Title of Invention

"AN ACYCLIC NUCLEOSIDE PHOSPHONATE DERIVATIVE"

Abstract The present invention relates an acyclic nucleoside phosphonate derivative which is useful as anantivriral agent openlly against hepataus B strust pharmacutically apparatus salts. stereoisomers and a process for the preparation thereof
Full Text NOVEL ACYCLIC NUCLEOSIDE PHOSPHONATE DERIVATIVES SALTS THEREOF AND PROCESS FOR THE PREPARATION OF
THE SAME
TECHNICAL FIELD
The present invention relates to an acyclic nucleoside phosphonate derivative represented by the following formula (1):
(Formula Removed ) in which
represents single bond or double bond,
R1, R2. R3. R7 and R8 independently of one another represent hydrogen, halogen, hydroxy. amino. C1-C7-alkyl, C2-C6-alkenyl, C1-C5-alkylamino. C1-C5-aminoalkyl. or C1-C5-alkoxy,
R4 and R" independently of one another represent hydrogen, or represent C1-C4alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine). C1-C4-alkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5acyloxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl. or represent -(CH2)m-OC(=O)-R6 wherein m denotes an integer of 1 to 12 and R" represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7-alkylamino, di(C1-C-alkyl)amino, C3-C6,-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen,
Y represents -O-. -S-. -CH'Z- =C(Z) -N(Z) =N-, -SiH(Z)-. or =Si(Z)-. where represents hydrogen, hydroxy or halogen, or represents C1-C7alkyl, C1-C5alkoxy. alkyl. hydroxy-C1-C7-alkyl. C1-C7-aminoalkyl or phenyl.
Q represents a group having the following formula:
(Formula Removed ) wherein
X1, X2, X3 and X4 independently of one another represent hydrogen, amino, hydroxy or halogen, or represent C1-C7-alkyl. C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, phenyl or phenoxy each of which is optionally substituted by nitro or C1-C5-alkoxy, or represent C6-C10-arylthio which is optionally substituted by nitro. amino. C1-C6-alkyl or C1-C4-alkoxy. or represent C6-C12-arylamino. C1-C-alkylamino. di(C1-C7-a!ky!)amino.
C3-C6)-cycloalkylamino or a structure of (Formula Removed ) wherein n denotes an integer of 1 or
2 and Y' represents O. CH: or N-R (R represents C1-C7-aIkyl or C,-C12-aryl).
which is useful as an antiviral agent (particularly, against hepatitis B virus).
pharmaceutically acceptable salts, stereoisomers, and a process for the preparation thereof.
BACKGROUND ART
Purine or pyrimidine derivatives have anti-cancer and antiviral activities, and more than 10 kinds of the compounds including AZT. 3TC and ACV have already been commercialized. Particularly, since acyclic nucleoside phosphonate derivatives show a potent antiviral effect, cidopovir has been commercialized as an antiviral agent and man\ compounds including PMEA and PMPA now entered into the step of clinical trials. However, the earlier developed compounds were not perfect in the aspects of toxicity or pharmaceutical activity, and thus, it is still desired to develop a compound having no toxicity as well as a superior activity. The prior researches for purine or pyrimidine derivatives or acyclic nucleoside phosphonate derivatives as reported heretofore are as follows. Patents: US 5817647; US 5977061; US5886179; US 5837871; US 6069249; WO 99/09031; W096 09307: W095-212:-'., US 5935946; US 58"io6; US 5~9275o; Journals International Journal of Antimicrobial Agents 12 (1999), 81-95; Nature 323 (1986), 4M: Heterocycles 31(1990), 1571: J. Med. Chem. 42 (1999). 2064; Pharmacology 857-564; Antimicrobial Agent and Chemotherapy 42 (1999) 28S5-2892.
DISCLOSURE OF INVENTION
Thus, the present inventors extensively studied to develop a compound having a superior biological activity (pharmaceutical effect) to as well as a lower toxicity than the existing acyclic nucleoside phosphonates commercialized or entered into the step of clinical trials. As a result, we found that the above compound of formula (1) characterized by its unique chemical structure exhibits a potent pharmaceutical activity, and then completed the present invention.
Therefore, one object of the present invention is to provide the compound of formula (1) having a good use of antiviral agent, pharmaceutically acceptable salts or isomers thereof.
It is another object of the present invention to provide a process for the preparation of the compound of formula (1).
It is still another object of the present invention to provide intermediates which are advantageously used for the preparation of the compound of formula (I).
BEST MODE FOR CARRYING OUT THE INVENTION
The compound of formula (1) according to the present invention, as represented below, is a type of acyclic nucleoside phosphonate derivative having a natural base, such as for example, adenine, guanine, uracil, cytosine, thymine or derivatives thereof:
(Formula Removed ) in which
represents single bond or double bond,
R1 R2 R3. R7 and R9 independentl y of one another represent hydrogen, halogen, hydroxy.
amino, C1-C7-alkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or C1-C5-alkoxy,
R4and R5 independently of one another represent hydrogen, or represent C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), C1-C4-alkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyloxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=O)-R6 wherein m denotes an integer of 1 to 12 and Rb represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C -C7-alkylamino. di(C1-C7-alkyl)amino. C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen.
Y represents -0-, -S-, -CH(Z)-, =C(Z)-, -NlZ)-. =N-, -SiH(Z)-, or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents C1-Calkyl, C10-alkoxy. alkyl, hydroxy-C1-C-alkyl, C1-C7-aminoalkyl or phenyl.
Q represents a group having the following formula:
(Formula Removed ) wherein
X1, X2, X"1 and X4 independently of one another represent hydrogen, amino, hydroxy or halogen, or represent C1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C-alkyl. phenyl or phenoxy each of which is optionally substituted by nitro or C1-C5-alkoxy. or represent C6-C10-arylthio which is optionally substituted by nitro, amino. C1-C6-alkyl or C1-C4-alkoxy, or represent C6-C12-arylamino, C1-C7-alkylamino. di(C -C7-alkyl)amino.
C3-C6-cycloalkylamino or a structure of (Formula Removed ) wherein n denotes an integer of 1 or
2 and Y1 represents 0. CH2 or N-R (R represents C1-C7-alkyl or C6-C12-aryl).
Since the compound of formula (1) according to the present indention may have one or more asymmetric carbon atoms in the structure depending on the kind of substituents, it can be present in the form of the individual enantiomers. diastereomers, or mixtures thereof including racemate. Further, when a double bond is included in the structure, it can be present in the form of E or Z isomer. Thus, the present invention also includes all of these isomers and their mixtures.
Also, the compound of formula (1) according to the present invention can form a pharmaceutically acceptable salt. Such salt includes non-toxic acid addition salt containing pharmaceutically acceptable anion, for example a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic ar.d, hydriodic acid, etc., a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid. lactic acid. fumaric acid, maleic acid, etc., or a salt with sulfonic acids such as methanes-lfonic acid. benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.. particularly preferably with sulfuric acid, methanesulfonic acid or hydrohalic acid, etc.
Among the compound of formula (1) showing a potent pharmaceutical activity. :he
preferred compounds are those wherein
represents single bond,
R1. R". RJ. R and R8 independently of one another represent hydrogen, fluorine. hydroxy. C1-C7-alkyl, C1-C6-alkenyl, C1-C5-alky!amino. C1-C5-aminoalkyl. or C1-C5-alkoxy.
R and R" independently of one another represent hydrogen, or represent C1-C5-alkyl optionally substituted by one or more substituenls selected from the group consisting of fluorine, C1-C4-alkoxy and phenoxy, or represent carbamoyl substituted by C1-C5-alkyl, or represent -(CH2)m-OC(=O)-Rc> wherein m denotes an integer of 1 to 12 and R° represents G-C|2-alkyl. C2-C-alkenyl, C1-C5-alkoxy, C1-C7-iikylamino. di(C1-C7-alkyl)amino, C3-C6-cycloalkyl. or 3 to 6-membered heterocycle ha. ing 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen.
Y represents -0-. -S-, or -N(Z)-, wherein Z represents hydrogen, hydroxy, C1-C-alkyl. or hydroxy-C1-C-alkyl,
Q represents a group having the following formula:
(Formula Removed ) wherein
X represents hydrogen, amino, hydroxy or halogen, or represents C1-C7-alkyl. C1-C5-alkoxy, hydroxy-C1-C7-alkyl or phenoxy each of which is optionally substituted by nitro or C1-C5-alkoxy, or represents C1-C10-arylthio which is optionally substituted by nitro. amino, C1-C6-alkyl or C1-C4alkoxy, or represents C6-C12-arylamino. C1-C7-alkylamino, di(C1-C-alkyl)amino, C3-C6cycloalkylamino or a structure of
(Formula Removed ) wherein n denotes an integer o: 1 or 2 and Y represents O. CH2 or N-R (R represents C1-C7-alkyl), and X2, X3 and X4 independently of one another represent hydrogen, amino, hydroxy, halogen, C1-C7-alkyl, C1-C5-alkoxy, or C1-C7-alkylamino.
Most preferred compounds are those -vherein — represents single bond, R1. R3 R and R independently of one another represent hydrogen, R2 represent hydrogen or methyl, R4 and R' independently of one ar.other represent t-butylcarbcr.yloxymethyl. isopropoxycarbonyloxymethyl or 2.2.2-trifluoroethyl. Y represents -O-. Q represents
wherein X1 represents hydrogen, hydroxy, ethoxy. --metho.v-rhenyhhio or 4-nitrophenylthio, and X" represents amino.
Typical examples of the compound of formula (1) according :: the present invention are described in the following Tables '. and 7.
Table la Table 2a Table 3a Table 4 Table 5 Table 6 Table 7 (Tables Removed )

