WO2008029294A2 - Procédé de fabrication de dérivés d'anthracycline - Google Patents

Procédé de fabrication de dérivés d'anthracycline Download PDF

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WO2008029294A2
WO2008029294A2 PCT/IB2007/003700 IB2007003700W WO2008029294A2 WO 2008029294 A2 WO2008029294 A2 WO 2008029294A2 IB 2007003700 W IB2007003700 W IB 2007003700W WO 2008029294 A2 WO2008029294 A2 WO 2008029294A2
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group
alkyl
anthracycline
heteroatom
aryl
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PCT/IB2007/003700
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WO2008029294A3 (fr
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Wieslaw Szeja
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Prochem Szeja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention generally relates to the fields of synthetic organic chemistry and anticancer agents.
  • methods of the present invention provide facile synthetic access to anthracycline derivatives.
  • anthracyclines are known to show high anti-tumor activity and may be utilized as chemotherapeutics.
  • the methods discussed herein offer regioselective control over functionalizing various positions of anthracyclines. Thus, a diverse range of anthracycline derivatives may be produced using such methods.
  • a number of classes of antibiotics and other natural compounds used in chemotherapy are glycosides in which the aglycone displays a complex structure.
  • the aglycone is a system of four condensed rings containing hydroxyl, alkoxy and acyl substituents.
  • O-glycoside bond e.g., daunosamine, acosamine, ristosamine
  • the present invention generally provides methods of obtaining anthracycline derivatives. In general, these methods permit manipulation of select functional groups without the disturbance of other portions of the molecule. In particular embodiments, functional groups on the sugar moiety of an anthracycline may be specifically manipulated. Methods described herein permit, in certain embodiments, regioselective functionalization of hydroxy groups of anthracyclines, such as alkylation of a C-4' hydroxy group of the sugar ring. Protection of a C-3 ' amino group of the sugar ring is also encompassed by the present invention, and can facilitate later hydroxy alkylation.
  • anthracyclines produced via the methods described herein, including any intermediates formed may find use as antibiotics, DNA intercalating agents, and/or anticancer agents and methods relating thereto.
  • the present invention contemplates a method of synthesizing a product anthracycline compound comprising: protecting the C-3' amino group of a first anthracycline via an amide or carbamate, wherein the first anthracycline comprises a C-3' amino group and a C-4' hydroxy group; alkylating the C-4' hydroxy group in the presence of an alkylating agent and a chlorinated hydrocarbon solvent; and obtaining a product anthracycline.
  • the first anthracycline can be any anthracycline known to those of skill in the art. In certain embodiments, the first anthracycline is daunorubicin.
  • protecting groups may be employed to protect the C-3' amino group and agents used to install such groups are well-known to those of skill in the art, as described below.
  • the C-3' amino group is protected by a trifluoroacetyl, trichloroacetyl, chloroacetyl, benzyloxycarbonyl, allyloxycarbonyl, or butoxycarbonyl protecting group.
  • Alkylating agents are well-known to those of skill in the art.
  • the alkylating agent is a benzyl halide, such as benzyl chloride, benzyl iodide, or benzyl bromide.
  • the alkylating agent is an alkyl or aryl sulfonate, such as methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate, or 4-nitrobenzenesulfonate.
  • the alkylating agent is a benzyl sulfate or a benzyl phosphate.
  • the alkylation step may take place in the presence of a base.
  • a base may be, for example, a metal hydride, such as sodium hydride, potassium hydride, or calcium hydride.
  • the base may be a non-nucleophilic organic base, examples of which are well-known to those of skill in the art.
  • the non-nucleophilic organic base is DBU.
  • a chlorinated hydrocarbon solvent is employed, such as in the alkylation step.
  • the chlorinated hydrocarbon solvent may be, for example, dichloromethane or 1,2-dichloroethane.
  • Other solvents that may be employed in the alkylation step include DMF, DMSO, N-methylpyrrolidone, HMPA, or acetonitrile.
  • the first anthracycline comprises a -C(O)CH 3 group at the C- 9 position of the anthracycline.
  • This -C(O)CH3 group may be further manipulated in certain methods of the present invention.
  • the -C(O)CH3 group may be converted to a - C(O)CH 2 OH group via, e.g., bromination and then hydrolysis.
  • methods of the present invention may undergo further reaction in order to produce a product anthracycline of interest.
  • methods of the present invention may further comprise deblocking the C-3 ' amide or carbamate. Other substituents may then be introduced at the C-3 ' position, if desired.
  • a variety of intermediates may be formed during the synthesis of a product anthracycline.
