US2005038058A1PendingUtilityA1
Novel compounds and methods for therapy
Assignee: ACAD OF SCIENCE CZECH REPUBLICPriority: Jun 29, 2001Filed: Sep 21, 2004Published: Feb 17, 2005
Est. expiryJun 29, 2021(expired)· nominal 20-yr term from priority
A61P 31/12A61P 35/00A61P 31/20A61P 31/18C07F 9/6512Y02P20/55
54
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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)
where
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 H or halo;
X independenly is oxygen, sulfur or a bond;
Z independently is hydroxy, an ester or amide;
R 5 is independently H, C 1 -C 8 alkyl or a protecting group; and
* designates a chiral carbon atom; and
salts and solvates thereof.
2 . The compound of claim 1 wherein R 1 , and R 2 are amino, R 3 is hydrogen 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, R 3 is hydrogen and X is sulfur.
6 . The compound of claim 1 wherein R 1 is amino, R 2 is hydroxy, R 3 is hydrogen 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 . 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine.
12 . 2,4-diamino-6-(R)-[2-(phosphonomethoxy)propoxy]pyrimidine.
13 . 2-amino-4-hydroxy-6-[2-(phosphonomethoxy)ethoxy]pyrimidine.
14 . 2,4-diamino-6-[(S)-3-hydroxy-2-(phosphonomethoxy)propoxy]pyrimidine.
15 . 2,4-diamino-6-[(RS)-3-hydroxy-2-(phosphonomethoxy)propoxy]pyrimidine.
16 . 2-amino-4-hydroxy-6-[(R)-2-(phosphonomethoxy)propoxy]pyrimidine.
17 . 2-amino-4-hydroxy-6-[(RS)-3-hydroxy-2 (phosphonomethoxy)propoxy]pyrimidine.
18 . 2-amino-4-hydroxy-6-[(S)-3-hydroxy-2-(phosphonomethoxy)propoxy]pyrimidine.
19 . 2,4-diamino-5-bromo-6-[2-(phosphonomethoxy)ethoxy]pyrimidine.
20 . 2-amino-5-bromo-4-hydroxy-6-[2-(phosphonomethoxy)ethoxy]pyrimidine.
21 . A composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .
22 . A method of preparation of compounds of formula (I)
where
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 H or halo;
X independently is oxygen, sulfur or a bond;
Z independently is hydroxy, an ester or amide;
R 5 is independently H, C 1 -C 8 alkyl or a protecting group; and
* designates a chiral carbon atom; and
comprising (a) reacting a compound of formula (II)
where
R 2 is H, methyl, halo, —N(R 5 ) 2 , hydroxy or protected hydroxy; and
X is O or S;
with a compound of the formula (III)
Y—CH 2 CH(R 3 )—O—CH 2 P(O)(Z) 2 (III)
where
Z is an ester or an amide;
* designates a chiral carbon atom;
R 3 is H, methyl, halomethyl or protected hydroxymethyl; and
Y is a leaving group
in dipolar aprotic solvent in the presence of a base.
23 . The method of claim 22 further comprising isolating the resulting compound of the formula (I).
24 . The method of claim 22 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.
25 . The method of claim 22 where Z is (OR 4 ) 2 and R 4 is isopropyl.
26 . The method of claim 22 where R 3 is methyl and Y is p-toluenesulfonyloxy.
27 . A method for the preparation of compounds of formula (I)
where
R 1 is H, amino or methylsulfanyl;
R 2 is —N(R 5 ) 2 ;
R 3 is independently H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 4 is H or halo;
X is oxygen or sulfur;
Z independently is hydroxy, ester or amide;
R 5 is independently H, C 1 -C 8 alkyl or a protecting group; and
* designates a chiral carbon atom
comprising reacting a compound (IV)
where
R 3 is H, methyl, halomethyl or protected hydroxymethyl;
X is O or S; and
Z is amidate or ester;
with N(R 5 ) 2 .
28 . The method of claim 27 further comprising hydrolyzing one or both Z groups to produce the compound of formula (I) where one or both of Z are hydroxyl.
29 . A method for preparation of compounds of formula (V)
where
R 3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 5 independently is H, C 1 -C 8 alkyl or a protecting group;
X is oxygen or sulfur;
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.
30 . A method of preparation of the compounds of formula (VI)
where
R 1 is H, amino or methylsulfanyl;
R 3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
Z independently is hydroxy, an ester or amide; and
* designates a chiral carbon atom;
comprising (a) reacting a compound of formula (VII)
where
R 1 is H, amino or methylsulfanyl
with a compound of the formula (VIII)
*
HOCH 2 CH 2 (R 3 )OCH 2 P(O)(Z) 2 (VIII)
where
Z is amide or ester
in the presence of a base.
31 . The method of claim 30 further comprising hydrolyzing Z group to produce a compound of formula (VI) where 1 or 2 Z groups are hydroxy.
32 . A method of preparation of compounds of formula (XIII)
where
R 1 is H, amino or methylsulfanyl;
* is a chiral carbon atom;
R 2 is H, chloro, hydroxy or amino;
R 3 is H, methyl, halomethyl or hydroxymethyl;
Z is amide or ester
comprising (a) reacting a compound of the formula (IX)
where
R 1 is H, amino or methylsulfanyl;
R 2 is H, chloro or amino;
with a compound of the formula (X)
where
R 3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
* is a chiral carbon atom;
R 6 is hydroxy or protected hydroxy;
or R 3 and R 6 are joined by a cyclic acetal or ketal protecting group; in the presence of a base without solvent or in the presence of an aprotic solvent, to produce a compound of formula (XI)
where
R 1 is H, amino or methylsulfanyl;
* is a chiral carbon atom;
R 2 is H, chloro or amino; and
R 3 is H, methyl, halomethyl or protected hydroxymethyl; and
(b) reacting compound (XI) with a compound of the formula (XII)
Y—CH 2 P(O)(OZ) 2 (XII)
where
Y is a leaving group;
Z is amide or ester
in the presence of a base in dimethylformamide or tetrahydrofurane to produce a compound of formula (XIII).
33 . The method of claim 32 further comprising hydrolyzing Z group to produce a compound of formula (XIII) where 1 or 2 Z groups are hydroxyl.
34 . A method of preparation of a compound of formula (I)
where
R 1 is H, amino or methylsulfanyl;
R 3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R 4 is halo;
X is oxygen;
Z independently is hydroxy, an ester or amide; and
* designates a chiral carbon atom;
comprising (a) reacting a compound of the formula (VI)
where
R 1 is H, amino or methylsulfanyl;
R 3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
Z independently is an ester; and
* designates a chiral carbon atom;
with elemental halogen in an inert solvent to produce a compound of formula (I).
35 . The method of claim 34 further comprising hydrolyzing Z group to produce a compound of formula (I) where 1 or 2 Z groups are hydroxyl.
36 . 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.
37 . The method of claim 36 where the virus is a DNA virus.
38 . The method of claim 37 where the virus is a retrovirus or hepadnavirus.Join the waitlist — get patent alerts
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