More particularly preferable compounds among the compounds described in the abo\e Tables 1 and ~ are as follows:
{ 1 -[{6-amino-9H-purin-9-yl)methyl]cyclopropy oxy)methylphosphonic acid (Compound 1);
3-[(| l-[(6-amino-9H-punn-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trio\a-3 5-phosphanon-1-\i pivaJate(Compound 2);
([ l-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl]oxy)methylphosphonic
acid(Compound 3);
3-[({l-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methy]]-8,8-dimethyl-3,7-dioxo-2.4,6-trioxa-3 3-phosphanon-l-yl pivalate(Compound 4);
({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl'roxy)methyl phosphonic acid(Compound 5);
3-[(!l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl;oxy)methyl]-8.8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 D-phosphanon-l-yl pivalate(Compound 6);
(! l-[(2-amino-6-tluoro-9H-punn-9-yl]mnethyl]cyclopropyl|oxy)medhyphosphonic acid(Compound 7):
3-[( J l-[(2-amino-6-fluoro-9H-purm-9-;.i)methyl]cyclopropyl;o\y)methyl]-8,8 dimethyl-3.7-dioxo-2.4.6-tnoxa-3 "-phosphanon-1-yl pivalate(Compound S):
(11 -[(2-amino-9H-punn-9-yl )methy l]c;.clopropyl J oxy)methy I phosphonic acu: (Compound 9):
3-[( {l-[(2-amino-9H-purm-9-yl (methyl. cyclopropyl; oxy)methyl-8.8-.nmetln I-3.7-dioxo-2.4.6-tnoxa-3 '-phosphanon-l-vl pi\ alatef Compound 10):
(11 -[(2-amino-(vcyclopropyiamino-9H-punn-9-yl(methyl]c\cloprop\ 1: ox meth-ylphosphonic aeid(Compound 1 1):
3-[( 1 l-[(2-amino-6-cyclopropylamino-9H-purin-9-yi (methyl]cyciopropypyloxy ) methyl]-8,8-dimeth\l-3.7-dio\o-2.4.6-tno\a-3 -phosphanon-1 -yl prvalatelCompound 12).
[(l-|[2-ammo-6-(dimethylaniino)-9H-pLirin-9-yl]methyl]cyclopropyl)oxy]methyl phosphonic acid(Compound 15):
3- [(1 -1[2-ammo-6-(dimethylamino)-9H-purin-9-yl]methyl J cycl propyloxyl ] methyl j -8,8-dimethyl-3.7-dioxo-2.4.6-tno\a-3 -phosphanon-1-yl pivalate( Compound 16);
[(1-![2-ammo-6-(isopropylamino)-9H-purin-9-yl]methyl!cyelopropyI)ocy]methyl phosphonic acid(Compound 17);
3-{[(l-![2-amino-6-(isopropylamino)-9H-purin-9-yl]methyl!cyclopropl)oy methyl|-8,8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 -phosphanon-1-yl pivalate(Compound 18);
({l-[(2.6-diamino-9H-purin-y-yl)ire:hy!!cyclopropylJoxy)methyiphosphonic acid(Compound 19);
3-[( ] l-[(2.b-diamino-9H-punn-9-yl)methyl]cyclopropyl!oxy)methyl]-N.S-dimethyl-3,7-dioxo-2.4.6-trioxa-3 "-phosphanon-1-yl pivalatelCompound 20);
(! 1 -[(2-amino-9H-methoxy-9H-punn-9-yl imethyl]cyclopropyl! oxymethy1 phosphonic acid (Compound 21):
3-[({ l-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyoxy)methyl]-8,8-
dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivaJate(Compound 22);
({l-[(2-amino-6-ethoxy-9H-purin-9-yI)methyl]cyclopropyl}oxy)methyl phosphonic acid (Compound 23);
3-[({l-[(2-amino-6-ethoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethy!-3,7-dioxo-2.4.6-trioxa-3 '-phosphanon-1-yl pivalate(Compound 24);
(! l-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropyl \ oxy)methyl phosphonic acid(Compound 25);
3-[( I l-[(2-arnino-6-methyl-9H-punn-9-yi)methyl]cyclopropyl[oxy)methyl]-1S.S-dimethyl-3.7-dioxo-2.4.6-tnoxa-3 ~-phosphanon-l-yl ptivalate( Compound 261.
[(l-![5-methyi-2.4-dioxo-3.4-dihydro-l(2H)-pynmidinyl]methylcyclpropyl)ox. ]methylphosphonic acid( Compound 31);
8.8-dimethyl-3-! [(1-1 [5-methyl-2.4-dioxo-3.4-dihydro- 1 (211 )-pyrimidimyl]methyl cy ciopropyl)oxy]methyl] -3.7-dioxo-2.4.6-tnoxa-3 '-phosphanon-1 -yl privlate (Compound 32);
[(1- ;[2-amino-6-(4-morpholinyl)-9H-purin-9-yl]methyl [eyclopropyl)ylmethyl phosphonic acid(Compound 37);
3-! [(1 -! [2-amino-6-(4-morpholinyl)-9H-purin-9-yl]methyl! cycloprop\ i to \y) met-hyl!-8,8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 "-phosphanon-1-yl pivalatei Compound 38);
bis(2.2.2-trifluoroethyl) ({l-[(2-ammo-6-hvdroxy-9H-purin-9-yl)mcth\ ii cyclopropyl|oxy)methylphosphonate (Compound 45);
bis(2.2,2-rnfluoroethyl) ( j l-[(2-ammo-()-chloro-9H-punn-9-yl)meth\i' cyclopropyl | oxy)methylphosphonate(Compound 40);
bis(2.2,2-tritluoroethyl) ({ l-[|2,6-diamino-9H-purm-9-vl)methyl]cycloprop\l; oxy)methylphosphonate bis(2,2,2-tritluoroethyl) ({l-[(6-amino-9/Y-purin-9-yi)metliyl]cycloprop\l; o.w imcthylphosphonatet Compound 48);
bis(2.2,2-tnfluoroethyl) (j l-[(2-amino-9H-punn-9-yl)merhyl]cycloprop\ I,' oxy)methylphosphonate(Compound 49);
bis(2.2,2-trifluoroethyl) ({l-[(2-amino-6-dirnethylamtno-9H-punn-9-vl imethyl] cyclopropyl }oxy)methy:phospnonate^Compound 52 V.
bis(2.2.2-trifluoroethyl) ({1 -[(2-amino-6-isopropylamino-9/y-purin-9-yl) methyl]cyclopropyl!oxy)methylphosphonate(Compound 53);
bis(2,2.2-trifluoroethyl) ({l-[(2-amino-6-methoxy-9H-punn-9-yl)meth>H cyclopropyl }oxy)methylphosphonate(Compound 541;
bis(2.2.2-trifluoroctliyl) [(l-{[2-ammo-6-(4-morpholin\l)-9H-punn-9-\ I jmethyl J cyclopropyl )o\y]methylphosphonate(Compound 58);
bisi2,2,2-trii:uoroethyl)[(l-{[2-amino-6-(pheny]sulfanyl)-9H-punn-9-y]] methyl }cyclopropyl>oxy]rnethylphosphonate(Cornpound 61);
bis(2,2,2-trif:uoroethyl) {[l-({2-amino-6-[(4-methylphenyl)sulfanvi]-9H-purin-9-yl ! methyl )c}ciopropyl]oxyj methylphosphonate(Compound 62);
bis-2,2,2-trifloroethyl) {[l-(|2-amino-6-[(4-methoxyphenyl)sulfanyI]-9H-purin-9-yl] meth;.. icyclopropyljoxy) methylphosphonate(Compound 63): bib'2.2,2-trioroethyl) J[ 1 -(J2-amino-6-[(4-nitrophenyl)sulfanyl)- 9H-punn-9-yl ] methylicyclopropyljoxy; methylphosphonate(Compound 6-i i:
[(1 - [2-amino 6-(phenylsulfanyi)-9H-purin-9-yl]methyl]cyclopropyhoxy]methyl pnosphomc acid(Corr.pound 65):
;[i- ,'2-amir.:-6-[(4-methylphenyl)sulfanyli-9H-purin-9-yl]methyl)cyciopropyl] oxymethyphosphor.. acid(Compound 66);
3--2-a~:no-6-[(4-inethylphenyl)sulfanyl]-9H-purin-9-yl] methylcyclo propl]oxy methyl)- 8, 8-dimethyl-37-dioxo-2.4.6-tnoxa-3'"-phosphanon-l-yl pryalrate (Compounc'-08);
bia ~(t-buto\ carbonyl)oxy]methylJ( | l-[(2-amino-9H-punn-9-ylmethyl cyclo propyl | ox} :nethylph:sphonate(Compound 69);
bis [(isoprorxycarbonyl)oxy]methyl|( j l-[(2-amino-9H-punn-9-;.yl)methyl |cyclo propyl | ox} :nethylpr.:sphonate (Compound 70);
bis !(ethox\;irbonyl)oxy]methyl}({ l-[(2-ammo-9H-punn-9-yl)meth}ljcyclo propyl!ox} nethylpi".:sphonate (Compound 71);
bis [(isobuto.ycarbonyl)oxy]methyl}( JI -[(2-amino-9H-punn-9-} i imethyl]cycio propyl! ox} methylphosphonate (Compound 72);
3-[i l-[(2-arr..no-9H-purin-9-yl)methyl]cyclopropyl]oxy)methyl]-9-meth}l-3.-dioKo-2.4.6-:rioxa-3 -phosphadec-1-yl 3-methylbutanoate(Compound 74):
3-[i 1 -[(2-an-..no-9H-purin-9-yl)methyl]cyclopropyllJ oxy)methyl]-8-nieth\ 1-3. -d;oKo-2.4.6-:noxa-3 -phosphanon-1-yl 2-methyIpropanoate(Compound 7S);
3-( l-( [2-ai:..no-6-[(4-methoxyphenyl)sulfanyl]-9H-punn-9-yl]meth}l)c}clo propyljoxyl methyl)-8,8-dimethyl-3.7-dioxo-2.4.6-tnoxa-3 -phosphanon-l-yl pivalate (Compound ~9);
3-[! 1-[(2-amino-9H-purin-9-yl}methyl]cycloprop;]oxy)methyl]-3.oxo- 1-pvrrolidinyl -2.4.6-tr:;\a-3 -phosphahept-1-yl l-pyrrolidinecarboxylate( Compound S(J): 3-[i l-[(2-anv.no-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3."7-dio\o-7-( I-pipendinyl)-2.4.6-tric3 3-phosphahept-l-yl l-pipendinecarboxylate(Compound 81);
3-[( !-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-~-(4-morpholi-nyl )-3.7-dioxo-2,4.6-trioxa-3 5-phosphahept-1 -yl 4-moipholmecarboxylatei Compound 82):
bis{[(/-butoxycarbonyl)oxy]methyl}[(l-{[2-amino-6-hydroxy-9H-purin-9-yI] methyl} cyclopropyl)oxy]methylphosphonate(Compound 83);
bis {[(isopropoxycarbonyl)oxy]methyl} [(1 - {[2-amino-6-hydroxy-9H-purin-9-yl] methyl J cyclopropyl)oxy]methylphosphonatefCompound 84);
bis {[(isopropoxycarbonyl)oxy]methyl J {[ 1 -({2-amino-[6-(4-methoxyphenyl) sulf'anyl]-9H-purin-9-yl]methyl)cyclopropyl]oxy;methylphosphonate(Compound 85);
3-[( j l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyljoxy)methyl]-7-cvclopentyl-3,7-dioxo-2.4.6-trioxa-3 3-phosphahept-1 -yl cyclopentanecarboxylate (Compound 86):
3-( J[l-( J2-amino-[6-(4-nitrophenyl)su!fanyl]-9H-purin-9-yl]methyl)cyclopropyl] oxyl methyl)-8.8-dimethyl-3.7-dioxo-2,4,6-tno\a-3 "-phosphanon-1 -yl pivalate (Compound 87);
bis|[(isopropoxycarbonyl)oxy]meth\i: ![l-( !2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yljmethyl)cyciopropyI]oxy|meth;-lphosphonate( Compound 88):
bis![(isopropoxycarbonyl)oxy]methyl:( J l-[(6-ammo-9H-punn-9-yl)methyl]cyclo-propyl] oxy)methylphosphonate(Compound 89):
3-[( 11 -[(6-amino-9H-purin-9-yl)methyl]cycIopropyl J oxy)methyl]-9-methyl-3,7-dioxo-2.4,6-trioxa-3 5-phosphadec-l-yl 3-methylbutanoate(Compound 90);
3-[( J l-[(6-amino-9H-purin-9-yl)meth>l]cyclopropyl}oxy)methyl]-7-cyclopentyl-3.7-dioxo-2,4.6-trioxa-3 "-phosphahept-1-yl cyclopentanecarboxylate(Compound 91);
bis j [(t-butoxycarbonyi)oxy]methyl J ;[!-({2-amino-[6-(4-methoxyphenyl )sul tanyl] -9H-punn-9-yl}methyl)cyclopropyl]oxy}methylphosphonate(Compound 92);
bisj[(t-butoxycarbonyl)oxy]methyl) |[l-(;2-amino-[6-(4-nitrophenyl)sulfanyl]-9// -punn-9-yl J methyl)cyclopropyl]oxyJ methylphosphonate(Compound 93);
|[l-({2-amino-[6-(4-nitrophenyl)suIfanyl]-9H-purin-9-yl!methyl)cyclopropyl]oxy ; methylphosphonic acid(Compound 95);
|[l-( !2-amino-[6-(4-methox\phenyl)sulfanyl]-9H-purin-9-yl!methyl)cyclopropyl] o\y| methylphosphonic acid(Compound 96);
(j 1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2-methylcyclopropyl | oxy) methylphosphonic acid(Compound 97);
( , i -[(2-amino-9H-purin-9-yl)methyi]-2-methylcy ciopropyl; oxy)methylphosphonic acid(Compound 98);
! [ 1 -({2-amino-[6-( 4-methox\phenyl)sultanyl]-9H-purin-9-yl \ methyl)-2-methyl cyclopropyl]oxy| methylphosphonic acid(Compound 99);
{[ l-( !2-amino-[6-(4-nitrophenyl)sultan\l]-9H-punn-9-yl}methyl)-2-methylcyclo-propyl]oxyl methylphosphonic acid(Compound 100);
|[l-( {2-amino-[6-(4-methylphenyl)sulfanyl]-9H-purin-9-yl|methyl)-2-methyl
cyclopropyl]oxy}methylphosphonic acid(Compound 101);
({1 -[(2,6-diamino-9H-purin-9-yl)methyl]-2-methylcyclopropyl} oxy)methyl phosphonic acid(Compound 102);
({1 -[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl} oxy)methylphosphonic acidfCompound 103);
3-[( {1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2-methylcyclopropyl J oxy) methyl]-8,8-dimethyl-3.7-dioxo-2,4,6-tnoxa-3 -phosphanon-1 -yl pivalate(Compound 105):
3-[({l-[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl|oxy)methyl]-8.8-dimethy!-3.7-dioxo-2.4.6-tno\a-3 "-phosphanon-1-yl pivalate(Compound 106);
3-[( i l-[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl | oxy)methyl]-8.8-dimethy|-3.7-dioxo-2.4.6-tno\a-3 "-phosphanon-1-yl pivalate(Compound 10"):
3-( ![l-(|2-amino-6-[(4-methox>phcnvl)sulfanyl]-9H/-purin-9-yl| methyl)-2-metliyl cyclopropyl]oxy|methyI)-8.8-dimethyl-3."-dio\o-2.4.6-tnoxa-3 "-phosphanon-1-yl pnaiate (Compound 108):
bis ! [(isopropoxycarbonyl )oxy]methyi! [(1 - i [2-amino-6-hydroxy-9H-purm-9-\ 1 j methyl |-2-methylcyclopropyl)oxy]methylphosphonate( Compound 109);
bis{[(isopropoxycarbonyl)oxy]methyl!(| l-[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate(Compound 110):
bis{[(isopropoxycarbonyl)oxyjmethyl,' j [ 1 -(J 2-amino-[6-(4-methoxyphenyl) sulfanyl]-9H-purin-9-yl j methyl)-2-methylcyclopropyl]oxy I methylphosphonate (Compound 112);
bis{[(t-butoxycarbonyl)oxy]methyl! |[!-( ;2-ammo-[6-(4-methoxyphenyl)sulfanylj -9/y-purin-9-yl}methyl)-2-methylcyclopropyl]oxy;methylphosphonate(Compound 113);
bis(2,2,2-trifluoroethyl) {[ 1 -(\ 2-amino-6-[( 4-methoxyphenyl)suifanyl]-9H-punn-9-yl! methyl)-2-methylcyclopropyl]oxy! methylphosphonate(Compound 114);
bis(2,2,2-trifluoroethyl) ,'[!-(|2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-punn-9-yl! methyl)-2-methylcyclopropyl] oxyjmethylphosphonate(Compound 115);
bis{[(t-butoxycarbonyl)oxy]methyl| }[l-( ;2-amino-[6-(4-nitrophenyl)sult'anyl]-9/-/ -purin-9-ylj methyI)-2-methylcyclopropyl]oxy! methylphosphonate(Compound 116):
bis][(isopropoxycarbonyi)oxyjmethyi; ;[';-, ,2-amino-[6-(4-nitrophenyl)sulfan\ 1]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy! methylphosphonate(Compound 117);
3-( {[ 1 -({2-amino-6-[(4-nitropheny!)sulfanyl]-9H-purin-9-y! j methyl)-2-methyl cyclopropyl]oxy|methyl)-8.8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 '"'-phosphanon-1-yl pivalate (Compound 118);
(! l-[(2-amino-6-hydroxy-9H-punn-9-yl)methyl]cyclopropyl|amino)meth\l phosphonic acid(Compound 119);
({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}amino)methylphosphonic acid(Compound 120);
({l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}amino)methylphosphonic acid(Compound 121);
[! l-[(2-amino-6-hydroxy-9H-punn-9-yl)methyl]cyclopropyl| (methyl)amino] methylphosphonic acid(Compound 122):
[|l-[(6-amino-9H-punn-9-yl)methyl]cyclopropyl!(ethyl)amino]meth>lphosphonic acid(Compound 125);
3- {[ {(1 -[(6-amino-9H-punn-9-yl )methyl]cycloprop\ 1)(methyl )aminomethyl)-8,8-dimethyl-3,7-dioxo-2.4.6-trioxs-3 :-phosphanon-l-yl pivalate(Compound 126 :
bis [(isopropoxycarbonyl)oxy]methyl | [! 1 -[(6-amino-9H-punn-9-yl )methyl]cyclo propyl! (methyl )amino]methyIphosphonate( Compound 127).
3-{[) l-[(2-amino-9H-punn-9-yl)methyl]cyclopropyl:(ethyl)amino]methyl xs-dimethyl-3,7-dioxo-2.4.6-tno\a-3 -phosphanon-l-yl pivalate(Compound 129.
(E)-2-11 -[(2-amino-o-hydroxy-9H-purin-9-yl )methyl]cyclopropyl; ethenyl phosphonic acid(Compound 130);
(E)-2-{ l-[(2-amino-9H-punn-9-yl)methyl]cyclopropyl j ethenyiphosphonic acid (Compound 131);
(E)-2-{ l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl!ethenylphosphonic acid (Compound 132);
3-((£>2-| l-[(2-amino-6-hydroxy-9H-purin-9-yl)metiwl]cyciopropylhenyl)-8,8-dimethyl-3,7-dioxo-2,4.6-tnoxa-3 -phosphanon-1-yl pivalate(Compound 133i:
3-((E)-2-{ l-[(6-amino-9H-purin-9-vl)methyl]cyclopropyl;ethenyl)-8,8-dimc[h\l-3.7-dioxo-2,4,6-trioxa-3 -phosphanon-l-yl pivalate(Compound 134);
(E)-2-{1 -[(6-amino-9H-purin-9-yl)methyl]eyclopropyl J -1 -propenylphosphonic acid(Compound 137);
2-{ l-[(2-amino-6-hydroxy-9/y-punn-9-\l)methyl]cyclopropyl;ethylphosphonic acid(Compound 138);
2-{l-[(2-amino-9H-purin-9-yl)methyljcyclopropyl|ethylphosphonic acid (Compound 139);
2- {1 -[(6-amino-9H-purm-9-yl)mehyl]cyclopropyl }ethylphosphonic acid (Compound 140);
2-[l-({2-amino-6-[(4-methylphenyl)sullanyl]-9H-punn-9-yl) methyl )cyclopropyl] ethylphosphonic acid(Compound 141);
2-{ l-[(2-amino-6-hydroxy-9H-punn-9-yl)methyl]cyclopropyl!propylphosphonic acidf Compound 142);
2-{ l-[(6-amino-9H-purin-9-yl)methyl]c\clopropyl J propylphosphonic .acid
(Compound 143);
2-{ l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}propylphosphonic acic (Compound 144);
3-(2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl)-8,8-dimeth;:-3.7-dioxo-2,4,6-trioxa-3 "-phosphanon-1-yl pivalate(Compound 145);
({1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2.2-dimethylcyclopropy oxyl methylphosphonic acid(Compound 146);
({ 1 -[(2-amino-9H-purin-9-yl)methyl]-2.2-dimethylcyclopropyl {oxyimeth phosphonic acid(Compound 147);
({ l-[(6-amino-9H-purin-9-yl)methyl]-2.2-dimethylcyclopropyl]; oxy meth phosphonic acid(Compound 148);
3-[( J l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2.2-dimethylcyciopro". oxy methyl]-8.8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 "'-phosphanon-1 -yl pivalarei Con:p. ..;id 149);
3-[(P{ l-[(2-amino-9H-purin-9-yl)methyl]-2.2-dimethvlcyclopropyloxymethyl]xy -dimethyl-3.7-dioxo-2.4.6-tnoxa-3 '-phosphanon-1-yl pivaiate(Compounu 150 .
3-[( i l-[(6-amino-9H-purin-9-yl)niediyl]-2.2-dimethylcyclopropyloxy )mc".methyl] -dimethyl-3,7-dioxo-2,4.6-tnoxa-3 "-phosphanon-1-yl pivalate(Compound 151 :
bis ![(isopropoxycarbonyl)oxy]methyl}({ l-[(6-amino-9H-purin-9-\l)me:lr. "-2.2-dimethylcyclopropyl | oxy)methylphosphonate(Compound 152); and
bis{ [(isopropoxycarbonyl)oxy]methyl{ [(1-{ [2-amino-6-hydroxy-9H-punix'-yl] methyl} -2.2-dimethy!cyclopropyl)oxy]methylphosphonateiCompound 153>.
The compound of formula (1) according to the present invention can be repareed by a process as explained below, and thus, it is another object of the present invention to provide such a preparation process. However, conditions of the process, such as for example, reactants. solvents, bases, amounts of the reactants used, etc. are not restreted to those explained below. The compound of the present invention may also be com enienth prepared by optionally combining the various synthetic ways described in the present specification or known in the arts, and such a combination can be easily performed by one of ordinary- ski il in the an to which the present invention pertains.
The compound of formula (1) of the present invention can be prepared characterized in that
(a) a compound represented by the following formula (2):
(Formula Removed )
in which R1, R2 R3. R4, R5 R7, R8 and Y are defined as previously described, and L represents a leaving group, preferably methanesulfonyloxy. p-toluenesulfonyloxy or halogen, is reacted with a compound represented by the following formula (3):
(Formula Removed )
in which Q is defined as previously described, to produce the compound of formula (1). (b) a compound represented by the following formula (9):
(Formula Removed )
in which R1, R2, R3 R7 , R8 Y and L are defined as previously described, and R' and R ' independently of one another represent optionally substituted alkyl. is reacted with the compound of formula (3) to produce a compound represented by the following formula (10):
(Formula Removed )
in which R1, R2 R3 R7, R8 Y, Q, R9; and R10are defined as previously described, and the resulting compound ot formula (10) is hydrolyzed in the presence of a Lewis acid u> produce a compound represented by the following formula (la):
(Formula Removed ) in which R , R", R\ R . R'. Y and Q are defined as previously described, or
(c) groups R4 and R5 are introduced into the compound of formula car to produce a compound represented by the following formula (lb):
(Formula Removed )
in which R1, R2, R3 R7, R8 Y and Q are defined as previously described, and R1 and R5 represent R4 and R5 with the exception of hydrogen, respectively, or further ti-.e compounds thus obtained are subjected to conventional conversions (see: USP 6.03~..v5. 5.'-)}5.'-)4b. and 5.792,756).
In the above process variants (a) to (c) for preparing the compound of formula (1). the reactions may be carried out in a solvent and in the presence of a base. As the solvent, one or more selected from a group consisting of dimethylformamide. dickloromethane. tetrahydrofuran. chloroform, l-inethyl-2-pyrrolidinone and dimethylacetaimde can be mentioned, and as the base one or more selected from a group consisting of sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium t-butoxide, hydrogen bis(trimethylsilyl)amide. sodium amide. cesium carbonate and potassium bis(trimethylsilyl)amide can be mentioned. The Lewis acid which can be used in the process variant (b) includes trimethylsiiylhahce. Further, in the process variant (c) for introducing the groups R and R" into the compound of formula (la), this compound is subjected to an ether-forming reaction with an alk\ihahde in the presence of a base, or is treated with thionyl chloride, oxalyl chloride o: phosphoric pentachloride to produce a dichlorophosphonate derivative which is then reacted with a
suitable alcohol or amine to give the desired compound.
The phosphonate compound of formula (2) used as a starting material in the above process is itself a novel compound. Therefore, it is another object of the present invention to provide the compound of formula (2).
The compound of formula (2) wherein Y is O. R1 is hydrogen, and each of R2. R3 R' and R8 is hydrogen or alkyl. that is, a compound of the following formula (8). can be prepared characterized in that ( ii ) an ethylglycolate. the alcohol group of which is protected, represented by the following formula (4)-
(Formula Removed ) in which P' represents an alcohoi-protecting group, preferably benzyl(Bn). tetrahydropyranylTHP), t-butyldiphenylsilyl(TBDPS), or t-butyldimethylsilyl(TBDMS). is reacted with ethyl magnesium bromide[C2H5MgBr] or the corresponding alky 1 magnesium bromide or alkyl magnesium chloride in the presence of titanium tetraisopropoxide(Ti(OiPr)4], ( ii) the resulting cyclopropanol represented by the following formula (5):
(Formula Removed )
in which P1 is defined as previously described and each of R", RJ, R' and R's represents hydrogen or alkyl. is subjected to an ether-forming reaction :n the presence of a base with a compound represented by the following formula {by.
(Formula Removed ) in which L, R and R are defined as previously described, to produce a phosphonate compound represented by the following formula (7):
(Formula Removed )
in which P1, R". R". R , R'\ R4and R" are defined as previously described, and i:;. i the alcohol-protecting group of the resulting compound of formula (~j is removed and a Iea\;ng group(L) is introduced to produce a compound represented by the following fonr.aia |S):
(Formula Removed )
in which L. R". R'. R . R'\ R and R" are defined as previously described.
The process for preparing the simplest compound of formula (8) (that is. all or' R". R'. R and R's are hydrogen) is briefly depicted in the following Reaction Scheme 1 •
Reaction Scheme 1
((Scheme Removed ) The specific reaction conditions of the above process can be referred to the following Preparations and Examples.
Further, the compound of formula (2) wherein Y is -CH2-, and each of R1. R~. R . R and R's is hydrogen, that is a compound of the following formula (11):
(Formula Removed ) in which L. R4 and R~" are defined as previously described, car. be prepared In a process is depictd m the following Reaction Scheme 2:
Reaction Scheme 2
(Scheme Removed ) Reaction Scheme 2 is briefly explained below. 1 : ) According to a known method (see: JOC, 1975, Vol.40, 2969-2970), diaikylmalonate is reacted with dihaloethane to gi\e malonic acid wherein cyclopropyl group :s introduced into its 2-position. ( ii ) The malonic acid is reduced to give diol compound, one Indroxy group of which is then
protected with a suitable protecting group (P1 is defined as previously described). Then, the other hydroxy group is oxidized to an aldehyde group, (iii) The resulting aldehyde compound is reacted with tetraalkylmethylenediphosphonate to give the desired phosphonate compound, (ivi The phosphonate compound thus obtained is reduced to give a compound having no unsaturated bond, alcohol-protecting group (P1) is removed, and a leaving group (L) is introduced to give the compound of formula (11).
Further, the compound of formula (2) wherein Y is -N(CH3)- and each of R'. R~. R3. R and R8 is hydrogen, that is a compound of the following formula (12):
(Formula Removed ):n which L. R4and R" are derlned as previously described, can be prepared by a procus.- a>. depictd in the following Reaction Scheme 3:
Reaction Scheme 3
(Scheme Removed ) Reaction Scheme 3 :s briefly explained below i . ) Diethyl l.l-cyclopropyl
dicarboxylate is selectively hydrolyzed to give a monocarboxylic acid. (i i) An amine group is introduced into the monocarboxylic acid according to the known Curtious Reaction (see: S. Linke, G. T. Tisue and W. Lowowski,/. Am. Chem. Soc. 1967, 89, 6308). (iii) The amine group is protected with a suitable protecting group [P2 may be carbamate or various benzyl protecting groups, or alkyl group (methyl, ethyl, etc.)]. (iv) The opposite ester group is reduced into a hydroxy group, which is then protected (P1 is defined as previously described), (v) The compound protected with protecting groups is reacted with methyl iodide in the presence of sodium hydride to introduce methyl group into :ne amine group. ( vi) The amine-protecting group is removed and the resulting compound :s reacted with dialkylbromomethylphosphonate to give the desired phosphonate compound.' I) The alcohol-protecting group (P1) is removed from the phosphonate compound thus obtained and then a leaving group (L) is introduced to give the compound of formula (12).
The specific reaction conditions of the above processes can be referred to the following Preparations and Examples.
After the reaction is completed, the resulting product may be further separated and purified by usual work-up processes, such as for example, chromatography. recrystallization. etc.
The compound of formula (1) of the present invention can be effectively used as an antiviral agent. Therefore, it is another object of the present invention to provide a composition for the treatment of viral diseases, which comprises as an active ingredient the compound of formula (1). pharmaceutically acceptable salt, hydrate, solvate or isomer thereof together with the phannaceutically acceptable carrier.
When the active compound according to the present invention is used for clinical purpose, it is preferably administered in an amount ranging generally from 0.1 to 10000mg. preferably from 0.5 to 100mg per kg of b ody weight a day. The total daily dosage maybe administered in once or over several times. However, the specific administration dosage for the patient can be varied with the specific compound used, body weight, sex or hygienic condition of the subject patient, diet, time or method of administration, excretion rate, mixing ratio of the agent, severity of the disease to be treated, etc.
The compound of the present invention may be administered in the form of injections or oral preparations.
njections, for examination, sterilized aqueous or oily suspension for njection, can be prepared according to the known procedure using actable dispersing agent, wetting agent, or suspending agent. Solvents vhich can be used for preparing injections include water, Ringer's fluid and isotonic NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-stimulative fixing oil including mono-, di-glyceride may be used for this Durpose. Fatty acid such as oleic acid may also be used for injections.
\s the solid preparation for oral administration, capsules, tablets, pills, powders and granules, etc., preferably capsules and tablets can be nentioned. It is also desirable for tablets and pills to be formulated nto enteric-coated preparation. The solid preparations may be prepared by mixing the active compound of formula (1) according to the present invention with at least one carrier selected from a group consisting of inactive diluents such as sucrose, lactose, starch, etc., ubricants such as magnesium stearate, disintegrating agent and inding agent.
Vhen the compound according to the present invention is clinically applied for obtaining the desired antiviral effect, the active compound of formula (1) can be administered in combination with one or more substances selected from the known anti-cancer or antiviral agents. As the anti-cancer or antiviral agents which can be administered together vith the compound of the present invention in such a manner, 5-Fluorouracil, Cisplatin, Doxorubicin, Taxol, Gemcitabine, Lamivudine, etc. can be mentioned.
iowever, preparations comprising the compound of the present nvention are not restricted to those explained above, but may contain any substances useful for the treatment or prevention of cancers or 'iral diseases.
n accordance with the present invention it relates to an acyclic lucleoside phosphonate derivate represented by the following formula I):

