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WO1998021211A1 - Marcfortines et paraherquamides substitues en position 1 et 2 utilises comme antiparasitaires - Google Patents

Marcfortines et paraherquamides substitues en position 1 et 2 utilises comme antiparasitaires Download PDF

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Publication number
WO1998021211A1
WO1998021211A1 PCT/US1997/018980 US9718980W WO9821211A1 WO 1998021211 A1 WO1998021211 A1 WO 1998021211A1 US 9718980 W US9718980 W US 9718980W WO 9821211 A1 WO9821211 A1 WO 9821211A1
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Prior art keywords
alkyl
group
formula
desoxo
preparation
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Inventor
Byung H. Lee
Michael F. Clothier
William W. Mcwhorter, Jr.
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Pharmacia and Upjohn Co
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Pharmacia and Upjohn Co
Upjohn Co
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Priority to AU49110/97A priority Critical patent/AU4911097A/en
Publication of WO1998021211A1 publication Critical patent/WO1998021211A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention is N-l, C-2 and N-l,C-2 substituted marcfortines and paraherquamide A including 1,2-cyclic forms which are useful as antiparasitic agents.
  • the marcfortines are known compounds, see Journal of the Chemical Society Chemical Communications, 601-602 (1980) for Marcfortine A and Tetrahedron Letters, 22, 1977-1980 ((1981) for Marcfortines B and C. These compounds are fungal metabolites of Penicillium roqueforti.
  • the marcfortines are structurally related to the paraherquamides which are also known compounds.
  • WO 91/09961 discloses various derivatives of marcfortine and paraherquamide, and 12a-N-oxides thereof, as well as the production the production of VM 29919 (paraherquamide) and VM 55596 (the 12a-N- oxide of paraherquamide) inter aha from Penicillium Sp. IMI 332995.
  • US Patent 4,873,247 discloses derivatives of paraherquamide and a strain of Penicillium charlessi MF 5123 (ATCC 20841) for the production of paraherquamide.
  • US Patent 4,978,656 discloses various synthetic derivatives of paraherquamide as well as the production of paraherquamide from Penicillium charlessi MF 5123 (ATCC 20841).
  • R 14 is ⁇ -R 14-1 : ⁇ -R 14 . 2 and R 15 is cc-R 15 . 1 : ⁇ -R 15 . 2 where:
  • R 14 ⁇ is -H or C r C 4 alkyl
  • R 15 . 2 is -H with the provisos: (1) that when n 16 is 0, R N is -CH 3 and R 14 ⁇ is -OH and
  • R 14p is -CH 3
  • n 16 is 0 or 1;
  • R N is -H or -CH 3 ;
  • R j is ⁇ -H: ⁇ -R 2.2 where R ⁇ is selected from the group consiting of
  • R 14 and R 15 are as defined above and pharmaceutically acceptable salts thereof.
  • n 16 is 0 or 1;
  • R N is -H or -CH 3 ;
  • R 14 and R 15 are as defined above;
  • X L is -O- or -CH 2 - and pharmaceutically acceptable salts thereof. Additionally disclosed are esters of formula (XXTV) where:
  • n 16 is 0 or 1;
  • R N is -H or -CH 3 ;
  • R 18 is:
  • the invention here is the novel ANTIPARASITIC AGENTS which refers to the 2-desoxo-l-substituted compounds (XIII), 2-desoxo-2-substituted compounds (XV), oxygen fused ring compounds (XVI) and 1,2-cyclic compounds (XXI) of the present invention.
  • n 16 is 0 (paraherquamides) or 1 (marcfortines).
  • R N is -H (marcfortine B and C) or -CH 3 (paraherquamide A, marcfortine A and D).
  • R : is:
  • R j is ⁇ -H: ⁇ -R 2.2 where R 2 _ 2 is selected from the group consiting of:
  • R 14 is ⁇ - ⁇ -R ⁇ a and R 15 is ⁇ -R 15 . 1 : ⁇ -R 15 _ 2 where: (A) R 14 ⁇ is -H or -OH, (B) R 14 ⁇ is -H or C r C 4 alkyl,
  • (C) R 15 . ! is -H or C r C 4 alkyl
  • the 2-desoxo- marcfortines A and paraherquamides A (XII) and 1,2-dehydro or ⁇ imines (XTV) starting materials for the present invention are either known to those skilled in the art, can be readily prepared from known compounds by methods known to those skilled in the art from their corresponding 2-oxygenatged derivatives.
  • the chemistry used to produce the ANTIPARASITIC AGENTS compound is not inventive. Known chemistry is used. By starting with the appropriate starting material and using known chemistry processes in a particular designated order the desired ANTIPARASITIC AGENTS are produced.
  • CHART A discloses the preferred process to produce the 15-alkyl-14-hydroxy marcfortine A compounds (III).
