents; R 5 and R 6 can together be a carbonyl oxygen or R 5 can be a hydrogen, an alkyl or a substituted alkyl while R 6 is a hydrogen, a hydroxyl, an alkyl ether, a carboxylic ester, a carbonate, a carbamate, an amide, or a urea, and R 10 is a hydrogen or an alkyl or aryl
  • the synthesis process of this invention when used to prepare the tetracycles of General Formula I includes subjecting to ozonolysis a vinylsilane compound of General Formula II.
  • R 1 through R 6 and X are as defined with the polyoxa tetracyclic compounds of General Formula I and R 7 , R 8 and R 9 are independently selected from lower hydrocarbyls.
  • this invention provides a method for synthesizing artemisinin by ozonolysis of the vinylsilane
  • the process of this invention can also be applied to prepare seco analogs of artemisinin which substantially retain the activity of the more complicated parent compound. These analogs have the structure shown in General Formula III.
  • R 1 and R 2 are independently hydrogen, methyl or ⁇ -unsubstituted organic moieties containing up to about 12 carbon atoms, with the total size of R 1 plus R 2 being not greater than about 20 carbons;
  • R 6 is hydrogen, alkyl, or a substituted alkyl while R 7 is hydrogen, hydroxyl, alkyl ethers, carboxylic ester, carbonate, carbamate, amide, or urea or R 6 and R 7 together form a carbonyl oxygen;
  • R 8 and R 9 are independently hydrogen, alkyl, or substituted alkyl or R 8 and R 9 together form an organic ring; and
  • R 10 and R 1 1 are independently hydrogen or organic groups.
  • seco materials can be prepared by the process described above, which involves ozonolysis of a vinylsilane and acid-catalyzed condensation of the hydroperoxide compound which result with a carbonyl (aldehyde or ketone).
  • This process involves a. subjecting a vinylsilane of General Formula IV to ozonolysis to yield a hydroperoxide of General Formula V, and
  • General Formula IV General Formula V. b. reacting the hydroperoxide of Formula V. and a carbonyl of General Formula VI. in the presence of an acid catalyst to yield the desired seco analog.
  • the vinylsilane itself is a bridged (bicyclic) material of General Formula VII. dervied from a bicyclic bridging ketone of General Formula VIII. having non-enolizable bridgehead moieties for both of its alpha positions.
  • This vinylsilane is subjected to ozonolytic cleavage of its olefinic bond to yield a member of a family of unique carboxyl/carbonyl-substituted vinylsilanes which may in turn optionally be subjected to a wide range of reactions prior to a final ozonolysis/acidification step which closes the oxygen-containing ring structure.
  • This variation of the process can yield desired artemisinin analogs and the like in several fewer steps. It can yield artemisinin analogs not easily obtainable otherwise.
  • the process is also characterized by permitting control of the stereochemistry of the "1", "4", "5", "6", and “7” centers (as these positions are defined in artemisinin).
  • This embodiment of the invention offers additional versatility in that its intermediates can be protected and modified by alkylation or chain extension techniques so as to yield as ultimate products artemisinin analog tetracycles represented by General Formula IX.
  • X and Y together can equal a carbonyl oxygen or X can be hydrogen, while Y is selected from hydrogen, hydroxyl, or alkyl ethers; carboxylic esters; carbonates, carbamates, amides and ureas; m is 0 or 1, n is 0, 1, 2, 3 or 4, p is 0, 1 or 2 with the sum of m plus p equal to 0, 1 or 2, and the R's are independently hydrogen, lower alkyl or substituted lower alkyl.
  • this invention provides antimalarial pharmaceutical compositions incorporating the oxygen-substituted products set forth above.
  • Figure 1 is a flow diagram showing the total synthesis of an artemisinin analog
  • Figure 2 is a flow diagram showing a total synthesis of artemisinin
  • Figures 3, 4, and 5 are each a flow diagram showing routes to artemisinin analogs
  • Figure 6 is a flow diagram for preparing seco compounds
  • Figure 7 is a flow diagram for introducing substituents into the seco compounds
  • Figures 8 and 9 are each a flow diagram for preparing artemisinin analogs using vinylsilanes of ketones with nonenolizable bridgeheads.
  • polyoxa artemisinin analog compounds are prepared by ozonolysis of vinylsilanes.
  • These artemisinin analog compounds can be tetracycles of General Formula I., seco analogs of General Formula III. or bridgehead-substituted analogs of General Formula IX., depending upon the particular materials upon which the ozonolysis is carried out.
  • R's in these General Formulas and likewise in General Formulas II. and IV-VIII. reference is made to the possibility of "substituting" these groups.
  • a possible substituent is a chemical group, structure or moiety which, when present in the compounds of this invention, does not substantially interfere with the preparation of the compounds or which does not substantially interfere with subsequent reactions of the compounds.
  • suitable substituents include groups that are substantially inert at the various reaction conditions presented after their introduction such as the ozonolysis and acidification.
  • Suitable substituents can also include groups which are predictably reactive at the conditions to which they are exposed so as to reproducably give rise to desired moieties.
  • R* can be any substituent meeting the above functional definition.
  • Common R* groups include saturated aliphatic groups including linear and branched alkyls of 1 to 20 carbon atoms such as methyl, ethyl isopropyl, n-butyl, t-butyl, the hexyls including cyclohexyl, decyl, hexadecyl, eicosyl, and the like.
