US2006241081A1PendingUtilityA1
Novel compounds and methods for therapy
Est. expiryJun 16, 2023(expired)· nominal 20-yr term from priority
A61P 31/20A61P 31/18C07F 9/6512A61P 31/12A61P 31/00A61K 31/505
50
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Claims
Abstract
Novel compounds are provided having formula (I) where R 1 , R 2 , R 3 , R 4 , Z, X and * are defined herein. Also provided are antiviral methods for use and processes for synthesis of the compounds of formula (I).
Claims
exact text as granted — not AI-modified1 . A compound of the formula (I):
wherein
* designates a chiral carbon atom;
R 1 is H, amino, or methylsulfanyl;
R 2 is H, methyl, halo, —N(R 5 ) 2 , hydroxy, or protected hydroxy;
R 3 is independently methyl, hydroxymethyl, halomethyl, or protected hydroxymethyl;
R 4 is selected from:
(i) C 1 to C 10 alkyl,
(ii) C 2 to C 10 alkenyl, or,
(iii) C 2 to C 10 alkynyl,
(iv) C 3 -C 8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C 7 -C 14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH 2 OH,
(x) —CH 2 OR 5
(xi) —CH 2 C(O)R 5 ,
(xii) —CH 2 R 6 ,
(xiii) —CH 2 OC(O)R 5
(xiv) —CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xv) —CH 2 NR 9 R 10 ,
(xvi) —CH 2 CN,
(xvii) —CO 2 R 5
(xviii) —CH 2 CH 2 OH,
(xix) —CH 2 CH 2 OR 5
(xx) —CH 2 CH 2 OC(O)R 5
(xxi) —CH 2 CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xxii) —CH 2 SH,
(xxiii) —C(O)H,
(xxiv) —CH 2 CO 2 R 9 ,
(xxv) —CH 2 SO 3 H,
(xxvi) —CH 2 CH 2 SO 3 H,
(xxvii) —CH 2 CH 2 PO 3 H 2 ,
(xxviii) —CH 2 CH 2 OCH 2 PO 3 H 2 ,
(xxix) —CH 2 OPO 3 H 2 ,
(xxx) —OCH 2 PO 3 H 2 ,
(xxxi) —OH,
(xxxii) —OR 10
(xxxiii) —NH 2 ,
(xxxiv) —NR 11 R 12 ,
(xxxv) —SH,
(xxxvi) —SR 5 ,
(xxxvii) —SCN,
(xxxviii) —N 3 ,
(xxxix) —CN,
(xl) —CONR 11 R 12
(xli) —CH 2 CONR 11 R 12
(xlii) —NHOH,
(xliii) —NHOR 5 ,
(xliv) —NO,
(xlv) —NO 2 ,
(xlvi) —NHNR 11 R 12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C 1 -C 10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl; and
(lvi) —CH 2 N 3 ;
X independently is oxygen, sulfur, or a bond;
Z independently is hydroxy, an ester or amide;
R 5 is independently H, C 1 -C 10 alkyl or a protecting group;
R 6 is F, Cl, Br or I;
R 7 is the side chain of any of the unprotected or N-protected α-amino acids;
R 8 is H or —C(O)CH(R 7 )(NH 2 );
R 9 and R 10 are independently selected from H, C 1 -C 10 alkyl, carboxyalkyl, aminoalkyl, and C 2 -C 10 alkenyl, or both together form a cycle with or without participation of heteroatom; and
R 11 and R 12 are independently selected from H, C 1 to C 10 alkyl, C 3 -C 8 cycloalkyl, heteroaryl and C 7 -C 12 arylalkyl, or both together form a cycle with or without participation of heteroatom; and
salts and solvates thereof.
2 . The compound of claim 1 wherein R 1 and R 2 are amino and X is oxygen.
3 . The compound of claim 1 wherein R 1 and R 2 are simultaneously amino, R 3 is methyl, X is oxygen and the R 3 configuration is (R).
4 . The compound of claim 1 wherein R 1 and R 2 are simultaneously amino, R 3 is hydroxymethyl, X is oxygen and the R 3 configuration is (R).