  • the starting 14-hydroxy- ⁇ , ⁇ -unsaturated compound (I) is known, see International Publication WO94/29319.
  • the 14-hydroxy- ⁇ , ⁇ - unsaturated compounds (I) can be transformed to the corresponding 15-alkyl-17-oxo compounds (II) by reaction with an alkylating agents such as a Grignard reagent or alkylcuprates; it is preferred that the alkylating reagent be a Grignard reagent of the formula CH 3 -(CH 2 ) nl -Mg-X 0 , where n x is 0 thru 3 and XQ is halogen.
  • n, ⁇ is 1 and X ⁇ , is -Br.
  • the preferred process is to react the 14- hydroxy- ⁇ , ⁇ -unsaturated compound (I) with ethylmagnesium bromide and copper (I) iodide under standard 1,4-addition conditions to produce the 15-alkyl-17-oxo compounds (II).
  • the 15-alkyl-17-oxo compounds (II) are then reduced my means known to those skilled in the art for reduction of a carbonyl group to an alkylene moiety such as reduction with borane dimethyl sulfide complex or other reducing agents such as borane THF complex or lithium aluminum hydride.
  • n x is 1.
  • the 15-alkyl-14-hydroxy compounds (III) where n x is 0 are known, see International Publication WO94/29319.
  • CHARTS B-G disclose the production of the 14-alkyl-14-hydroxymarcfortine A and 15-alkyl-14-hydroxyrnarcfortine A compounds. See also PREPARATIONS 1-31.
  • CHARTS B-G and the PREPARATIONS primarily exemplify methyl as the alkyl substituent (CHART E, compound 19 discloses 14 ⁇ -ethyl), however ethyl, propyl and butyl (including isomers thereof where such exist) are prepared in an analogous fashion as is known to those skilled in the art.
  • the process to produce 15-alkyl-14- hydroxymarcfortine A compounds is equally applicable to the paraherquamide A and the marcfortine B, C and D compounds.
  • CHART H discloses processes to produce 2-deoxo-14-hydroxy compounds (VTI) starting with 14-hydroxy- ⁇ , ⁇ -unsaturated amides (IV) where R 14 is -H or C r C 4 alkyl and where R 15 is -H or C ⁇ C,, alkyl.
  • the 14-hydroxy- ⁇ , ⁇ -unsaturated amides (W) have the ⁇ 15 -double bond reduced by reaction with the appropriate lithium reagent R 15 -Li in the presence of lithium bromide to give the 14-hydroxy-17-oxo compounds (V).
  • the C 15 -position can be alkylated during this reaction if so desired.
  • the 14- hydroxy- 17-oxo compounds (V) next have the 17-oxo group reduced by means of borane dimethyl sulfide complex (as previously described with regard to CHART A). This reduction produces the 14-hydroxy compound (VI) as well as the compound where both the 2- and 17-carbonyl groups are reduced, the desired 2-deoxo-14- hydroxy (VII) compound.
  • CHART I discloses a process to produce the 2-desoxo compounds (DC), see PREPARTION 50.
  • CHART J discloses a process to produce the corresponding 14-hydroxy 2- desoxoparaherquamide (XI).
  • CHART K discloses a process to produce the 1,2-dehydro or ⁇ imine compounds (XTV) which are starting materials for some of the aaas of present invention. It further discloses how the 1,2-dehydro or ⁇ imine compounds (XTV) can be transformed to the corresponding 2-desoxo-2-substituted compounds (XV).
  • CHART L discloses that the 2-desoxo-l-substituted compounds (XIII) are produced from the corresponding 2-desoxy compounds (XII). This is well known chemistry of the transformation of a secondary a ine to a tertiary amine.
  • CHART M discloses that the 1,2-dehydro or ⁇ mine compounds (XTV) are transformed to the corresponding 2-desoxo-2-substituted compounds (XV) by alkylation of an olefin (EXAMPLES 5-9) or to the corresponding oxygen fused ring compounds (XVI) by the process of EXAMPLE 12.
  • CHART N discloses the conversion of the 2-desoxo-l-substituted compounds (XIII) to the corresponding 1,2-disubstituted compounds (XVIII).
  • 1-substituted compounds includes those that are substituted at Nl alone or both at Nl and C2. Therefore, as used herein the term 2-desoxo-l- substituted compounds (XIII) includes 1,2-disubstituted compounds.
  • CHART O discloses the conversion of the 1,2-dehydro or ⁇ mine compounds (XTV) to the corresponding 1,2-cyclic compouds (XXI) by first forming a 2-allyl compounds (XLX) by standard alkylation of an olefin followed by oxidation of the olefin group to the 2-(3-hydroxypropyl) compound (XX) which is then cyclized to the desired 1,2-cyclic compound (XXI).
  • CHART P discloses the process to produce the desired ester (XXTV).