  • methods of the present invention may be defined as a process wherein a compound of formula (I) is formed as an intermediate during the synthesis:
  • R 1 is alkyl, aryl, aralkyl, acyl, alkoxy, or aryloxy; R and R are each independently -H, -OH, or alkoxy; R 4 is -H, -OH, alkoxy, or a halide;
  • Y 1 and Y 2 are each independently a double bonded oxygen, sulfur, or nitrogen atom;
  • Z is a -H, -OH, or acyl;
  • R 5 and R are each independently -H, alkyl, aryl, aralkyl, acyl, alkoxy, aryloxy, or - NR 19 R 20 , wherein: R 19 is -H, alkyl, aryl, or aralkyl; and R is an amide or carbamate protecting group, provided that either R 5 or R 6 is -NR 19 R 20 ;
  • R 7 and R 8 are each independently -H or -OR 21 , wherein R 21 is -H, alkyl, aryl, or aralkyl, provided that at least one of R 7 or R 8 is -OR 21 ; R 9 is -H, alkyl, or aryl; and
  • R 10 , R 11 and R 12 are each independently -H, alkyl, a halide, -OR 23 , -SR 23 , -NH 2 , - NHR 23 , -N(R 23 ) 2 , wherein R 23 is -H, alkyl, or aralkyl.
  • the C-4' hydroxy group of a product anthracycline made via a method of the present invention is a hydroxy group or is alkylated (to form an -OR group).
  • the C-3' amino group of the product anthracycline is -NHR 24 , wherein R >24 is -H, alkyl, aryl, or aralkyl.
  • a product anthracycline may also be a compound of formula (II):
  • R 1 is alkyl, -COCH 2 R 13 , or -C(OH)-CH 2 R 13 , wherein:
  • R and R are each independently -H, -OH, or alkoxy;
  • R 4 is -H, -OH, alkoxy, or a halide;
  • Y 1 and Y 2 are each independently a double bonded oxygen, sulfur, or nitrogen atom;
  • Z is a -H, -OH, or acyl;
  • R 9 is -H, alkyl, or aryl;
  • R 10 , R 11 and R 12 are each independently -H, alkyl, a halide, -OR 19 , -SR 19 , -NH 2 , - NHR 19 , -N(R 19 ) 2 , wherein R 19 is -H, alkyl, or aralkyl; and either: (i) one of R 5 and R 6 is -H, and one of R 5 and R 6 is an X-alkyl-aromatic ring (-XAAr) substituent, wherein: X is -N, -S, -SO, or -SO 2 ;
  • A is alkyl
  • Ar is a substituted five-member ring, a heteroatomic five- member ring, a heteroatomic six-member ring, or a substituted phenyl ring of the form: wherein:
  • R 14 -R 18 are each independently -H, -OH, -NO 2 , -NH 2 , a halide, an alkoxy group having 1-20 carbon atoms, an alkyl group having 1-20 carbon atoms, an aryl group having 1-20 carbon atoms, an alkylamino group, an alkylthio group, a cyano group, a thiocyano group, or an acyl group; and
  • R 19 is -H, alkyl, or aralkyl; or R 7 and R 8 are each independently -H, alkyl, a halide, -OR 19 , -SR 19 , -
  • R 5 and R 6 are each independently -H, alkyl, a halide, -OR 19 , -SR 19 , -
  • R 19 is -H, alkyl, or aralkyl
  • one of R 7 and R 8 is H
  • one of R 7 and R 8 is an X-alkyl-aromatic ring (-XAAr) substituent, wherein:
  • X is -O, -N, -S, -SO, or -SO 2 ;
  • A is alkyl
  • Ar is a substituted five-member ring, a heteroatomic five- member ring, a heteroatomic six-member ring, or a substituted phenyl ring of the form: wherein:
  • R 14 -R 18 are each independently -H, -OH, -NO 2 , -NH 2 , a halide, an alkoxy group having 1-20 carbon atoms, an alkyl group having 1-20 carbon atoms, an aryl group having 1-20 carbon atoms, an alkylamino group, an alkylthio group, a cyano group, a thiocyano group, or an acyl group; and
  • R 7 is not; or R 7 and R 8 are each independently -H, alkyl, a halide, -OR 19 , -SR 19 , -
  • the product anthracycline may be further comprised in a pharmaceutically acceptable composition.
  • a pharmaceutically acceptable composition Such compositions are described in more detail below.
  • a product anthracycline may be administered or delivered to a target cell, or may be administered to a subject.
  • a product anthracycline may be administered in an amount effective to treat a subject, such as a subject suffering from cancer or a bacterial infection, to produce a therapeutic benefit.
  • a subject may also be susceptible to acquiring a bacterial infection: administration of a product anthracycline may provide a prophylactic therapeutic benefit for such a subject.
  • contacted and “exposed,” when applied to a cell are used herein to describe the process by which a compound of the present invention is administered or delivered to a target cell or are placed in direct juxtaposition with the target cell.
  • administered and “delivered” are used interchangeably with “contacted” and “exposed.”
  • an effective amount means adequate to accomplish a desired, expected, or intended result.
  • an "effective amount” may be an amount of a compound sufficient to produce a therapeutic benefit (e.g. , effective to reproducibly inhibit decrease, reduce, inhibit or otherwise abrogate the growth of a cancer cell; or to treat a bacterial infection).
  • Treatment and “treating” as used herein refer to administration or application of a therapeutic agent to a subject or performance of a procedure or modality on a subject for the purpose of obtaining a therapeutic benefit of a disease or health-related condition.
