WO2009082247A1 - Procédé de préparation d'immucillines à liaison méthylène - Google Patents

Procédé de préparation d'immucillines à liaison méthylène Download PDF

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WO2009082247A1
WO2009082247A1 PCT/NZ2008/000348 NZ2008000348W WO2009082247A1 WO 2009082247 A1 WO2009082247 A1 WO 2009082247A1 NZ 2008000348 W NZ2008000348 W NZ 2008000348W WO 2009082247 A1 WO2009082247 A1 WO 2009082247A1
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methyl
amino
pyrimidin
pyrrolo
hydroxy
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PCT/NZ2008/000348
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English (en)
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Keith Clinch
Ben William Greatrex
Jennifer Mary Mason
Peter Charles Tyler
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Industrial Research Limited
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Publication of WO2009082247A1 publication Critical patent/WO2009082247A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to a process for the preparation of nucleosidase and phosphorylase inhibitors known as Immucillins.
  • the invention relates to a process for preparing DAD-Me-lmmucillins, and related compounds, having a methylene link between the two parts of the lmmucillin molecule, namely the nucleoside base analogue moiety and the sugar analogue moiety, via an amino nitrogen of the sugar analogue moiety.
  • Purine nucleoside phosphorylase PNP
  • purine phosphoribosyltransferase PPRT
  • nucleoside hydrolase NH
  • Immucillins are nucleoside analogues where the "sugar” part of the molecule has been replaced with an "irnino sugar” moiety or with an hydroxylated aminoalkyl moiety.
  • PNP catalyses the phosphorolytic cleavage of the ribo- and deoxyribonucleosides of guanine and hypoxanthine to give the corresponding sugar-1 -phosphate and guanine, hypoxanthine, or other purine bases.
  • Humans deficient in PNP suffer a specific T-cell immunodeficiency due to an accumulation of dGTP which prevents stimulation of T lymphocytes.
  • Inhibitors of PNP are therefore immunosuppressive, and are active against T-cell malignancies and T-cell proliferative disorders.
  • NH enzymes catalyse the hydrolysis of nucleosides. They are not found in mammals, but are required for nucleoside salvage in some protozoan parasites. Certain protozoan parasites use nucleoside phosphorylases instead of, or as well as, nucleoside hydrolases for this purpose. Inhibitors of nucleoside hydrolases and phosphorylases can be expected to interfere with the metabolism of the parasite and therefore be usefully employed against protozoan parasites.
  • Immucillins that are inhibitors of PNP and PPRT. These Immucillins are useful for treating parasitic infections, T-cell malignancies, autoimmune diseases and inflammatory disorders. They are also useful for immunosupression in organ transplantation. US 6,693,193 and US 7,022,852 describe a process for preparing certain lmmucillin compounds.
  • the imino sugar part of an lmmucillin molecule has the nitrogen atom located between C-1 and C-4 so as to form a 1 ,4-dideoxy-1 ,4-imino-D-ribitol compound.
  • the location of the nitrogen atom in the ribitol ring may be important for binding to enzymes.
  • the location of the link between the imino sugar moiety and the nucleoside base analogue may be critical for enzyme inhibitory activity.
  • the compounds described above have that link at C-1 of the imino sugar ring.
  • DAD-Me-lmmucillins Two sub-classes of the lmmucillins are known as the DAD-Me-lmmucillins and their acyclic amine analogues. Another sub-class has an azetidine ring linked to the base moiety. The location of the nitrogen atom in the imino sugar ring of the DAD-Me- lmmucillins is varied. In these sub-classes, the imino sugar moiety or the acyclic amine is linked to the nucleoside base analogue via a methylene bridge. DAD-Me-lmmucillins are described in US 2006/0160765 and WO 2004/018496. Their acyclic amine analogues are described in WO 2008/030119. The azetidine analogues are described in WO 2008/079028.
  • the Mannich route is the more efficient method, but it has limitations and product yields vary considerably depending on the particular substrate. In particular, where the amine is a primary amine the yield is often low. This is because reaction products are able to undergo further reaction and mixtures are therefore commonly obtained.
  • the reductive amination route also has serious limitations. The route is multi-step and lengthy, and requires the use of low temperature and air sensitive reagents which adds to the cost of manufacture.