5 . The compound of claim 1 wherein R 1 and R 2 are simultaneously amino and X is sulfur.
6 . The compound of claim 1 wherein R 1 is amino, R 2 is hydroxy and X is oxygen.
7 . The compound of claim 1 which is crystalline.
8 . The compound of claim 1 which is a substantially pure enantiomer at the chiral carbon.
9 . The compound of claim 8 which is in the (R) configuration.
10 . The compound of claim 8 which is in the (S) configuration.
11 . A compound of the formula (Iaa):
wherein
R 1 is H, amino, or methylsulfanyl;
R 2 is H, methyl, halo, —N(R 5 ) 2 , hydroxy, or protected hydroxy;
R 3 is independently H, methyl, hydroxymethyl, halomethyl, or protected hydroxymethyl;
R 4 is selected from:
(i) C 1 to C 10 alkyl,
(ii) C 2 to C 10 alkenyl, or,
(iii) C 2 to C 10 alkynyl,
(iv) C 3 -C 8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C 7 -C 14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH 2 OH,
(x) —CH 2 OR 5
(xi) —CH 2 C(O)R 5 ,
(xii) —CH 2 R 6 ,
(xiii) —CH 2 OC(O)R 5
(xiv) —CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xv) —CH 2 NR 9 R 10 ,
(xvi) —CH 2 CN,
(xvii) —CO 2 R 5
(xviii) —CH 2 CH 2 OH,
(xix) —CH 2 CH 2 OR 5
(xx) —CH 2 CH 2 OC(O)R 5
(xxi) —CH 2 CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xxii) —CH 2 SH,
(xxiii) —C(O)H,
(xxiv) —CH 2 CO 2 R 9 ,
(xxv) —CH 2 SO 3 H,
(xxvi) —CH 2 CH 2 SO 3 H,
(xxvii) —CH 2 CH 2 PO 3 H 2 ,
(xxviii) —CH 2 CH 2 OCH 2 PO 3 H 2 ,
(xxix) —CH 2 OPO 3 H 2 ,
(xxx) —OCH 2 PO 3 H 2 ,
(xxxi) —OH,
(xxxii) —OR 10
(xxxiii) —NH 2 ,
(xxxiv) —NR 11 R 12 ,
(xxxv) —SH,
(xxxvi) —SR 5 ,
(xxxvii) —SCN,
(xxxviii) —N 3 ,
(xxxix) —CN,
(xl) —CONR 11 R 12
(xli) —CH 2 CONR 11 R 12
(xlii) —NHOH,
(xliii) —NHOR 5 ,
(xliv) —NO,
(xlv) —NO 2 ,
(xlvi) —NHNR 11 R 12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C 1 -C 10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl; and
(lvi)-CH 2 N 3 ;
X independently is oxygen, sulfur, or a bond;
Z independently is hydroxy, an ester or amide;
R 5 is independently H, C 1 -C 10 alkyl or a protecting group;
R 6 is F, Cl, Br or I;
R 7 is the side chain of any of the unprotected or N-protected α-amino acids;
R 8 is H or —C(O)CH(R 7 )(NH 2 );
R 9 and R 10 are independently selected from H, C 1 -C 10 alkyl, carboxyalkyl, aminoalkyl, and C 2 -C 10 alkenyl, or both together form a cycle with or without participation of heteroatom; and
R 11 and R 12 are independently selected from H, C 1 to C 10 alkyl, C 3 -C 8 cycloalkyl, heteroaryl and C 7 -C 12 arylalkyl, or both together form a cycle with or without participation of heteroatom; and
salts and solvates thereof.
12 . The compound of claim 11 wherein R 1 and R 2 are amino, R 3 is hydrogen and X is oxygen.
13 . The compound of claim 11 wherein R 1 and R 2 are simultaneously amino, R 3 is hydrogen and X is sulfur.
14 . The compound of claim 11 wherein R 1 is amino, R 2 is hydroxy, R 3 is hydrogen and X is oxygen.
15 . A composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .
16 . A method of preparation of compounds of formula (I)
comprising reacting a compound of formula (II):
with a compound of the formula (III):
where Y is a leaving group;
in dipolar aprotic solvent in the presence of a base;
wherein * designates a chiral carbon atom;
R 1 is H, amino, or methylsulfanyl;
R 2 is H, methyl, halo, —N(R 5 ) 2 , hydroxy, protected hydroxy or a group of the formula (Ia)
R 3 is independently methyl, hydroxymethyl, halomethyl, or protected hydroxymethyl;
R 4 is selected from:
(i) C 1 to C 10 alkyl,
(ii) C 2 to C 10 alkenyl, or,
(iii) C 2 to C 10 alkynyl,
(iv) C 3 -C 8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C 7 -C 14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH 2 OH,
(x) —CH 2 OR 5
(xi) —CH 2 C(O)R 5 ,
(xii) —CH 2 R 6 ,
(xiii) —CH 2 OC(O)R 5
(xiv) —CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xv) —CH 2 NR 9 R 10 ,
(xvi) —CH 2 CN,
(xvii) —CO 2 R 5
(xviii) —CH 2 CH 2 OH,
(xix) —CH 2 CH 2 OR 5
(xx) —CH 2 CH 2 OC(O)R 5
(xxi) —CH 2 CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xxii) —CH 2 SH,
(xxiii) —C(O)H,
(xxiv) —CH 2 CO 2 R 9 ,
(xxv) —CH 2 SO 3 H,
(xxvi) —CH 2 CH 2 SO 3 H,
(xxvii) —CH 2 CH 2 PO 3 H 2 ,
(xxviii) —CH 2 CH 2 OCH 2 PO 3 H 2 ,
(xxix) —CH 2 OPO 3 H 2 ,
(xxx) —OCH 2 PO 3 H 2 ,
(xxxi) —OH,
(xxxii) —OR 10
(xxxiii) —NH 2 ,
(xxxiv) —NR 11 R 12 ,
(xxxv) —SH,
(xxxvi) —SR 5 ,
(xxxvii) —SCN,
(xxxviii) —N 3 ,
(xxxix) —CN,
(xl) —CONR 11 R 12
(xli) —CH 2 CONR 11 R 12
(xlii) —NHOH,
(xliii) —NHOR 5 ,
(xliv) —NO,
(xlv) —NO 2 ,
(xlvi) —NHNR 11 R 12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C 1 -C 10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl; and
(lvi) —CH 2 N 3 ;
X is O or S;
Z independently is hydroxy, an ester or amide;
R 5 is independently H, C 1 -C 10 alkyl or a protecting group;
R 6 is F, Cl, Br or I;
R 7 is the side chain of any of the unprotected or N-protected α-amino acids;
R 8 is H or —C(O)CH(R 7 )(NH 2 );
R 9 and R 10 are independently selected from H, C 1 -C 10 alkyl, carboxyalkyl, aminoalkyl, and C 2 -C 10 alkenyl, or both together form a cycle with or without participation of heteroatom; and
R 11 and R 12 are independently selected from H, C 1 to C 10 alkyl, C 3 -C 8 cycloalkyl, heteroaryl and C 7 -C 12 arylalkyl, or both together form a cycle with or without participation of heteroatom.
17 . The method of claim 16 further comprising isolating the resulting compound of the formula (I).
18 . The method of claim 16 wherein Z is ester or amide and additionally hydrolyzing one or both Z groups to produce the compound of formula (I) where at least one Z is hydroxy.
19 . The method of claim 16 where Z is (OR 4 ) 2 and R 4 is isopropyl.
20 . The method of claim 16 where R 3 is methyl and Y is p-toluenesulfonyloxy or bromo.