  • a subject e.g., a mammal, such as a human
  • a bacterial infection may be subjected to a treatment comprising administration of a compound of the present invention.
  • a therapeutically effective amount of a compound of the present invention may be administered to a subject having a cancerous tumor, such that the tumor shrinks.
  • a therapeutically effective amount of a compound of the present invention may be admininstered to a subject suffering from a bacterial infection to ameliorate the infection, or may be given to a subject to prevent a bacterial infection.
  • compositions of the present invention comprise an effective amount of one or more candidate substances (e.g., an anthracycline or derivative thereof) or additional agents dissolved or dispersed in a pharmaceutically acceptable carrier.
  • candidate substances e.g., an anthracycline or derivative thereof
  • additional agents dissolved or dispersed in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.
  • the preparation of a pharmaceutical composition that contains at least one candidate substance or additional active ingredient will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, incorporated herein by reference.
  • any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention.
  • any composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any composition of the invention.
  • the present invention overcomes the deficiencies of the prior art by providing methods that enable facile access to anthracycline derivatives.
  • the present inventors have discovered, for example, how to selectively modify a C-3' amino group of an anthracycline by conversion to, for example, an amide or carbamate derivative, such that certain other positions (particularly positions that are not protected by a protecting group) of the anthracycline are left undisturbed and thus may be further modified.
  • substituted carboxylic acid esters e.g., methyl trifluoroacetate, ethyl trifluoroacetate, or ethyl benzyloxycarbonate
  • Carbamates may also be produced.
  • hydroxy positions present in an anthracycline such as a C-4' hydroxy position of an anthracycline sugar
  • may be functionalized e.g., alkylated
  • benzyl bromide in the presence of a chlorinated hydrocarbon solvent, such as dichloromethane permits selective alkylation of the C-4' hydroxy group in the sugar ring.
  • a chlorinated hydrocarbon solvent such as dichloromethane
  • Anthracyclines have a tetracyclic ring structure to which a sugar moiety is attached via a glycosidic linkage.
  • Cytotoxic agents of this class typically have quinone and hydroquinone moieties that permit them to function as electron-accepting and electron donating agents.
  • Doxorubicin and daunorubicin are examples of compounds of this class. These compounds act by intercalating with DNA.
  • Non-limiting examples of anthracyclines include daunorubicin, doxorubicin, epirubicin, idarubicin, pyrromycin, aclacinamycine, isorhodomycine, carminomycine, doxorubicine 14-esters (e.g., doxorubicin 14-acetate, doxorubicin 14-propionate, doxorubicin 14-octanoate, doxorubicine 14-benzoate and doxorubicine 14-phenylacetate), 4'-epidaunorubicin, 4'-epidoxorubicin, 4'-iododaunorubicin, 4'-iododoxorubicin, 4'-deoxydaunorubicin, 4'-deoxydoxorubicin, 3'-hydroxydaunorubicin, 3'- hydroxydoxorubicin, 4-demethoxydaunorubicin,
  • anthracyclines are known in the art, such as those described in U.S. Patent No. 6,673,907, which is incorporated by reference herein it its entirety. Methods of the present invention can be used in synthetic protocols to access certain of these and other known anthracyclines as well as novel anthracyclines. Moreover, those anthracyclines comprising, for example, a C-4' hydroxy group and a C-3' amine group may be used as synthetic starting materials in certain methods of the present invention. Such starting materials may be obtained by known synthetic methods or by purchase from commerical chemical companies such as Sigma-Aldrich (Milwaukee, WI).
  • amino means -NH 2 ; the term “nitro” means -NO2; the term “halo” or “halide” designates -F, -Cl, -Br or —I; the term “mercapto” or “thiol” means -SH; the term “cyano” means -CN; the term “azido” means -N 3 ; the term “silyl” means -S1H3, and the term "hydroxy" means -OH.
  • alkyl includes straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic), cyclic alkyl, heteroatom-unsubstituted alkyl, heteroatom-substituted alkyl, heteroatom-unsubstituted C n -alkyl, and heteroatom-substituted C n -alkyl.
  • lower alkyls are contemplated.
  • lower alkyl refers to alkyls of 1-6 carbon atoms (that is, 1, 2, 3, 4, 5 or 6 carbon atoms).
  • heteroatom-unsubstituted C n -alkyl refers to a radical, having a linear or branched, cyclic or acyclic structure, further having no carbon-carbon double or triple bonds, further having a total of n carbon atoms, all of which are nonaromatic, 3 or more hydrogen atoms, and no heteroatoms.
  • a heteroatom-unsubstituted Ci-Cio-alkyl has 1 to 10 carbon atoms.
  • heteroatom-substituted alkyl group examples include -CH 2 -cycloalkyl, such as -CH 2 - cyclopropyl.
  • heteroatom-substituted C n -alkyl refers to a radical, having a single saturated carbon atom as the point of attachment, no carbon-carbon double or triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, all of which are nonaromatic, 0, 1, or more than one hydrogen atom, at least one heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted Ci-Cio-alkyl has 1 to 10 carbon atoms.