  • the invention provides a process for preparing a compound of formula (1):
  • R 1 and R 2 together with the nitrogen to which they are attached form a 4-6 membered azacarbocyclic ring which is substituted by at least one halogen, SQ, OQ, or Q; or R 1 and R 2 together with the nitrogen to which they are attached form a 4-6 membered azacarbocyclic ring which is substituted by at least one CH 2 Z and at least one halogen, SQ or OQ; or
  • R 1 and R 2 are independently selected from H and alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl and aryl each of which is optionally substituted with one or more hydroxy, alkoxy, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, halogen, carboxylic acid, carboxylate, carboxamide, alkyl ester or nitro groups, where each alkylthio, arylthio, cycloalkylthio and aralkylthio group is optionally substituted with one or more alky I, halogen, amino, hydroxy, or alkoxy groups; provided that R 1 and R 2 are not both H;
  • Q is hydrogen or an alkyl, aralkyl, cycloalkyl or aryl group each of which may be substituted with one or more substituents selected from hydroxy, halogen, alkoxy, amino, and carboxy;
  • Z is halogen, SQ, OQ or Q
  • A is selected from N, CH and CR 3 , where R 3 is selected from hydroxy, halogen, alkoxy, alkyl, aralkyl, cycloalkyl, aryl, NH 2 , NHR 4 , NR 4 R 5 and SR 6 , where R 4 , R 5 and R 6 are each alkyl, aralkyl or aryl groups optionally substituted with hydroxy or halogen, and where R 3 is optionally substituted with hydroxy or halogen when R 3 is alkyl, aralkyl or aryl;
  • B is OQ, NH 2 or NHR 8 , where R 8 is selected from alkyl, aralkyl, cycloalkyl and aryl, each of which may be substituted with one or more substituents selected from hydroxy and halogen;
  • D is selected from H, hydroxy, NH 2 , and NHR 7 , where R 7 is an alkyl, aralkyl, cycloalkyl or aryl group optionally substituted with hydroxy or halogen;
  • E is selected from N and CH; or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or a prodrug thereof;
  • (iii) forming the compound of formula (1) by: a. conversion of the OH of the hydroxymethylene group of the compound of formula (3) to OL, where OL is alkylsulfonyloxy or arylsulfonyloxy, each of which is optionally substituted with one or more alky!, halogen or alkoxy groups; b. reaction with a primary or secondary amine to displace the OL group; and c. removal of any of the one or more protecting groups to give the compound of formula (1).
  • the invention provides process for preparing a compound of formula (1'):
  • R 1 and R 2 together with the nitrogen to which they are attached form a 4-6 membered azacarbocyciic ring which is substituted by at least one SQ or OQ, where Q is hydrogen or an alky I, aralkyl or aryl group each of which may be substituted with one or more substituents selected from hydroxy, halogen, alkoxy, amino, and carboxy; or
  • R 1 and R 2 are H or alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, or aryl each of which is optionally substituted with one or more hydroxy, alkoxy, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, or nitro groups, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups; provided that R 1 and R 2 are not both H; A is selected from N, CH and CR 3 , where R 3 is.
  • R 4 , R 5 and R 6 are each alkyl, aralkyl or aryl groups optionally substituted with hydroxy or halogen, and where R 3 is optionally substituted with hydroxy or halogen when R 3 is alkyl, aralkyl or aryl;
  • B is OQ where Q is hydrogen or an alkyl, aralkyl or aryl group each of which may be substituted with one or more substituents selected from hydroxy, halogen, alkoxy, amino, and carboxy;
  • D is selected from H, hydroxy, NH 2 , and NHR 7 , where R 7 is an alkyl, aralkyl or aryl group optionally substituted with hydroxy or halogen;
  • E is selected from N and CH; or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or a prodrug thereof;
  • Ri and R 2 together with the nitrogen to which they are attached form a 4-6 membered azacarbocyclic ring which is substituted by at least one SQ or OQ, where Q is hydrogen or an alkyl, cycloalkyl, aralkyl or aryl group each of which may be substituted with one or more substituents selected from hydroxy, halogen, alkoxy, amino, and carboxy; and preferably B is OQ where Q is hydrogen or an alkyl, aralkyl or aryl group each of which may be substituted with one or more substituents selected from hydroxy, halogen, alkoxy, amino, and carboxy.
  • R 1 and R 2 together with the nitrogen to which they are attached form a radical of formula (4):
  • - ⁇ p- V is CH 2 or NH
  • Y 1 is H, halogen or hydroxy; provided that when V is NH then Y is H;
  • X is CH 2 or CHOH in the R- or S-configuration
  • Z 1 is halogen, SQ, OQ or Q, where Q is as defined above.
  • R 1 and R 2 together with the nitrogen to which they are attached form a radical of formula (5):
  • W and T are each independently selected from the group consisting of hydrogen, CH 2 OH 1 CH 2 OQ and CH 2 SQ;
  • Y 2 and Z 2 are each independently selected from the group consisting of halogen
  • Z 2 is not hydrogen; where Q is as defined above.