In which
represents single bond or double bond,
R1, R2, R3, R7and R8 independently of one another represent hydrogen, halogen, hydroxyl, amino, C1-C7alkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or C1-C5-alkoxy,
R4 and R5 independently of one another represent hydrogen, or represent C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, (particulary, fluorine), C1-C4-alkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyloxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=0)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7- alkylamino, di (C1-C7-alkyl)amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen,
Y represents -O-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-, -SiH(Z)-, OR =Si(Z)-, wherein Z represents hydrogen, hydroxyl or halogen, or represents C1 C7-alkyl, C1-C5-alkoxy, allyl, hydroxyl- C1-C7-alkyl, C1-C7-aminoalkyl or phenyl,
Q represents a group having the following formula:
(Formula Removed ) Wherein
X«V,X2,X3 and X4 independently of one another represent hydrogen, amino, hydroxyl or halogen, or represent C1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxyl- C1-C7-alkyl, phenyl or phenoxy each of which is optionally substituted by nitro or C1-C5-alkoxy, or represent C6 -C10-arylthio which is optionally substituted by nitro, amino, C1- C6-alkyl or C1 -C4-alkoxy, or represent C6-C12-arylamino, C1-C7-alkylamino, di(C1 C7-alkyl)amino, C3-C6-cycloalkylamino or a structure of(Formula Removed )
wherein n denotes an integer of 1 or 2 and Y1 represents O,
CH2 or N-R (R represents C1-C7-alkyl or C6 -C12-aryl), pharmaceutically acceptable salt, or stereoisomer thereof.
The present invention will be more specifically explained in the following Examples and Experiments. However, it should be understood that these Examples and Experiments and intended to illustrate the present invention but not in any manner to limit the scope of the present invention.
Preparation 1
Synthesis of 1 -({[t-butyl(diphenyl)silyl]oxy}methyl)cyciopropanol
(Formula Removed ) The compound prepared in Preparation 4 (430mg) was dissolved in 18mℓ of dimethylformamide, 57.6mg (60% purity) of sodium hydride and 162mg of adenine were added thereto, and the resulting mixture was heated under reflux over 4 hours. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate, and the ethyl acetate extract was distilled under reduced pressure. The residue was purified by silica gel column chromatographyeluent: dichioromefhane/methanol=20 1. \ \) to gi\e 20 lmg( Yield 44%) of the title compound.
1H NMR(CDC13) δ" 0.86 (t, 2H). 1.01 it. 2H), 1.24 id. 6H). 1.34 id. 6H). 3 So id. 2H). 4.34 (s. 2H), 4.71 (m, 2H). 5.97 (br s. 2H). S.32 (s. 1 H). S.58 (s. 1H) ESI: 384 (M+If. C16H25N504P
Preparation 6
Synthesis of diisopropyl({l-|(2-amino-6-chloro-9H-purin-9-vl)methyl| cyclopropyl} oxy)methylphosphonate
(Formula Removed )
The compound prepared in Preparation 4 (1.64gi was dissolved m 70mℓ of dimethylformamide, 219mg(60% purity) of sodium hydride and 773mg of 2-amino-6-chloro-9H-purine were added thereto, and the resulting mixture was stirred for 4 hours while heating at a temperature of up to SO'C. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate, and the eth\i acetate extract was distilled under reduced pressure. The residue was purified by silica gel column chromatography(eluent: dichloromethane,'methanol=20/l, v/v) to gne ~comg( Yield 40%o) of the title compound.
1H NMR(CDC13) δ 0.80 (t. 2H), 1.02 (t. 211), 1.27 td. 6H). 1.28 (d. 6H). 3.82 (d. 2HK4.2I (s, 2H), 4.68 (m, 2H), 5.13 (brs, 2H). S. 15 (s. 1H)
ESI: 418 (M+l)+, C16H25C1N504P
Preparation 7
Synthesis of diisopropyl[(l {[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-
pyrimidinyllmethyl} cycIopropyl)oxy|methylphosphonate
(Formula Removed ) The compound prepared in Preparation 4 (118mg) and thymine were reacted according to the same procedure as Preparation 6 to give 26mg( Yield 21%) of the title compound.
1H NMR(CDC13) δ 0.82 (t, 2H), 0.95 (t. 2H), 1.31 (m. 12H), 1.92 (s. 311). 3."4 (d, 2H). 3.89 (s,2H), 4.71 (m, 2H), 7.62 (s, 1H), 9.15 (s, 1H) ESI:375hVM)\CI6H27N206P
Preparation 8
Synthesis of l-({|t-butyl(diphenyl)silvlloxy}methyl)-2-methylcyclopropanol
(Formula Removed )
According to the description in a reference (see: Syn. Leu. 07, 1053-1054. 1999), the title compound was prepared as follows. 50g(146 mmole) of ethyl 2-{[t-butyl(diphenyl)silyi]oxy} acetate was dissolved in 700niC. of tetrahydrofuran(THF; and 30.0mℓ. of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 290mℓ of propylmagnesiumchloride(2.0M in THF) at -10°C, and the reaction solution was stirred for 12 hours at room temperature. 200mℓ of saturated ammonium chloride was added to stop the reaction. The tetiahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted
twice with 2000mℓ of n-hexane. The n-hexane extract was distilled under reduced pressure and purified by silica gel column to give 42g of the title compound.
1H NMR(CDC13) δ 0.06 (t, 1H), 0.88 (dd, 2H), 0.97 (d, 3H), 1.09 (s, 9H) 1.1 (m, 1H), 2.78 (s, 1H), 3.70 (d, 1H), 3.86 (d, 1H), 7.41 (m, 6H), 7.70 (m. 4H) ESI: 363 (M+Na)\ C21H2802Si
Preparation 9
Synthesis of diisopropyl {[l-({[t-buryl(diphenyl)silvl|oxy}methyl)-2-methvl cyclopropylloxy}methylphosphonate
(Formula Removed ) The compound prepared in Preparation 8 (4.2g) was reacted according to the sumo procedure as Preparation 2 to give 3.3g of the title compound.
1H NMR(CDC13) δ' 0.04 (t, 1H), 0.96 (dd. 1H), 0.9" id. 3H), 1.05 (m, 1H), 1.06 (s, 9H), 1.23 (t, 12H), 3.72 (d, 1H), 3.95 (d, 2H), 3.98 (d. IH). 4."5 (m. 211). 7.40 (m. 611), 7.68 (m, 4H)
Preparation 10
Synthesis of diisopropyl{l-[(hydroxymethyl)-2-methylcyclopropyl|oxy} methylphosphonate
(Formula Removed )
The compound prepared in Preparation 9 (3.3g) was reacted according to the same procedure as Preparation 3 to give 1.7g of the title compound.
1H NMR(CDC13) δ 0.03 (t, IH), 0.95 (dd. IH), 0.96 (m. IH), 1.11 (a. 3H), 1.35 (d, 12H),2.17(brs, IH), 3.80 (d, 2H), 3.96 (d, IH), 4.80 (m. 2H)
ESI: 303 (M+Na)\ C12H22504
Preparation 11
Synthesis of diisopropyl({l-[(6-amino-9H-purin-9-yl)methyll-2-methyl cyclopropyl}oxy)methylphosphonate
(Formula Removed ) The compound prepared in Preparation 10 (1.5g) was dissolved in 50mℓ of dichloromethane. 0.85mℓ of triethylamine and 0.84g of methanesulfonylchloride were added thereto, and the resulting mixture was stirred for 30 minutes at room temperature. Saturated ammonium chloride was added to stop the reaction. The product was extracted with dichloromethane and the dichloromethane extract was concentrated by distillation under reduced pressure. The residue was used in the next reaction without any purification.
1H NMR(CDC13) δ 0.42 The methanesulfonate thus obtained (430mg) was dissolved in 18mℓ of dimethylformamide, and 57.6mg (60% purity) of sodium hydride and 162mg of adenine were added thereto. The reaction mixture was refluxed under heating over 4 hours. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate and the ethyl acetate extract was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v v) to give 201mg(YieId 44%) of the title compound.
1HNMR(CDCl3) δ 0.53 (t. 1H). 1.13 (d,3H), 1.15 (m, 1H), 1.30 (m, 12H), 1.41 (m, 1H). 1.85 (brs, 2H), 3.81 (m, 2H). 4.43 (m. 2H). 4.70 (m. 2H). 5.65 (br s. 2H), 8.26 (s. 1H), 8.34 (s, 1H)
ESI: 398 (M+l)\ C17H28N504P
Preparation 12
Synthesis of diisopropyl({l-|(2-amino-6-chloro-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate
(Formula Removed ) The compound prepared in Preparation 10 was reacted according to the same procedure as Preparation 11 except that 6-chloroguanine (2-amino-6-chloro-9H-purine) was used instead of adenine to give the title compound.
1H NMR(CDC13) δ 0.47 (t. J=6.4Hz. IH), 1.12 (m. 4H), 1.24 (dd. J= 2.8Hz. 6.4Hz. 6H). 1.28 (t, J=6.0Hz. 6H). 1.3S (m. IH), 3.80 (m. 2H), 4.28 (m. 2H). 4.68 im. 2H). 5.13 (brs,2H), 8.15 (s, IH)
ESI: 432 (M+1)T, C17H27C1N504P
Preparation 13
Synthesis of diisopropyl((l{[5-methyl-2,4-dioxo-3.4-dihydro-l(2H)-
pyrimidinyl|methyI}-2-methylcyclopropyl)oxy|methyIphosphonate
(Formula Removed )
The compound prepared in Preparation 10 was reacted according to the same procedure as Preparation 11 except that thymine was used instead of adenine to give the title compound.
1H NMR(CDC13) δ 0.48 (t, IH), 1.10 (m, 4H), 1.24 (dd, 6H). 1.28 (t. J= 6H). 1.38 (m, IH), 1.92 (s, 3H), 3.80 (m. 2H), 4.28 (m, 2H), 4.68 (m, 2H), 7.62 (s, IH), 9.15 (s. IH)
ESI: 389 (M+1)*C17H29N206P
Preparation 14
Synthesis of l-(ethoxycarbonyl)cyclopropanecarboxylic acid
(Formula Removed )
Diethyl 1,1 -cyclopropane dicarboxylate (20g) was hydrolyzed in IN NaOH (107 mℓ and ethanol (220mℓ) for 16 hours, and the ethanol was removed by distillation under reduced pressure. The remaining starting material was removed by using ethyl acetate and the aqueous layer was acidified by IN HC1. The reaction mixture was extracted with ethyl acetate and distilled under reduced pressure. The residue was purified by silica iv. column to give the title compound in a yield of 94%.
1H MR(CDCl3) δ; 1.06 (t.3H), 1.53 (m.2H). 1.62 im. 2H). 4.21 u:. 2H> ESI: 159 Preparation 15
Synthesis of ethyl H[(l)enzyloxy)carbonyl|amino|cyclopropanecarboxvlati-
(Formula Removed )
The carboxylic acid prepared in Preparation 14 (16g) was dissolved to dichloromethane, 10.8ml' of oxalyl chloride was added dropwise, and 2 drops or dimethylformamide was added. The reaction mixture was stirred at room temperature for 3 hours and distilled under reduced pressure to give ethoxxearbonyl l.l-cvclopropane carbonylchloride. This compound, not purified, was dissolved in 30mℓ OF dimethylformamide and the resulting solution was cooled with water-ice. 36g of NATR was added and the reaction was carried out at room temperature for 3 hours. The reaction solution was extracted with l00mℓ of water and 200mℓ' of diethylether. and the diethylether extract was concentrated to give crude compound which was purified by silica gel column to give an azide compound.
1'HNMR(CDCl3) δ 1.28 (t. 3H), 1.54 (m, 4H). 4.19 (q. 2H)
To the azide compound thus obtained (13g) was added dropwise I I ..'M of ben/> i alcohol and the reaction mixture was heated to 100 C, by which the reactants were vigorously reacted with each other with the generation of gas. The reaction mixture was
heated at 100"C for further 1 hour, cooled to room temperature, and distilled under reduced pressure to remove benzyl alcohol. The residue was purified by silica gel column ro give the title compound.
1H NMR(CDC13) δ 1.19 (m, 5H), 1.54 (m. 2H), 4.11 (m, 2H), 5.15 (br.s. 2H), "\32im.5H)
Preparation 16
Synthesis of benzyl l-{ft-butyl(diphenylsilyl)oxy|methvlc\clopropyl| (meth\ I (carbamate
(Formula Removed ) The carboxylate prepared in Preparation 15 (I3.2g) was dissolved in dietlnlether. to which 1.3g of UBH4 dissolved in diethylether was slowly added dropwise The reaction misture was stirred at room temperature for 16 hours, and 50mC of methanol and 5 in' of IN HC1 were added dropwise thereto. The reaction mixture was stirred for 2 hours, the precipitate was removed by suction filtration, and the solvent in the filtrate was remo\ed by distillation under reduced pressure. The residue was purified b\ silica gel column :o give benzyl l-(hydroxymethyl)cyclopropylcarbamate.
This compound (9.3g) was dissoKed in dichloromethane. and 4.2g of imidazole and 13.5:n(' of t-butyldiphenylsilylchloride were added in order. The reaction mixture was stirred at room temperature for 4 hours and the solvent was removed b\ distillation under reduced pressure. The residue was purified by silica gel column to give benzyl l-( |[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropylcarbamate.
1H NMR(CDCl3) δ 0.71-1.19 (m.4H). 1.04 (s. 9H). 3.68 (br.s. 2H). 5.04 is. 2H), ~.25--45(m, HH). 7.62 (d,4H)
The carbamate thus obtained (5.5g) was dissolved m THF, 3.5) 5 of methane iodide (Mel) was added dropwise and then lg of NaH was added. The reaction mixture was stirred at room temperature for 4 hours and then extracted with l00) 5 of diethylether
Preparation 18
Synthesis of diisopropyI(l-{((6-amino-9H-purin-9-yl)methyl]cyclopropyl} (methyl)amino)methylphosphonate
(Formula Removed ) The compound prepared in Preparation 17 (0.32g) was dissolved in methanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture uas reacted under stirring at 60°C for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give methylaminediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol.
1H NMR(CDCl3) δ 0.56 (m. 2H), 0.73 (m, 2H). 1.31 (m. 121-1). 2.56 (s. 3H). 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m, 2H)
The compound thus obtained was consecutively reacted according to the same procedure as Preparations 4 and 5 to give the title compound.
1H NMR(CDC13) δ 0.78 (m, 2H), 0.86 (m, 2H), 1.25 (m. I2H). 2.35 (s, 3H), 4.1U (s, 2H), 4.68 (m, 2H), 5.13 (m, 2H), 8.32 (s. 1H), 8.58 (s, 1H) ESI: 397 (M+l)\ C17H29N603P
Preparation 19
Synthesis of diisopropyl(l-{[(2-amino-6-chIoro-9H-purin-9-yl)methyI| cyclopropyl}(methyl)amino)methylphosphonate
(Formula Removed )
The compound prepared in Preparation 17 (0.32g) was dissolved in methanol and ' 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60°C for 24 hours and then the solvent was removed by distillation under
reduced pressure. The residue was purified by silica gel column to give methylaminediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol.
1H NMR(CDC13) δ 0.56 (m, 2H), 0.73 (m, 2H), 1.31 (m, 12H), 2.56 (s. 3H). 3.11 (d. 2H). 3.55 (s. 2H), 4.70 (m, 2H)
The compound thus obtained was consecutively reacted according :: the same procedure ;s Preparations 4 and 6 to give the title compound.
'H \MR(400MHZ. CD^OD): 8 0 ^9 (m. 2H). 0.89 (m. 2H). 1.26 (m. :2H). 2.2^ (s. 3H). 2."*) (d. 2H. J=7Hz), 4.11 (s, 2H), 4.65 (m. 2H). 5.13 (m. 2H). 8.u2 (s. . H > ES.':431(M-lf. C17H28C1N603P
Preparation 20
Synthesis of diisopropyl[(l-{|5-methyl-2,4-dioxo-3.4-dihydro-l(2H)-
pyrimidin>l|methyl}cyclopropyl)(methyl)amino|methylphosphonate
(Formula Removed ) The compound prepared in Preparation 17 (0.32g) was dissolved in merhanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at oO'C for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to gi\e methylamir.ediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol.
1H NMR(CDCl3) δ 0.56 (m, 2H), 0.73 (m. 2H), 1.31 (m, 12H), 2.:n (s. 3H). 3.1 1 (d. 2H). 3.55 (s, 2H), 4.70 (m, 2H)
The compound thus obtained was consecutively reacted according tc the same procedure a 1H NMR(CDC13) δ C.79 (m. 2H), 0.90 2 (s. 3H). 2.3S (s. 3H). 3.75 (d. 2H). 4.10 (s, 2H). 4.65 (m. 2H), 7.62 (s, 1H). 9.15 (s. 1H)