  • R* can also include aromatic groups generally having from 1 to 20 aromatic carbon atoms; for example aryls such as quinolines, pyridines, phenyls, naphthyls, and aralkyls of up to about 20 total carbon atoms such as benzyls, phenylethyls and the like, and alkaryls of up to about 20 total carbon atoms such as the xylyls, ethylphenyls and the like.
  • aryls such as quinolines, pyridines, phenyls, naphthyls, and aralkyls of up to about 20 total carbon atoms such as benzyls, phenylethyls and the like
  • alkaryls of up to about 20 total carbon atoms such as the xylyls, ethylphenyls and the like.
  • R* substituents may themselves include olefinic carbon-carbon double bonds, subject to the understanding that the ozonolysis may attack and oxidatively cleave this unsaturation if it is present during that reaction, amides, sulfonates, carbonyls, carboxyls, alcohols, esters, ethers, sulfonamides, carbamates, phosphates, carbonates, sulfides, sulfhydryls, sulfoxides, sulfones, nitro, nitroso, amino, imino, oximino, *a*, B-unsaturated variations of the above, and the like, subject to the understanding that many of these functional groups may be subject to attack during the overall reaction sequence and thus may need to be appropriately protected. They can then be deprotected at some later stage as desired.
  • General Formula I.
  • R 1 is an organic covalent bridge joining the "7" and "12" carbon atoms.
  • the R 1 bridge can be a methylene (-CH 2 -) unit or a two or three carbon atom long alkylene chain, (-CH 2 -CH 2 -, or -CH 2 -CH 2 -CH 2 -) with or without R* substituents.
  • R 1 is substituted, the substituents replace hydrogens.
  • R 1 is a one or two carbon alkylene, with up to two lower alkyl R* substituents.
  • the term "lower" when used as a qualifier of organic group size means from one to ten carbons. More preferably R 1 is a one carbon alkylene, especially with a lower alkyl substituent, e.g., methyl.
  • R 3 is a one carbon atom through three carbon atom long alkylene chain, between the "1" and "4" carbons. The carbon atom of the R 3 chain which is adjacent to the "4" carbon can be substituted with one or two R* groups when R 3 is two or three carbon atoms long.
  • Preferred R* groups for substituenting R 3 are lower alklys.
  • Preferred R 3 groups are the one or two carbon atom long alkylenes with two carbon atom long alkylenes being most preferred.
  • R 4 is a hydrogen, a methyl or a methyl substituted with an R*.
  • Methyl and methyl substituted with a lower alkyl are preferred with methyl being most preferred.
  • R 5 and R 6 can together be a carbonyl oxygen attached to the "12" carbon position.
  • R 5 can be a hydrogen, a methyl or an R*-substituted methyl
  • R 6 is a hydrogen, a hydroxyl, an alkyl—preferably lower alkyl—ether, an ester formed by the hydroxyl with a carboxylic acid of the formula HOOC-CH 3 or HOOC-CH 2 R* (i.e., acetic acid or a substituted acetic acid), a carbonate, a carbamate, an amide, or a urea.
  • Carbonyl is preferred.
  • R 6 is hydroxyl
  • hydrogen, methyl and lower alkyl-substituted methyl are preferred R 5 groups.
  • X is a heteroatom bridge selected from -O-, -S-, and R 10 is hydrogen or R*.
  • X groups are -O-, -S-, and wherein
  • R 10 is a lower alkyl.
  • the most preferred X is -O-.
  • R 4 and X have the meanings set forth above with reference to General Formula I.
  • R 5 and R 6 are a carbonyl oxygen and R 7 , R 8 and R 9 are lower hydrocarbyls.
  • Typical hydrocarbyls for this application are lower alkyls, aryls, alkaryls and aralkyls. In selecting these three R's, generally two or three of them are methyls.
  • Typical silyl groups include trimethyl silyl, t-butyl dimethyl silyl and phenyldimethyl silyl.
  • R 1 and R 2 are independently selected from hydrogens, methyls and alpha-unsubstituted organic moieties containing up to about 12 carbon atoms subject to the proviso that the total size of R 1 and R 2 is not greater than about 20 carbons as noted. These moieties are unsubstituted at the alpha position but can be substituted in other positions.
  • Typical R 1 and R 2 groups include the alkyls; unsaturated groups such as alkenyls, hexyls and the like; hydroxy-subst ituted alkyls; aryls such as benzyls; fluorinated, sulfonated or phosphorated alkyls and the like. Simple lower alkyls are preferred.
  • R 6 and R 7 are selected as set forth for R 5 and
  • R 8 and R 9 are hydrogen, lower alkyls or substituted lower alkyls and can in addition be joined into an alkylene chain linking the "1" and "7" carbons into a cycloalkylene ring such as of 3 to 8 carbons.
  • a preferred configuration for R 8 and R 9 is to have them joined into a 6-membered cycloalkylene ring, with or without substituents.
  • R 10 and R 11 are independently selected f rom hydrogen , lower alkyls and substituted lower alkyls. It is often attractive to be able to alter the hydrophobicity/hydrophilicity of the seco analogs. Alkyls in these positions will decrease hydrophilicity and increase hydrophobicity. Alkyl substituents which are themselves substituted with an ionic group such as a carboxylic acid or sulfonic acid group will enhance hydrophilicity.
  • R 10 is a lower alkyl, and especially a methyl
  • R 11 is a hydrogen.