21 . A method of preparation of compounds of formula (Iaa)
comprising reacting a compound of formula (II):
with a compound of the formula (III):
Y—CH 2 CH(R 3 )—O—CH 2 P(O)(Z) 2 (III)
where Y is a leaving group;
in dipolar aprotic solvent in the presence of a base;
wherein
R 1 is H, amino, or methylsulfanyl;
R 2 is H, methyl, halo, —N(R 5 ) 2 , hydroxy, protected hydroxy or a group of the formula (Ia)
R 3 is independently H, methyl, hydroxymethyl, halomethyl, or protected hydroxymethyl;
R 4 is selected from:
(i) C 1 to C 10 alkyl,
(ii) C 2 to C 10 alkenyl, or,
(iii) C 2 to C 10 alkynyl,
(iv) C 3 -C 8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C 7 -C 14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH 2 OH,
(x) —CH 2 OR 5
(xi) —CH 2 C(O)R 5 ,
(xii) —CH 2 R 6 ,
(xiii) —CH 2 OC(O)R 5
(xiv) —CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xv) —CH 2 NR 9 R 10 ,
(xvi) —CH 2 CN,
(xvii) —CO 2 R 5
(xviii) —CH 2 CH 2 OH,
(xix) —CH 2 CH 2 OR 5
(xx) —CH 2 CH 2 OC(O)R 5
(xxi) —CH 2 CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xxii) —CH 2 SH,
(xxiii) —C(O)H,
(xxiv) —CH 2 CO 2 R 9 ,
(xxv) —CH 2 SO 3 H,
(xxvi) —CH 2 CH 2 SO 3 H,
(xxvii) —CH 2 CH 2 PO 3 H 2 ,
(xxviii) —CH 2 CH 2 OCH 2 PO 3 H 2 ,
(xxix) —CH 2 OPO 3 H 2 ,
(xxx) —OCH 2 PO 3 H 2 ,
(xxxi) —OH,
(xxxii) —OR 10
(xxxiii) —NH 2 ,
(xxxiv) —NR 11 R 12 ,
(xxxv) —SH,
(xxxvi) —SR 5 ,
(xxxvii) —SCN,
(xxxviii) —N 3 ,
(xxxix) —CN,
(xl) —CONR 11 R 12
(xli) —CH 2 CONR 11 R 12
(xlii) —NHOH,
(xliii) —NHOR 5 ,
(xliv) —NO,
(xlv) —NO 2 ,
(xlvi) —NHNR 11 R 12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C 1 -C 10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl; and
(lvi) —CH 2 N 3 ;
X is O or S;
Z independently is hydroxy, an ester or amide;
R 5 is independently H, C 1 -C 10 alkyl or a protecting group;
R 6 is F, Cl, Br or I;
R 7 is the side chain of any of the unprotected or N-protected α-amino acids;
R 8 is H or —C(O)CH(R 7 )(NH 2 );
R 9 and R 10 are independently selected from H, C 1 -C 10 alkyl, carboxyalkyl, aminoalkyl, and C 2 -C 10 alkenyl, or both together form a cycle with or without participation of heteroatom; and
R 11 and R 12 are independently selected from H, C 1 to C 10 alkyl, C 3 -C 8 cycloalkyl, heteroaryl and C 7 -C 12 arylalkyl, or both together form a cycle with or without participation of heteroatom.
22 . A method for the preparation of compounds of formula (I):
where R 2 of formula (I) is —N(R 5 ) 2 ;
comprising reacting a compound (IV)
with an amine HN(R 5 ) 2 ;
wherein:
* designates a chiral carbon atom;
R 1 is H, amino or methylsulfanyl;
R 3 is independently methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 4 is selected from:
(i) C 1 to C 10 alkyl,
(ii) C 2 to C 10 alkenyl, or,
(iii) C 2 to C 10 alkynyl,
(iv) C 3 -C 8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C 7 -C 14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH 2 OH,
(x) —CH 2 OR 5
(xi) —CH 2 C(O)R 5 ,
(xii) —CH 2 R 6 ,
(xiii) —CH 2 OC(O)R 5
(xiv) —CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xv) —CH 2 NR 9 R 10 ,
(xvi) —CH 2 CN,
(xvii) —CO 2 R 5
(xviii) —CH 2 CH 2 OH,
(xix) —CH 2 CH 2 OR 5
(xx) —CH 2 CH 2 OC(O)R 5
(xxi) —CH 2 CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xxii) —CH 2 SH,
(xxiii) —C(O)H,
(xxiv)—CH 2 CO 2 R 9 ,
(xxv) —CH 2 SO 3 H,
(xxvi) —CH 2 CH 2 SO 3 H,
(xxvii) —CH 2 CH 2 PO 3 H 2 ,
(xxviii) —CH 2 CH 2 OCH 2 PO 3 H 2 ,
(xxix) —CH 2 OPO 3 H 2 ,
(xxx) —OCH 2 PO 3 H 2 ,
(xxxi) —OH,
(xxxii) —OR 10
(xxxiii) —NH 2 ,
(xxxiv) —NR 11 R 12 ,
(xxxv) —SH,
(xxxvi) —SR 5 ,
(xxxvii) —SCN,
(xxxviii) —N 3 ,
(xxxix) —CN,
(xl) —CONR 11 R 12
(xli) —CH 2 CONR 11 R 12
(xlii) —NHOH,
(xliii) —NHOR 5 ,
(xliv) —NO,
(xlv)—NO 2 ,
(xlvi) —NHNR 11 R 12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C 1 -C 10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl; and
(lvi) —CH 2 N 3 ;
X is O or S;
Z independently is hydroxy, an ester or amide; and
R 5 is independently H, C 1 -C 8 alkyl or a protecting group.