  • Z is hydrogen, SQ or OQ.
  • Q is alkyl or cycloalkyl e.g. methyl, ethyl, n-propyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl; aryl e.g. phenyl, 4-chlorophenyl, 4-fluorophenyl or 3-chlorophenyl or 4-pyridyl; or aralkyl, e.g. benzyl or 4-chlorobenzyl.
  • V is CH 2 . It is also preferred that X is CH 2 .
  • Y 1 is hydrogen or hydroxy. More preferably Y 1 is hydrogen.
  • Z 1 is OH, SQ or OQ
  • Q is alkyl e.g. methyl, ethyl, n-propyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl, aryl e.g. phenyl, 4-chlorophenyl, 4- fluorophenyl or 3-chlorophenyl or 4-pyridyl, or aralkyl, e.g. benzyl or 4-chlorobenzyl.
  • Q is hydrogen or lower alkyl e.g. methyl, ethyl, n-propyl or n-butyl.
  • Z 2 is selected from hydrogen, halogen, CH 2 OH, CH 2 OQ and CH 2 SQ. More preferably Z 2 is CH 2 OH. Alternatively it is preferred that Z 2 is CH 2 SQ. In another preferred embodiment, Z 2 is Q.
  • one of Y 2 and Z 2 is CH 2 OQ and the other is hydrogen.
  • one of Y 2 and Z 2 is CH 2 SQ and the other is hydrogen.
  • Q is alkyl, e.g. methyl.
  • one of Y 2 and Z 2 is CH 2 OH.
  • W is H or CH 2 OH.
  • T is H or CH 2 OH.
  • W and T are both H.
  • W and T are both CH 2 OH.
  • one of W and T is H and the other is CH 2 OH.
  • R 1 and R 2 in the compound of formula (1) or (1') are independently selected from H and alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl and aryl, each of which is optionally substituted.
  • R 1 or R 2 in the compound of formula (1) or (1') is an optionally substituted alkyl group
  • the alkyl group is preferably substituted with one or more hydroxyl groups, e.g. R 1 or R 2 may be hydroxymethyl, hydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, dihydroxybutyl, trihyroxybutyl, hydroxypentyl, dihydroxypentyl, or trihydroxypentyl.
  • R 1 or R 2 may also be alkyl substituted by one or more hydroxy groups and/or one or more optionally substituted thiol, alkylthio, arylthio, or aralkylthio groups.
  • R 1 or R 2 may be methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiohydroxypropyl, methylthiodihydroxypropyl, methylthiobutyl, methylthiohydroxybutyl, methylthiodihydroxybutyl, methylthiotrihydroxybutyl, methylthiopentyl, methylthiohydroxypentyl, methylthiodihydroxypentyl, methylthiotrihydroxypentyl, or methylthiotetrahydroxypentyl.
  • B is hydroxy.
  • B is NH 2 .
  • A is CH.
  • D is H or NH 2 .
  • E is N.
  • B is hydroxy, A is CH, E is N and D is H.
  • B is NH 2 , A is CH, E is N and D is H.
  • B is hydroxy, A is CH, E is N and D is NH 2 .
  • B is hydroxy
  • A is CH
  • E is N
  • D is H
  • R 1 and R 2 together with the nitrogen to which they are attached form a radical of formula (4).
  • B is NH 2
  • A is CH
  • E is N
  • D is H
  • R 1 and R 2 together with the nitrogen to which they are attached form a radical of formula (4).
  • B is hydroxy
  • A is CH
  • E is N
  • D is NH 2 and R 1 and R 2 together with the nitrogen to which they are attached form a radical of formula (4).
  • B is hydroxy
  • A is CH
  • E is N
  • D is H
  • R 1 and R 2 together with the nitrogen to which they are attached form a radical of formula (5).
  • B is NH 2
  • A is CH
  • E is N
  • D is H
  • R 1 and R 2 together with the nitrogen to which they are attached form a radical of formula (5).
  • B is hydroxy
  • A is CH
  • E is N
  • D is NH 2 and R 1 and R 2 together with the nitrogen to which they are attached form a radical of formula (5).
  • B is hydroxy
  • A is CH
  • E is N
  • D is H
  • R 1 and R 2 are independently selected from H and alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl and aryl each of which is optionally substituted with one or more hydroxy, alkoxy, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, halogen, carboxylic acid, carboxylate, carboxamide, alkyl ester or nitro groups, where each alkylthio, arylthio, cycloalkylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups; provided that R 1 and R 2 are not both H.