  • a vinylsilane of General Formula IV. is subjected to ozonolysis in the preparation of the seco analogs.
  • R 3 , R 4 and R 5 are hydrocarbyls like R 7 , R 8 and R 9 in Formula II.
  • the ozonolysis produces the silyloxy-hydroperoxides represented by General Formula V.
  • R 3 through R and R 8 through R 11 have the meanings set forth above.
  • Carbonyl compounds of General Formula VI. are reacted with the hydroperoxide in the preparation of the seco compounds.
  • R 1 and R 2 are as defined with reference to General Formula III.
  • the carbonyl includes ketones and aldehydes.
  • the ozonolysis process of this invention is used with bridgehead ketones of Formula VIII. to yield tetracyclic artemisinin analogs of Formula IX.
  • n is 1 or 2 or 3.
  • materials wherein the various R's are selected from hydrogen, lower alkyls and substituted lower alkyls. Materials wherein at most one or two of the R's in the m methylenes and at most one of the R's in the m methylenes are other than hydrogen are especially preferred.
  • bridgehead ketones are shown in more detail by General Formula VIII*. in which m, n and the R's are as previously described.
  • General Formula VIII* Several of the materials encompassed by General Formulas VIII. and VIII*., are known compounds. (See Still, supra, for a disclosure of materials wherein n is 1, m is 1 and all the R's are hydrogen; wherein n is 2, m is 1 and all the R's are hydrogen; wherein n is 3, m is 1 and all the R's are hydrogen; and wherein n is 2 , m is 1 and all the R's are hydrogen except for one R Cl , which is a methyl.)
  • the bridgehead ketone materials of General Formulas I. and I* can be prepared as follows: When both of the R B substituents are hydrogen, the materials can be prepared by the cyclodialkylation of appropriate enamines.
  • the pyrrolidine enamines are a well-known family of materials whose preparation from commercial cyclic ketones is well documented, and for this reason they are preferred.
  • cyclohexanone is converted to the cyclohexeneamine, which is then reacted with a l,4-dichlorobut-2-ene to give a bicyclic ketone as shown in Reaction 1.
  • Reaction 1 The reaction of the dialkylation reagent and the enamine is carried out under effective alkylation conditions. These include anhydrous conditions; an aprotic reaction medium such as dimethylformamide, tetrahydrofuran, or the like; and the general exclusion of oxygen from the reaction vessel such as by an inert gas cap.
  • the reaction is generally promoted by the addition of a base such as an amine or the like, for example a trialkyl amine, and by the presence of a halide alkylation promoter such as an alkali metal iodide.
  • approximately equimolar amounts of the dialkylation reagent and the enamine are employed.
  • a representative preparation taken from Still (supra) is provided in Example 15.
  • the bridgehead ketones have R B substituents other than hydrogen, they can be prepared using the methods set forth by Taguchi et al (supra) and Warnhoff et al (supra).
  • Taguchi et al saturated bridgehead ketones containing a carboxylic acid functionality at one of the bridgeheads are prepared.
  • the carboxyl group can be used as a point of attachment for other R B substituents as called for.
  • the Warnhoff et al work discloses a method for introducing carboxyl and halo substituents on both of the bridgehead carbons of saturated bicyclic ketones. Again, these groups can serve as active sites for the coupling of other R B groups as desired. With suitable modification, the desired olefinic bond can be introduced into the bicyclic structure.
  • the bicyclic bridgehead ketones of Formula VI I I . are converted to the v inyls i lanes of Formula VII.
  • the three R S substituents in the silyl functionality are independently selected from lower hydrocarbyls as previously defined.
  • the vinylsilanes can also be represented by General Formula VII*.
  • R E is a protective esterifymg group.
  • the vinylsilanes of Formula VIII. are versatile intermediates.
  • the carbonyl-containing arm can be extended using conventional chain-extension techniques such as the Wittig reaction. This introduces a unit wherein R is a hydrogen, an alkyl or a substituted alkyl and p is an integer of from 0 to 2, subject to the proviso that p plus m has a value not greater than 2.
  • the product of this chain extension has the structure shown in Formula XI*.
  • R F group is a lower alkyl or substituted lower alkyl.
  • the process of this invention employs an ozonolysis reaction in its formation of the desired artemisinin analogs.
  • This reaction is carried out at low temperatures in a liquid reaction medium.
  • Ozone is extremely reactive and it is advantageous to employ low temperatures to avoid side reactions between the ozone and other regions of the vinyl silane molecule.
  • the low temperature can range from a high of about 15° to a low equal to the freezing point of the reaction solvent, which can be as low as -100° C or lower. Excellent results are obtained at dry ice/acetone bath temperatures (-78°C) and a preferred temperature range is from -100°C to about -25°C, with most preferred temperatures being in the range of from -70°C to -80°C.
  • the reaction solvent employed in this reaction is selected to assure compatibility with the highly reactive ozone.
  • ethers both linear and cyclic, are to be avoided as they are likely to be converted to peroxides which present an explosion hazard.
  • the solvents employed are polar organics, preferably lower alcohols such as methanol, ethanol, the propanols and ethylene and propylene glycols; lower ketones such as acetone and methyl-ethyl ketone; and the and liquid esters such as ethyl acetate.
  • the lower alcohols, and especially methanol are preferred.
  • the reaction is carried out by mixing the vinyl silane in the reaction medium and then adding the ozone.