Preparation 21
Synthesis of 1,1-cyclopropanedicarboxylic acid
(Formula Removed )
In 50% NaOH 187mℓ. was dissolved 15g of diethylmalonate at room temperature. Benzyltriethylammoniumchloride (21.3g) was added and the resulting mixture was stirred for 10 minutes. 1.2-Dibromoethane (12.3g) was added to the reaction solution and the resulting mixture was stirred for more than 18 hours at room temperature. The reaction mixture was neutralized by adding dropwise cone, sulfuric acid and then extracted with ethyl acetate. The extract was distilled under reduced pressure to give j.2g of the title compound as a white solid.
1H NMR(CDC13) δ' 1.88 (s. 4H)
Preparation 22
Synthesis of [l-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyljmethanol
(Formula Removed )
Lithium aluminum hydride (LAH) 15.3g was dissolved in 39g of tetrahydrofuran, and 1 l."*g of the carboxylic acid prepared in Preparation 21 was slowly added dropwise at 0°C. The reaction solution was refluxed for 17 hours. The reaction was stopped by adding 10% HC1 at room temperature and the mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and the residue was purified by silica gel column to give 8.2g of diol compound.
1H NMR(CDC13) δ 0.56 (s. 4H). 2.22 (s, 2H), 3.63 (s, 4H) The compound thus obtained (400mg) was dissolved in 12m(' of THF, 184mg of
NaH and 1.16g of t-butyldiphenylsilylchloride (TBDPSC1) were added, and the resulting mixture was refluxed for 6 hours. The reaction was stopped by adding 10mℓ of water and the mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and the residue was purified by silica gel column to give l.lg of the title compound.
1H NMR (CDCl3) δ 0.33 (t, 2H), 0.48 (t, 2H), 1.23 (s. 9H), 3.59 (d. 4H), 7.42 (m, 6H), 7.68 (m. 4H)
Preparation 23
Synthesis of diethyl(E)-2-[l-({[t-butyI(diphenyl)silyl|oxyjmethyl)cyclopropyll ethenylphosphonate
(Formula Removed ) The compound prepared in Preparation 22 (2g) was dissolved in 50mC of dichloromethane, and 1.03g of N-methylmorpholine N-oxide and 103mg of tetrapropylammoniumperruthenate (TPAP) were added thereto at room temperature. The reaction mixture was stirred for about 1 hour at room temperature and the reaction was stopped by adding 20mℓ of water. The reaction solution was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 2.0g of aldehyde compound.
1H NMR(CDCl3) δ 1.03 (s, 9H). 1.04 (t. 2H), 1.05 (t, 2H). 3.94 (s, 2H), 7.37 (m. 6H), 7.64 (m.4H), 9.10 (s, 1H)
Tetraethylmethylene diphosphonate (1.7g) was dissolved in 60mℓ of tetrahydrofuran (THF). At -78 °C, 264mg of NaH was added, the resulting mixture was stirred for 20 minutes, and then 1.9g of the aldehyde compound as obtained above was added. The reaction solution was stirred at room temperature for 1 hour, and the reaction was stopped by adding 20mℓ, of water. The reaction solution was extracted with ethvl acetate and the extract was concentrated under reduced pressure. The residue was purified
by silica gel column to give 2.32g of the title compound.
1H NMR(CDC13) δ 0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (t, 6H), 3.71 (s. 2H), 4.05 (m, 4H), 5.70 (m, 1H), 6.42 (m, 1H), 7.43 (m, 6H), 7.64 (d, 4H) ESI: 501 (M+l)+'C28H4104PSi
Preparation 24
Synthesis of diethyl 2-[l-(hydroxymethyl)cyclopropyl)ethenyIphosphonate
(Formula Removed ) The compound prepared in Preparation 23 was reacted according to the same procedure as Preparation 3 to give the title compound.
1H NMR(CDCl3) δ 0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (t. 6H). 3.71 is. 2H), 4.05 (m. 4H). 5.70 (m, 1H), 6.42 (m, 1H), 7.43 (m, 6H), 7.64 (d, 4H) ESI: 501 (M-l)*C28H4104PSi
Preparation 25
Synthesis of diethyl 2-{l-[(6-amino-97/-purin-9-yl)methyl|cyclopropyl} ethenylphosphonate
(Formula Removed )
The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 5 to give the title compound.
1H NMR(CDCl3) δ 1.07 (t, 2H), 1.19 (t, 2H), 1.22 (t, 6H), 3.93 (s, 4H). 4.33 (s. 2H), 5.55 (s, 2H), 5.63 (m. 1H), 6.49 (m, 1H), 7.8S (s, 1H). 8.37 (s, 1H) ESI:352 (M-lf C15H22N503P
Preparation 26
Synthesis of diethyl 2-{l-[(2-amino-6-chIoro-9H-purin-9-yl)methyl] cyclopropyljethenylphosphonate
(Formula Removed ) The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 6 to give the title compound.
1H NMR(CDC13) δ 1.06 (t, 2H), 1.15 (t, 2H), 1.23 (t, 6H), 3.93 (s, 4H), 4.18 (s, 2H), 5.12 (s, 2H). 5.59 (m. 1H), 6.58 (m, 1H), 7.81 (s, 1H) ESI.-386 (M-lf C15H21C1N503P
Preparation 27
Synthesis of diethyl 2-(l-{[5-methyI-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyIl methyl}cyciopropyi)ethenylpbosphonate
(Formula Removed )
The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 7 to give the title compound.
1H NMR(CDC13) δ 0.93 (t, 2H), 1.01 (t, 2H), 1.24 (t, 6H), 1.92 (s, 3H), 3.91 (s, 2H), 3.96 (m, 4H), 5.49 (m. 1H), 5.87 (m, 1H), 7.62 (s, 1H). 9.15 (s, 1H) ESL343 (M~1)+>C15H23N205P
Preparation 28
Synthesis of l-({[t-butyl(diphenyl)silylloxy}methyl)-2,2-dimethylcycio-propanol
(Formula Removed ) According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 10g(29 mmole) of ethyl 2- {[t-butyl(diphenyl)silyl]oxy} acetate was dissolved in l00mℓ' of tetrahydrofuran (THF) and 6.0mℓ. of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 37mℓ of isobutylmagnesiumbromidet 2.0M in THF at -10°C. and the reaction solution was stirred for 12 hours at room temperature. fOmt1 of saturated ammonium chloride was added to stop the reaction. The tetrahydrofuran (THF) used as a sohent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 500mℓ of n-hexane. The n-hexane extract was distilled under reduced pressure and purified by silica gel column to give 5.0g of the title compound.
1H NMR(CDCl3) δ 0.25 (d. 1H), 0.51 (d. 2H), 0.99 (s. 3H), 1.07 (s, 9Hi. 1.22 (s. 3H), 3.71 (d. 1H), 3.91 (d, 1H), 7.41 (m, 6H). 7.70 im. 4H) ESI: 355 (M+lf, C22H30O2Si
Preparation 29
Synthesis of diisopropyl {[l-({|t-butyl(diphenyl)siIyl|oxy}methyl)-2,2-dimeth\i cyclopropyl|oxy}methylphosphonate
(Formula Removed )
The compound prepared in Preparation 2S was reacted according to the same procedure as Preparation 2 to give the title compound.
1H NMR(CDC13) δ 0.29 (d. 1H). 0.60 fd. 1H). l.Ob.s. 3H). 1.09 (s. 9H). 1.27 (s, 3H). 1.30 (m. 12H), 3.75 (m. 2H), 3 92 (m, 2H), 4.72 (m, 2H). ".41 (m..6H), 7.67 (n, 4H) ESI: 519 iM+1)". C28H4305PSi
and l00mℓ of water. The diethylether extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound.
1H NMR(CDCl3) δ 0.78-0.84 (m, 4H), 1.03 (s, 9H), 3.03 (s, 3H). 3.55- 3.80 (m, 2H), 5.10 (s. 2H), 7.24-7.45 (m, 11H), 7.61 (m. 4H)
Preparation 17
Synthesis of diisopropyl[l-({[t-buryl(diphenyl)silyl|oxy}methyl)cyclopropyI) (methyl)amino|methylphosphonate
(Formula Removed ) The carbamate prepared in Preparation 10 (l.0g) was dissolved in ethanol. 100mg of 10°o Pd'C was added, and the reaction mixture was subjected to a hydrogenation under hydrogen atmosphere. After the reaction was completed, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gei column to give l-(|[t-butyl(diphenyl)silyl]oxy}methyl)-N-methylcyclopropaneamine.
1H NMR(CDC13) δ 0.36 (m, 2H), 0.65 (m, 2H). 1.05 (s, 9H). 2.36 (s. 3H). 3.57 (s, 2H), 7.37-7.45 (m. 11H), 7.66 (d. 4H)
The methylcyclopropaneamine thus obtained (l.0g) was dissolved in dichloromethane, to which l.03mℓ of diisopropylethylamine and l.3mℓ of (diisopropyl phosphoryl)methyl trifluoromethansulfonate were added dropwise. The reaction mixture was reacted under stirring at room temperature for 4 hours, and then extracted with l00mℓ' of diethylether and l00mℓ of water. The solvent in the diethylether extract was removed by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound.
1H NMR(CDCl3) δ 0.42 (m, 2H), 0.69 (m, 2H). 1.04 (s, 9H), 1.25 (d. 6H), 1.30, (d, 6H), 2.62 (s. 3H), 3.25 (d, 2H), 3.64 (s, 2H), 4.68 (m, 2H), 7.39 (m. 6H). 7.65 (d. 4H)
Preparation 30
Synthesis of diisopropyI{l-[(hydroxymethyl)-2,2-dimethylcycIopropyl]oxy} methylphosphonate
(Formula Removed )
The compound prepared in Preparation 29 was reacted according to the same procedure as Preparation 3 to give the title compound.
1H NMR(CDC13) δ" 0.39 (d. 1H). 0.59 (d. 1H), 1.13 (s.3H). 1.2! is. 3H). 1.33 id. 12H). 3.76 (m, 2H), 3.86 (m. 2H). 4.76 (m. 2H) ESI:295(M+1), C13H2704P
Preparation 31
Synthesis of diisopropyl({l-[(6-amino-9H-purin-9-y|)methyl|-2,2-dimethyl cyclopropyl}oxy)methy!phosphonate
(Formula Removed )
The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 11 to give the title compound.
1H NMR(500MHZ, CDC13): δ 0.62 (d, J=5.9Hz. 1H), 0.81 (d, J=5.9Hz, 1H). 1.10 (s.3H), 1.23 (m, 15H), 3.72 (dd, J=15.1, 11.0Hz, 1H). 3.85 (dd. J=15.1, 5.5Hz, 1H). 4.23 (d. J=15.1Hz, 1H), 4.58 (d, J=15.1Hz, 1H), 4.68 (m. 2H), 5.79 (bs. 2H), 8.19 (s, 1H), S.32(s, 1H)
ESI: 412 (M+l)+, C1SH30N5O4P
Preparation 32
Synthesis of diisopropyl({l-((2-amino-6-iodo-9H-purin-9-yI)methyl)-2.2-dimethyIcycIopropyl}oxy)methylphosplionate
(Formula Removed ) The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 12 except that 6-iodoguanine was used instead of 6-chloroguanine to give the title compound.
1H NMR(500MHZ, CDCl3): δ 0.58 (d, J=6.4Hz, 1H), 0.80 (d, J=6.4Hz. 1Hi. 1.10 (s. 3H), 1.24 (m, 8H), 3.72 (dd. J=13.0, 11.0Hz. 1H), 3.88 (dd, J=13.0, 9.3Hz. :H) 4.08(d,J=15.1Hz, lH),4.47(d,J=15.1Hz, 1H), 4.67 (m. 2H). 5.05 (bs, 1H), 8.10 (s. :H)
ESI: 538 (M+lf, C18H29IN504P
Preparation 33
Synthesis of diisopropyl[(l{[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-
pyrimidinyl]methyl}-2,2-dimethylcycIopropyI)oxy|methylphosphonate
(Formula Removed )
The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 13 to give the title compound.
1H NMR(CDCl3) δ 0.58 (d, 1H), 0.80 (d, 1H), 1.10 (s. 3H), 1.24 (dd, 6H). :.2S (t, 6H), 1.58 (s, 3H), 1.92 (s, 3H), 3.72 (dd, 1H), 3.88 (dd, 1H), 4.08 (d, 1H), 4.47 (d. \H). 4.67 (m, 2H), 7.62 (s, 1H), 9.15 (s. 1H)
ESI: 403 (M+lf-C18H31N206P
Preparation 34
Synthesis of l-[l-({|t-butyl(diphenyl)snylloxy}methyl)cyclopropyll-l-methyl alcohol
(Formula Removed )6g of the compound prepared in Preparation 22 was dissolved in 150mℓ of dichloromethane. 3.0g of N-oxide and 103mg of tetrapropylammoniumperruthenate (TPAP) were added thereto at room temperature. The reaction mixture was stirred for about 1 hour at room temperature and quenched by adding 20mℓ of water. The reaction mixture was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 6.0g of aldehyde compound which went to next reaction without further purification.
5.23g of the aldehyde was dissolved in 350mℓ of THF. The solution was cooled to -78'C and 10.3in- of methylmagnesiumbromide (3.0M solution) was slowly added to the solution and then, stirred for 1 hour a; room temperature. The reaction mixture was quenched by 0.5mℓ' of water and 0.5mℓ of methanol and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=L8. v/v) to 3.5~g of title compound.
1H NMR(CDCl3) δ' 0.22 (m, 1H). 0.39 (m. 2H), 0.61 (m. 1H), 1.06 (s, 9H). 1.24 (d, 3H), 3.3 (d, 1H). 3.47 (s, 2H). 3.9 (d, 1H), 7.43 (m, 6H), 7.64 (m, 6H)
Preparation 35
Synthesis of diethyl (E)-2-l-(l-(([t-buryl(diphenyl)silyl|oxy}methyl)cyclopropyll-1-propenylphosphonate
(Formula Removed ) 4g of the compound prepared in preparation 34 was dissolved in l0mℓ of dichloromethane. 2.1g of n-morpholine N-oxide and 209mg of tetrapropylammoniumperruthenate (TPAP) were added thereto at room temperature. The reaction mixture was stirred for about 1 hour at room temperature and quenched by adding 20mℓ. of water. The reaction mixture was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 4.0g of compound which went to next reaction without further purification.
Tetraethylmethylene diphosphonate (2.7g) was dissolved in 30m?, of tetrahydrofuran (THF) at -78 and 4mℓ of n-butyllithium was added. The resulting mixture was stirred for 20 minutes, and then 1.0 g of the ketone compound as obtained above was added. The reaction mixture was stirred at room temperature for 1 hour and was stopped by adding 20mℓ of water. The reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column to give 654mg of the title compound.
1H NMR(CDCl3) δ 0.58 (m, 1H), 0.69 (m, 2H), 1.02 (s, 9H), 1.20 (t, 6H), 2.09 (d, 3Hj. 3.59 (s. 2H). 4.05 (m, 4H), 5.61 (d, 1H), 7.38 (m, 6H), 7.63 (d, 4H)
Example 1
Synthesis of ({l-{(6-amino-9H-purin-9-yl)methyljcyclopropyl}oxy)methyl phosphonic acid (Compound 1)
The compound prepared in Preparation 5 (159mg) was dissolved in 15mℓ' of dichloromethane. 1.27g of trimethylsilylbromide was added thereto, and the resulting mixture was heated under reflux for 18 hours.1 After the completion of reaction, the reaction mixture was extracted with water, and the water extract was distilled under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) to give 0.89g(Yield 90%) of the title compound as a white powder.
1H NMR(MeOH-d4) δ 1.02 (d, 4H), 3.95 (d, 2H). 4.55 (s, 2H), 8.40 (s, 1H). 8.55 (s. 1H)
ESI: 300 (M-lf, C10H14N5O4P
Example 2
Synthesis of 3-(({l-[(6-amino-9H-purin-9-yl)methyllcyclopropyl}oxy)methyl]-8,8-dimethyl-3.7-dioxo-2,4,6-trioxa-385-phosphanoii-l-yl pivalate (Compound 2)
The title compound was prepared according to the method known in a reference(see: J. Med. Chem., 37(12), 1857 (1994)) and USP 5,663,159 (1998).
The compound prepared in Example 1 (l.00g) was dissolved in 150mℓ of dry dimethylformamide. and 2.08g(7.32 mmol) of N,N-dicyclohexyl-4-morpholine-
carboxamidine and 2.75g(l8.3 mmol) of chloromethyl pivalatc were added thereto. When the reaction mixture became homogeneous after about 1 hour, it was stirred for 5 days at room temperature. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was fractionated with 50at of water and 50mℓ of toluene to separate the organic layer. The aqueous layer was extracted twice with 50mℓ of toluene. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatographyfeluent: methanol/dichloromethane^ 1/20, v/v) to give 0.'59g(YieId 32% of the title compound as a white solM.
lH NMR(500MHz, CDCl3) δ" 0.91 (m, 2H), 1.12 im, 2H), 1.20 (m, 18H), 1.90
(br s. 2H), 3.90 (d, 2H), 4.32 (s. 2H), 5.65 (m, 4H), 8.141 s. 1H), 8.31 (s. 1H)
ESI: 528 (M+l)", C22H34N508P
Example 3
Synthesis of ({l-{(2-amino-6-chloro-9H-purin-9-yl)methyl|cyclopropyl} oxy)metbyl phosphonic acid(Compound 3)
The compound prepared in Preparation 6 (73mg) was reacted according to the same procedure as Example 1 to give 46mg(Yield 80%) of the title compound.
1H NMR(MeOH-d4) δ 1.00 (s, 2H), 1.07 (s. 2H), 3.94 (d, 2H). 4.52 (s, 2H), 9.50 (S.1H)
ESI:334(M+l)',C10H!3ClN5O4P •
e
Example 4
Synthesis of ({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl)cycIopropyl}ox\) methylptaosphonic acid(Compound 5)
The compound prepared in Example 3 (41mg) was dissolved in 5mℓ of 2N hydrochloric acid and heated under reflux for 6 hours. Water was removed by distillation under reduced pressure to give 37mg(Yield95%) of the title compound as a white solid.
1H NMR(MeOH-d4) δ 0.98 (m, 2H). 1.06 (m, 2H). 3.92 id. 2H). 4.45 (s, 2H). 9.20 (s.lH)
ESI: 316 (M+l)+, C10H14N5O5P
Example 5
Synthesis of ({l-[(2-amino-9H-purin-9-yl)methyljcyclopropyl}oxy)methy| phosphonic acid(Compound 9)
The compound prepared in Preparation 6 (150mg) was dissolved in 15mℓ of tetrahydrofuran, 15mg of 5% palladium/carbon was added thereto, and the compound was reduced under 1 atm of hydrogen atmosphere for 18 hours. After completion of reaction, palladium/carbon was removed by suction filtration and the filtrate was distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/vi to give 130mg of diisopropyl compound(ESI: 384iM+l)+, C16H26N504P). This compound was treated with trimethylsilylbromide according to the same procedure as Example i to give 91mg(Yield 90%) of the title compound.
1H NMR(MeOH-d4) δ 0.94 tm. 2H), 1.03 (m, 2H). 3.93 (d. 2H), 4.40 (s, 2H). 8.66 (s. 1H), 8.74 (s, 1H)
ESI: 300 (M+l)\ C10H14N5O4P
Example 6
Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyI|-8,8-dimethyl-3,7-dioxo-2,4,6--trioxa-385-phosphanon-l -yl pivalate(Compound 10)
The compound prepared in Example 5 was reacted according to the same procedure as Example 2 to give the title compound.
1H NMR(CDCl3-d4) δ 0.90 (m, 2H), 1.05 (m, 2H), 1.20 fan, 18H), 3.96 (d, 2H), 4.22 is, 2H), 5.65 (m, 4H), 8.03 (s, 1H), 8.69 (s, 1H) ESI: 528 (M+l)+, C22H34N508P
Example 7
Synthesis of ({l-[(2-amino-6-cyclopropylamino-9#-purin-9-yl)methyl] cyclopropyl}o.\y)methylphosphonic acid(Compound 11)
The compound prepared m Preparation 6 (200mg) was dissolved in 20mℓ of ethar.:I. 53mℓ of triethylamine and S2mg of cyclopropylamine were added thereto, and the resuiv.ng mixture was heated under reflux for 18 hours. Water A as added to stop the reaction. and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated b;. distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane,methanoi=20/l, v.v) to give 178rr.4 Yield S5%) of the diisopropU compound.
1H NMR(CDC13) δ 0.59 u. 2H), 0.83 (m, 4H), 1.00 (t, 2H). 1.24 (d. 6H), 1.29 (d, 6H). 3.0 (brs. 1H). 3.80 (d, 2H), 4.15 (s, 2H), 4.70 (m, 2H), 4.71 ibrs, 2H), 5.71 (s, 1H), 7.68is. 1H)
The compound thus obtained was treated with trimethylsilyibromide according to the same procedure as Example 1 to give 128mg( Yield 90%) of the title compound.