  • B is NH 2
  • A is CH
  • E is N
  • D is H
  • R 1 and R 2 are independently selected from H and alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl and aryl each of which is optionally substituted with one or more hydroxy, alkoxy, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, , halogen, carboxylic acid, carboxylate, carboxamide, alkyl ester or nitro groups, where each alkylthio, arylthio, cycloalkylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups; provided that R 1 and R 2 are not both H.
  • B is hydroxy
  • A is CH
  • E is N
  • D is NH 2
  • R 1 and R 2 are independently selected from H and alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl and aryl each of which is optionally substituted with one or more hydroxy, alkoxy, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, halogen, carboxylic acid, carboxylate, carboxamide, alkyl ester or nitro groups, where each alkylthio, arylthio, cycloalkylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups; provided that R 1 and R 2 are not both H.
  • any halogen in the compound of formula (1) or (1') is fluorine or chlorine.
  • the hydroxymethylation of the compound of formula (2) or (2') in step (i) is carried by reaction using formaldehyde in the presence of a base, e.g. a mild inorganic or organic base, e.g. potassium carbonate.
  • a base e.g. a mild inorganic or organic base, e.g. potassium carbonate.
  • the hydroxymethylation of the compound of formula (2) or (2') in step (i) is carried out by reaction using paraformaldehyde in the presence of a base, e.g. a mild inorganic or organic base, e.g. potassium carbonate.
  • the solvent is an aqueous organic solvent, e.g. aqueous dioxane.
  • the oxidation of the hydroxymethylene group of the compound of formula (3) or (3') in step (ii) a. is carried out using 2,3-dichloro-5,6-dicyano-1 ,4- benzoquinone (DDQ) or Dess-Martin periodinane.
  • DDQ 2,3-dichloro-5,6-dicyano-1 ,4- benzoquinone
  • Dess-Martin periodinane is carried out in acetic acid solution.
  • the reductive amination of step (ii) b. is preferably carried out using sodium borohydride to reduce an imine adduct formed between the aldehyde and the primary or secondary amine.
  • the reductive amination of step (ii) b. is carried out using sodium cyanoborohydride can be used directly on a mixture of the aldehyde and the primary or secondary amine without prior formation of an imine.
  • the OL group in step (iii) a is preferably carried out using sodium borohydride to reduce an imine adduct formed between the aldehyde and the primary or secondary amine.
  • methanesulfonyloxy is selected from the group comprising methanesulfonyloxy, p-toluenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 4-bromobenzenesulfonyloxy and trifluoromethanesulfonyloxy.
  • the invention provides a compound of formula (1) or (1 1 ) when prepared by a process of the first or second aspect of the invention.
  • alkyl is intended to include straight- and branched-chain groups.
  • the non- aromatic moiety of an aralkyl radical is intended to include straight- and branched-chain alkyl groups.
  • alkyl groups include, but are not limited to: methyl group, ethyl group, n-propyl group, /so-propyl group, n-butyl group, /so-butyl group, sec-butyl group, f-butyl group, n-pentyl group, 1 ,1-dimethylpropyl group, 1 ,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1- methyl-2-ethylpropyl cyclobutyl group, cyclopentyl group and cyclohexyl group.
  • alkenyP means any hydrocarbon radical having at least one double bond, and having up to 30 carbon atoms, and includes any C 2 -C 2S , C 2 -C 2 O, C 2 -Ci 5 , C 2 -C 10 , or C 2 -C 6 alkenyl group, and is intended to include both straight- and branched-chain alkenyl groups.
  • alkenyP means any hydrocarbon radical having at least one double bond, and having up to 30 carbon atoms, and includes any C 2 -C 2S , C 2 -C 2 O, C 2 -Ci 5 , C 2 -C 10 , or C 2 -C 6 alkenyl group, and is intended to include both straight- and branched-chain alkenyl groups.
  • the same terminology applies to the non-aromatic moiety of an aralkenyl radical.
  • alkenyl groups include, but are not limited to: ethenyl group, n- propenyl group, /so-propenyl group, n-butenyl group, /so-butenyl group, sec-butenyl group, f-butenyl group, n-pentenyl group, 1 ,1-dimethylpropenyl group, 1 ,2- dimethylpropenyl group, 2,2-dimethylpropenyl group, 1-ethylpropenyl group, 2- ethylpropenyl group, n-hexenyl group and 1-methyl-2-ethylpropenyl group.
  • alkynyl means any hydrocarbon radical having at least one triple bond, and having up to 30 carbon atoms, and includes any C 2 -C 25 , C 2 -C 20 , C 2 -C 15 , C 2 -C 10 , or C 2 -C 6 alkynyl group, and is intended to include both straight- and branched-chain alkynyl groups.
