Oligonucleotide mimics having nitrogen-containing linkages

• US 5,783,682 A
• Filed: 01/11/1994
• Issued: 07/21/1998
• Est. Priority Date: 07/27/1990
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Cook, Phillip D., Sanghvi, Yogesh S.
• Primary Examiner(s): LeGuyader, John L.
• Application Number:
  US08/180,124
• Time in Patent Office: 1,652 Days
• Field of Search: 514/44, 536/24.3, 536/24.31, 536/24.32, 536/24.5, 536/22.1, 536/18.7
• US Class Current: 536/24.3
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• 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: C08G 73/02 Polyamines
• CPC Class Codes: C08G 75/30 Polysulfonamides; Polysulfonimides
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/318 where the PO2 is completely replaced, e.g. MMI or formacetal
• CPC Class Codes: C12Q 1/68 involving nucleic acids
• CPC Class Codes: C12Y 113/11012 Linoleate 13S-lipoxygenase (1.13.11.12)

Abstract

Novel compounds that mimic and/or modulate the activity of wild-type nucleic acids. In general, the compounds contain a selected sequence of nucleosidic bases or other reactive groups that are covalently bound through nitrogen-containing linear, hairpin, dumbbell, and circular shaped tethers.

Claims

1. A compound having structure:

##STR5## wherein;

each R_N is, independently, H, -T-L, alkyl having 1 to about 10 carbon atoms;

alkenyl having 2 to about 10 carbon atoms;

alkynyl having 2 to about 10 carbon atoms;

aryl having 7 to about 14 carbon atoms;

or heterocyclic;

provided that at least one R_N is not H or alkyl;

each Q is, independently, N--R_N, O, or CH₂, provided that at least one Q is not CH₂ ;

k is zero or 1;

each A is, independently, an aromatic ring;

N--R_N ;

C(O);

a single bond;

or (CH₂)_m where m is 1-5;

each T is, independently, a single bond, a methylene group or a group having structure II;

space="preserve" listing-type="equation">-- CR.sup.1 --R.sup.2 !.sub.n --B-- CR.sup.1 R.sup.2 !.sub.o -- D!.sub.p-- N(R.sub.N)!.sub.q -- II

where;

D is C(O), C(S), C(R¹) (NR³ R⁴), CH₂ R¹, CHR¹ R², or NR³ R⁴ ;

B is a single bond, CH═

CH, C.tbd.C, O, S or NR⁴ ;

each R¹ and R² is independently selected from the group consisting of hydrogen, alkyl or alkenyl having 1 to about 12 carbon atoms, hydroxy- or alkoxy- or alkylthio-substituted alkyl or alkenyl having 1 to about 12 carbon atoms, hydroxy, alkoxy, alkylthio, amino and halogen;

R³ and R⁴, independently, are H, -T-L, alkyl having 1 to about 10 carbon atoms;

alkenyl having 2 to about 10 carbon atoms;

alkynyl having 2 to about 10 carbon atoms;

aryl having 7 to about 14 carbon atoms;

heterocyclic;

or

R³ and R⁴, together, are cycloalkyl having 3 to about 10 carbon atoms or cycloalkenyl having 4 to about 10 carbon atoms;

n and o, independently, are zero to 5;

q is zero or 1;

p is zero to about 10; and

each L is, independently, a nucleosidic base, an amino acid side chain, an aromatic hydrocarbon, a heterocycle moiety containing nitrogen, sulfur, and/or oxygen;

a carbohydrate, a drug, a reporter molecule;

an RNA cleaving group;

a group for improving the pharmacokinetic properties of the compound;

or a group for improving the pharmacodynamic properties of the compound;

or group capable of hydrogen bonding.

2. A compound having the structure:

##STR6## each R_N is, independently, H, -T-L, alkyl having 1 to about 10 carbon atoms;

alkenyl having 2 to about 10 carbon atoms;

alkynyl having 2 to about 10 carbon atoms;

aryl having 7 to about 14 carbon atoms;

or heterocyclic;

provided that at least one R_N is not H or alkyl;

each Q is, independently, N--R_N, O, or CH₂, provided that at least one Q is not CH₂ ;

k is zero or 1;

zz is from 1 to about 90;

each A is, independently, an aromatic ring;

N--R_N ;

C(O);

a single bond;

or (CH₂)_m where m is 1-5;

each T is, independently, a single bond, a methylene group or a group having structure II;

space="preserve" listing-type="equation">-- CR.sup.1 R.sup.2 !.sub.n--B-- CR.sup.1 R.sup.2 !.sub.o -- D!.sub.p -- N(R.sub.N)!.sub.q -- II

where;

D is C(O), C(S), C(R¹) (NR³ R⁴), CH₂ R¹, CHR¹ R², or NR³ R⁴ ;

B is a single bond, CH═

CH, C.tbd.C, O, S or NR⁴ ;

each R¹ and R² is independently selected from the group consisting of hydrogen, alkyl or alkenyl having 1 to about 12 carbon atoms, hydroxy- or alkoxy- or alkylthio-substituted alkyl or alkenyl having 1 to about 12 carbon atoms, hydroxy, alkoxy, alkylthio, amino and halogen;

R³ and R⁴, independently, are H, -T-L, alkyl having 1 to about 10 carbon atoms;

alkenyl having 2 to about 10 carbon atoms;

alkynyl having 2 to about 10 carbon atoms;

aryl having 7 to about 14 carbon atoms;

heterocyclic;

or

R³ and R⁴, together, are cycloalkyl having 3 to about 10 carbon atoms or cycloalkenyl having 4 to about 10 carbon atoms;

n and o, independently, are zero to 5;

q is zero or 1;

p is zero to about 10; and

each L is, independently, a nucleosidic base, an amino acid side chain, an aromatic hydrocarbon, a heterocycle moiety containing nitrogen, sulfur, and/or oxygen;

a carbohydrate, a drug, a reporter molecule;

an RNA cleaving group;

a group for improving the pharmacokinetic properties of the compound;

or a group for improving the pharmacodynamic properties of the compound;

or group capable of hydrogen bonding.

3. The compound of claim 2 wherein at least one of said Q is O or CH₂.

4. The compound of claim 3 wherein at least one of said Q is O.

5. The compound of claim 2 wherein said zz is from 10 to about 30.

6. The compound of claim 2 wherein said zz is from 15 to about 25.

7. The compound of claim 2 wherein at least one of said A is an aromatic ring, N--R_N, a single bond, or (CH₂)_m where m is 1-5.