1H NMR(MeOH-d4) δ 0.S6 (m, 2H), 0.94 (m, 2H), 1.02 im, 2H),1.07 (m, 2H), 2.90 (br s. 1H). 3.93 (d, 2H), 4.39 (s. 2H), 8.43 (or s, 1H) ESI: 355 (M+l)\ C13H19N604P
Example 8
Synthesis of ({l-|(2-amino-6-ethylamino-9H-purin-9-yl)rnethyI]cyclopropyl} oxy) methylphosphonic acid(Compound 13)
The compound prepared in Preparation 6 (115mg) was dissolved in 20ml'. of ethanoi. 31mℓ of triethylamine and 0.07mℓ of ethylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the
reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give l04mg(Yield 89%) of the diisopropyl compound.
1H NMR(CDC13) δ 0.82 (m, 2H), 1.00 (m, 2H), 1.24 (d, 6H), 1.27 (t, 3H), 1.29 (d, 6H), 3.60 (brs, 2H), 3.81 (d, 2H), 4.15 (s, 2H), 4.65 (m, 4H), 5.50 (br s, 1H), 7.78 (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give 75mg( Yield 90%) of the title compound.
1H NMR(MeOH-d4) δ 0.89 (m, 2H), 1.04 (m, 2H), 1.31 (t, 3H). 3.59 (br s, 2H), 3.92 (d, 2H), 4.35 (s, 2H), 9.95 (br s, 1H) ESI: 343 (M+l)+, C13H19N604P
Example 9
Synthesis of [(l-{[2-amino-6-(dimethyIamino)-9H-purin-9-yllmethyl} cyclopropyl)oxy]methylphosphonic acid(Compound 15)
The compound prepared in Preparation 6 (115mg) was dissolved in 20mℓ of ethanol, 38.6mℓ of triethylamine and 1.74ml' of N,N-dimethyiamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 119mg(Yield 81%) of the diisopropyl compound.
1H NMR(CDC13) δ 0.75 (t, 2H), 0.93 (t, 2H), 1.16 (d. 6H), 1.22 (d, 6H), 3.3 (brs, 6H), 3.74 (d, 2H), 4.09 (s, 2H), 4.60 (m, 2H), 4.69 (brs, 2H), 7.6S (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give 86mg( Yield 90%) of the title compound.
1H NMR(MeOH-d4) δ 0.89 (m, 2H), 1.05 (m, 2H), 3.30 (br s, 6H), 3.90 (d, 2H),
4.37 (s,2H), 7.92 (brs, 1H)
ESI: 343 (M+l)+, C12H19N604P
Example 10
Synthesis of [(l-{[2-amino-6-(isopropylamino)-9H-purin-9-yl]methyI} cyclopropyl) oxyjmethylphosphonic acid(Compound 17)
The compound prepared in Preparation 6 (133mg) was dissolved in 20mℓ, of ethanol. 0.049mℓ of triethylamine and 0.082mℓ' of isopropylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 95mg(Yield 68%) of the diisopropyl compound.
H NMR(CDCI3) δ 0.83 (m. 2H), 0.98 (m, 2H), 1.28 (m, 18H), 3.79 (d, 2H). 4.15 (s, 2H), 4.60 (br s, 1H), 4.68 (s, 2H), 4.70 (m, 2H), 5.40 (br s, 1H), 7.77 (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give 72mg( Yield 91%) of the title compound.
H NMR(MeOH-d4) δ 0.89 (m, 2H), 1.05 (m, 2H), 1.34 (d. 6H), 3.30 (br s, 1H). 3.90 (d, 2H), 4.36 (s, 2H), 8.01 (br s, 1H) ESI: 357 (M+l)+, C12H19N604P
Example 11
Synthesis of ({l-[(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl-phosphonic acid(Compound 19)
The compound prepared in Preparation 4 (246mg) and 2.6-diaminopurine were reacted according to the same procedure as Preparation 5 to give 78.5mg(Yield 29%) of the diisopropyl compound.
H NMR(CDC13) δ 0.85 (t, 2H), 1.00 (t, 2H), 1.25 (d. 6H), 1.29 (d, 6H), 1.83 (brs, 2H), 3.82 (d, 2H), 4.15 (s, 2H), 4.68 (m. 2H), 5.39 (d, 2H), 7.S5 (s. 1H)
ESI: 399 (M+1), C16H27N604P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 72mg( Yield 91%) of the title compound.
1H NMR(DMSO-d6 + CF3COOH) δ 0.70 (m, 2H), 0.82 (m, 2H), 3.58 (d, 2H). 4.21 (s,2H), 8.16 (brs, 1H)
ESI: 315 (M+lf, C10H15N6O4P
Example 12
Synthesis of ({l-[(2-amino-6-ethoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy) methylphosphonic acid (Compound 23)
6-Chloroguanine derivative prepared in Preparation 6 (100mg) was dissolved in 10 mℓ, of ethanol, 32mℓ' of triethylamine and 53mg of sodium methoxide were added, and the resulting mixture was refluxed for 4 hours. The reaction was stopped by adding 10mℓ. of water. The reaction solution was extracted with dichloromethane and distilled under reduced pressure. The residue was purified by silica gel column to give a compound wherein 6-position of guanine was substituted by ethoxy group. i
'HNMR(CDCl3) δ 0.83 (t, 2H). LOO (t, 2H), 1.24-1.28 (m. 12H), 1.45 (t. 3H). 3.82 (d, 2H), 4.21 (s. 2H), 4.53 (m, 2H), 4.67 im. 1H). 5.76 (s, 2H), 7.90 (s. 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR(MeOH-d4) δ 0.99 (t. 2H). 1.06 (t, 2H), 1.48 (t, 3H). 3.91 (d, 2H), 4.51 (s, 2H), 4.65 (m,2H), 9.18 (s, 1H)
ESI: 344 (M+l). C12H18N505P
Example 13
Synthesis of ({l-[(2-amino-6-meth yl-9H-^urin-9-yl)methyl|cyclopropyl}oxy) methylphosphonic acid(Compound 25)
10mℓ flask was dried under vacuum and 53mg(0.238mmol) of zinc bromide was
introduced bit by bit under nitrogen atmosphere. 2ml of dry tetrahydrofiiran was added dropwise thereto, the temperature was lowered to -78 , 0.08mℓ(20.238mmol) of methylmagnesium bromide was added, and the resulting mixture was stirred for 1 hour. After the reaction mixture was warmed to room temperature, about 10mol% of palladiumtetrakistriphenylphosphine was added bit by bit. 50mg(0.119mmol) of the compound prepared in Preparation 6 in 1 mℓ of tetrahydrofiiran was added to the above reaction solution dropwise. The resulting mixture was heated for 1 hour. The solvent was removed by distillation under reduced pressure, the residue was participated with water and ethyl acetate, and the organic layer was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography(eluent. methylene chloride/methanol=90/10. v/v) to give 20mg(Yield 42%) of the diisopropyl compound.
1H NMR(MeOH-d4) δ 0.95 (m, 2H), 0.98(m, 2H), 1.17(d, 6H), t.23 (d, 6H|. 2.59(s. 3H), 4.02(s, IH), 4.10(s, 1H), 4.32(s, 2H), 4.59(m. 2H), 8.12(s, 1H) ESI: 398 (M+l)~, C17H28N504P
The compound thus obtained was reacted according to the same procedure as Example I to give 8.0mg(Yield 50%) of the title compound.
1H NMR(D:.0) δ 0.87 (m. 2H), 1.02 (m, 2H), 3.79 (s, IH), 3.81 (s, IH), 4.53 (s. 2H). 8.25 is. IH)
ESI:3l4(M+ir,C11Hl6N504P
Example 14
Synthesis of ((1 {[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyl|methyl! cyclopropyl)oxylmethylphosphonic acid(Compound 31)
The compound prepared in Preparation 7 (19mg) was reacted according to the same procedure as Example 1 to give 14mg(Yield 95%) of the title compound.
ESI: 291 (M+l)+,C10HllN2O6P
1H NMR(MeOH-d4) δ 0.82 (t, 2H), 0.97 (t, 2H), 1 .87 (s, 3H), 3.83 (d, 2H), 3.97 (s,2H).7.55(s, IH)
Example 15
Synthesis of [(l-{[2-amino-6-(4-morpholmyI)-9#-purin-9-yl]methyl} cyclopropyl)oxy]methylphosphonic acid(Compound 37)
The compound prepared in Preparation 6 (134mg) was dissolved in 20mℓ of ethanol, 0.049mℓ of triethylamine and 0.085mℓ, of morpholine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/I. v/v) to give 66mg(Yield 44%) of the diisopropyl compound.
1H NMR(CDCl3) δ 0.83 (m, 2H), 0.99 (m, 2H). 1.24 (d, 6H), 1.30 (d. 6H). 3.79 (m, 6H), 4.18 (s, 2H), 4.21 (br s, 4H), 4.67 (m, 2H), 4.80 (br s. 2H), 7.78 (s. .H) ESI: 469 (M+l f. C20H33N6O5P
The compound thus obtained was treated with trimethylsilylbromice according to the same procedure as Example 1 to give 49mg(Yield 91%) of the title compound.
1H NMR(MeOH-d4) δ 0.89 (m, 2H), 1.07 (m, 2H), 3.81 (m, 4Ht. 3.92 (d, 2H), 4.40(br s, 6H), 7.87 (s. 1H)
ESI: 384 (M+1)'. C14H21N605P
Example 16
Synthesis of [(l-{[2-amino-6-(l-piperidinyl)-9H-purin-9-yl]methyl}
cyclopropyl)oxy]methylphosphonic acid(Compound 39)
The compound prepared in Preparation 6 (154mg) was dissolved in 20mℓ, of ethanol, 0.049mℓ' of triethylamine and 0.llmℓ of piperidine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) :o give 123mg (Yield 72%o) of the diisopropyl compound.
1H NMR(CDC13) δ 0.80 (m, 2H), 0.99 (m, 2H), 1.22 (d, 6H), 1.26 (d, 6H), 1.63 (m, 4H), 1.67 (m, 2H), 3.78 (d, 2H), 4.14 (s, 6H). 4.54 (br s. 2H), 4.65 (m, 2H), 7.72 (s, 1H)
ESI: 467 (M+l)+, C21H35N604P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 87mg( Yield 91%) of the title compound.
1H NMR(MeOH-d4) δ 0.89 (m, 2H). 1.06 (m. 2H). 1.73 (m. 4H). 1.79 (m. 2H),
3.90 (d. 2H), 4.37 (s, 2H), 4.43(br s, 4H), 7.89 (s. 1H)
ESI: 383 (M+lf. C15H23N604P
Example 17
Synthesis of [(l-{[2-amino-6-(4-methyI-l-piperazinyl)-9H-purin-9-yIjmethyI} cyclopropyl)oxy]methylphosphonic acid(Compound 41)
The compound prepared in Preparation o (128mg) was dissolved in 20mℓ of ethanol, 0.10mℓ of 4-methyl-l-piperazine was added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l. v/vi to give 123mg(Yield 83%) of the diisopropyl compound.
1H NMR(CDC13) δ 0.80 (m, 2H), 0.98 (m. 2H), 1.21 (d, 6H), 1.27 (d, 6H), 2.30 (s, 3H), 2.48 (m, 4H), 3.78 (d. 2H), 4.13 (s, 2H), 4.22 (br s, 4HI 4.57 (s, 2H), 4.66 (m. 2H), 7.73 (s, 1H)
ESI: 482 (M+l)+, C21H36N704P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 87mg(Yield 85%) of the title compound.
1H NMR(MeOH-d4) δ 0.89 (m, 2H), 1.0" (m, 2H). 3.00 (s, 3H), 3.72 (m. 4H),
3.91 (d, 2H), 4.45 (s, 2H), 4.89 (m, 2H), 5.70 (br, 2H). 7.91 (s. 1H)
ESI: 398 (M+l)+, C15H24N704P
Example 18
Synthesis of [(l-{[2-amino-6-(l-pyrroIidinyl)-9H-purin-9-yl]methyI}
cyclopropyI)oxy] methyl phosphonic acid (Compound 43)
The compound prepared in Preparation 6 (122mg) was dissolved in 20mℓ of ethanol, 0.07mℓ of pyrrolidine was added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20'l, v/v) to give 110mg(Yield 83%) of the diisopropyl compound.
1H NMR(CDCl3) δ 0.78 (m, 2H), 0.96 (m. 2H), 1.20 (d, 6H), 1.26 (d, 6H), 2.00 (br s. 4H), 3.60 (br, 3H), 3.78 (d. 2H), 4.09 (br, 2H). 4.12 (s, 2H), 4.63 (m, 2H), 7.69 (s, 1H)
ESI: 453 (M-l)+, C20H33N6O4P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 76mg(Yield 85%) of the title compound.
1H NMR(MeOH-d4) δ 0.94 (m, 2H), 1.03 (m. 2H), 2.15 (m, 4H), 3.76 (m, 2H), 3.91 (d, 2H), 4.18 (m, 2H), 4.40 (s, 2H), 5.70 (br, 2ri), S.42 (s, 1H) ESI: 369 (M+l)+, C14H21N604P
Example 19
Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyllcyclopropyl}oxy) methyl] -9-methyl-3,7-dioxo-2,4,6-trioxa-385-phosphadec-l-yl 3-methylbutanoate (Compound
74)
The compound prepared in Example 5 (100mg) was dissolved in dimethylformamide (2mℓ) and then reacted with chloromethyl 3-methvlbutyrate in the presence of triethylamine (3 equivalents) at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 41%.
1H NMR(CDC13) δ 0.89 (t, 2H), 0.94 (d, 12H), 1.04 (t, 2H), 2.10 (m, 2H), 2.22 (d, 4H), 3.97 (d, 2H), 4.23 (s, 2H), 5.21 (s, 2H), 5.65 (m, 4H), 8.00 (s, 1H), 8.69 (s, 1H) ESI: 527 (M+l)+, C23H35N408P
Example 20
Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl]cycIopropyl}oxy) methyl] -3,7-dioxo-2,4,6-trioxa-385-phosphadec-l-yl butyrate(Compound 75)
The compound prepared in Example 5 was reacted with chloromethyl butyrate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 24%.
1H NMR(CDC13) δ 0.88 it. 2H), 0.92 (d, 6H), 1.60 (m, 4H), 2.32 (t. 4H). 3.96 (d. 2H), 4.22 (s, 2H), 5.00 (s, 2H), 5.62 (m, 4H), 8.00 (s. 1H). 8.68 (s, 1H) ESI: 499 (M+iy, C21H31N408P
Example 21
Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyljcyclopropyl}oxy) methyl]-
8-methyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl 2-methylpropanoate
(Compound 78)
The compound prepared in Example 5 was reacted with chloromethyl isobutyrate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 21%.
1H NMR(CDC13) δ 0.84 (t. 2H), 0.97 (t, 2H), 1.11 (d, 12H), 2.52 (m, 2H), 3.91 (d, 2H), 4.16 (s, 2H), 5.21 (s, 2H), 5.58 (m, 4H). 7.96 (s, 1H), 8.61 (s, 1H) ESI: 499 (M+l)\ C21H31N408P
Example 22
Synthesis of 3-[({l-((2-amino-9H-purin-9-yl)methyl)cycIopropyl}oxy) methyl) -3,7-dioxo-7-(l-pyrrolidinyI)-2,4,6-trioxa-385-phosphahept-l-yl -pyrrolidiaecarboxylate (Compound 80)
The compound prepared in Example 5 was reacted with chloromethyl 1-pyrrolidinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 35%.
1H NMR(CDC13) δ 0.82 (t, 2H), 0.37 (m, 8H), 0.98 it, 2H). 1.57 (d, 4H), 2.26 (t. 4H), 3.91 (d, 2H), 4.16 (s, 2H), 5.12 (s, 2H). 5.57 (m, -iH), 7.9S (s. IH), 8.62 (s, IH) ESI: 553 (M+l)~, C23H33N608P
Example 23
Synthesis of 3-[({l-[(2-amino-9H-purin-9-y|)methyl|cyclopropyl}ox\) methyl]-3,7-dioxo-7-(l-piperidinyl)-2.4,6-trioxa-385-phosphahept-l-yl l-piperidinecarboxylate(Compound 81);
The compound prepared in Example 5 was reacted with chlorometh\i 1-piperidinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 39%.
1H NMR(CDC13) δ 0.86 (t, 2H), 1.02 (t. 2H. 1.47-1.58 brm. 12H), 3.40 (brm. 8H), 3.99 (d, 2H), 4.22 (s, 2H), 5.00 (s, 2H), 5.69 (m, 4H), 8.00 is. IH), 8.67 (s, IH) ESI: 581 (M-+), C25H37N608P
Example 24
Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl)cyclopropyl}oxy)
methyll-7-(4-morphoIinyl)-3,7-dioxo-2,4,6-trioxa-385-phosphahept-l-yl 4-morpholinecarboxylate(Compound 82)
The compound prepared in Example 5 was reacted with chloromethyl 4-morpholinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 40%.
1H NMR(CDCl3) δ 0.89 (t, 2H), 1.03 (t, 2H), 3.47 (brm, 8H), 3.65 (brm, 8H), 4.00 (d, 2H), 4.24 (s, 2H), 5.04 (s, 2H), 5.70 (m, 4H), 8.07 (s, 1H), 8.69 (s, 1H) ESI: 586 (MM)+, C23H33N6O10P
Example 25
Synthesis of {[l-({2-amino-6-[(4-methylphenyI)suIfanyl)-9H-purin-9-yl} methyl)cyclopropyl]oxy}methylphosphonic acid(Compound 66}
6-Chloroguanme derivative prepared in Preparation 6 (4.86g) was dissolved in 85 \\\i of methanol and '. 4g of triethylamine and 2.9g of 4-methylthiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20.;.' of water, and the methanol was removed b\ distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified by silica gel column to give a compound wherein 6-position of guanine was substituted by 4-methylphenylthio group.
1H NMR(CDCI;.) δ 0.84 (t, 2H), 1.02 (t. 2H), 1.25-1.31 (m, 12H), 2.40 (s, 3H), 4.20 (d, 2H), 4.69 (m. 2H), 4.74 (s, 2H), 7.22 (d, 2H), 7.50 (d, 2H), 8.00 (s. 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 and then recrystallized from a mixture of methanol-diethylether (1/20, v/v) to give the title compound.
1H NMR(MeOH-d4) δ 0.98 (t, 2H), 1.06 (t, 2H), 2.42 (s, 3H), 3.92 (d, 2H), 4.4S (s, 2H), 7.35 (d, 2H), 7.55 (d, 2H), 9.05 (s, 1H) ESI: 421 (M+l.". C18H21N404PS
Example 26
Synthesis of 3-({[l-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38:'-phosphanon-1-yl pivalate(Compound 68)
The methylphosphonic acid prepared in Example 25 was reacted according to the same procedure as Example 2 to give the title compound.
1H NMR(CDC13) δ 0.82 (t, 2H), 0.98 (t, 2H), 1.18 (s, 18H), 2.36 (s, 3H), 3.93 (d, 2H), 4.15 (s, 2H), 4.93 (s, 2H), 5.60 (m, 4H), 7.18 (d, 2H), 7.48 (d, 2H), 7.88 (s, 1H) ESI: 649 (M+lf, C30H41N4O8PS
Example 27
Synthesis of {[l-({2-amino-6-[(4-methoxyphenyl)sulfanylI-9H-purin-9-yl} methyl)cyclopropyl]oxy}methylphosphonic acid(Compound 96)
6-Chloroguanine derivative prepared in Preparation 6 (4.86g) was dissolved in 85 mℓ of methanol and 1.4g of triethylamine and 2.9g of 4-methoxythiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20mℓ' of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichlorometnane and purified by silica gel column to give a compound wherein 6-position of guanine was substituted by 4-methoxyphenylthio group.
The compound thus obtained was reacted according to the same procedure as Example 1 and then recrystallized from a mixture of methanol-diethylether (1/20, v/v) to give the title compound.
1H NMR(MeOH-d4) δ 0.77 (m, 2H), 1.05 (m, 2H), 3.87 (s. 3H). 3.92 (d. 2H). 4.45 (s, 2H), 7.10 (d, 2H). 7.59 (d, 2H), 8.09 (s, 1H) ESI: 438 (M+l)~. C17H2CN505PS
Example 28
Synthesis of {[l-({2-amino-6-[(4-nitrophenyl)suIfanyl|-9H-purin-9-yl}methyl) cyclopropyl]oxy}methylphosphonic acid(Compound 95)
The compound prepared in Preparation 6 was reacted according to tlie same procedure as Example 27 except that 4-nitrothiocresol was used instead of 4-methoxythiocresol to give the title compound.
1H NMR(MeOH-d4) δ' 0.86 (m, 2H). 0.95 (m. 2H), 3.S2 (d. 2H). 4.35 (s, 2H). 7.81 (d, 2H), 8.22 (d, 2H). 8.72 (s. 1H)
ESI: 453 (M+lf. C16H17N606PS
Example 29
Synthesis of ({l-[(2-amino-6-hydroxy-9/7-purin-9-yI)methyI]-2-methyl cyclopropyl}oxy)methylphosphonic acid(Compound 97)
The 6-chloroguanine derivative prepared in Preparation 12 was consecutively reacted according to the same procedure as Examples 3 and 4 to give the title compound.
1H NMR(MeOH-d4) δ 0.73 (t, 1H), 1.15 (m. 1H), 1.21(d, 3H), 1.38 (t, 1H), 1.48 (m. 1H), 3.85 (t. 1H), 3.96 (t, 1H), 4.42 (d, 1H). 4.69 (d, 1H), 9.12 (s, 1H)
Example 30
Synthesis of {[l-({2-amino-[6-(4-rnethoxyphenyl)sulfanyl|-9H-purin-9-yl; methyl)-2-methylcyclopropyl]oxy}methylphosphonic acid(Compound 99)
The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 27 to give the title compound.
1H NMR(MeOH-d4) δ 0.67 (t, 1H), 1.13 (m, 2H), 1.20 (d, 3H), 1.45 (m, 1H). 3.85 (m, 1H). 3.S6 (s, 3H), 3.94 (m, 1H), 4.42 (d, 1H). 4.68 (d. 1H), 7.09 (d. 2H), 7.59 (d, 2H).9.00(s, 1H)
ESI: 452 (M+1)T, C18H22N505PS
Example 31
Synthesis of {[l-({2-amino-{6-(4-methylphenyl)suifanyll-9H-purin-9-yl} methyl)-2-methyicyciopropyl]oxy}methylphosphonic acid(Compound 101)
The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 25 to give the title compound.
1H NMR(MeOH-d4) δ 0.68 (t, 1H), 1.15 (m. 2H), 1.20 (d, 3H), 1.45 (m, 1H), 2.42 (s, 3H), 3.84 (m, 1H), 3.96 (m, 1H), 4.43 (d. 1H). 4.68 (d. 1H), 7.36 (d. 2H). 7.55 (d, 2H),9.05(s, 1H)
ESI: 436 (M+lf, C18H22N504PS
Example 32
Synthesis of {[l-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yI}methyl) -2-methyIcyclopropyI]oxy}methylphosphonic acid(Compound 100)