  • marcfortine or paraherquamide A or B is converted to the known thio intermediate (XXIII) by use of Lawesson's reagent in non-polar aromatic solvents at elevated temperatures, preferably at about 110°.
  • the thio intermediate (XXIII) is transformed to the desired ester (XXTV) by reaction with the appropriate ⁇ -haloester in a polar aprotic solvent at room temperature (about 20-25°).
  • the reagent is ethyl iodoacetate in DMF.
  • the ANTIPARASITIC AGENTS are amines, and as such form acid addition salts when reacted with acids of sufficient strength.
  • Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The pharmaceutically acceptable salts are preferred over the corresponding free amines since they produce compounds which are more water soluble and more crystalline.
  • the preferred pharmaceutically acceptable salts include salts of the following acids methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH 3 -(CH 2 ) n -COOH where n is 0 thru 4, HOOC-(CH 2 )n-COOH where n is as defined above.
  • the 2-desoxo-l-substituted compounds (XIII), 2-desoxo-2-substituted compounds (XV), 1,2-cyclic compounds (XXV) and the esters (XXTV) collectively are all "ANTIPARASITIC AGENTS" for purposes of this patent.
  • 1,2-cyclic compounds (XXV) includes both the oxygen fused ring compounds (XVI) and the all carbon ring compound (XXI).
  • the ANTIPARASITIC AGENTS of this invention are unexpectedly potent antiparasitic agents against endo and ecto parasites, particularly helminths and arthropods, which cause numerous parasitic diseases in humans, animals, and plants.
  • Parasitic diseases may be caused by either endoparasites or ectoparasites.
  • Endoparasites are those parasites which live inside the body of the host, either within an organ (such as the stomach, lungs, heart, intestines, etc.) or simply under the skin.
  • Ectoparasites are those parasites which live on the outer surface of the host but still draw nutrients from the host.
  • the endoparasitic diseases generally referred to as helminthiasis are due to infection of the host with parasitic worms known as helminths. Helminthiasis is a prevalent and serious worldwide economic problem due to infection of domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats, and poultry.
  • nematodes which cause diseases in various species of animals throughout the world. These diseases are frequently serious and can result in the death of the infected animal.
  • the most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris, and Parascaris.
  • Infections by ectoparasitic arthropods such as ticks, mites, lice, stable flies, hornflies, blowflies, fleas, and the like are also a serious problem. Infection by these parasites results in loss of blood, skin lesions, and can interfere with normal eating habits thus causing weight loss. These infections can also result in transmission of serious diseases such as encephalitis, anaplasmosis, swine pox, and the like which can be fatal.
  • ANTIPARASITIC AGENTS have unexpectedly high activity against these parasites, and in addition, are also active against Dirofilaria in dogs, Nematospiroides and Syphacia in rodents, biting insects and migrating dipterous larvae such as Hypoderma sp. in cattle, and Gastrophilus in horses.
  • the ANTIPARASITIC AGENTS are also useful against endo and ecto parasites which cause parasitic diseases in humans.
  • endoparasites which infect man include gastro intestinal parasites of the genera Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris, Enterobius, and the like.
  • Other endoparasites which infect man are found in the blood or in other organs.
  • Examples of such parasites are the filarial worms Wucheria, Brugia, Onchocerca, and the like as well as extra intestinal stages of the intestinal worms Strongylides and Trichinella.
  • Ectoparasites which parasitize man include arthropods such as ticks, fleas, mites, lice, and the like and, as with domestic animals, infections by these parasites can result in transmission of serious and even fatal diseases.
  • the ANTIPARASITIC AGENTS are active against these endo and ecto parasites and in addition are also active against biting insects and other dipterous pests which annoy humans.
  • the ANTIPARASITIC AGENTS when administered orally or parenterally are administered at a dosage rate of from 0.05 to 20 g/kg of animal body weight.
  • the ANTIPARASITIC AGENTS are also useful against common household pests such as Blatella sp. (cockroach), Tineola sp.
  • the ANTIPARASITIC AGENTS are furthermore useful against agricultural pests such as aphids (Acyrthiosiphon sp.), locusts, and boll weevils as well as against insect pests which attack stored grains such as Tribolium sp. and against immature stages of insects living on plant tissue.
  • the ANTIPARASITIC AGENTS are also useful as a nematocide for the control of soil nematodes which may be agriculturally important.
  • the ANTIPARASITIC AGENTS may be administered internally either orally or by injection, or topically as a liquid drench or as a shampoo.
  • the ANTIPARASITIC AGENTS may be administered in capsule, tablet, or drench bolus form or alternatively they can be mixed in the animals feed.
  • the capsules, tablets, and drenches boluses are comprised of the active ingredient in combination with an appropriate carrier vehicle such as starch, talc, magnesium stearate, or di-calcium phosphate.
  • suitable carrier vehicle such as starch, talc, magnesium stearate, or di-calcium phosphate.