  • the following groups are all non-limiting examples of heteroatom- substituted alkyl groups: trifluoromethyl, -CH 2 F, -CH 2 Cl, -CH 2 Br, -CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CF 3 , -CH 2 OC(O)CH 3 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 Cl, -CH 2 CH 2 OH, CH 2 CH 2 OC(O)CH 3 , -CH 2 CH 2 NHCO 2 C(CH 3 ) 3 , -CH 2 Si(CH 3 ) 3 , and -C(OH)- CH 2 OH.
  • aryl includes heteroatom-unsubstituted aryl, heteroatom-substituted aryl, heteroatom-unsubstituted C n -aryl, heteroatom-substituted C n -aryl, heteroaryl, heterocyclic aryl groups, carbocyclic aryl groups, biaryl groups, and single-valent radicals derived from polycyclic fused hydrocarbons (PAHs).
  • PAHs polycyclic fused hydrocarbons
  • heteroatom-unsubstituted C n -aryl refers to a radical, having a single carbon atom as a point of attachment, wherein the carbon atom is part of an aromatic ring structure containing only carbon atoms, further having a total of n carbon atoms, 5 or more hydrogen atoms, and no heteroatoms.
  • a heteroatom- unsubstituted C ⁇ -Cio-aryl has 6 to 10 carbon atoms.
  • heteroatom- unsubstituted aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C 6 H 4 CH 2 CH 3 , -C 6 H 4 CH 2 CH 2 CH 3 , -C 6 H 4 CH(CH 3 ) 2 , -C 6 H 4 CH(CH 2 ) 2 ,
  • heteroatom-substituted C n -aryl refers to a radical, having either a single aromatic carbon atom or a single aromatic heteroatom as the point of attachment, further having a total of n carbon atoms, at least one hydrogen atom, and at least one heteroatom, further wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-unsubstituted Ci-Cio-heteroaryl has 1 to 10 carbon atoms.
  • Aryl groups may be di-, tri-, terra-, or penta- substituted, for example.
  • Substituents include, but are not limited to, hydroxy, methoxy, nitro, amino, halide, alkoxy, aryl, alkylamino, alkylthio, cyano, thiocyano, and acyl.
  • Non-limiting examples of heteroatom-substituted aryl groups include the groups: -C 6 H 4 F, -C 6 H 4 Cl, -C 6 H 4 Br, -C 6 H 4 I, -C 6 H 4 OH, -C 6 H 4 OCH 3 , -C 6 H 4 OCH 2 CH 3 , -C 6 H 4 OC(O)CH 3 , -C 6 H 4 NH 2 , -C 6 H 4 NHCH 3 , -C 6 H 4 N(CH 3 ) 2 , -C 6 H 4 CH 2 OH, -C 6 H 4 CH 2 OC(O)CH 3 , -C 6 H 4 CH 2 NH 2 , -C 6 H 4 CF 3 , -C 6 H 4 CN, -C 6 H 4 CHO, -C 6 H 4 CHO, -C 6 H 4 C(O)CH 3 , -C 6 H 4 C(O)C 6 H 5 , -C 6 H 4
  • aralkyl includes heteroatom-unsubstituted aralkyl, heteroatom-substituted aralkyl, heteroatom-unsubstituted C n -aralkyl, heteroatom-substituted C n -aralkyl, heteroaralkyl, and heterocyclic aralkyl groups. In certain embodiments, lower aralkyls are contemplated.
  • lower aralkyl refers to aralkyls of 7-12 carbon atoms (that is, 7, 8, 9, 10, 11 or 12 carbon atoms).
  • heteroatom-unsubstituted C n -aralkyl refers to a radical, having a single saturated carbon atom as the point of attachment, further having a total of n carbon atoms, wherein at least 6 of the carbon atoms form an aromatic ring structure containing only carbon atoms, 7 or more hydrogen atoms, and no heteroatoms.
  • a heteroatom-unsubstituted C ⁇ -Cio-aralkyl has 7 to 10 carbon atoms.
  • Non-limiting examples of heteroatom-unsubstituted aralkyls are: phenylmethyl (benzyl, Bn) and phenylethyl.
  • heteroatom-substituted C n -aralkyl refers to a radical, having a single saturated carbon atom as the point of attachment, further having a total of n carbon atoms, O, 1 , or more than one hydrogen atom, and at least one heteroatom, wherein at least one of the carbon atoms is incorporated an aromatic ring structures, further wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted C 2 -Cio-heteroaralkyl has 2 to 10 carbon atoms.
  • acyl includes straight-chain acyl, branched-chain acyl, cycloacyl, cyclic acyl, heteroatom-unsubstituted acyl, heteroatom-substituted acyl, heteroatom-unsubstituted C n -acyl, heteroatom-substituted C n -acyl, alkylcarbonyl, alkoxycarbonyl and aminocarbonyl groups. In certain embodiments, lower acyls are contemplated.
