Pyrimidine derivatives for labeled binding partners

• US 5,763,588 A
• Filed: 06/07/1995
• Issued: 06/09/1998
• 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., Matteucci, Mark D.
• Primary Examiner(s): Houtteman, Scott W.
• Application Number:
  US08/481,719
• Time in Patent Office: 1,098 Days
• Field of Search: 536/26.1, 536/26.7, 536/22.1, 435/6, 534/768
• US Class Current: 536/22.1
• 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

Compounds having particular interest as labels and various novel uses in diagnostics and therapeutics are provided which have structure (1) ##STR1## wherein R¹ is a binding partner, a linker or H; a and b are 0 or 1, provided that the total of a and b is 0 or 1;

A is N or C;

X is S, O, --C(O)--, NH or NCH₂ R⁶ ;

Y is --C(O)--;

Z is taken together with A to form 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 or ═O;

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;,

R³ is a protecting group or H; and tautomers, solvates and salts thereof; and provided that where a is 0, b is 1, and R¹ is ##STR2## in which D² is independently hydroxyl, blocked hydroxyl, mono, di or triphosphate, or an oligodeoxyribonucleotide otherwise containing only the bases A, G, T and C; and

D³ is H or OH;

then Z is not unsubstituted phenyl. Also provided are novel intermediates and methods for the preparation and use of the structure (1) compounds.

Claims

1. A compound having the structure:

##STR20## wherein R¹ is a polymer, H or 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--O--C.sub. 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 a coupling group;

O 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, CHR or CF₂ ;

R¹² is independently H or halogen;

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

R¹³ 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 O 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, CHR 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 ;

a and b are 0;

A is independently N or C;

X is independently S, 0, --C(0)--, NH or NCH₂ R⁶ ;

Y is --C(O)--;

Z is taken together with A to form 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 or ═

O;

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 selected from the group consisting of cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl, thiazolyl, imidozolyl, oxazolyl, pyridinyl and pyrimidinyl;

R³ is a protecting group or H; and

tautomers, solvates and salts thereof; and

provided that where a is 0, b is 1, and R¹ is ##STR22## in which D² is independently hydroxyl, blocked hydroxyl, mono, di or triphosphate, or an oligodeoxyribonucleotide otherwise containing only the bases A, G, T and C; and

D³ is H or OH;

then Z is not unsubstituted phenyl.

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

HOCH(CHR¹³)CH₂ ;

ECH₂ OCH(CHR¹³)CH₂ ;

or ##STR23##

3. The compound of claim 1 wherein Z is ##STR24## A¹ is N or CR⁶ ;

and G is CH, S, O or NR⁴ ; and

R⁴ is H or C₁ -C₆ alkyl.

4. The compound of claim 3 wherein Z is ##STR25## R⁴ is H or C₁ -C₆ alkyl;

and R⁵ is H,NO₂ or C₁ -C6alkyl.

5. The compound of claim 3 wherein Z is ##STR26## R² is C₁ -C₆ alkyl and R⁶ is H.

6. The compound of claim 3 wherein Z is ##STR27##

7. The compound of claim 3 wherein adjacent R⁶ are taken together to complete a phenyl, thiazole, imidazole, oxazole, pyridine or pyrimidine ring.

8. The compound of claim 3 wherein G is S, O or NR⁴.

9. The compound of claim 3 wherein Z is ##STR28##

10. The compound of claim 3 wherein Z is ##STR29##

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

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

13. The compound of claim 3 wherein A is N.

14. The compound of claim 3 wherein A is CH.

15. The compound of claim 1 wherein Z together with CH--A completes a aryl ring containing 6 ring atoms.

16. The compound of claim 15 wherein the aryl ring contains a nonbridging ring carbon atom which is singly substituted with R⁶.

17. The compound of claim 1 wherein Z together with CH--A completes a heteroaryl residue containing 1 ring N atom, 2 ring N atoms, 1 ring oxygen atom, 1 ring nitrogen and 1 ring sulfur atom separated by at least 1 carbon atom, and 3 ring N atoms, two of which are separated by at least 1 carbon atom.

18. The compound of claim 1 wherein Z together with CH--A completes a heteroaryl ring containing 5 ring atoms, one of which is N.

19. The compound of claim 1 wherein R¹ is an oligonucleotide.