The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 28 to give the title compound.
1H NMR(MeOH-d4) δ 0.49 (t, 1H), 0.93 (m, 1H), 1.00 (d, 3H), 1.25 (m. 1H), 3.64 (m, 1H). 3.76 (m, 1H), 4.28 (d, 1H), 4.53 (d. 1H). 7.72 (d. 2H), 8.14 (d. 2H). 9.10 (s. 1H)
ESI: 467 (M+l)+, C17H19N606PS
Example 33
Synthesis of ({l-[(6-amino-9H-purin-9-yl)methylj-2-methyIcyclopropyl}oxy) methylphosphonic acid(Compound 103)
The adenine derivative prepared in Preparation 11 was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR(MeOH-d4) C5 0.64 (t, 1H), 1.09 (m. 1H), 1.20 (d, 3H), 1.43 (m. 1H). 3.83 (m, 1H), 3.95 (m, 1H), 4.49 (d. 1H), 4.75 (d, 1H). 5.49 (s. 2H), 8.39 (s. 1H). 8.55 ESI: 314 (M-lf, CI 1H16N504P
Example 34
Synthesis of bis{[(r-butoxycarbonyl)oxy]methyl}({l-[(2-amino-9H-purin-9-yI) methyl)cyclopropyl}oxy)methyIphosphonate(Cornpound 69)
The compound prepared in Example 5 (187mg) was mixed with 6111C of N-methyl-2-pyrrolidone, and 300mg of triethylamine and 150mg of chloromethyl t-butylcarbonate were added. The reaction solution was stirred at room temperature for 4 hours. The reaction was stopped by adding 10mℓ of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and purified by silica gel column to give the title compound.
1H NMR(CDC13) δ 0.86 (m, 2H), 1.06 (m, 2H), 1.47 (s, 18H), 4.01 (d, 4H), 4.22 (s, 2H), 5.00 (bis, 2H), 5.61 (m, 4H), 7.99 (s, 1H), 8.69 (s, 1H) ESI: 344 (M+l)+, C22H34N5O10P
Example 35
Synthesis of bis{[(isopropoxycarbonyl)oxy]methyl}({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyIphosphonate(Compound70)
The compound prepared in Example 5 (100mg) was mixed with 5mℓ of N-methyl-2-pyrrolidone, and 110mg of triethylamine and 150mg of chloromethyi isopropylcarbonate were added. The reaction solution was stirred at 50 for 4 hours. The reaction was stopped by adding l0mℓ of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled ande;' reduced pressure and purified by silica gel column to give the title compound.
1H NMR(CDCI3) δ 0.88 (s. 2H). 1.06 (s, 2H), 1.29 (d, 2H), 1.31 (d, 2H), 4.01 (d. 4H), 4.21 (s, 2H), 4.92 (m, 2H), 5.01 (brs, 2H), 5.64 (m. 4H). 7.99 (s, 1H), 8.69 (s, 1H) ESI: 532 (M+l)\ C20H30N5O10P
Example 36
Synthesis of ({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2,2-dimethyl cyclopropyl}oxy)methylphosphonic acid(Compound 146)
The compound prepared in Preparation 32 was consecutively reacted according to the same procedure as Examples 1 and 4 to give the title compound.
1H NMR(MeOH-d4) δ 0.78 (d, 1H), 0.82 (d, 1H), 1.21 (s, 3H), 1.27 (s. 3H). 3.90 (d, 1H), 3.91 (d, 1H), 4.58 (s, 2H), 9.12 (s, 1H) ESI: 344 (M+l)\ C12H18N505P
Example 37
Synthesis of ({l-((2-amino-9H-purin-9-yl)methylI-2,2-dimethylcyclopropyl} oxy)methylphosphonic acid(Compound 147)
The compound prepared in Preparation 32 was reacted according to the same
procedure as Example 5 to give a compound wherein 6-position of guanine was reduced by hydrogen.
1H NMR(CDC13) δ 0.60 (d. 1H), 0.82 (d, 1H), 1.21 (s, 3H), 1.22 (s, 3H), 1.22 (m, 15H), 3.73 (m, 1H), 3.87 (m, 1H). 4.13 (d, 1H), 4.49 (d, 1H), 4.67 (m, 2H), 4.98 (brs, 2H), 8.09 (s,lH), 9.67 (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR(MeOH-d4) δ' 0."4 (d. 1H). 0.S1 id, 1H). 1.21 (s. 3H). 1.26 (s. 3H). 3.91 (d, 2H), 4.49 (d. 1H), 4.57 (d. 1H). 3.63 (s. 1H). S."4 (s. 1H) ESI:328(M+1)'.C12H18N504P
Example 38
Synthesis of ({l-[(6-amino-9H-purin-9-yl)methyl|-2,2-dimethylcyclopropyl} oxy)methylphosphonic acid(Compound 148)
The compound prepared in Preparation 31 was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR(MeOH-d4) δ 0." (d, 1H), 0.79 (d, 1H). 1.25 (s. 3H), 1.28 (s. 3H). 3.90 (d, 2H), 4.61 (d. 1H), 4.70 (d, 1H). S.38 (s. 1H). 8.51 (s. IK) ESI: 328 (M+1 f, C12H18N504P
Example 39
Synthesis of (£)-2-{l-[(2-amino-6-hydroxy-9f/-purin-9-yl)methylJcyclopropyl} ethenylphosphonic acid(Compound 130)
The compound prepared in Preparation 26 was reacted according to the same procedure as Example 1 to give phosphonic acid derivative.
1H NMR(MeOH-d4) δ" 1.07 (t. 2H). 1.33 (t. 1H), 4.41 (s. 2H). 5.76 (dd, 1H), 6.45 (dd, 1H), 9.18 (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 4 to give the title compound.
1H NMR(MeOH-d4) δ 1.08 (t, 2H), 1.34 (t, 1H), 4.38 (s, 2H), 5.78 (dd, 1H), 6.46 (dd, 1H), 9.11 (s, 1H)
ESI: 312 (M+l)\ CI 1H14N504P
Example 40
Synthesis of 2-{l-((2-amino-9H-purin-9-yl)methyl]cyclopropyl}ethyl
phosphonic acid(Compound 139)
The compound prepared in Preparation 26 was reacted according to the san:e procedure as Example 5 to give the title compound.
1H NMR(MeOH-d4) δ 0.58 (t. 2H). 0.85 (t. 2H). 1.42 (m. 2H). 1.95 (m, 2H». 4.11 (s, 2H), 5.78 (dd, 1H), 8.55 (s. 1H), 8.75(s, 1H) ESI: 298 (M+l)~, CI 1H16N503P
Example 41
Synthesis of (E) 2-{ l-((6-amino-9H-purin-9-yl)methyllcyclopropyl}ethenyl phosphonic acid(Compound 132)
The compound prepared v: Preparation 25 was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR(MeOH-d4) δ 0.94 (t, 2H), 1.20 (t, 2H). 4.36 (s. 2H), 5.63 (dd, 1H. 6.37 (dd, 1H). 8.30 (s, 1H), 8.31 (s, 1H)
ESI: 296 (M+l)\ CI 1H14N503P
Example 42
Synthesis of 2-{l-((6-amino-9H-purin-9-yl)methyllcycIopropyl}ethy|
phosphonic acid(Compound 140)
The compound prepared in Preparation 25 was reacted according to the same procedure as Example 5 to give the title compound.
1H NMR(MeOH-d4) δ 0.58 (t, 2H), 0.87 (t, 2H), 1.37 (m, 2H), 1.97 (m, 2H), 4.24 (s, 2H), 8.31 (s, 1H), 8.42 (s, 1H)
ESI: 298 (M+lf, CI 1H16N503P
Example 43
Synthesis of 2-{l-l(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl} ethylphosphonic acid(Compound 138)
The compound prepared in Preparation 26 was reacted according to the same procedure as Example 12 to give a compound wherein 6-position of guanine was substituted by ethoxy group.
1H NMR(CDC13) δ 1.00 (t. 2H), 1.10 (t, 2H), 1.16-1.21 (m. 9H). 3.90 (m, 4H), 4.01 (m. 2H), 4.13 (s, 2H), 4.92 (s, 2H), 5.58 (dd, 1H), 6.49 (dd, 1H). 7.62 (s, 1H)
The compound thus obtained (80mg) was dissolved in methanol and reacted under hydrogen atrmosphere in the presence of 20mg of 10% Pd/C to give a compound wherein double bond was reduced.
1H NMR(CDC13) δ 0.49 (t, 2H), 0.66 (t, 2H), 1.21 (t, 6H). 1.42 (m. 2H). 2.01 (m, 2H), 3.99 (m, 6H), 4.96 (s, 2H), 7.59 (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give the title compound.
!H NMR(MeOH-d4) δ 0.60 (t, 2H), 0.87 (t, 2H), 1.47 (m. 2H). 1.97 (m, 2H), 4.16 (s,2H), 9.12 (s,lH)
ESI: 314 (M+If, C11H16N504P
Example 44
Synthesis of 2-{l-[(2-amino-9H-purin-9-yl)methyl|cyclopropyl} propyl phosphonic acid(Compound 144)
The compound prepared in Preparation 35 was consecutively reacted according to
the same procedure as Preparations 24, 26 and Example 5 to give the title compound.
1H NMR(MeOH-d4) δ 0.62-0.77 (m, 4H), 1.04 (d, 3H), 1.52 (m, 2H), 1.90 (m, 1H), 4.24 (m, 2H), 8.58 (s, 1H), 8.74 (s, 1H) ESI: 312 (M+l)+, C12H18N503P
Example 45
Synthesis of (E)-2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}-l-propenyIphosphonic acid(Compound 137)
The compound prepared in Preparation 35 was consecutively reacted according to ne same procedure as Preparations 24. 25 and Example 1 to give the title compound.
H NMR(MeOH-d4) δ* 0.86 (t. 2H). 1.10 (t, 2H), 2.19 (d, 3H), 4.38 (s, 2H), 5.23 i. 1H). S34(s. 1H), 8.37(s, 1H)
ESI:310(M+1)~, C12H16N503P
Example 46
Synthesis of 2-{l-[(6-amino-9H-purin-9-yl)methyl|cyclopropyl}propyl phosphonic acid(Compound 143)
The compound prepared in Preparation 35 was consecutively reacted according to the same procedure as Preparations 24, 25 and Example 5 to give the title compound.
K NMR(MeOH-d4) δ 0.65 (t. 2H), 0.78 (t, 2H), 0.95 (m, 1H). 1.00 (d, 3H). 1 53 (s. IK). 1.90 (m, 1H), 4.3 (q, 2H), 8.41 (s, 1H). 8.45 (s, 1H) ESI: 312 (M+l)~, C12H18N503P
Example 47
Synthesis of bis(2,2,2-trifluoroethyI) ({l-[(6-amino-9H-purin-9-yl)methyll cyclopropyl}oxy)methylphosphonate(Compound 48)
To the methylphosphonic acid prepared in Example 1 (150mg) was added dropwise uichloromethane, 0.73mℓ of N,N-diethyltrimethylsilylamine was added dropwise thereto, and the resulting mixture was stirred at room temperature for 2 hours. Oxah 1
chloride (0.15mℓ) and 2 drops of dimethylformamide were added to the reaction vessel. The mixture was stirred for further 2 hours and the solvent was removed by distillation under reduced pressure. To the residue were added 1(M of pyridine and 2mℓ of trifluoroethanol, which was then reacted under stirring for 16 hours. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound.
1H NMR(CD3OD) δ 1.02 (m. 4H), 4.30 (d, 2H). 4.53 (m. 6H), 8.40 (s, 1H), 8.46(s, 1H)
ESI: 464 [M-H]+: C14H16F6N504P
Example 48
Synthesis of bis(2.2.2-triiluoroethyI) {{l-{(2-amino-9H-purin-9-yl)methyl] cyclopropyl}oxy)methylphosphonate(Compound 49)
The compound prepared in Example 5 was reacted according to the same procedure as Example 47 to give the title compound.
1H NMR(CDCl3) δ 0.88 (m, 2H). 1.04 (m. 2H). 4.07 (d, 2H), 4.22 (s, 2H), 4.33 (m, 4H), 5.06 (br.s, 2H), 7.92 (s. 1H), 8.68 (s. 1H) ESI: 464 [M+H]T, C14H16F6N504P
Example 49
Synthesis of bis(2,2,2-trifluoroethyl) [l-({2-amino-[6-(4-methylphenyl) sulfanyl]-9H-purin-9-yl}methyI)cyclopropyl]oxy}methylphosphonate(Compound 62)
The compound prepared in Example 25 was reacted according to the same procedure as Example 47 to give the title compound.
1H NMR(CDCl3) δ 0.S8 (m, 2H), 1.03 (m, 2H), 2.39 (s, 3H), 4.06 (d, 2H), 4.19 (s, 2H), 4.33 (m, 4H), 4.76 (br.s. 2H), 7.22 (d, 2H), 7.50 (d, 2H), 7.82 (s. 1H) ESI: 586 [M+H]+ , C21H22F6N504PS
Example 50
Synthesis of bis(2,2,2-trifluoroethyl) |(l-{|2-amino-6-hydroxy-9H-purin-9-ylj
methyl}cyclopropyl)oxyJmethylphosphonate(Compound45)
The compound prepared in Example 4 was reacted according to the same procedure as Example 47 to give the title compound.
1H NMR(CDC13) δ 0.91 (m, 2H), 1.05 (m, 2H), 4.08 (d. 2H), 4.17 (s, 2H), 4.35 (m, 4H), 4.70 (s, 2H), 7.69 (s, 1H)
MW=478 [M+H]+479C14H16F6N505P
Example 51
Synthesis of bis(2,2,2-trifluoroethyl)(l-{[2-amino-6-cyclopropylamino-9H-purin-9-yl]methyl}cyclopropyl)oxy]rnethylphosphonate(Compound 50)
The compound prepared in Example 7 was reacted according to the same procedure as Example 47 to give the title compound.
1H NMR(CDCl3) δ 0.60 (br.s, 2H), 0.84 (br.s, 4H), 1.01 im. 2H). 2.98 (br.s, 1H). 4.05 (d. 2H), 4.14 (m, 4H), 4.70 (br.s, 2H), 5.67 (br.s. 1H), 7.60 (s. 1H) ESI: 519, [M+H]+, C17H21F6N604P
Example 52
Synthesis of ({l-((2-amino-9H-purin-9-yl)methyl|-2-methylcyclopropyl}oxy) methylphosphonic acid(Compound 98)
The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 5 to give the title compound.
1H NMR(MeOH-d4) δ 0.68 (t, 1H), 1.13 (m, 1H), 1.21 (d, 3H). 1.42 (t, 1H), 3.84 (t, 1H), 3.97 (t, 1H), 4.40 (d, 1H), 4.66 (d. 1H), 8.63 (s, IH), 8.73 (s. 1H) ESI: 314 (M-lf, CI 1H16N504P
The compound of the present invention exhibits a potent pharmacological effect to a hepatitis B cell line. HepG2.2.15, and a transgenic mouse, widely used for development of a therapeutic agent against hepatitis B, when intravenously or orally administered. The experimental procedures and results are described below.
Experiment 1
Measurement and Analysis of Inhibition Effect against Hepatitis B Virus (HBV)
(1) Cell Culture and Treatment with Drugs
HepG2.2.15 cell (M.A Shells et al., P.N.A.S. 84, 1005(1987)), a hepaiocarcinoma cell line producing hepatitis B virus, was cultured in DMEM medium!GIBCO BRL. -430-2200) containing 10% FBS(Fetus bovine serum, GIBCO BRL. = 1600 0-044). 1% ABAM (Antibiotic-Antimycotic, GIBCO BRL, #16000-028) and 400µg/mℓ of geneticin(Sigma, =G-9516) in a T-75 flask under the conditions of 5% CO: incubator and 37°C by dividing in a ratio of 1:3 at an interval of 3 days. The cells were distributed into a 96-well plate in the amount of 4x 104/well and then when 80-90% of cell tensity was achieved, the old medium was changed with 200µℓ of DMEM medium containing 2% FBS, 1% ABAM and 400µg/mℓ; of geneticin. The drug solution was sequentially diluted five-fold each time, from 100 M to 0.16 M. In order to minimize an experimental error, each treatment was repeated 2-3 times for the respective drugs. The n-.edium was changed every two days. On 10 days after the treatment with drug, 100µℓ of .he medium was collected and the degree of inhibition of viral replication by drugs was determined through quantitative PCR (Polymerase Chain Reaction).
(2) Determination of Cytotoxicity
After 100µℓ' of the medium was collected on 10th day from the treatment with drug, 7.5mg/mℓ of MTT (Thiazolyl Blue Tetrazolium Broide, Amresco, =0793-5G) solution was added to each well in the amount of 30,o?./well and each cell was cultured for 2 hours in a 5% CO: incubator at 37°C. The solution was discarded, and an isopropanol solution containing 10% Triton X-100 and 0.4µℓ of c-HCl was added to each well in the amount of 120µℓ./well. The cells thus dyed were transferred to the isopropanol solution by shaking for 2 hours. Absorbance at 540nm was measured by Elisa Reader.
(3) PCR Estimation of Inhibition Effect on Hepatitis B Virus Replication
The degree of inhibition by drugs on the replication of hepatitis B virus was determined using the cell culture solution collected on 10th day after the treatment with the drug. The cell culture solution treated with each drug was diluted ten-fold with distilled water and subjected to a pretreatment to destroy the cells by heating them for 15 minutes at 95°C. For the PCR amplification of the gene fragment of about 320bp, the 2001-base position that is conserved in all sub-strain of hepatitis B virus and 2319-base position that is between the core antigen gene and polymerase gene were used as 5'-end and 3'-end primer, respectively. Then, the amount of genomic DNA of hepatitis B virus was quantified, and the inhibitory effect by drugs on the replication of hepatitis B virus was determined on :he basis thereof.
First, "he cell culture solution of hepatitis B virus that was not treated with drug was sequentially diluted and amplified through the PCR. The amplified DNA was subjected to electrophoresis on 2% agarose gel and stained with ethidium bromide (EtBr) to be analyzed by IS-1000 (Innotech Scientific Corporation) Digital Imaging System. Analysis of the cell culture solution treated with drug was then carried out using the dilution fold in the range where linearity is maintained. The DNA obtained from the group treated with drug was amplified through the same PCR method, subjected to electrophoresis on 2% agarose gel. stained with ethidium bromide, and analyzed by IS-1000. The degree of inhibition by drugs in the viral replication was quantified by calculating the ratio of test group to control group. Table 8 summarizes the inhibitory effect (pharmaceutical activity and toxicity) of the typical compounds of the present invention.
Table 8 (Table Removed )
As can be seen from the results of Table 8, the compound according to the present
invention exhibits 4 to 10-fold greater activity than the comparative compound PMEA that is on Phase IE in clinical trials.
Experiment 2
Pharmacological Test on Transgenic mouse (T/G mouse)
The compounds were administered via subcutaneous and oral routes in the folowing animal test.
The test compounds were administered to 4-5 weeks old HBV transgenic mice, which were obtained from FVB strain mice according to a method described in a reference (see, Jone D. Morrey, Kevin W. Bailey, Brent E. Korba. Robert W. Sidwell, "Utilization of transgenic mice replicating high levels of hepatitis B virus for antiviral evaluation of lamivudine" Antiviral research. 1999, 42. 97-108). subcutaneously for 9 days in the amount of l0mg/kg/day and oraily for 9 days in the amount of 10, 2 and 0.4mg/kg/day, once a day, respectively (the same number of males and females were used). Blood was cciected from the tail of the mouse and 5µl of serum was obtained. To this serum was added 15ml. of Genereleaser sol. which was then pretreated in different temperatures. HBV DNA was taken from the pretreated solution. The DNA was amplified by the PCR (Polymerase Chain Reaction) in the presence of 4,µl of 10 x buffer (Perkin Elmer), 0.8.µl' of l0mM dNTP, 500ng of the same HBV primers as used in Experiment 1, 2.125mM of M;C1:, DMSO and Taq polymerase. The amount of HBV DNA was analyzed by electrophoresis in order to evaluate a pharmacological effect of the compound of t e present invention. The results are described in the following Table 9. In the following Table 9, mice showing pharmacological effectj means the mice whose blood does not contain HBV DNA.
Table 9 (Table Removed )
I The result means rnumber of mice showing pharmacological effect / number of total micej
As can be seen in the above Table 9, the compound of the present invention shows a potent hepatitis B therapeutic effect in the tested anirr.als when orally or subcutaneously administered. Particularly, since the compound of the present invention is superior to the comparative compound PMEA. which is on Phase II in clinical trials, it is expected that the compound of the present invention may be usee very effectively for the tr-atment of hepatitis B.