  • lower acyl refers to acyls of 1-6 carbon atoms (that is, 1, 2, 3, 4, 5 or 6 carbon atoms).
  • heteroatom- unsubstituted C n -acyl refers to a radical, having a single carbon atom of a carbonyl group as the point of attachment, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 1 or more hydrogen atoms, a total of one oxygen atom, and no additional heteroatoms.
  • a heteroatom-unsubstituted Ci-Cio-acyl has 1 to 10 carbon atoms.
  • the groups, -CHO, -C(O)CH 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 CH 2 CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)CH(CH 2 ) 2 , -C(O)C 6 H 5 , -C(O)C 6 H 4 CH 3 , -C(O)C 6 H 4 CH 2 CH 3 , and -COCgH 3 (CH 3 ) 2 are non-limiting examples of heteroatom-unsubstituted acyl groups.
  • heteroatom-substituted C n -acyl refers to a radical, having a single carbon atom as the point of attachment, the carbon atom being part of a carbonyl group, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, at least one additional heteroatom, in addition to the oxygen of the carbonyl group, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted Ci-Cio- acyl has 1 to 10 carbon atoms..
  • the groups, -C(O)CH 2 CF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH 2 CH 2 CH 3 , -CO 2 CH(CH 3 ) 2 , -CO 2 CH(CH 2 ) 2 , -C(O)NH 2 (carbamoyl), -C(O)NHCH 3 , -C(O)NHCH 2 CH 3 , -CONHCH(CH 3 ) 2 , -CONHCH(CH 2 ) 2 , -CON(CH 3 ) 2 , and -CONHCH 2 CF 3 , are non-limiting examples of heteroatom-substituted acyl groups.
  • alkoxy includes straight-chain alkoxy, branched-chain alkoxy, cycloalkoxy, cyclic alkoxy, heteroatom-unsubstituted alkoxy, heteroatom-substituted alkoxy, heteroatom-unsubstituted C n -alkoxy, and heteroatom-substituted C n -alkoxy.
  • lower alkoxys are contemplated.
  • lower alkoxy refers to alkoxys of 1-6 carbon atoms (that is, 1, 2, 3, 4, 5 or 6 carbon atoms).
  • heteroatom- unsubstituted C n -alkoxy refers to a group, having the structure -OR, in which R is a heteroatom-unsubstituted C n -alkyl, as that term is defined above.
  • Heteroatom-unsubstituted alkoxy groups include: -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , and OCH(CH 2 ) 2 .
  • heteroatom-substituted C n -alkoxy refers to a group, having the structure -OR, in which R is a heteroatom-substituted C n -alkyl, as that term is defined above.
  • R is a heteroatom-substituted C n -alkyl, as that term is defined above.
  • -OCH 2 CF 3 is a heteroatom-substituted alkoxy group.
  • aryloxy includes heteroatom-unsubstituted aryloxy, heteroatom- substituted aryloxy, heteroatom-unsubstituted C n -aryloxy, heteroatom-substituted C n -aryloxy, heteroaryloxy, and heterocyclic aryloxy groups.
  • heteroatom-unsubstituted C n - aryloxy refers to a group, having the structure -OAr, in which Ar is a heteroatom- unsubstituted C n -aryl, as that term is defined above.
  • a non-limiting example of a heteroatom- unsubstituted aryloxy group is -OC 6 H 5 .
  • heteroatom-substituted C n -aryloxy refers to a group, having the structure -OAr, in which Ar is a heteroatom-substituted C n -aryl, as that term is defined above.
  • alkylamino includes straight-chain alkylamino, branched-chain alkylamino, cycloalkylamino, cyclic alkylamino, heteroatom-unsubstituted alkylamino, heteroatom-substituted alkylamino, heteroatom-unsubstituted C n -alkylamino, and heteroatom- substituted C n -alkylamino.
  • lower alkylaminos are contemplated.
  • the term “lower alkylamino” refers to alkylaminos of 1-6 carbon atoms (that is, 1, 2, 3, 4, 5 or 6 carbon atoms).
  • heteroatom-unsubstituted C n -alkylamino refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two saturated carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, containing a total of n carbon atoms, all of which are nonaromatic, 4 or more hydrogen atoms, a total of 1 nitrogen atom, and no additional heteroatoms.
  • a heteroatom-unsubstituted Ci-Cio-alkylamino has 1 to 10 carbon atoms.
  • heteroatom-unsubstituted C n -alkylamino includes groups, having the structure -NHR, in which R is a heteroatom-unsubstituted C n -alkyl, as that term is defined above.
  • a heteroatom- unsubstituted alkylamino group would include -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -NHCH(CH 2 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 2 CH 3 , -NHCH 2 CH(CH 3 ) 2 , -NHC(CH 3 ) 3 , -N(CH 3 ) 2 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 ) 2 , N- pyrrolidinyl, and N-piperidinyl.
  • heteroatom-substituted C n -alkylamino refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two saturated carbon atoms attached to the nitrogen atom, no carbon-carbon double or triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, all of which are nonaromatic, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of ⁇ , O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted Ci-Cio-alkylamino has 1 to 10 carbon atoms.