  • the amount of ozone preferably is controlled so that excesses are avoided. Good results are obtained when the amount of ozone is limited to not more than 1.25 equivalents, based on the amount of vinyl silane present, with ozone levels of from about 0.75 to about 1.25 equivalents based on the amount of vinyl silane present being preferred. Lower ozone levels can be used, but are not preferred because of the lower yields which result from them.
  • the reaction is very quick, being complete in a few minutes at most. Excellent results are obtained at times in the range of 15 seconds to about 15 minutes. It is advantageous to limit this reaction period.
  • reaction product is then treated with acid.
  • the product contains a dioxetane which is isolated and then treated. This can be carried out by stripping the solvent off with vacuum or other like processes which minimize the possibility of degradative reaction.
  • the acidification can be carried -out without isolating the intermediate.
  • the ozonolysis reaction product or isolated dioxetane is treated with acid to bring about rearrangement of these transitory intermediates and give rise to the desired product tetracycles or seco analogs.
  • This reaction can be carried out in an nonaqueous liquid reaction phase with halohydrocarbons such as chloroform and the like being preferred.
  • the acid employed should be of at least moderate strength as shown by a pKa of from about 5 to about 0.1 and can be an organic or an inorganic acid. Mixtures of acids can be used, if desired.
  • Typical acids include acetic acid; the substituted acetic acids such as trichloroacetic acid, trifluoroacetic acid and the like, and other strong organic acids such as alkyl sulfonic acids and the like.
  • the mineral acids such as the hydrohalic acids, e.g., HCl, HBr, etc., the oxyhalo acids such as HCIO 3 and the like; sulfuric acid and phosphoric acid and the like may be used as well but should be checked before use to assure that they do not cause unwanted side reactions.
  • the rearrangement reaction is merely catalyzed by the acid, thus in principle only a trace amount of acid is needed. However, the use of more than a trace amount of acid may be preferred. In practice, the best approach is to monitor the course of the reaction and add acid as needed to achieve and sustain a reasonable reaction rate. In particular, the amount of acid added is generally at least about one equivalent based on the amount of product present. Large excesses while not needed, can be used, and the preferred amount of acid is from about one to about ten, and especially from about one to about two, equivalents based on the amount of product present. This reaction does not require high temperatures. It will go to completion overnight at room temperature. The reaction may also proceed to completion either more rapidly or more slowly, depending on the acid and solvent system employed.
  • Temperatures from about -100°C to about +50°C can be used with temperatures of from about-20°C to about +30°C being preferred and temperatures of from about 0°C to about +20°C being more preferred. As would be expected, times are inversely related to temperature with times in the range of 1 hour to about 24 hours being useful.
  • the product of the acid-catalyzed rearrangement can be worked up and purified using chromatographic techniques and the like.
  • the techniques illustrated in Figure 5 can be used.
  • the carbonyl can be reduced without affecting the reduction-sensitive peroxy group by the use of sodium borohydride as reported by M.-m Liu et al. in Acta Chim Sinica, Vol 37, 129 (1979).
  • This reduction converts the carbonyl into a lactol.
  • the lactol hydroxyl can be converted to an ester by reaction with an appropriate acid anhydride or acid halide or active ester.
  • Typical examples of these reactants include acetic anhydride, propionic anhydride, maleic anhydride and substituted analogs thereof, alkanoyl chlorides, and the like.
  • This reaction is carried out in an aprotic solvent such as an ether or halohydrocarbon (for example, dichloromethane) at a moderate temperature of from about 0°C to room temperature in from about 0.5 to 5 hours.
  • An ether can also be formed such as by contacting the alcohol with methanol or a R*-CH 2 -OH alcohol corresponding to the remainder of the ether in the presence of a Lewis acid such as BF3.
  • the BF 3 is presented as an etherate and forms a complex with the alcohol and effects the ether formation at -10°C to room temperature in from 0.5 to 5 hours.
  • the added alcohol is a good solvent.
  • a carbonate can be formed from the alcohol such as by reacting it with an organic chloroformate such as an alkyl chloroformate. This is again carried out at -10°C to room temperature in from 0.5 to 5 hours in an aprotic solvent such as was used in the formation of the ester. All of these products can be recovered using a conventional organic workup.
  • the ozonolysis reaction is incorporated into an overall synthesis scheme to provide the desired artemisinin analogs.
  • the carboxylic acid 11 could be converted to 13-desmethylartemisinin 13 in the following manner.
  • Treatment of 11 with oxalic acid impregnated silica gel gave the keto-acid 12.
  • Ozonolysis of 12 at low temperature in methanol gave an unstable intermediate dioxetane which was treated immediately with CF 3 CO 2 H in CDCI 3 to afford (Scheme I) the nor analog of artemisinin, 13.
  • (Scheme II, Figure 2.) 11 could be esterified to give the ester 14. which could be methylated to provide a mixture of monomethylated products, 15 and 16, in a 3:1 ratio respectively.
  • This ester mixture was sequentially treated with KOH in methanol followed by oxalic acid on wet silica gel to provide, after chromatography, the stereoisomerically pure keto-acid 17.
  • this synthetic sequence can be modified slightly to produce radiolabelled artemisinin. This can be carried out effectively and simply by using carbon 14-based CH 3 I in the alkylation of compound 14. This will insert the radiolabel at the 13 position where it is stable and nonlabile.
  • the product of this synthesis is of particular usefulness in biological testing of artemisinin where its metabolic fate, absorption and the like can be easily tracked because of the added radiolabel.