  • suitable carrier vehicle such as starch, talc, magnesium stearate, or di-calcium phosphate.
  • These unit dosage forms are prepared by intimately mixing the active ingredient with suitable finely-powdered inert ingredients including diluents, fillers, disintegrating agents, suspending agents, and/or binders such that a uniform mixture solution or suspension is obtained.
  • An inert ingredient is one that will not react with the ANTIPARASITIC AGENTS and which is non toxic to the animal being treated.
  • Suitable inert ingredients include starch, lactose, talc, magnesium stearate, vegetable gums and oils, and the like. These formulations may contain a widely variable amount of the active and inactive ingredients depending on numerous factors such as the size and type of the animal species to be treated and the type and severity of the infection.
  • the active ingredient may also be administered as an additive to the feed by simply mixing the ANTIPARASITIC AGENTS with the feedstuff or by applying the compound to the surface of the feed. Alternatively the active ingredient may be mixed with an inert carrier and the resulting composition may then either be mixed with the feed or fed directly to the animal.
  • Suitable inert carriers include corn meal, citrus meal, fermentation residues, soya grits, dried grains and the like.
  • the active ingredients are intimately mixed with these inert carriers by grinding, stirring, milling, or tumbling such that the final composition contains from 0.001 to 5.0% by weight of the active ingredient.
  • the ANTIPARASITIC AGENTS may alternatively be administered parenterally via injection of a formulation consisting of the active ingredient dissolved in an inert liquid carrier. Injection may be either intramuscular, intraruminal, intratracheal, or subcutaneous.
  • the injectable formulation consists of the active ingredient mixed with an appropriate inert liquid carrier.
  • Acceptable liquid carriers include the vegetable oils such as peanut oil, cotton seed oil, sesame oil and the like as well as organic solvents such as solketal, glycerol formal and the like.
  • aqueous parenteral formulations may also be used.
  • the vegetable oils are the preferred liquid carriers.
  • the formulations are prepared by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from 0.005 to 20% by weight of the active ingredient.
  • Topical application of the ANTIPARASITIC AGENTS is possible through the use of a liquid drench or a shampoo containing the ANTIPARASITIC AGENTS as an aqueous solution or suspension.
  • These formulations generally contain a suspending agent such as bentonite and normally will also contain an antifoaming agent.
  • Formulations containing from 0.005 to 20% by weight of the active ingredient are acceptable.
  • Preferred formulations are those containing from 0.5 to 5% by weight of the ANTIPARASITIC AGENTS.
  • the ANTIPARASITIC AGENTS are primarily useful as antiparasitic agents for the treatment and/or prevention of helminthiasis in domestic animals such as cattle, sheep, horses, dogs, cats, goats, swine, and poultry. They are also useful in the prevention and treatment of parasitic infections of these animals by ectoparasites such as ticks, mites, lice, fleas and the like. They are also effective in the treatment of parasitic infections of humans. In treating such infections the ANTIPARASITIC AGENTS may be used individually or in combination with each other or with other unrelated antiparasitic agents.
  • the dosage of the ANTIPARASITIC AGENTS required for best results depends on several factors such as the species and size of the animal, the type and severity of the infection, the method of administration and the particular ANTIPARASITIC AGENTS used. Oral administration of the ANTIPARASITIC AGENTS a dose level of from 0.005 to 50 mg per kg of animal body weight either in a single dose or in several doses spaced a few days apart, generally gives good results. A single dose of one of the ANTIPARASITIC AGENTS normally gives excellent control however repeat doses may be given to combat re-infection or for parasite species which are unusually persistent.
  • the techniques for administering the ANTIPARASITIC AGENTS to animals are known to those skilled in the veterinary field.
  • the ANTIPARASITIC AGENTS may also be used to combat agricultural pests which attack crops either in the field or in storage.
  • the ANTIPARASITIC AGENTS are applied for such uses as sprays, dusts, emulsions and the like either to the growing plants or the harvested crops.
  • the techniques for applying the ANTIPARASITIC AGENTS in this manner are known to those skilled in the agricultural arts.
  • the exact dosage and frequency of administration depends on the particular ANTIPARASITIC AGENTS used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the ANTIPARASITIC AGENTS in the patient's blood and/or the patient's response to the particular condition being treated.
  • R, and R would represent monovalent variable substituents if attached to the formula CH 3 -CH 2 -C(R 1 )(R J )-H.
  • variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis.
  • each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
  • both R ⁇ and ⁇ are bonded to the preceding carbon atom.
  • C Pain for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as C Comp where "i" is the integer corresponding to the carbon atom number.
  • C 6 represents the 6 position or carbon atom number in the steroid nucleus as tradition- ally designated by those skilled in the art of steroid chemistry.
  • R 6 represents a variable substituent (either monovalent or bivalent) at the C 6 position.
  • Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion.