  • the term "heteroatom-substituted C n - alkylamino" includes groups, having the structure - ⁇ HR, in which R is a heteroatom- substituted Cn-alkyl, as that term is defined above.
  • amide or "amido” includes straight-chain amido, branched-chain amido, cycloamido, cyclic amido, heteroatom-unsubstituted amido, heteroatom-substituted amido, heteroatom-unsubstituted C n -amido, heteroatom-substituted C n -amido, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, acylamino, alkylaminocarbonylamino, arylaminocarbonylamino, and ureido groups.
  • heteroatom-unsubstituted C n -amido refers to a radical, having a single nitrogen atom as the point of attachment, further having a carbonyl group attached via its carbon atom to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 1 or more hydrogen atoms, a total of one oxygen atom, a total of one nitrogen atom, and no additional heteroatoms.
  • a heteroatom-unsubstituted C 1 - Cio-amido has 1 to 10 carbon atoms.
  • heteroatom-unsubstituted C n -amido includes groups, having the structure -NHR, in which R is a heteroatom-unsubstituted C n - acyl, as that term is defined above.
  • the group, -NHC(O)CH3 is a non-limiting example of a heteroatom-unsubstituted amido group.
  • heteroatom-substituted C n -amido refers to a radical, having a single nitrogen atom as the point of attachment, further having a carbonyl group attached via its carbon atom to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, further having a total of n aromatic or nonaromatic carbon atoms, 0, 1, or more than one hydrogen atom, at least one additional heteroatom in addition to the oxygen of the carbonyl group, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted Ci-Cio-amido has 1 to 10 carbon atoms.
  • the term "heteroatom-substituted C n -amido" includes groups, having the structure -NHR, in which R is a heteroatom-unsubstituted C n -acyl, as that term is defined above.
  • the group, -NHCO 2 CH 3 is a non-limiting example of a heteroatom-substituted amido group.
  • Protecting groups, as described herein, may also comprise an amide, such as amides used to protect amine groups.
  • alkylthio includes straight-chain alkylthio, branched-chain alkylthio, cycloalkylthio, cyclic alkylthio, heteroatom-unsubstituted alkylthio, heteroatom-substituted alkylthio, heteroatom-unsubstituted C n -alkylthio, and heteroatom-substituted C n -alkylthio.
  • lower alkylthios are contemplated.
  • the term “lower alkylthio” refers to alkylthios of 1-6 carbon atoms (that is, 1, 2, 3, 4, 5 or 6 carbon atoms).
  • heteroatom-unsubstituted C n -alkylthio refers to a group, having the structure -SR, in which R is a heteroatom-unsubstituted C n -alkyl, as that term is defined above.
  • the group, -SCH3 is an example of a heteroatom-unsubstituted alkylthio group.
  • heteroatom-substituted C n -alkylthio refers to a group, having the structure -SR, in which R is a heteroatom- substituted C n -alkyl, as that term is defined above.
  • Compounds of the present invention may contain one or more asymmetric centers and thus can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In certain embodiments, a single diastereomer is present. All possible stereoisomers of the compounds of the present invention are contemplated as being within the scope of the present invention. However, in certain aspects, particular diastereomers are contemplated.
  • the chiral centers of the compounds of the present invention can have the S- or the ⁇ -configuration, as defined by the IUPAC 1974 Recommendations. In certain aspects, certain compounds of the present invention may comprise S- or ⁇ -configurations at particular carbon centers.
  • derivative refers to a chemically modified compound that still retains the desired effects of the compound prior to the chemical modification.
  • An “anthracycline derivative,” therefore, may refer to a chemically modified compound that still retains the desired effects of the parent anthracycline prior to its chemical modification. Such effects may be enhanced (e.g., slightly more effective, twice as effective, etc.) or diminished (e.g., slightly less effective, 2-fold less effective, etc.) relative to the parent anthracycline, but may still be considered an anthracycline derivative.
  • Anthracycline derivatives may be generated that do not have the same activity or action as the parent anthracycline: indeed, such derivatives may show opposite effects.
  • Derivatives may, for example, have the addition, removal, or substitution of one or more chemical moieties on the parent molecule.
  • Non- limiting examples of the types modifications that can be made to the compounds and structures disclosed herein include the addition or removal of lower unsubstituted alkyls such as methyl, ethyl, propyl, or substituted lower alkyls such as hydroxymethyl or aminomethyl groups; carboxyl groups and carbonyl groups; hydroxyls; nitro, amino, amide, and azo groups; sulfate, sulfonate, sulfono, sulfhydryl, sulfonyl, sulfoxido, phosphate, phosphono, phosphoryl groups, and halide substituents.
  • Additional modifications can include an addition or a deletion of one or more atoms of the atomic framework, for example, substitution of an ethyl by a propyl; substitution of a phenyl by a larger or smaller aromatic group.
  • heteroatoms such as N, S, or O can be substituted into the structure instead of a carbon atom.