  • the present invention permits the stereospecif ic synthesis of many polyoxa tetracyclic compounds beyond artemisinin. In these cases, one could use the synthetic schemes set forth in the Figures with appropriate modifications.
  • R 1 from the one carbon alkylene bridge shown in Figures 1 and 2 to a two or three carbon bridge by homologating the -CH 2 -COOH group in compound 11. or compound 15 to the corresponding higher analogs.
  • the Ri bridge can be substituted with R* groups by alkylation with X-R* where X is a leaving group such as a halide (e.g. I or Br) a tosylate, a mesylate or the like.
  • This alkylation can take place before or after the homol ⁇ gation, depending upon the particular site on the R 1 group sought to be substituted.
  • the R 2 bridge is set by the ring structure in compound 1.
  • compound 1 is shown as a cyclohexanone-based material. One could as well start with cyclopropanone (thereby obtaining a carbon-carbon single bond R 2 ). cyclobutanone (thereby obtaining a -CH 2 R 2 ), cyclopentanone, etc. In every case, the carbons of the starting aldehyde can be substituted with R* groups as desired on R 2 .
  • R 3 is determined by the nature of the leaving- group containing side chain in alkylation agent 2 in Figure 1. Thus, if this side chain is varied in length or substitution, so is R 3 .
  • R 4 can be altered by varying the other substituent on the carbon atom between the two ether oxygens on compound 2 .
  • this group is a methyl and R 4 is a methyl. If this group is altered to be a hydrogen or an R* substituted methyl, R 4 will follow accordingly.
  • the preparation schemes set forth on Figures 1 and 2 result in products of General Structures 1-4 where X is -O-.
  • Figure 3 a variation of the scheme of Figure 1 is depicted which will produce compounds where X is -S- or The scheme of Figure 3 begins with acid 11.
  • This material is converted to the acid chloride 19 by conventional treatment with oxalyl chloride ClCOCOCl, thionyl chloride, or the like. Acid chloride 19. can then enter into a nucleophilic substitution with H2S or the amine NH 2 R 10 to insert an
  • esters 15/16 can be hydrolyzed with methanolic KOH to the mixture of acids 25 and 26.
  • This mixture can be converted to the corresponding mixed acid chlorides by the method described with Figure 3 and the acid chlorides reacted with to give the mixture of amides 21. and 22.
  • the mixture of amides 21 and 22 is then treated with methanolic base followed by treatment with oxalic acid-impregnated silica gel to yield the keto-amide 23 of the General Formula II.
  • This material is subjected to ozonolysis to yield the NR 10 analog 24 of arteminisin.
  • This reduction converts the carbonyl to a lactol (hemiacetal wherein R 5 is H and R 6 is OH.
  • the R 5 hydrogen can be replaced with an R* group by alkylation with X-R*.
  • An R 6 OH can be converted to an ether or ester by art known techniques.
  • the mixed esters 15 and 16 are reduced with lithium aluminum hydride to alcohols 31 and 32. After side-chain deprotection, ozonolysis yields compound 33 where R 5 and R 6 are hydrogen. In the next variation, 31 and 32 are oxidized into aldehyde 34 which after deprotection and ozonolysis yields 35 where R 5 and R 6 equal OH and H.
  • Aldehyde 34 can be alkylated with Grignard reagent to give alcohol 36. This alcohol can be carried forward to give compound 37 of Formula I., where R 5 and R 6 are R* and H.
  • Alcohol 36 can be oxidized to aldehyde 38. This material can be deprotected and subjected to oxonolysis to give 39 where R 5 and R 6 are R* and OH.
  • aldehyde 38 can be treated again with Grignard to add an additional R* group (the same or different than the R* of 38), and this product can be deprotected and ozonized to give 40. It will be appreciated in this last sequence that if the two R*s are identical, one could add them at once to esters 15 and 16 by using excess Grignard reagent.
  • Figure 6 illustrates a preparation scheme in which two representative seco derivatives are prepared.
  • an unsaturated (allylic) alcohol shown representatively in Figure 6 as cyclohexenylmethanol
  • Allylic silyl ether 5 is then deprotonated in TMEDA with s-butyllithium to afford a Brook rearrangement product 6.
  • the hydroxyl of 6 is then esterified (such as acetylated) to yield ester 7.
  • Ester 7 is then deprotonated such as with lithium N-cyclohexyl-N-isopropylamide (LICA) in THF followed by in situ ester/enolate Claisen rearrangement to give carboxylic acid-substituted vinylsilane 8.
  • LICA lithium N-cyclohexyl-N-isopropylamide
  • This vinylsilane 8 is then subjected to ozonolysis.
  • the ozonolysis reaction product contains a transitory dioxetane which is observable spectroscopically.
  • the dioxetane material rearranges to give the hydroperoxide 1.
  • the hydroperoxide is converted to the desired seco analog by reaction with a ketone of General Formula IV. in the presence of acid as previously described.
  • the present invention provides a range of seco analogs of artemisinin wherein R 6 and R 7 together are a carbonyl oxygen.
  • R 6 and R 7 together are a carbonyl oxygen.
  • R 8 and R 9 are set by the structure of allyl alcohol 4.