  • the cyclic molecular fragment, 4-(ethyl)-l-piperazinyl can be represented by -N * -(CH 2 ) 2 -N(C 2 H 5 )-CH 2 -C * H 2 .
  • a rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound.
  • the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial.
  • the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other.
  • a substituent (X : ) which is "below” another substituent (Xj) will be identified as being in the alpha ( ⁇ ) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol "- - -” or "!.
  • the corresponding substituent attached “above” (X 2 ) the other (X is identified as being in the beta ( ⁇ ) configuration and is indicated by an unbroken line attachment to the carbon atom.
  • variable substituent when a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable.
  • R when a bivalent variable, R, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form " ⁇ -R ⁇ B-R ⁇ " or some variant thereof. In such a case both ⁇ -R,.
  • bivalent variable may be defined as two separate monovalent variable substituents
  • two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable.
  • R ⁇ and R may be defined to be taken together to form (1) a second bond between C x and C 2 or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide.
  • the first method uses a prefix to the entire name of the variable such as "C ⁇ C 4 ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable.
  • the prefix is separated from the variable by a space.
  • C r C 4 alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given).
  • the prefix indicates the entire carbon atom content of the variable being defined.
  • C 2 -C 4 alkoxycarbonyl describes a group CH 3 -(CH 2 ) n -O-CO- where n is zero, one or two.
  • C 2 -C 6 alkoxyalkyl and (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms
  • the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
  • TLC refers to thin-layer chromatography.
  • DMF refers to dimethylformamide.
  • AIBN refers to 2,2'-azobisisobutyronitrile.
  • Lawesson's reagent refers to [2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4- diphosphetane-2,4-disulfide].
  • DAST diethylamino sulfur trifluoride.
  • Chromatography column and flash chromatography refers to purification separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
  • NMR nuclear (proton) magnetic resonance spectroscopy
  • chemical shifts are reported in ppm ( ⁇ ) downfield from tetramethylsilane.
  • - ⁇ refers to phenyl (C 6 H 5 ).
  • MS refers to mass spectrometry expressed as m e, m/z or mass/charge unit.
  • [M + H] + refers to the positive ion of a parent plus a hydrogen atom.
  • El refers to electron impact.
  • CI refers to chemical ionization.
  • FAB refers to fast atom bombardment.
  • HRMS refers to high resolution mass spectrometry.
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • the ratios of solvents used are volume/volume (v/v).
  • the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).
  • ANTIPARASITIC AGENTS refers to 2-desoxo-l-substituted compounds (XIII), 2-desoxo-2-substituted compounds (XV), 1,2-cyclic compounds (XXV) and the esters (XXTV) collectively.
  • 1,2-cyclic compounds (XXV) includes both the oxygen fused ring compounds (XVI) and the all carbon ring compound (XXI).
  • 2-Desoxo-l-substituted compounds (XIII) include the 2-desoxo- 1,2- disubstituted compounds (XVIII) since these are 2-desoxo-l-substituted compounds.
  • 16-Iodo-17-cyanomarcfortine A PREPARATION 1, 9.5 g, 15 mmol is dissolved in methanol (150 mL), and aqueous potassium hydroxide (45%, 3 mL) is added. The reaction mixture is stirred at 20-25° for 2 hr. Water is added and the resulting precipitate collected by filtration, washed with water and dried overnight under reduced pressure to give the title compoound.
  • PREPARATION 3 17-Ketomarcfortine A (Formula 7)
  • the title compound can be synthesized by using p-toluenesufonic acid.
  • p-toluenesulfonic acid monohydrate (1 g) is to a solution of 16,17-dehydro-17-cyanomarcfortine A (10 g) in 95% methanol (50 mL) and the reaction mixture stirred at 20-25° for 1 hr.
  • Triethylamine (2 mL) is added to the mixture and the solvent is evaporated. The residue is triturated with aqueous sodium carbonate solution (10%, 100 mL) and the solid is filter and dried to give the title compound as a solid (90% yield).
  • PREPARATION 4 15,16-Dehydro-17-ketomarcfortine A (Formula 8)
  • a solution of lithium diisopropylamide is prepared from a solution of n-butyl lithium (1.6 M, 9.9 mL, 15.4 mmol) in hexane and diisopropylamine (2.2 mL, 15.7 mmol). This is diluted with anhydrous tetrahydrofuran (THF, 20 mL) and cooled to at -78°. A solution of 17-ketomarcfortine A (PREPARATION 3, 2.0 g, 4.1 mmol) in anhydrous THF (20 mL) is added dropwise and the reaction mixture allowed to warm to -40° during 1 hr.
  • THF tetrahydrofuran
  • reaction mixture is cooled to -78°, stirred 15 min and then treated by the dropwise addition of a solution of 2-phenylsulfonyl-3- phenyloxaziridine (42 mg, 0.16 mmol) in THF (2 mL).