  • the same terminology applies to the non-aromatic moiety of an aralkynyl radical.
  • alkynyl groups include, but are not limited to: ethynyl group, n- propynyl group, /so-propynyl group, n-butynyl group, /so-butynyl group, sec-butynyl group, f-butynyl group, n-pentynyl group, 1 ,1-dimethylpropy ⁇ yl group, 1 ,2- dimethylpropynyl group, 2,2-dimethylpropynyl group, 1-ethylpropynyl group, 2- ethylpropynyl group, n-hexynyl group and 1-methyl-2-ethylpropynyl group.
  • cycloalkyl means a saturated or partially saturated non-aromatic carbocyclic group, preferably comprising from 3 to 8 carbon atoms.
  • cycloalkyl groups include, but are not limited to: cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and cyclooctyl group.
  • Preferred cycloalkyl groups are 3-, 4- or 5-membered rings, e.g. cyclopropyl group, cyclobutyl group or cyclopentyl group.
  • aryl means an aromatic radical having 4 to 18 carbon atoms and includes heteroaromatic radicals. Examples include monocyclic groups, as well as fused groups such as bicyclic groups and tricyclic groups. Some examples include, but are not limited to: phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, azulenyl group, heptalenyl group, biphenyl group, indacenyl group, acenaphthyl group, fluorenyl group, phenalenyl group, phenanthrenyl group, anthracenyl group, cyclopentacyclooctenyl group, and benzocyclooctenyl group, pyridyl group, pyrrolyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazoly
  • aralkyl means an alkyl radical having an aryl substituent.
  • alkoxy means an hydroxy group with the hydrogen replaced by an alkyl group.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • prodrug means a pharmacologically acceptable derivative of a compound, such that an in vivo biotransformation of the derivative gives the compound.
  • Prodrugs of compounds of formula (1) or (1') may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to give the compounds. Examples of suitable prodrugs include, but are not limited to, esters and acetals.
  • salts are intended to apply to non-toxic salts derived from inorganic or organic acids, including, for example, the following acid salts: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,
  • leaving group means a group that is capable of being displaced by another group, typically by way of a nucleophilic substitution reaction.
  • leaving groups include, but are not limited to, halogen atoms and alkyl or aryl sulfonates such as methanesulfonates and benzenesulfonates, or substituted forms thereof such as bromobenzenesulfonates, trifluoromethanesulfonat.es, p-toluenesulfonates nitrobenzenesulfonates, nonafluorobutanesulfona.es, 2,2,2-trifluoroethanesulfonates, fluorosulfonates, or perchlorates.
  • protecting group means a group that selectively protects an organic functional group, temporarily masking the chemistry of that functional group and allowing other sites in the molecule to be manipulated without affecting the functional group.
  • Suitable protecting groups are known to those skilled in the art and are described, for example, in Protective Groups in Organic Synthesis (3 rd Ed.), T. W. Greene and P. G. M. Wuts, John Wiley & Sons lnc (1999).
  • Examples of protecting groups include, but are not limited to: benzyl group, benzyl group substituted with one or more substituents e.g. halogen or alkyl or alkoxy (e.g.
  • trialkyl(aryl)silyl alkylorthoester, alkylacetal, ester, O-methyl, O-benzyloxymethyl, O-methoxymethyl, trialkylsilyl, e g tert-butyldimethylsilyl, alkyldiarylsilyl, e.g. tert-butyldiphenylsilyl, trityl, alkylcarbonyl, arylcarbonyl, akyloxycarbonyl, e.g. methoxycarbonyl, aryloxycarbonyl, and aralkyloxycarbonyl, e.g. benzyloxycarbonyl.
  • suitable O-protecting groups that can be used in the process of the invention include, but are not limited to, (i), alkyl ethers such as methyl, ethyl, tert-butyl, allyl, allyloxycarbonyl, p-methoxybenzyl, 3,4-dimethoxybenzyl or (ii) silyl ethers, e.g. trimethylsilyl, tert butyldimethylsily, tert- butyldiphenylsilyl or triisopropylsilyl.