  • R 10 and R 11 are determined by the nature of the esterifying group reacted with the hydroxyl group of compound 6. With the propionic anhydride shown in Figure 6, one obtains a methyl and a hydrogen in these positions. With acetic anhydride one obtains two hydrogens. When these esterifying agents are replaced by agents having other substituted and unsubstituted groups, the R 10 and R 11 groups are altered correspondingly. It is also possible to alter the R 10 and R 11 groups by alkylation and the like.
  • R 6 and R 7 are other than a carbonyl oxygen
  • the carbonyl can be reduced as previously described.
  • An ether such as ether 11 can also be formed such as by contacting the alcohol 9 with methanol or a R*-CH 2 -OH alcohol corresponding to the remainder of the ether in the presence of a Lewis acid such as BF 3 .
  • the BF 3 is presented as an etherate and forms a complex with the alcohol and effects the ether formation at -10°C to room temperature in from 0.5 to 5 hours.
  • the added alcohol is a good solvent.
  • a carbonate such as carbonate 12 can be formed from 9 or the like such as by reacting 9 with an organic chloroformate such as an alkyl chloroformate. This is again carried out at -10°C to room temperature in from 0.5 to 5 hours in an aprotic solvent such as was used in the formation of ester 10. All of these products can be recovered using a conventional organic work up.
  • the silylation is carried out by contacting the ketone and the silylation reagent at about equimolar levels (0.75 to about 1.33 equivalents of silylation complex based on the ketone present) at low temperatures such as -100°C to about 0°C, once again in an aprotic anhydrous reaction phase.
  • the product of this silyation can be extracted into a nonpolar organic phase and can be worked up by rinsing with water, brine, and the like.
  • the product can be purified, such as by chromatographic techniques.
  • the ozonolytic cleavage reaction employed in Figures 8 and 9 is an adoption of the method described by R.E. Claus and S.L. Schreiber, Org. Syn., 64, 150 (1985). This reaction is carried out at essentially the conditions used in the ozonolysis.
  • the reaction solvent employed in this reaction is similar to the materials used in the ozonolysis and is selected to assure compatibility with the highly reactive ozone. Of these solvents, the lower alcohols, especially methanol mixed with halohydrocarbons and especially dichloroethylene, are preferred. In the case shown in Figure 8 an optimum solvent was a 5:1 volume ratio of methylene chloride and methanol, respectively.
  • the product of the ozonolytic cleavage can be worked up and recovered.
  • the workup is carried out under reductive conditions, for example in the presence of an alkylamine and an anhydride such as acetic anhydride.
  • the conditions need not be reductive.
  • the recovered product can then be treated with a strong acid such as a mineral acid and preferably hydrochloric acid to yield the tetracycles of Formula VI.
  • a strong acid such as a mineral acid and preferably hydrochloric acid
  • This product can be recovered by extraction into an organic layer which is then washed, dried and, if desired, subjected to column chromatography and the like.
  • the optional chain extension and alkylation steps can be carried out as previously described.
  • the compounds of this invention all contain the peroxy linkage which can lead to free radical intermediates in vivo and have antiprotozoan activities against a broad range of parasites such as Toxoplasma, Leishmania, Trypanosoma, etc., in addition to Plasmodia. In tests, they have been demonstrated to have high activity in this application. They offer activity against drug-resistant forms of malaria and can even intervene in cerebral malaria, where they can interrupt coma and reduce fever. These materials should also have anthelminthic activity against such diseases as Schistosoma and Trichinella, etc. (R. Docampo et al., Free Radicals in Biology, Vol. VI, Chapter 8, p. 243, 1984, Academic Press, Inc.).
  • the compounds are generally compounded into vehicles or carriers known in the art for administration to patients in need of such treatment.
  • the mode of administration can be oral or by injection.
  • Typical vehicles are disclosed in Remington's Pharmaceutical Sciences, Alfonso R. Gennaro, ed., Mack Publishing Company, Easton, PA. (1985).
  • the compounds can be prepared as elixirs and suspensions in sterile aqueous vehicles, and also can be presented admixed with binders, carriers, diluents, disintegrants and the like as powders, as pills, or as capsules.
  • Typical liquid vehicles include sterile water and sterile sugar syrup.
  • Typical solid materials include starch, dextrose, mannitol microcrystalline cellulose and the like.
  • the materials can be presented as solutions/suspensions in aqueous media such as injectable saline, injectable water and the like. They can also be presented as suspensions or solutions in nonaqueous media such as the injectable oils including injectable corn oil, peanut oil, cotton seed oil, mineral oil, ethyl oleate, benzyl benzoate and the like.
  • aqueous media such as injectable saline, injectable water and the like.
  • nonaqueous media such as the injectable oils including injectable corn oil, peanut oil, cotton seed oil, mineral oil, ethyl oleate, benzyl benzoate and the like.
  • the nonaqueous media can, in some cases, permit substantial quantities of the medication to be administered as a depot in the patient's fat layer so as to obtain a prolonged release of the agent to the patient.
  • the materials of this invention are used in fairly large doses. Commonly, dose levels of from about 100 mg/day to as much as 10,000 mg/day are employed. The actual use level will vary depending upon the particular patient's response to the drug and to the patient's degree of affliction. In a particularly preferred utility, the compounds are used against Plasmodia and, in that use, require dosages from 0.1 to 10 times that used with the natural product artemisinin.
  • the aldehyde (6, Figure 1) (1.1 g, 4.04 mmoles) in dry THF (10 ml) was added dropwise via syringe to diisobutylaluminum hydride (DIBAL) (4.21 ml of 1.2 M solution in toluene, 5.05 mmoles) in dry THF (30 ml) at -78°C under argon.