  • the mixture is stirred 5 min after which the reaction is quenched by adding sodium bicarbonate.
  • the mixture is extracted with methylene chloride (2 x 25 mL). The extracts are combined, dried (magnesium sulfate) and concentrated to give crude material.
  • the residue contains a mixture of the two epimers which are readily separated by chromatography (silica gel; methanol/ethyl acetate, 1/20) - 14 ⁇ -hydroxy-17-ketomarcfortine A (90 mg, 19%) and 14 ⁇ -hydroxy-17- ketomarcfortine A (94 mg, 20%).
  • a solution of 14 ⁇ -hydroxy-14 ⁇ -methyl-17-ketomarcfortine A (PREPARATION 13, 5mg, 0.01 mmol) in THF (5 mL) is treated with a solution of lithium aluminum hydride (IM, 0.03 mL, 0.03 mmol) in THF at 0°.
  • IM lithium aluminum hydride
  • the mixture is stirred for 0.5 hr at 0° after which a solution of sodium bicarbonate (10%) is added.
  • the mixture is extracted with methylene chloride (2 x 5 mL). The extracts are combined, dried (magnesium sulfate) and the solvent evaporated.
  • a solution of 14-ketomarcfortine A (PREPARATION 15, 25 mg, 0.05 mmol) in THF (5 mL) at -78° is treated with a solution of ethylmagnesium bromide (3 M, 0.15 mL, 0.45 mmol) in ether at -78°.
  • the resulting mixture is stirred for 0.5 hr at -78°.
  • the reaction mixture is allowed to warm to 20-25° during 20 min.
  • the reaction is quenched by adding sodium carbonate (10%, a few drops).
  • the mixture is diluted with methylene chloride (10 mL), dried (magnesium sulfate) and concentrated.
  • PREPARATION 19 Preparation of 14 ⁇ -methylmarcfortine A from 14 ⁇ -hydroxy-14 ⁇ - methylmarcfortine A
  • a solution of potassium bis(trimethylsilyl)amide in toluene 0.5 M, 1 mL, 0.5 mmol
  • 14 ⁇ -hydroxy-14 ⁇ -methylmarcfortine A Formulamula 15, PREPARATION 14, 66 mg, 0.14 mmol
  • THF 2 mL
  • reaction mixture is cooled -78°, stirred 15 min, and then treated by the dropwise addition of a solution of phenylchlorothionoformate (0.094 mL, 0.7 mmol) in THF (2 mL). After 10 min the dry ice bath is removed. After further reaction for 3 hr, the reaction is quenched by adding sodium bicarbonate. The mixture is extracted with methylene chloride (2 x 25 mL). The extracts are combined, dried (magnesium sulfate) and concentrated to give crude material. This is purified by preparative TLC (silica gel, ethyl acetate) to give 14 ⁇ -O-phenoxythiocarbonyl-14 ⁇ -methylmarcfortine A.
  • the crude 17-ketomarcfortine A (PREPARATION 20, 5 g, 10.2 mmol) is added via a cannula in THF (150 mL) at -78° to an LDA solution which was prepared by adding ⁇ .-butyllithium (1.6 M, 24.8 mL, 0.04 mol) dropwise to diisopropyl amine (5.7 mL, 0.041 mol) at O° in THF (100 mL). The reaction mixture is allowed to slowly warm to -50° over one hr. The resulting mixture is then treated with phenyl disulfide (4.4 g, 0.02 mol).
  • PREPARATION 27 14 ⁇ -Hydroxy-14 ⁇ -methylmarcfortine A N-oxide
  • a solution of 14 ⁇ -hydroxymarcfortine A (PREPARATION 11, 30 mg) in methylene chloride (3 mL) is treated with m-chloroperoxybenzoic acid (20 mg) at 0°. After the mixture is stirred for 0.5 hR, then partitioned between aqueous sodium bicarbonate (5%, 10 mL) and methylene chloride (20 mL). The layers are separated and the aqueous layer extracted with methylene chloride (10 mL).
  • 14 ⁇ -Hydroxy-15 ⁇ -methyl-17-ketomarcfortine A (CHART G, formula 34, 90 mg, 0.18 mmol) is dissolved in THF (10 mL) and treated with borane dimethyl sulfide complex (12 M, 0.18 mL) at 0°. The mixture is stirred for 2 hr at 0°, then methanol (0.4 mL) is added and stirred for an additional 1 hr.
  • Paraherquamide A 70 mg, 0.14 mmol in THF (10 mL) and potassium hydride (35 weight %, 0.062 g, 0.55 mmol) are stirred for 2 hr at 20-25°.
  • di-tert-butyl dicarbonate 86 mg, 0.42 mmol is added.
  • the mixture is stirred for 0.5 hr, quenched with 10% potassium carbonate solution (50 mL), and extracted into ethyl acetate (150 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated.