23 . The method of claim 22 further comprising hydrolyzing one or both Z groups to produce the compound of formula (I) where one or both of Z are hydroxyl.
24 . A method for the preparation of compounds of formula (Iaa):
where R 2 of formula (I) is —N(R 5 ) 2 ;
comprising reacting a compound (IV)
with an amine HN(R 5 ) 2 ;
wherein:
R 1 is H, amino or methylsulfanyl;
R 3 is independently H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 4 is selected from:
(i) C 1 to C 10 alkyl,
(ii) C 2 to C 10 alkenyl, or,
(iii) C 2 to C 10 alkynyl,
(iv) C 3 -C 8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C 7 -C 14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH 2 OH,
(x) —CH 2 OR 5
(xi) —CH 2 C(O)R 5 ,
(xii) —CH 2 R 6 ,
(xiii) —CH 2 OC(O)R 5
(xiv) —CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xv) —CH 2 NR 9 R 10 ,
(xvi) —CH 2 CN,
(xvii) —CO 2 R 5
(xviii) —CH 2 CH 2 OH,
(xix) —CH 2 CH 2 OR 5
(xx) —CH 2 CH 2 OC(O)R 5
(xxi) —CH 2 CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xxii) —CH 2 SH,
(xxiii) —C(O)H,
(xxiv) —CH 2 CO 2 R 9 ,
(xxv) —CH 2 SO 3 H,
(xxvi) —CH 2 CH 2 SO 3 H,
(xxvii) —CH 2 CH 2 PO 3 H 2 ,
(xxviii) —CH 2 CH 2 OCH 2 PO 3 H 2 ,
(xxix) —CH 2 OPO 3 H 2 ,
(xxx) —OCH 2 PO 3 H 2 ,
(xxxi) —OH,
(xxxii) —OR 10
(xxxiii) —NH 2 ,
(xxxiv) —NR 11 R 12 ,
(xxxv) —SH,
(xxxvi) —SR 5 ,
(xxxvii) —SCN,
(xxxviii) —N 3 ,
(xxxix) —CN,
(xl) —CONR 11 R 12
(xli) —CH 2 CONR 11 R 12
(xlii) —NHOH,
(xliii) —NHOR 5 ,
(xliv) —NO,
(xlv) —NO 2 ,
(xlvi) —NHNR 11 R 12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C 1 -C 10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl; and
(lvi) —CH 2 N 3 ;
X is O or S;
Z independently is hydroxy, an ester or amide; and
R 5 is independently H, C 1 -C 8 alkyl or a protecting group.