  • anthracycline prepared by methods of the present invention may be a prodrug and/or a solvate.
  • prodrug as used herein, is understood as being a compound which, upon administration to a subject, such as a mammal, undergoes chemical conversion by metabolic or chemical processes to yield a compound any of the formulas herein, or a salt and/or solvate thereof (Bundgaard, 1991; Bundgaard, 1985). Solvates of the compounds of the present invention are preferably hydrates.
  • Anthracyclines prepared by methods of the present invention may comprise one or more pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to salts of compounds of this invention that are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of a compound of this invention with an inorganic or organic acid, or an organic base, depending on the substituents present on the compounds of the invention.
  • Non-limiting examples of inorganic acids which may be used to prepare pharmaceutically acceptable salts include: hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and the like.
  • organic acids which may be used to prepare pharmaceutically acceptable salts include: aliphatic mono- and dicarboxylic acids, such as oxalic acid, carbonic acid, citric acid, succinic acid, phenyl- heteroatom-substituted alkanoic acids, aliphatic and aromatic sulfuric acids and the like.
  • Pharmaceutically acceptable salts prepared from inorganic or organic acids thus include hydrochloride, hydrobromide, nitrate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydroiodide, hydrofluoride, acetate, propionate, formate, oxalate, citrate, lactate, p- toluenesulfonate, methanesulfonate, maleate, and the like.
  • Pharmaceutically acceptable salts include the salts formed between carboxylate or sulfonate groups found on some of the compounds of this invention and inorganic cations, such as sodium, potassium, ammonium, or calcium, or such organic cations as isopropylammonium, trimethylammonium, tetramethylammonium, and imidazolium.
  • any salt of this invention is typically not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, Selection and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002), which is incorporated herein by reference.
  • saccharides include oxidized, reduced or substituted saccharides.
  • Saccharides of this invention include, but are not limited to, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, fructose, glucose, idose, galactose, talose, ribulose, sorbose, tagatose, gluconic acid, glucuronic acid, glucaric acididuronic acid rhamnose, fucose, N- acetyl glucosamine, N-acetyl galactosamine, N-acetyl neuraminic acid, sialic acid, derivatives of saccharides such as acetals, amines, and phosphorylated sugars, oligosaccharides, as well as open chain forms of various sugars, and the like.
  • nucleophile or “nucleophilic” generally refers to atoms bearing lone pairs of electrons. Such terms are well known in the art and include -NH 2 , thiolate, carbanion and hydroxyl.
  • leaving group generally refers to a group readily displaceable by a nucleophile, such as an amine, an alcohol, or a thiol nucleophile.
  • a nucleophile such as an amine, an alcohol, or a thiol nucleophile.
  • Such leaving groups are well known and include carboxylates, N-hydroxysuccinimide, N- hydroxybenzotriazole, triflates, tosylates, mesylates, alkoxy, thioalkoxy and the like.
  • a "protecting group,” as used herein, is defined as a group used for the purpose of this temporary blockage.
  • protecting groups or protecting agents
  • functional groups necessary for the desired transformation should remain unprotected.
  • the term "functional group” generally refers to how persons of skill in the art classify chemically reactive groups. Examples of functional groups include hydroxyl, amine, sulfhydryl, amide, carboxyls, carbonyls, etc. Protecting groups exist for each of these types of functional groups. In certain methods of the present invention, it is specifically contemplated that an anthracycline may contain one or more protecting groups.
  • a protecting group is to protect one or more functionalities ⁇ e.g., -NH 2 , -SH, -COOH) during subsequent reactions which would not proceed well, either because the free (in other words, unprotected) functional group would react and be functionalized in a way that is inconsistent with its need to be free for subsequent reactions, or the free functional group would interfere in the reaction.
  • the same protecting group may be used to protect one or more of the same or different functional group(s).
  • different protecting groups can be used to protect the same type of functional group within a single compound in multiple steps.
  • a protecting group When a protecting group is no longer needed, it is removed by methods well known to those skilled in the art.
  • Agents used to remove the protecting group are sometimes called deprotecting or deblocking agents.
  • Protecting groups must be readily removable (as is known to those skilled in the art) by methods employing deprotecting agents that are well known to those skilled in the art. It is well known that certain deprotecting agents remove some protective groups and not others, while other deprotecting agents remove several types of protecting groups from several types of functional groups. Thus, a first deprotecting agent may be used to remove one type of protecting group, followed by the use of a second deprotecting agent to remove a second type of protecting group, and so on.
  • Amino protecting groups are well known to those skilled in the art. See, for example, Greene and Wuts, 1999, Chapter 7.
  • Amino protecting groups that may, in certain embodiments, be employed in methods of the present invention include ⁇ -butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, acetyl, trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl, difluoroacetyl, fluoroacetyl, benzyl chloroformate, 4- phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4- fiuorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2- chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyl
  • Solvent choices for the methods of the present invention may depend, for example, on which one(s) will facilitate the solubilizing of all the reagents or, for example, which one(s) will best facilitate the desired reaction (particularly when the mechanism of the reaction is known).