  • alkyl ethers such as methyl, ethyl, tert-butyl, allyl, allyloxycarbonyl, p-methoxybenzyl, 3,4-dimethoxybenzyl
  • silyl ethers e.g. trimethylsilyl, tert butyldimethylsily, tert- butyldiphenylsilyl or triisopropy
  • N-protecting groups that can be used in the process of the invention include, but are not limited to, (i) N-acyl derivatives such as tert-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetamide, allyloxycarbonyl, 9- fluorenylmethoxycarbonyl, 2-(trimethylsily)ethoxycarbony, 2,2,2-trichloroethoxycarbonyl, acetate, benzoate, pivaloate, or (ii) N,O-acetal derivatives such as benzyloxy methyl, methyloxymethyl, tert-butoxymethyl, methoxyethoxyethyl, or (iii) N-alkyl such as p- methoxy benzyl, allyl, trityl.
  • N-acyl derivatives such as tert-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetamide, allyloxycarbonyl, 9- fluoren
  • the invention provides a new way, in the synthesis of compounds of formula (1) or (1'), of introducing the methylene group that links their 9-deazapurine base and their cyclic or acyclic amine moieties.
  • the process involves two steps.
  • direct substitution of the 9-hydrogen atom by a 9-hydroxymethyl substituent is a novel and efficient approach.
  • the reagent of choice is formaldehyde, and the reaction can be suitably promoted by use of a mild inorganic or organic base in an aqueous organic solvent.
  • Potassium carbonate has proven to be an effective mild inorganic base, and aqueous dioxane a useful solvent.
  • Other bases include, but are not limited to, sodium bicarbonate or triethylamine in aqueous THF.
  • the 9-deazapurine substrate can be unprotected or protected.
  • deazapurine substrates that can be used in the process of the invention include, but are not limited to, 9-deazahypoxanthine, 4-(benzyloxy)-5H-pyrrolo[3,2-d]pyrimidine, N-(A- methoxybenzyl)-5/-/-pyrrolo[3,2-c(]pyrimidin-4-amine or ⁇ /-benzyl-5H-pyrrolo[3,2- d]pyrimidin-4-amine.
  • the base 9-deazahypoxanthine itself undergoes the reaction, as does the protected base 6-benzyloxy-9-deazapurine.
  • the use of such a 6-O- protected 9-deazahypoxanthine derivative can be advantageous for the easier removal of unwanted impurities from the final product due to its better crystallinity and/or chromatographic purification.
  • the first step of the process is preferably carried out by heating the reaction mixture, e.g. the 9-deazapurine substrate and aqueous formaldehyde.
  • the reaction mixture can be heated at a temperature of up to about 100 0 C, preferably about 80-100 0 C, more preferably about 90-100 0 C.
  • Work-up of the reaction mixture is preferably via chromatography on silica gel. The work-up also preferably involves treatment with methanolic ammonia.
  • the 9-hydroxymethyl substituent in the product from the first step is oxidized to a 9-formyl substituent, then subjected to a reductive amination reaction with the desired cyclic'or acyclic amine, or a protected version thereof.
  • the oxidation can be achieved with a variety of oxidants.
  • DDQ 2,3-dichloro-5,6- dicyano-1 ,4-benzoquinone
  • Dess-Martin periodinane in acetic acid have proved effective.
  • Other possible oxidants include, but are not limited to, dimethyl sulfoxide in a Swern type reaction, chromium oxidants e.g. chromium trioxide, pyrididinium dichromate or pyridinium chlorochromate, TEMPO/BA IB, TEMPO/sodium hypochlorite.
  • Suitable solvents include chloroform, dichloromethane or acetic acid.
  • the reductive amination can be effected by a number of hydride reducing agents.
  • hydride reducing agents In the case of primary amines it is convenient to first form the imine-adduct between the amine and the aldehyde and then apply a reducing agent.
  • Sodium borohydride in an organic solvent has proven effective.
  • Other possible reducing agents include, but are not limited to, sodium cyanoborohydride, lithium aluminium hydride, borane and its complexes with ethers or amines, sodium triacetoxyborohydride, or hydrogen and a palladium catalyst.
  • Sodium cyanoborohydride can be used directly on a mixture of aldehyde and amine without prior formation of the imine.
  • the 9-hydroxymethyl substituent in the product from the first step is converted into a sulfonate leaving group, and this is then displaced with the desired cyclic or acyclic amine, or a protected version thereof.
  • Suitable sulfonylation reagents include methanesulfonyl chloride, p-toluenesulfonyl chloride 2,4,6-trimethylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, trifluoromethanesulfonyl chloride and a base.
  • Suitable bases include, but are not limited to, pyridine, diisopropyethylamine, 2,6-lutidine and triethylamine. The displacement of the leaving group occurs following addition of the amine to the reaction mixture.
  • the amine moiety that is linked to the base substrate via the methylene link can be a cyclic or an acyclic amine.
  • the amine is a cyclic amine, it is preferably a 5- membered azacarbocycle, such as pyrrolidine, or a four membered azacarbocycle, such as azetidine.