25 . A method for preparation of compounds of formula (V):
where
R 3 is methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 4 is selected from:
(i) C 1 to C 10 alkyl,
(ii) C 2 to C 10 alkenyl, or,
(iii) C 2 to C 10 alkynyl,
(iv) C 3 -C 8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C 7 -C 14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH 2 OH,
(x) —CH 2 OR 5
(xi) —CH 2 C(O)R 5 ,
(xii) —CH 2 R 6 ,
(xiii) —CH 2 OC(O)R 5
(xiv) —CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xv) —CH 2 NR 9 R 10 ,
(xvi) —CH 2 CN,
(xvii) —CO 2 R 5
(xviii) —CH 2 CH 2 OH,
(xix) —CH 2 CH 2 OR 5
(xx) —CH 2 CH 2 OC(O)R 5
(xxi) —CH 2 CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xxii) —CH 2 SH,
(xxiii) —C(O)H,
(xxiv) —CH 2 CO 2 R 9 ,
(xxv) —CH 2 SO 3 H,
(xxvi) —CH 2 CH 2 SO 3 H,
(xxvii) —CH 2 CH 2 PO 3 H 2 ,
(xxviii) —CH 2 CH 2 OCH 2 PO 3 H 2 ,
(xxix) —CH 2 OPO 3 H 2 ,
(xxx) —OCH 2 PO 3 H 2 ,
(xxxi) —OH,
(xxxii) —OR 10
(xxxiii) —NH 2 ,
(xxxiv) —NR 11 R 12 ,
(xxxv) —SH,
(xxxvi) —SR 5 ,
(xxxvii) —SCN,
(xxxviii) —N 3 ,
(xxxix) —CN,
(xl) —CONR 11 R 12
(xli) —CH 2 CONR 11 R 12
(xlii) —NHOH,
(xliii) —NHOR 5 ,
(xliv) —NO,
(xlv) —NO 2 ,
(xlvi) —NHNR 11 R 12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C 1 -C 10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl; and
(lvi) —CH 2 N 3 ;
R 5 independently is H, C 1 -C 8 alkyl or a protecting group;
X is O or S;
Z independently is hydroxy, an ester or amide; and
* designates a chiral carbon atom;
comprising reacting compound (IVa)
with N(R 5 ) 2 in anhydrous solvent, alkali hydroxide or alkali carbonate in aqueous solution.
26 . A method for preparation of compounds of formula (V):
where
R 3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 4 is selected from:
(i) C 1 to C 10 alkyl,
(ii) C 2 to C 10 alkenyl, or,
(iii) C 2 to C 10 alkynyl,
(iv) C 3 -C 8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C 7 -C 14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH 2 OH,
(x) —CH 2 OR 5
(xi) —CH 2 C(O)R 5 ,
(xii) —CH 2 R 6 ,
(xiii) —CH 2 OC(O)R 5
(xiv) —CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xv) —CH 2 NR 9 R 10 ,
(xvi) —CH 2 CN,
(xvii) —CO 2 R 5
(xviii) —CH 2 CH 2 OH,
(xix) —CH 2 CH 2 OR 5
(xx) —CH 2 CH 2 OC(O)R 5
(xxi) —CH 2 CH 2 OC(O)CH(R 7 )(NHR 8 ),
(xxii) —CH 2 SH,
(xxiii) —C(O)H,
(xxiv) —CH 2 CO 2 R 9 ,
(xxv) —CH 2 SO 3 H,
(xxvi) —CH 2 CH 2 SO 3 H,
(xxvii) —CH 2 CH 2 PO 3 H 2 ,
(xxviii) —CH 2 CH 2 OCH 2 PO 3 H 2 ,
(xxix) —CH 2 OPO 3 H 2 ,
(xxx) —OCH 2 PO 3 H 2 ,
(xxxi) —OH,
(xxxii) —OR 10
(xxxiii) —NH 2 ,
(xxxiv) —NR 11 R 12 ,
(xxxv) —SH,
(xxxvi) —SR 5 ,
(xxxvii) —SCN,
(xxxviii) —N 3 ,
(xxxix) —CN,
(xl) —CONR 11 R 12
(xli) —CH 2 CONR 11 R 12
(xlii) —NHOH,
(xliii) —NHOR 5 ,
(xliv) —NO,
(xlv) —NO 2 ,
(xlvi) —NHNR 11 R 12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C 1 -C 10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl; and
(lvi) —CH 2 N 3 ;
R 5 independently is H, C 1 -C 8 alkyl or a protecting group;
X is O or S; and
Z independently is hydroxy, an ester or amide;
comprising reacting compound (IVa)
with N(R 5 ) 2 in anhydrous solvent, alkali hydroxide or alkali carbonate in aqueous solution.