  • DIBAL diisobutylaluminum hydride
  • the mixture was stirred at -78°C for 30 min. and then was allowed to warm to room temperature over 30 min.
  • the mixture was poured into ice-cold, saturated potassium sodium tartrate solution (50 ml) and was extracted with ethyl acetate (2 x 50 ml).
  • the resultant crude acid was dissolved in CH 2 CI 2 (about 0.5 ml) and added to a well-stirred slurry of silica gel, (50 mg, 70-230 mesh Keiselgel 60) in CH 2 CI 2 (0.5 ml) which had been treated with 10% aqueous oxalic acid (20 ⁇ l). After 18 hrs at room temperature under argon, the slurry was filtered and washed with CH 2 CI 2 (10 ml). The solvent was evaporated to give the crude acid 17 ( Figure 2) (21 mg). The crude acid was purified on a TLC plate (250 micron, silica gel) eluting with 40% EtOAc/hexane (containing 0.4% HOAc).
  • the keto-acid 17 (Figure 2) (3.5 mg or 0.0108 mmol) was dissolved in dry methanol (1 ml) and placed in a 1 dram vial under argon with a screw cap. The solution was cooled at -78°C, the cap removed, and a stream of O 3 /O 2 (7 psi, 0.4 1/min, 70 v) was bubbled in until a faint blue color was seen (about 10 sec). The cap was replaced and the solution stood at -78°C for 5 min. The solution was then purged with argon (5 min.) and warmed to room temperature. The solvent was carefully removed under high vacuum (0.02 mm Hg), and the resultant solid was kept under high vacuum for 30 min.
  • the bicyclic ketone 2 available in good yield from cyclohexanone by the method of Still (W.C. Still, Synthesis, 453 (1976)), was treated with bis(trimethylsilyl)methyl lithium to give the diene 3 in 56% yield.
  • the disubstituted double bond of 3 was selectively converted to the ozonide by treatment with ozone in methanol:dichloromethane (1:5, v/v) in the presence of sodium bicarbonate.
  • the crude ozonolysis product was then reacted with Et 3 N/Ac 2 O to afford the ester-aldehyde 4 in 43% yield.
  • Bis(trimethylsilyl)methyllithium was prepared according to a procedure of Grobel and Seebach (B.Th. Grobel and D. Seebach, Chem. Ber., 110, 852 (1977)); to a solution of bis(trimethylsilyl)methane (2.85 ml, 13.3 mmol) in THF (20 ml) and HMPT (5 ml) at -78°C was added dropwise via syringe a solution of s-BuLi (7.66 ml of 1.74 M in pentane). The resultant pale green solution was allowed to warm to -40°C.
  • the crude adduct mixture 5 ( Figure 8) was placed in THF (4 ml) and added via cannula to a stirring suspension of NaH (24 mg of an 80% oil dispersion, 0.80 mmol) in THF (8 ml). After 3 h at ambient temperature, the resultant suspension was stirred with sat. aq. NH 4 CI (15 ml) and hexane (50 ml). The separated organic layer was washed with sat. aq. NH 4 CI (15 ml) and brine (25 ml), dried over Na 2 SO 4 and evaporated to afford 344 mg of orange oil, which was purified by column chromatography with silica gel.
  • ketoacid 8 (Figure 8) (17 mg, 0.057 mmol) in absolute MeOH (2 ml) at -78°C was passed a stream of O 3 /O 2 until no starting material could be detected by TLC (HOAc/EtOAc/hexane).
  • TLC HOAc/EtOAc/hexane
  • the resultant pink solution was allowed to warm to ambient temperature and concentrated in vacuo to a yellow foam, which was placed in CDCI 3 (2 ml).
  • CDCI 3 2 ml
  • Example 20-24 The preparation of Examples 20-24 is repeated with the change that in Example 20 in place of 1-hydroxymethyl cyclohexene 4 ( Figure 6), 400 mmole of 1-hydroxymethylcyclopentene is used. This gives rise to artemisinin analogs similar to compounds 2 and 3 but having one less carbon in the alkylene bridge between the "1" and "7" carbons.
  • Example 20-24 The preparation of Examples 20-24 is repeated with the change that in Example 20 in place of 1-hydroxymethyl cyclohexene 4 ( Figure 4), 400 mmole of 1-hydroxy-2-ethylhex-2-ene is used. This gives rise to artemisinin analogs similar to compounds 2 and 3 but having an ethyl as R 8 and a butyl as R 9 .
  • drugs which are actively incorporated into erythrocytes will have slightly lower 50% inhibitory concentrations than in other assay systems employing higher red cell hematocrits.
  • the culture medium is folate-free.
  • the trace amount of PABA insures exponential growth of the sulfonamide-susceptible parasite clone without antagonizing the activity of antifol anti-malarials.
  • Sulfonamides and sulfones are 1, 000-10, 000-fold more active and DHFR inhibitors are 5-200-fold more active in this medium than in normal RPMI 1640 culture medium.
  • test compounds are solubilized in DMSO and diluted 400-fold (to rule out a DMSO effect) in culture medium with plasma for a starting concentration of at least 12,500 ng/ml.
  • Drugs are subsequently diluted fivefold using the Cetus Pro/Pette system utilizing a range of concentrations from 0.8 ng/ml to 12,500 ng/ml. Fifty percent inhibitory concentrations are reported in ng/ml.