  • N(l)-Phenoxycarbonylmarcfortine A PREPARATION 32, 2.4 g, 4.0 mmol
  • PREPARATION 32 2.4 g, 4.0 mmol
  • sodium borohydride 540 mg
  • the reaction mixture is quenched with potassium carbonate (10%, 100 mL).
  • PREPARATION 42 N(l)-9'-Fluorenylmethyloxycarbonyl-2 ⁇ -hydroxy-2- desoxomarcfortine A Following the general procedure of PREPARATION 40 and making non- critical variations but using N(l)-9'-fiuorenylmethyloxycarbonylmarcfortine A (PREPARATION 35, 30 mg, 0.043 mmol) the title compound is obtained, selected NMR (400 MHz, CDC1 3 ) 7.88-7.20, 6.72, 6.64, 6.38, 4.76, 4.28, 3.01, 2.85 and 2.60 ⁇ .
  • PREPARATION 45 N( l)-4'-Nitrophenoxycarbonyl- 14 ⁇ -hydroxy- 15 ⁇ -methyl-2 ⁇ - hydroxy-2-desoxomarcfortine A
  • PREPARATION 39 2 g, 2.97 mmol
  • PREPARATION 46 1,2-Dehydromarcfortine A Method A.
  • N(l)-Phenoxycarbonyl-2 ⁇ -hydroxy-2-desoxomarcfortine A PREPARATION 40, 1 g, 1.67 mmol
  • PREPARATION 40 1 g, 1.67 mmol
  • glyme 15 mL
  • sodium hydroxide 1 N, 20 mL
  • the mixture is refluxed for 1-2 hr. After the mixture is cooled to 20-25°, potassium carbonate (10%, 60 mL) is added.
  • N,N-dimethylethylamine complex (0.5 M, 2.6 mL, 13.4 mmol) dropwise.
  • the resulting mixture is stirred for 1 hr at 0° then quenched with methanol (5 mL) slowly dropwise.
  • 1,2-Dehydromarcfortine A (PREPARATION 46, 220 mg, 0.48 mmol) is dissolved in methanol (10 mL) and treated with sodium borohydride (30 mg) at 0° for 15 min. The reaction mixture is quenched with potassium carbonate (10%, 20 mL). The resulting precipitate is dried to give the title compound, NMR (400 MHz) is same as that of PREPARATION 50. Method B.
  • N(l)-tert-Butoxycarbonylmarcfortine A (PREPARATION 33, 100 mg, 0.17 mmol) is dissolved in diglyme (5 L) and treated with sodium borohydride (20 mg) at 20-25°. The mixture is then heated to reflux for 0.5 hr. After the mixture is cooled to 20-25°, potassium carbonate (10%, 10 mL) is added. The resulting precipitate is dried to give the title compound.
  • PREPARATION 53 2-Desoxoparaherquamide A Method A. 1,2-Dehydroparaherquamide A (PREPARATION 47, 1.5 g, 3.14 mmol) is dissolved in methanol (30 mL) and treated with sodium borohydride (250 mg) at 0° for 15 min.
  • N(l)-tert-Butoxycarbonylparaherquamide A (PREPARATION 36, 30 mg, 0.05 mmol) is dissolved in glyme (2 mL) and treated with sodium borohydride (20 mg) at 20-25°. The mixture is then heated to reflux for 4 hr. After the mixture is cooled to 20-25°, potassium carbonate (10%, 5 mL) is added, and extracted into ethyl acetate (10 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated to give the residue which is chromatographed (silica gel; methanol/methylene chloride, 5/95) to give the title compound.
  • Method C Method C.
  • EXAMPLE 5 2'-2-Desoxopropenylmarcfortine A (XV)
  • 1,2-dehydromarcfortine A (XTV, PREPARATION 46) at 0° is added allylmagnesium bromide (1 mL, 1.1 mmol) dropwise. The mixture is stirred for 0.25 hr, diluted with ammonium chloride (saturated, 50 mL) and extracted into ethyl acetate (50 mL). The organic layer is separated and dried over magnesium sulfate, filtered, and concentrated.
  • 1,2-dehydromarcfortine A (XTV, PREPARATION 46, 50 mg, 0.1 mmol) in THF (5 mL) at -78° is added n-butyllithium (1.6 M, 0.2 mL, 0.3 mmol) dropwise. The mixture is stirred for 1 hr at -78°, then quenched with water (25 L) and extracted into ethyl acetate (25 mL). The organic layer is separated and dried over magnesium sulfate, filtered, and concentrated.