We claim:
1. An acyclic nucleoside phosphonate derivate represented by the following formula (I):
In which (Formula Removed ) represents single bond or double bond,
R1, R2, R3, R7 and R8 independently of one another represent hydrogen, halogen, hydroxyl, amino, C1-C7-alkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or C1-C5-alkoxy,
R4 and R5 independently of one another represent hydrogen, or represent C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, (particulary, fluorine), C1-C4-alkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyloxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=O)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7- alkylamino, di (C1-C7-alkyl)amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen,
Y represents -O-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-, -SiH(Z)-, OR =Si(Z)-, wherein Z represents hydrogen, hydroxyl or halogen, or represents C1-C7-alkyl, C1-Cs-alkoxy, allyl, hydroxyl- C1-C7-alkyl, C1-C7-aminoalkyl or phenyl,
Q represents a group having the following formula:
(Formula Removed ) Wherein
X1,X2 ,X3 and X4 independently of one another represent hydrogen, amino, hydroxyl or halogen, or represent C1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxyl- C1-C7-alkyl, phenyl or phenoxy each of which is optionally substituted by nitro or C1-C5-alkoxy, or represent C6 -C10-arylthio which is optionally substituted by nitro, amino, C1 -C6-alkyl or C1-C4-alkoxy, or represent C6-C12-arylamino, C1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6-cycloalkylamino or a structure of
(Formula Removed ) wherein n denotes an integer of 1 or 2 and Y1 represents O,
CH2 or N-R (R represents C1-C7-alkyl or C6 -C12-aryl), pharmaceutically acceptable salt, or stereoisomer thereof.
2. The compound as claimed in claim 1 wherein the pharmaceutically acceptable salt is a salt with sulfuric acid, methanesulfonic acid or hydrohalic acid.
3. The compound as claimed in claim 1 wherein,
represents single bond,
R, R2, R3 , R7, and R8 independently of one another represent hydrogen, fluorine, hydroxy, C2-C6 -alkenyl, C1 -C5-alkylamino, C1 -C5-aminoalkyl, or C1 -C5-alkoxy, R4 and R5 independently of one another represent hydrogen, or represent C1 -C4-alkyl optionally substituted by one or more substituents selected from the group consisting of fluorine, C1 -C4-alkoxy and phenoxy, or represent carbamoyl substituted by C1 -C5-alkyl, or represent-(CH2)m-OC(=O)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1 -C12-alkyl, C2 -C7 -alkenyl, C1-C5-alkoxy, C1 -C7-alkylamino, di(C1 -C7-alkyl)amino, C3 -C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen,
Y represents -O-, -S-, or -N (Z)-, wherein Z represents hydrogen, hydroxy, C1-C7-
alkyl, or hydroxy-C1-C7-alkyl,
Q represents a group having the following formula:
Wherein
(Formula Removed ) X1 represents hydrogen, amino, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy, hydroxy- C1-C7-alkyl or phenoxy each of which is optionally substituted by nitro or C1-C5-alkoxy, or represents C6-C10-arylthio which is optionally substituted by nitro, amino, C1-C6-alkyl or C1-C4-alkoxy, or represents C6-C12-arylamino, C1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6-cycloalkylamino
ora structure of (Formula Removed ) wherein n denotes an integer of 1 or 2 and Y1 represents O, CH2 or
N-R (R represents C1-C7-alkyl), and
X2, X3 and X4, independently or one another represent hydrogen, amino, hydroxy, halogen, C1-C7-alkyl, C1-C7-alkoxy, or C1-C7-alkylamino.
4. The compound as claimed in claim 1 which is selected from a group consisting of:
({l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid
3-[({l-[6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8-8-dimethyl-3, 7-dioxo-2,4,6-
trioxa-385-phosphanon-1 -yl pivalate
({l-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid
3-[({l-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-
dioxo-2-4,6-trioxa-385-phosphanon-1 -yl pivalate;
({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid
3-[({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-
dioxo-2,4,6-trioxa-385-phosphanon-1-y1 pivalate;
({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid
3-[({l-[2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-
trioxa-385-phosphanon-1-y1 pivalate;
({l-[(2-amino-6-cyclopropylamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl phosphonic
acid
({l-[(2-amino-6-(dimethylamino) -9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl phosphonic
acid
3-{[l-{[2-amino-6-(dimethylamino)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methyl}-8,8-
dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl pivalate;
[(l-{[2-amino-6-(isopropylamino)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methyl phosphonic
acid
3- {[(1-{[2-amino-6-(isopropylamino)-9H-purin-9-yl]methyl}cyclopropyl]oxy]methyl} -8,8-
dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphnon-1 -yl pivalate;
({l-[(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid
3-[({l-[(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-
3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-ylpivalate
({l-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic
acid
3-[({l-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-
dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl pivalate(
({l-[(2-amino-6-ethoxy-9H-'purin-9-yl)methyl]cyclopropyljoxy)methyIphosphonic
acid
3-[({l-[(2-amino-6-ethoxy-9H-purin-9-yl)methyI]cyclopropyl}oxy)methyl]-8,8-
dimethyl-3,7-dioxo-2.4.6-trioxao8:!-phosphanon-l-yl pivalate(
[(1 {[5-methyl-2,4-dioxo-3.4-dihydro-1 (2H)-pyrimidinyl]methyl! cyclopropyl )oxy
methylphosphonic acid
8,8-dimethyl-3- {[(1 - {[5-methyl-2,4-dioxo-3.4-dihydro-1 (2H)-pyrimidinyl]methyl;
cyclopropyl)oxy]methyl)-3.7-dioxo-2.4.6-tnoxa-38"-phosphanon-l-vi pnaiate
[(]-{[2-amino-6-(4-morpholinyi )-9H-purin-9-y!]methyl j cyclopropyI)oxyjmethv I
phosphonic acid(
3--|[(l- ;[2-amino-6-(4-morpholinyl)-9H-punn-9-yl]methyl j cyclopropyl)oxy]methyl
-8,8-dimethyl-3,7-dioxo-2.4.6-tnoxa-385-phosphanon-l-yl) pivalate(Compound 38)
bis(2,2.2-trifluoroethyi) ( [ l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclo
propyl; oxy)methylphosphonate
bis(2.2.2-trifluoroethyl) ( | l-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl;
oxy)methylphosphonatci
bis(2.2.2-trifluoroethyl) ({ l-[(2.6-diamino-9H-punn-9-yl)methyl]cyclopropyl}oxy.)
methylphosphonatel
bis(2,2.2-trifluoroethyl) ({ l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)
methylphosphonate(
bis(2,2.2-trifluoroethyl) ({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl]oxy)
methylphosphonate
bis(2,2,2-trifluoroethyl) ({1 -[(2-amino-6-dimethylamino-9H-purin-9-yl)meth> 1]
cyclopropyl}oxy)methylphosphonate
bis(2,2,2-trifluoroethyl) ({1 -[(2-amino-6-isopropylamino-9H-purin-9-yl)methyl]
cyclopropyl} oxy)methylphosphonate(
bis(2,2,2-trifluoroethyl) ({1 -[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclo
propyl} oxy)methylphosphonate(
bis(2,2,2-trifluoroethyl) [(1 - {[2-ainino-6-(4-morpholinyl)-9H-purin-9-yl]methyl}
cyclopropyl)oxy]methylphosphonate(
bis(2,2.2-trifluoroethyl) [(1-[2-amino-6-(phenylsulfanyl)-9H-purin-9-yl]methyl}
cyclopropyl)oxy]methylphosphonate
bis(2,2,2-trifluoroethyl) {[l-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}
methyl)cyclopropyl]oxy}methylphosphonate(
bis(2,2,2-trifluoroethyl) {[l-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-
yl} methyl)cyclopropyl]oxy} methylphosphonate
bis(2,2,2-trifluoroethyl) {[ 1 -({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}
methyl)cyclopropyl]oxy}methylphosphonate
[(l-{[2-amino-6-(phenylsulfanyl)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methyl
phosphonic acid(
{[ 1 -({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl)cycloprop yl]oxy
}methylphosphonic acid(
3-({[l-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyI)cyclopropyl]
oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38"-phosphanon-l-yl pivalate
bis{[(/-butoxycarbonyl)oxy]methyl}({l-[(2-amino-9H-purin-9-yl)methyl]cyclo
propyl }oxy)methylphosphonate
bis {[(isopropoxycarbonyl)oxyjmethyl} ({1 -[(2-amino-9H-purin-9-yl)methyl]cyclo
propyl }oxy)methylphosphonate (
bis{[(ethoxycarbonyl)oxy]methyl}({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}
oxy)methylphosphonate (
bis{[(isobutoxycarbonyl)oxy]methyl}({ l-[(2-amino-9H-purin-9-yl)methyl]cyclo
propyl} oxy)methylphosphonate
3-[({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-9-methyl-3.~-
dioxo-2,4,6,-trioxa-385-phosphadec-1 -yl 3-methylbutanoate(
3-[({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8-methyl-3.~-
dioxo-2,4,6-trioxa-385-phosphanon-l-yl 2-methylpropanoate(
3-({[l-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]
oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl pivalate
3-[( {1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl} oxy)methyl]-3,7-dioxo-7-( 1 -pyrrolidinyl)-2,4,6-trioxa-385-phosphahept-l-yl 1-pyrrolidinecarboxylatel
3-[({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-dioxo-7-(l-piperidinyl)-2,4,6-trioxa-385-phosphahept-l-yl l-piperidinecarboxylate(
3-[({1-[(2-amino 9H-purin-yl)methyl]cyclopropyl}oxy)methyl]-7-(4-morpholinyl)-3,7-dioxo-2,4,6-trioxa-385-phosphahept-l-yl 4-morpholinecarboxylate
bis{[(t-butoxycarbonyI)oxy]methyl}[(l-{[2-amino-6-hydroxy-9H-purin-9-yl]methyl}
cyclopropyl)oxy]methylphosphonate(
bis{[(isopropoxycarbonyl)oxy]methyl}[(l-{[2-amino-6-hydroxy-9H-purin-9-yl]
methyl}cyclopropyl)oxy]methylphosphonate(
bis{[(isopropoxycarbonyl)oxy]methyl}{[l-({2-amino-[6-(4-methoxyphenyl)sulfanyl]
-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonatei
3-[({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-7-cyclo
pentyl-3,7-dioxo-2,4,6-trioxa-38"-phosphahept-l-yl cyclopentanecarboxylate
3-({[l-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy
J methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-1 -yl pivalate
bis {[(isopropoxycarbonyl)oxy]methyl} {[ 1 -({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H
-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate
bis {[(isopropoxycarbonyl)oxy]methyl} ({1 -[(6-amino-9H-purin-9-yl)methyl]cyclo
propyl} oxy)methylphosphonate(
3-[({l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-9-methyl-3,7-
dioxo-2,4,6-trioxa-385-phosphadec-l-yI 3-methylbutanoate(
3-[({l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)inethyl]-7-cyclopentyl-3,7
dioxo-2,4,6-trioxa-385-phosphahept-l-yl cyclopentanecarboxylate
bis {[(t-butoxycarbonyl)oxy]methyl} {[ 1 -({2-amino-[6-(4-methoxyphenyl)sulfanyl]-
9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate
bis{[(t-butoxycarbonyl)oxy]methyl}{[l-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-
purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate(
{[l-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy!
methylphosphonic acidi
{[l-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]
oxy} methylphosphonic acid(
({1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl
phosphonic acid(
({1 -[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl} oxy)methylphosphonic
acid(
{[l-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclo
propyljoxy} methylphosphonic acid
{[l-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclo
propyljoxy}methylphosphonic acid
{[l-({2-amino-[6-(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclo
propyl]oxy}methylphosphonic acidi
({l-[(2,6-diamino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl
phosphonic acid(
({1 -[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl} oxy)methylphosphonic
acid
3-[({l-[(2-amino-6-hydroxy-9H-purin-9-yI)methyl]-2-methylcyclopropyl}oxy)
methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-1 -yl pivalate
3-[(|l-[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl!oxy)methyl]-8,8-
dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl pivalate(Compound 106);
3-f(! 1 -[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl J oxy)methyl]-8.8-
dimethyl-3,7-dioxo-2,4,6-trioxa-3 85-phosphanon-l-yl pivalate(Compound 107);
3-( {[l-( {2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl} methyl)-2-methyl
cyclopropyl]oxy}methyl)-8.8-dimethyl-3,7-dioxo-2.4.6-trioxa-38'-phosphanon-l-yl
privalate
bis {[(isopropoxycarbonyl)oxy]methyl} [(1 - {[2-amino-6-hydroxy-9H-purin-9-yl]
methyl} -2-methylcyclopropyl)oxy]methylphosphonate|
bis{[(isopropoxycarbonyl)oxy]methyl}(j 1 -[(2-amino-9H-purin-9-yl)methyl]-2-
methylcyclopropyl}oxy)methylphosphonate
bis{[(isopropoxycarbonyl)oxy]methyl j {[ 1 -({2-amino-[6-(4-methoxyphenyl)sulfanyl]
-9H-purin-9-yl | methyl)-2-methylcyclopropyl]oxyJ methylphosphonate
bis{[(t-butoxycarbonyl)oxy]methyl}{[l-({2-amino-[6-(4-methoxvphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy} methylphosphonate!
bis(2,2,2-trifluoroethyl) {[l-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-
yl}methyl)-2-methylcyclopropyl]oxy} methylphosphonate)
bis(2,2,2-trifluoroethyl) {[ 1 -({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}
methyl)-2-methylcyclopropyl]oxy}methylphosphonate
bis{[(t-butoxycarbonyl)oxyjmethyl} {[ 1 -({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-
purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate
bis{[(isopropoxycarbonyl)oxy]methyl}{[l-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H
-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonatei
3-({[l-({2-amino-6-[(4-nitrophenyl)sulfapyl]-9H-purin-9-yl}methyl)-2-methylcyclo
propyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38:'phosphanon-l-yl pivalatei
({1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl} amino)methyl
phosphonic acid.
({1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl} amino)methylphosphonic
acid
({1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl} amino)methylphosphonic
acid
[{l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}(methyl)amino]methyI
phosphonic acid
[ {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl J (ethyl)amino]methylphosphonic
acid
3-{[{(l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl)(methyl)amino}-methyl]-8,8-
dimethyl-3.7-dioxo-2,4,6-trioxa-38'-phosphanon-l-yl pivalatei
bis! [(isopropoxycarbonyl)oxy]methyl J [ {1 -[(6-amino-9H-purin-9-yl)methyl]cyclo
propyl }(methyl)amino]methyIphosphonate
3- {[ {1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl} (ethyl)amino]methyl} -8,8-
dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl pivalate'
2-{1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}ethylphosphonic
acid
2-{ l-[(2-amino-9H-purin-9-yl)methyI]cyclopropyl|ethylphosphonic acid(
2-{1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl | ethylphosphonic acid
2-[l-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]
ethylphosphonic acid
2- {1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl J propylphosphonic
acid
2- {l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl} propylphosphonic acid
2- {1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl} propylphosphonic acid
3-(2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl)-8,8-dimethyl-3,7-
dioxo-2,4,6-trioxa-385-phosphanon-l-ylpivalate
({1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl} oxy)
methylphosphonic acid.
({1 -[(2-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl} oxy)methyl
phosphonic acid
({l-[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methyl
phosphonic acid ;
3-[({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2,2,-dimethylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-1-yl pivalate;
3-[({l-[(2-amino-9H-purin-9-yl)methyl]-2,2dimethylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2, 4, 6-trioxa-385-phosphanon-1-yl pivalate;
3-[({l-[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-385 phosphanon-1-yl pivalate;
bis{[(isopropoxycarbonyl)oxy]methyl}({l-[(6-amoni-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonate; and
bis{[(isopropoxycarbonyl)oxy]methyl}[(l-{[2-amino-6-hydroxy-9H-purin-9-yl]methyl}-2,2 -dimethylcyclopropyl) oxy] methylphosphonate.
5.The compound as claimed in claim 1 wherein represents single bond, R1 , R3
, R7 and R8 independently of one another represent hydrogen, R2 represents hydrogen or methyl, R4 and R5 independently of one another represent t-butylcarbonyloxymethyl, isopropoxycarbonyloxymethyl or 2,2,2-trifluoroethyl, Y represents -O-, Q represents
(Formula Removed ) Wherein X1 epresents hydrogen, hydroxy, ethoxy, 4-
methoxyphenylthio or 4-nitrophenylthio, and X2 represents amino.
6. The compound as claimed in claim 1 which is ({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid.
7. The compound as claimed in claim 1 which is ({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid.
8. The compound as claimed in claim 1 which is ({l-[(2-amino-9H-purin-9-
yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-
phosphanon-1-yl pivalate.
9. An acyclic nucleoside phosphonate derivative represented by the following
formula (1) substantially as herein described with reference to the foregoing
description and the accompanying example and tables.