  • Solvents may include, for example, polar solvents and non-polar solvents. Solvents choices include, but are not limited to, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dioxane, methanol, ethanol, hexane, dichloromethane, methylene chloride and acetonitrile. More than one solvent may be chosen for any particular reaction or purification procedure. Water may also be admixed into any solvent choice. Further, water, such as distilled water, may constitute the reaction medium instead of a solvent.
  • a chlorinated hydrocarbon solvent is employed in certain steps of the methods discussed herein, such as a C-4' -OH alkylation step.
  • chlorinated hydrocarbon solvents include dichloromethane, dichloroethane and methylene chloride.
  • addition of a chlorinated hydrocarbon solvent facilitates the alkylation step in that the yield is improved and/or side -product production is minimized.
  • Daunorubicin (1 g) is dissolved in methanol (4 mL) in a 25-mL flask.
  • Triethylamine (0.6 mL) and ethyl trifluoroacetate (0.6 mL) are introduced into the flask.
  • the mixture is subjected to rotary vacuum evaporation and the remainder is dissolved in chloroform (20 mL), washed with IN aqueous hydrochloric acid solution and then neutralized with water.
  • the chloroform solution is dried with sodium sulfate, the drying agent is removed, and the filtrate is evaporated under reduced pressure.
  • the residue was dissolved in chloroform (1 mL) and the product was precipitated with hexane (20 mL).
  • the product obtained (3-N-trifluoroacetyldaunorubicin) is chromatographically pure and may be used in a further step, such as the synthesis discussed below.
  • the reaction mixture is treated with an aqueous acetic acid solution to achieve a neutral pH, washed with water (10 mL), diluted with methylene chloride (100 mL), dried with sodium sulfate and, after removal of the drying agent, the solvent is evaporated in a rotary vacuum evaporator. The remainder is dissolved in methylene chloride (2 mL) and the product is precipitated with hexane.
  • the product obtained is purified by chromatography using a hexane-ethyl acetate mixture with an increasing amount of ethyl acetate. 1.5 g of the title compound is obtained (yield: 28%).
  • the compound obtained may be an intermediate product for producing doxorubicin derivatives, such as the following synthesis of 4-0- benzyldoxorubicin :

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Abstract

La présente invention concerne des procédés de synthèse de dérivés d'anthracycline. Entre autres avantages, ces procédés offrent une manipulation simple et efficace de substituants sur le cycle du sucre des anthracyclines. Par exemple, l'amino en C-3' de tels sucres peut être protégé de telle sorte qu'une alkylation des positions hydroxy, comme un hydroxy en C-4', peut être effectuée de façon régiosélective. Ces procédés permettent un accès à une diversité de dérivés d'anthracycline, qui peuvent montrer une activité antibiotique et/ou anti-cancer.
PCT/IB2007/003700 2006-09-05 2007-09-05 Procédé de fabrication de dérivés d'anthracycline WO2008029294A2 (fr)

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US8314137B2 (en) 2008-07-22 2012-11-20 Trustess Of Dartmouth College Monocyclic cyanoenones and methods of use thereof
CN104098628A (zh) * 2014-07-31 2014-10-15 大连大学 一类n-三氟乙酰柔红霉素的硒代衍生物，其制备方法及应用
CN104098629A (zh) * 2014-07-31 2014-10-15 大连大学 一类表柔红霉素的硒代衍生物，其制备方法及应用
WO2016176332A1 (fr) * 2015-04-27 2016-11-03 The Regents Of The University Of Colorado Promédicaments d'anthracyne et procédés de production et d'utilisation de ces derniers
US10358439B2 (en) 2015-09-16 2019-07-23 Board Of Regents, The University Of Texas System DNA binding agents with a minor groove binding tail

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8314137B2 (en) 2008-07-22 2012-11-20 Trustess Of Dartmouth College Monocyclic cyanoenones and methods of use thereof
US9000188B2 (en) 2008-07-22 2015-04-07 Trustees Of Dartmouth College Monocyclic cyanoenones and methods of use thereof
CN104098628A (zh) * 2014-07-31 2014-10-15 大连大学 一类n-三氟乙酰柔红霉素的硒代衍生物，其制备方法及应用
CN104098629A (zh) * 2014-07-31 2014-10-15 大连大学 一类表柔红霉素的硒代衍生物，其制备方法及应用
CN104098628B (zh) * 2014-07-31 2017-07-18 大连大学 一类n‑三氟乙酰柔红霉素的硒代衍生物，其制备方法及应用
WO2016176332A1 (fr) * 2015-04-27 2016-11-03 The Regents Of The University Of Colorado Promédicaments d'anthracyne et procédés de production et d'utilisation de ces derniers
US10912767B2 (en) 2015-04-27 2021-02-09 The Regents Of The University Of Colorado, A Body Corporate Anthracycline prodrugs and methods of making and using the same
US10358439B2 (en) 2015-09-16 2019-07-23 Board Of Regents, The University Of Texas System DNA binding agents with a minor groove binding tail

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