  • the azacarbocycle is substituted with one or more substituents such as halogen, hydroxy, alkoxy (e.g. methoxy), alkylthio, thiol, CH 2 OH, CH 2 (alkoxy), CH 2 (alkylthio) or alkyl. These substituents may optionally be protected by one or more protecting groups.
  • protecting groups have been employed in the process of the invention, they are removed using the appropriate deprotection conditions to give the compounds of formula (1).
  • benzyl and O-methyl protecting groups may be removed by treatment with a suitable acid, e.g. HCI.
  • the compounds of formula (1) or (1') prepared according to the invention are useful as pharmaceuticals.
  • the compounds are useful in both free base form and in the form of salts.
  • the compounds of formula (1) or (1'), e.g. where B and/or D is hydroxy or NH 2 group, can exist as tautomers.
  • the representation of a compound of formula (1) or (1') where B and/or D is hydroxy group is of the enol-type tautomeric form of a corresponding amide, and this will largely exist in the amide form.
  • the use of the enol-type tautomeric representation is simply to allow fewer structural formulae to represent the compounds of the invention. The scope of this invention is intended to encompass all possible tautomeric forms.
  • the compounds of formula (1) or (1') can exist in the form of optical isomers, diastereomers or racemates.
  • the scope of this invention is intended to encompass all possible such isomeric forms that the compounds of formula (1) or (1') may possess.
  • asymmetric carbons may have the R- or S-configuration.
  • the compounds preferably prepared by the process of the invention include, but are not limited to, the compounds of the following list: rac-(2R,3S)-3-((4-hydroxy-3H-pynrolo[3,2-d]pyrimidin-7-yl)methylamino)butane-1 ,2,4- triol;
  • the off-white solid comprised the title compound 20 (2.3 g, 80% purity, 7.29 mmol, 42% yield) contaminated with iodobenzoic acid. It was used without further purification. Chromatography gave a pure sample.
  • 1 H NMR 300 MHz, DMSO-Cf 6 , TMS) ⁇ 12 (bs, 1 H), 10.11 (s, 1H), 8.34 (s, 1H), 8.23 (s, 1 H), 7.71 (s, 1H), 7.5-7.2 (m, 5H), 4.74 (s, 2H).
  • the process of the invention provides an alternative to known processes for preparing compounds that are inhibitors of nucleoside phosphorylases and nucleosidases, which compounds may be useful for the treatment of diseases such as cancer, bacterial infection, protozoal infection (including malaria), and T-cell mediated diseases.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un procédé de préparation de composés inhibiteurs de nucléoside phosphorylases et nucléosidases, en particulier, de composés présentant une liaison méthylène entre une fraction d'analogue de base de nucléoside de la molécule et une fraction analogue de sucre, au moyen d'un azote d'amino de la fraction d'analogue de sucre.
PCT/NZ2008/000348 2007-12-21 2008-12-22 Procédé de préparation d'immucillines à liaison méthylène WO2009082247A1 (fr)

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WO2011008110A1 (fr) * 2009-07-17 2011-01-20 Albert Einstein College Of Yeshiva University Inhibiteurs 3-hydroxypyrrolidine de 5'-méthylthioadénosine phosphorylase et nucléosidase
US8173662B2 (en) 2002-08-21 2012-05-08 Industrial Research Limited Fused pyrimidines as inhibitors of nucleoside phosphorylases and nucleosidases
US8183019B2 (en) 2004-06-04 2012-05-22 Industrial Research Limited Method for preparing 3-hydroxy-4-hydroxymethyl-pyrrolidine compounds
CN102702117A (zh) * 2012-06-01 2012-10-03 浙江沙星医药化工有限公司 一种制备5-(4’-溴代甲基-2-联苯基)-1-三苯甲基四氮唑的方法
US8283345B2 (en) 2006-12-22 2012-10-09 Industrial Research Limited Azetidine analogues of nucleosidase and phosphorylase inhibitors
US8383636B2 (en) 2006-09-07 2013-02-26 Industrial Research Limited Acyclic amine inhibitors of 5-methytioadenosine phosphorylase and nucleosidase
US8394950B2 (en) 2006-02-22 2013-03-12 Industrial Research Limited Analogues of coformycin and their use for treating protozoan parasite infections