  • Table 1 summarizes differences in the susceptibility profiles of the two control P. falciparum clones (Oduola, A.M.J., N.F. Weatherly, J.H. Bowdre, R.E. Desjardins, Thirty-second Annual Meeting, American Society of Tropical Medicine and Hygiene, San Antonio, Texas, December 4-8, 1983) and provides results of testing.
  • the W-2 Indochina P. falciparum clone is resistant to chloroquine, pyrimethamine and sulfadoxine but susceptible to mefloquine.
  • the D-6 African P. falciparum clone is susceptible to chloroquine, pyrimethamine and sulfadoxine but resistant to mefloquine.
  • the WRAIR in vitro antimalarial screen was used to assess the intrinsic activity of compounds (2, Figure 6) and (3, Figure 6) as antimalarial drugs relative to simultaneous known controls such as chloroquine, mefloquine, pyrimethamine, sulfadoxine, tetracycline, qinghaosu or quinine.
  • Table 2 summarizes differences in the susceptibility profiles of the two control P. falciparum clones.

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0335717A3 (en) * 1988-03-30 1991-04-10 Oxaco S.A. 1,2,4-trioxanes related to arteannuin
WO1991014689A1 (en) * 1990-03-23 1991-10-03 Sri International Antimalarial analogs of artemisinin
EP0456149A1 (en) * 1990-05-07 1991-11-13 Hoechst Aktiengesellschaft 9-Substituted compounds of 3 alpha, 11 alpha-Epoxy-3,4,5, 5a alpha,6,7,8,8a,9,11,11a-undecahydro-3 beta, 6 alpha, 9-trimethylfurano[3,4-j][1,2]-benzodioxepin, processes for their preparation and their use as antiprotozoal and antiviral agents
WO1993008195A1 (en) * 1991-10-14 1993-04-29 The University Of Sydney Cyclic peroxyacetal compounds
EP0974593A1 (en) * 1998-07-14 2000-01-26 The Hong Kong University of Science & Technology Artemisinin derivatives as antiparasitic agents
EP1043988A4 (en) * 1997-12-30 2001-10-31 Hauser Inc ARTEMISININ TYPE C-10 CARBON-SUBSTITUTED TRIOXANE COMPOUNDS WITH ANTI-MALARIA, ANTIPROLIFERATIVE AND ANTITUMOR ACTION

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, volume 102, no. 9, 04 March 1985, (Columbus, Ohio, US), X. Luo et al.: "Detection of metabolites of Qing Hao Sau in nanomolar quantities: DADF-esters of dihyaroQing Hao Sau and its epoxy analog. The chamistry of drugs. V.", see page 12, abstract 72313b, & Heterocycles 1984, 22(11), 2559-62 *
Chemical Abstracts, volume 105, no. 3, 21 July 1986, (Columbus, Ohio, US), P. Yu et al.: "Analogs of Qing Hao Su (artemisinin, arteannuin). IV. Synthesis of derivatives of Qing Hao Su containing halogen, nitrogen, and sulfur heteroatoms", see page 658, abstract 24454p, & Yaoxue Xuebao 1985, 20(5), 357-65 *
Chemical Abstracts, volume 97, no. 11, 13 September 1982, (Columbus, Ohio, US). Y. Li et al.: "Studies on artemisinine analogs. I. Sythesis of ethers, carboxylates and carbonates of dihydroartemisinine", see page 768, abstract 92245n, & Yaoxue Xuebao 1981, 16(6), 429-39 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0335717A3 (en) * 1988-03-30 1991-04-10 Oxaco S.A. 1,2,4-trioxanes related to arteannuin
WO1991014689A1 (en) * 1990-03-23 1991-10-03 Sri International Antimalarial analogs of artemisinin
US5216175A (en) * 1990-03-23 1993-06-01 Sri International Antimalarial analogs of artemisinin
EP0456149A1 (en) * 1990-05-07 1991-11-13 Hoechst Aktiengesellschaft 9-Substituted compounds of 3 alpha, 11 alpha-Epoxy-3,4,5, 5a alpha,6,7,8,8a,9,11,11a-undecahydro-3 beta, 6 alpha, 9-trimethylfurano[3,4-j][1,2]-benzodioxepin, processes for their preparation and their use as antiprotozoal and antiviral agents
US5246930A (en) * 1990-05-07 1993-09-21 Hoechst Aktiengesellschaft 9-substituted compounds of 3α, 11α-epoxy-3,4,5,5aα,6,7,8,8a,9,11,11a-undecahydro-3β,6.alpha.,9-trimethylfurano[3,4-j][1,2]benzodioxepin, processes for their preparation and their use as antiprotozoal and antiviral agents
WO1993008195A1 (en) * 1991-10-14 1993-04-29 The University Of Sydney Cyclic peroxyacetal compounds
AU659505B2 (en) * 1991-10-14 1995-05-18 University Of Sydney, The Cyclic peroxyacetal compounds
EP1043988A4 (en) * 1997-12-30 2001-10-31 Hauser Inc ARTEMISININ TYPE C-10 CARBON-SUBSTITUTED TRIOXANE COMPOUNDS WITH ANTI-MALARIA, ANTIPROLIFERATIVE AND ANTITUMOR ACTION
EP0974593A1 (en) * 1998-07-14 2000-01-26 The Hong Kong University of Science & Technology Artemisinin derivatives as antiparasitic agents

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