  • n-butyllithium 1.6 M, 0.2 mL, 0.3 mmol
  • the crude product (0.950 g) is chromatographed (silica gel, 90 g; methylene chloride/acetone, 3/1) to give the title compound, NMR (CDC1 3 ) 0.84, 1.15, 1.28, 1.43, 1.45, 1.53-1.98, 1.80, 2.06, 2.46, 2.65, 2.71, 3.04, 3.12, 4.09-4.18, 4.23, 4.78, 4.87, 6.32, 6.65, 6.78 and 7.54 ⁇ ; IR (mull) 2924, 2855, 1710, 1668, 1633, 1590, 1579, 1504, 1464, 1330, 1186, 1156, 1048 and 729 cm 1 ; MS (FAB, m/z (rel.

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Abstract

L'invention porte sur divers marcfortines et paraherquamides substitués en position 1 et 2 comprenant des composés cycliques 1,2 représenté par la formule (XXV) et utilisés dans le traitement et la prévention de maladies parasitaires chez les animaux et les êtres humains.
PCT/US1997/018980 1996-11-15 1997-10-27 Marcfortines et paraherquamides substitues en position 1 et 2 utilises comme antiparasitaires Ceased WO1998021211A1 (fr)

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AU49110/97A AU4911097A (en) 1996-11-15 1997-10-27 1- and 2-substituted marcfortines and paraherquamides as antiparasitic agents

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US3094396P 1996-11-15 1996-11-15
US60/030,943 1996-11-15

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0354615A1 (fr) * 1988-08-12 1990-02-14 Merck & Co. Inc. Dérivés synthétiques de paraherquamide
EP0383513A2 (fr) * 1989-02-13 1990-08-22 Merck & Co. Inc. Dérivés d'avermectine
WO1991009961A2 (fr) * 1989-12-21 1991-07-11 Beecham Group Plc Nouveaux produits
WO1992000300A1 (fr) * 1990-06-26 1992-01-09 Pfizer Limited Agents antiparasitaires apparentes au paraherquamide
GB2247016A (en) * 1990-08-15 1992-02-19 Pfizer Ltd Antiparasitic agents
EP0508699A1 (fr) * 1991-04-04 1992-10-14 Merck & Co. Inc. Dérivés de 9-Deoxo-8a-aza-8a-homoérythromycin a modifiés aux positions 4'' et 8a
WO1992022555A1 (fr) * 1991-06-17 1992-12-23 Beecham Group Plc Derives de paraherquamide, precurseur de ces derives, procedes de preparation, microorganisme utilise et utilisation de ces derives comme agents parasiticides
WO1993010120A1 (fr) * 1991-11-22 1993-05-27 The Upjohn Company Derives de marcfortine/ paraherquamide utilises comme agents antiparasitaires
WO1994029319A1 (fr) * 1993-06-16 1994-12-22 The Upjohn Company Marcfortines a substitution en position 14 et derives utiles comme agents anti-parasitaires
WO1997003988A1 (fr) * 1995-07-21 1997-02-06 Pharmacia & Upjohn Company Marcfortines et paraherquamides antiparasitaires

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0354615A1 (fr) * 1988-08-12 1990-02-14 Merck & Co. Inc. Dérivés synthétiques de paraherquamide
EP0383513A2 (fr) * 1989-02-13 1990-08-22 Merck & Co. Inc. Dérivés d'avermectine
WO1991009961A2 (fr) * 1989-12-21 1991-07-11 Beecham Group Plc Nouveaux produits
WO1992000300A1 (fr) * 1990-06-26 1992-01-09 Pfizer Limited Agents antiparasitaires apparentes au paraherquamide
GB2247016A (en) * 1990-08-15 1992-02-19 Pfizer Ltd Antiparasitic agents
EP0508699A1 (fr) * 1991-04-04 1992-10-14 Merck & Co. Inc. Dérivés de 9-Deoxo-8a-aza-8a-homoérythromycin a modifiés aux positions 4'' et 8a
WO1992022555A1 (fr) * 1991-06-17 1992-12-23 Beecham Group Plc Derives de paraherquamide, precurseur de ces derives, procedes de preparation, microorganisme utilise et utilisation de ces derives comme agents parasiticides
WO1993010120A1 (fr) * 1991-11-22 1993-05-27 The Upjohn Company Derives de marcfortine/ paraherquamide utilises comme agents antiparasitaires
WO1994029319A1 (fr) * 1993-06-16 1994-12-22 The Upjohn Company Marcfortines a substitution en position 14 et derives utiles comme agents anti-parasitaires
WO1997003988A1 (fr) * 1995-07-21 1997-02-06 Pharmacia & Upjohn Company Marcfortines et paraherquamides antiparasitaires

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BLACHFLOWER,S.E. ET AL.: "Further novel metabolites of the Paraherquamide family", J.ANTIBIOT., vol. 46, no. 9, September 1993 (1993-09-01), pages 1355 - 1363, XP002056211 *
KUO,M.S. ET AL.: "Biosynthesis of Marcfortine A", J.ANTIBIOT., vol. 49, no. 10, October 1996 (1996-10-01), pages 1006 - 1013, XP002056212 *

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