27 . A method of preparation of the compounds of formula (VI)
comprising reacting a compound of formula (VII)
with a compound of the formula (VIII)
in the presence of a base;
where
* designates a chiral carbon atom;
R 1 is H, amino or methylsulfanyl;
R 3 is methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 4 is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, formyl (—CHO), azido (—N 3 ), amino (—NH 2 ), alkylamino (—NR 2 ), hydroxyl (—OH), alkoxy (—OR), cyano (—CN), carboxyl (—COOH), amido (—NRC(O)R, or alkoxycarbonylalkyl; and
Z independently is hydroxy, an ester or amide.
28 . The method of claim 27 further comprising hydrolyzing Z group to produce a compound of formula (VI) where 1 or 2 Z groups are hydroxy.
29 . A method of preparation of the compounds of formula (VI)
comprising reacting a compound of formula (VII)
with a compound of the formula (VIII)
HOCH 2 CH 2 (R 3 )OCH 2 P(O)(Z) 2 (VIII)
in the presence of a base;
where
R 1 is H, amino or methylsulfanyl;
R 3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 4 is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, formyl (—CHO), azido (—N 3 ), amino (—NH 2 ), alkylamino (—NR 2 ), hydroxyl (—OH), alkoxy (—OR), cyano (—CN), carboxyl (—COOH), amido (—NRC(O)R, or alkoxycarbonylalkyl; and
Z independently is hydroxy, an ester or amide.
30 . A method of preparation of compounds of formula (XIII)
comprising (a) reacting a compound of the formula (IX)
with a compound of the formula (X)
in the presence of a base without solvent or in the presence of an aprotic solvent, to produce a compound of formula (XI)
and (b) reacting compound (XI) with a compound of the formula (XII)
Y—CH 2 P(O)(OZ) 2 (XII)
in the presence of a base in dimethylformamide or tetrahydrofuran to produce a compound of formula (XIII);
where
* is a chiral carbon atom;
R 1 is H, amino or methylsulfanyl;
R 2 is H, chloro, hydroxy or amino;
R 3 is methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 4 is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, formyl (—CHO), azido (—N3), amino (—NH2), alkylamino (—NR 2 ), hydroxyl (—OH), alkoxy (—OR), cyano (—CN), carboxyl (—COOH), amido (—NRC(O)R, or alkoxycarbonylalkyl;
R 6 is hydroxy or protected hydroxy; or R 3 and R 6 are joined by a cyclic acetal or ketal protecting group;
Y is a leaving group; and
Z is hydroxy, amide or an ester.
31 . The method of claim 30 further comprising hydrolyzing Z group to produce a compound of formula (XIII) where 1 or 2 Z groups are hydroxyl.
32 . A method of preparation of compounds of formula (XIII)
comprising (a) reacting a compound of the formula (IX)
with a compound of the formula (X)
in the presence of a base without solvent or in the presence of an aprotic solvent, to produce a compound of formula (XI)
and (b) reacting compound (XI) with a compound of the formula (XII)
Y—CH 2 P(O)(OZ) 2 (XII)
in the presence of a base in dimethylformamide or tetrahydrofuran to produce a compound of formula (XIII);
where
R 1 is H, amino or methylsulfanyl;
R 2 is H, chloro, hydroxy or amino;
R 3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 4 is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, formyl (—CHO), azido (—N3), amino (—NH2), alkylamino (—NR 2 ), hydroxyl (—OH), alkoxy (—OR), cyano (—CN), carboxyl (—COOH), amido (—NRC(O)R, or alkoxycarbonylalkyl;
R 6 is hydroxy or protected hydroxy; or R 3 and R 6 are joined by a cyclic acetal or ketal protecting group;
Y is a leaving group; and
Z is hydroxy, amide or an ester.
33 . A method for the treatment of a viral infection comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.
34 . The method of claim 33 where the virus is a DNA virus.
35 . The method of claim 34 where the virus is a retrovirus or hepadnavirus.Join the waitlist — get patent alerts
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