Pyrimidine derivatives

• US 6,005,096 A
• Filed: 05/08/1995
• Issued: 12/21/1999
• Est. Priority Date: 09/17/1993
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: Gilead Sciences Inc.
• Inventors: Jones, Robert J., Lin, Kuei-Ying, Matteucci, Mark
• Primary Examiner(s): Houtteman, Scott W.
• Application Number:
  US08/436,991
• Time in Patent Office: 1,688 Days
• Field of Search: 536/26.6, 536/28.4, 536/28.5, 536/28.51, 536/28.52, 536/28.53, 536/28.54, 536/28.55, 544/300, 544/316, 544/317, 544/318
• US Class Current: 536/26.6
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07F 7/2208 Compounds having tin linked only to carbon, hydrogen and/or halogen
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/073 with 2-deoxyribosyl as the saccharide radical
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12Q 1/6816 characterised by the detection means C12Q1/6804 takes precedence
• CPC Class Codes: C12Q 1/686 Polymerase chain reaction [PCR]
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A compound having the structure ##STR1## wherein R¹ is H or a linker group; R²⁴ is independently halo or C₁ -C₂ haloalkyl;

R²⁵ is independently --SH, --OH, ═S or ═O;

A is independently N or C; and

M, taken together with the radical --A--C(--R²⁵), completes an aryl or heteroaryl ring structure comprising 5 or 6 ring atoms wherein the heteroaryl ring comprises a single O ring heteroatom, a single N ring heteroatom, a single S ring heteroatom, a single O and a single N ring heteroatom separated by a carbon atom, a single S and a single N ring heteroatom separated by a carbon atom, 2 N ring heteroatoms separated by a carbon atom, or 3 N ring heteroatoms at least two of which are separated by a carbon atom, and wherein the aryl or heteroaryl ring carbon atoms are unsubstituted with other than H or at least 1 nonbridging ring carbon atom is substituted with R⁶ ;

R⁶ is independently H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, NO₂, N(R³)₂, C.tbd.N or halo, or an R⁶ is taken together with an adjacent R⁶ to complete a ring containing 5 or 6 ring atoms; and

R³ is a protecting group or H;

and tautomers, solvates and salts thereof.

Claims

1. A compound having the structure ##STR19## wherein R¹ is H or a linker group;

R²⁴ is independently halo or C₁ -C₂ haloalkyl;

R²⁵ is independently --SH, --OH, ═

S or ═

O;

A is independently N or C; and

M, taken together with the radical --A--C(--R²⁵), completes an aryl or heteroaryl ring structure comprising 5 or 6 ring atoms wherein the heteroaryl ring comprises a single O ring heteroatom, a single N ring heteroatom, a single S ring heteroatom, a single O and a single N ring heteroatom separated by a carbon atom, a single S and a single N ring heteroatom separated by a carbon atom, 2 N ring heteroatoms separated by a carbon atom, or 3 N ring heteroatoms at least two of which are separated by a carbon atom, and wherein the aryl or heteroaryl ring carbon atoms are unsubstituted with other than H or at least 1 nonbridging ring carbon atom is substituted with R⁶ ;

R⁶ is independently H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, NO₂, N(R³)₂, C.tbd.N or halo, or an R⁶ is taken together with an adjacent R⁶ to complete a ring containing 5 or 6 ring atoms; and

R³ is a protecting group or H; and

tautomers, solvates and salts thereof.

2. The compound of claim 1 wherein R¹ is H;

HOCH(CHR¹³)CH₂ --;

ECH₂ OCH(CHR¹³)CH₂ --;

or ##STR20## D¹ is F, H, O-alkyl, S-alkyl or an oligonucleotide coupling group;

R¹³ is H, halogen, OR²⁰, CH₃, CH₂ OR² or C₃ -C₆ acyloxyalkyl;

R²⁰ is H or a protecting group; and

,

E is OH, OR²⁰, --PO₂ or --OP(O)₂.

3. The compound of claim 1 wherein R¹ is a linker group selected from the group consisting of:

E--CHR⁷ --R¹¹ --(CH₂)_m1 --C(R⁸)((CH²)_m1 (R⁹))--(CH₂)_m1 --R¹⁰ --(CH₂)_m1 --,

E--Q--C₆ H₄ --CH₂ --;

E--CHR⁷ --O--CHR⁷ --O--CHR⁷ --,

E--CHR⁷ --(CHR¹³)--_m1 --CHR¹⁴ --R¹⁰ --,

H(CH₂)_m1 CH(COOR²⁰)(CH₂)_m1 -- ##STR21## D is an oligonucleotide coupling group;

D¹ is independently F, H, O-alkyl, S-alkyl or an oligonucleotide coupling group, but only one D¹ is an coupling group;

Q is independently --C(R¹²)₂ --CH₂ --,C(R¹²)₂ --O--, --CR¹² ═

CR¹² --, or --C.tbd.C--;

R⁷ is independently H or C₁ -C₄ alkyl;

R⁸ is H or C₁ -C₄ alkyl, C₂ -C₄ alkenyl or azidomethyl;

R⁹ is halo, H or OR²⁰

R¹⁰ is O, CH₂ or a covalent bond;

R¹¹ is O, S, CH₂, CHF or CF₂ ;

R¹² is independently H or halogen;

R¹³ is H, halogen, OR²⁰, CH₃, CH₂ OR²⁰ or C₃ -C₆ acyloxyalkyl;

R¹⁴ is H, halogen, OR²⁰, CH₃, CH₂ OR²⁰, C₃ -C₆ acyloxymethyl, or C₂ -C₆ acyloxy,

R¹⁵ is CH₂, CHF or O;

R¹⁶ is CH or S, provided that when R¹⁹ is 0 or S, or R¹⁵ is CH, then R¹⁶ is not S;

R¹⁷ is H, OR²⁰, halogen, N₃, C₁ -C₄ alkyl or C₁ -C₄ alkoxy or is absent when R¹⁶ is S;

R¹⁸ is H, OR²⁰, halogen, N₃, C₁ -C₄ alkyl or C₁ -C₄ alkoxy;

R¹⁹ is O, S, CH₂, CHF or CF₂ ;

R²⁰ is H or a protecting group;

m1 is independently 0 or an integer from 1 to 4; and

E is OH, OR²⁰, --PO₂ or --OP(O)₂.

4. The compound of claim 3 wherein R¹ is H;

HOCH(CHR¹³)CH₂ --;

ECH₂ OCH(CHR¹³)CH₂ --;

or ##STR22##

5. The compound of claim 1 wherein A is C.

6. The compound of claim 1 wherein A is N.

7. The compound of claim 1 wherein A is N.

8. The compound of claim 1 wherein A is CH.