US8853224B2 (en) 2006-09-07 2014-10-07 Industrial Research Limited Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US9290501B2 (en) * 2010-11-29 2016-03-22 Albert Einstein College Of Medicine, Inc. Methods, assays and compounds for treating bacterial infections by inhibiting methylthioinosine phosphorylase
CN108602832A (zh) * 2016-02-05 2018-09-28 正大天晴药业集团股份有限公司 一种吡咯并[3,2-d]嘧啶类化合物的制备方法及其中间体
US10793572B2 (en) 2014-09-29 2020-10-06 The Provost Fellows Foundation Scholars And The Other Members Of Board Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Substituted pyrimidine derivatives useful in the treatment of autoimmune diseases

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US8173662B2 (en) 2002-08-21 2012-05-08 Industrial Research Limited Fused pyrimidines as inhibitors of nucleoside phosphorylases and nucleosidases
US8183019B2 (en) 2004-06-04 2012-05-22 Industrial Research Limited Method for preparing 3-hydroxy-4-hydroxymethyl-pyrrolidine compounds
US8394950B2 (en) 2006-02-22 2013-03-12 Industrial Research Limited Analogues of coformycin and their use for treating protozoan parasite infections
US8383636B2 (en) 2006-09-07 2013-02-26 Industrial Research Limited Acyclic amine inhibitors of 5-methytioadenosine phosphorylase and nucleosidase
US8853224B2 (en) 2006-09-07 2014-10-07 Industrial Research Limited Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8283345B2 (en) 2006-12-22 2012-10-09 Industrial Research Limited Azetidine analogues of nucleosidase and phosphorylase inhibitors
US9493465B2 (en) 2009-07-17 2016-11-15 Victoria Link Limited 3-hydroxypyrrolidine inhibitors of 5′-methylthioadenosine phosphorylase and nucleosidase
JP2012533538A (ja) * 2009-07-17 2012-12-27 アルバート・アインシュタイン・カレッジ・オブ・メディシン・オブ・イエシヴァ・ユニバーシティー ５’−メチルチオアデノシンホスホリラーゼ及びヌクレオシダーゼの３−ヒドロキシピロリジン阻害剤
WO2011008110A1 (fr) * 2009-07-17 2011-01-20 Albert Einstein College Of Yeshiva University Inhibiteurs 3-hydroxypyrrolidine de 5'-méthylthioadénosine phosphorylase et nucléosidase
US9957272B2 (en) 2009-07-17 2018-05-01 Victoria Link Limited 3-hydroxypyrrolidine inhibitors of 5′-methylthioadenosine phosphorylase and nucleosidase
EP2454263A1 (fr) * 2009-07-17 2012-05-23 The Albert Einstein College Of Medicine Of Yeshiva University Inhibiteurs 3-hydroxypyrrolidine de 5'-méthylthioadénosine phosphorylase et nucléosidase
AU2010271532B2 (en) * 2009-07-17 2016-03-03 Albert Einstein College Of Medicine, Inc. 3-hydroxypyrrolidine inhibitors of 5'-methylthioadenosine phosphorylase and nucleosidase
EP2454263A4 (fr) * 2009-07-17 2012-12-19 Einstein Coll Med Inhibiteurs 3-hydroxypyrrolidine de 5'-méthylthioadénosine phosphorylase et nucléosidase
US9290501B2 (en) * 2010-11-29 2016-03-22 Albert Einstein College Of Medicine, Inc. Methods, assays and compounds for treating bacterial infections by inhibiting methylthioinosine phosphorylase
CN102702117B (zh) * 2012-06-01 2016-04-13 浙江沙星医药化工有限公司 一种制备5-(4’-溴代甲基-2-联苯基)-1-三苯甲基四氮唑的方法
CN102702117A (zh) * 2012-06-01 2012-10-03 浙江沙星医药化工有限公司 一种制备5-(4’-溴代甲基-2-联苯基)-1-三苯甲基四氮唑的方法
US10793572B2 (en) 2014-09-29 2020-10-06 The Provost Fellows Foundation Scholars And The Other Members Of Board Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Substituted pyrimidine derivatives useful in the treatment of autoimmune diseases
US11518765B2 (en) 2014-09-29 2022-12-06 The Provost, The Fellows, Foundation Scholars, And The Other Members Of Board, Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth, Near Dublin Substituted pyrimidine derivatives useful in the treatment of autoimmune diseases
CN108602832A (zh) * 2016-02-05 2018-09-28 正大天晴药业集团股份有限公司 一种吡咯并[3,2-d]嘧啶类化合物的制备方法及其中间体
US10654856B2 (en) 2016-02-05 2020-05-19 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Method for preparing pyrrolo[3,2-D]pyrimidine compound, and intermediates thereof
CN108602832B (zh) * 2016-02-05 2020-10-09 正大天晴药业集团股份有限公司 一种吡咯并[3,2-d]嘧啶类化合物的制备方法及其中间体

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