Documents:

1069-delnp-2003-abstract.pdf

1069-delnp-2003-assignment.pdf

1069-delnp-2003-claims.pdf

1069-DELNP-2003-Correspondence-Others-(18-03-2010).pdf

1069-delnp-2003-correspondence-others.pdf

1069-delnp-2003-description (complete).pdf

1069-delnp-2003-form-1.pdf

1069-delnp-2003-form-13.pdf

1069-delnp-2003-form-19.pdf

1069-delnp-2003-form-2.pdf

1069-delnp-2003-form-3.pdf

1069-delnp-2003-form-5.pdf

1069-delnp-2003-pa.pdf

1069-delnp-2003-petition-137.pdf


Patent Number 244198
Indian Patent Application Number 1069/DELNP/2003
PG Journal Number 48/2010
Publication Date 26-Nov-2010
Grant Date 23-Nov-2010
Date of Filing 08-Jul-2003
Name of Patentee LG LIFE SCIENCES LTD.
Applicant Address 20, YOIDO-DONG, YOUNGDUNGPO-KU, SEOUL 150-010, REPUBLIEC OF KOREA
Inventors:
# Inventor's Name Inventor's Address
1 CHOI, JOGN-RYOO R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
2 ROH, KEE-YOON R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
3 CHO, DONG-GYU R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
4 LIM, JAE-HONG R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
5 HWANG, JAE-TAEG R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
6 CHO, WOO-YOUNG R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
7 JANG, HYUN-SOOK R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
8 LEE, CHANG-HO R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
9 CHOI, TAE-SAENG R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
10 KIM, CHUNG-MI R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
11 KIM, YONG-ZU R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
12 KIM, TAE-KYUN R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
13 CHO, SEUNG-JOO R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
14 KIM, GYOUNG-WON R & D PARK, LG LIFE SCIENCES LTD., 104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIEC OF KOREA
PCT International Classification Number C07H 19/10
PCT International Application Number PCT/KR2002/00086
PCT International Filing date 2002-01-18
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2001-3087 2001-01-19 Republic of Korea