Nucleic acid-binding oligomers possessing N-branching for therapy and diagnostics

• US 5,623,049 A
• Filed: 09/06/1994
• Issued: 04/22/1997
• Est. Priority Date: 09/13/1993
• Status: Expired due to Fees

• Current Assignee: Bayer AG
• Original Assignee: Bayer AG
• Inventors: L obberding, Antonius, P otter, Thorsten, Schwemler, Christoph, Stropp, Udo, Kretschmer, Axel, Springer, Wolfgang, Mielke, Burkhard, Schwenner, Eckhard
• Primary Examiner(s): RORIES, CHARLES
• Application Number:
  US08/300,884
• Time in Patent Office: 959 Days
• Field of Search: 514/44, 514/2, 536/24.5, 536/24.3, 536/24.31, 536/24.32, 536/18.7, 530/300, 562/575, 544/242, 544/244, 544/264
• US Class Current: 530/300
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07D 473/30 attached in position 6, e.g. hypoxanthine
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07K 14/003 Peptide-nucleic acids (PNAs)
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

Abstract

The invention relates to nucleic acid-binding oligomers possessing N-branching of the general formula (I), ##STR1## and their monomers, where the individual radicals have the meaning given in the description, and to their use as medicaments or as aids in diagnostics.

Claims

1. A compound of the formula I ##STR13## in which A represents --(CH₂)_n - or --CO--,

B represents all natural or unnatural nucleobases, or derivatives derived therefrom by chemical modification, or halogenated precursors thereof, optionally substituted on the amino groups by protective groups selected from the group consisting of acetyl, trifluoroacetyl, trichloroacetyl, benzoyl, phenylacetyl, benzyloxycarbonyl, tertbutyloxycarbonyl, allyloxycarbonyl or (9-fluorenyl)methoxycarbonyl, or other protective groups which are customary in peptide and nucleic acid chemistry, or possessing free amino groups,

D represents --(CO)_p --,

E and G, independently of each other, represent --CHR--, where

R represents H or a residue of a natural or unnatural amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, phenylalanine, tyrosine, histidine, tryptophan, lysine, ornithine, asparagine, aspartic acid, glutamine, glutamic acid, arginine, proline, hydroxyproline or sarcosine, dehydroamino acids selected from the group consisting of dehydroalanine or dehydro-α

-aminobutyric acid, phenylglycine, 4-nitrophenylalanine, 3-nitrophenylalanine, 2-nitrophenylalanine, 2-, 3- or 4-aminophenylalanine, 3,4-dichlorophenylalanine, 4-iodophenylalanine, 4-methoxyphenylalanine, 1-triazolylalanine, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylalanine, 1-naphthylalanine or 2-naphthylalanine, optionally possessing protective groups, in their D or L form, or, optionally,

E and G are linked together via an alkyl chain --(CH₂)_q --,

K represents --CO--, --SO₂ -- or --CH₂ --,

L can be a carrier system, reporter ligand, a solubility-mediating group or hydrogen,

M can, independently of L, be a carrier system, reporter ligand, a solubility-mediating group or hydrogen,

m can be 0, 1, 2 or 3,

n can be 0, 1, 2, 3 or 4,

p can be 0, 1 or 2,

q can be 0, 1 or 2, and

s can assume values of between 1 and 30 containing the radical of a compound selected from the group consisting of

4-tert-butyloxycarbonylamino-N-[(thymin-1-yl)acetyl]-L-cis-proline,

N-[(N⁴ -benzoylcytosin-1-yl)acetyl]-4-tert-butyloxycarbonylamino-L-cis-proline,

4-tert-butyloxycarbonylamino-N-[(thymin-1-yl)-acetyl]-L-trans-proline,

4-tert-butyloxycarbonylamino-N-[(N⁶ -benzyloxycarbonyl-adenin-9-yl)acetyl]-L-cis-proline,

4-tert-butyloxycarbonylamino-N-[(N⁶ -benzyloxycarbonyl-adenin-9-yl)acetyl]-L-trans-proline, and

4-tert-butyloxycarbonylamino-N-[(N⁴ -benzyloxycarbonyl-cytosin-1-yl)acetyl]-L-trans-proline.

2. A compound of the formula I according to claim 1

in which

A represents --(CH₂)_n -- or --CO--,

B represents all natural nucleobases or halogenated precursors thereof, optionally substituted on the amino groups by protective groups selected from the group consisting of acetyl, trifluoroacetyl, trichloroacetyl, benzoyl, phenylacetyl, benzyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl or (9-fluorenyl)methoxycarbonyl, or other protective groups which are customary in peptide and nucleic acid chemistry, or possessing free amino groups,

D represents --(CO)_-p --,

E and G, independently of each other, represent --CHR--, where

R represents H or a residue of a natural or unnatural amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, phenylalanine, tyrosine, histidine, triptophan, lysine, ornithine, asparagine, aspartic acid, glutamine, glutamic acid, arginine, proline, hydroxyproline or sarcosine, dehydroamino acids selected from the group consisting of dehydroalanine or dehydro-α

-aminobutyric acid, other unnatural amino acids selected from the group consisting of phenylglycine, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylalanine, 1-naphthylalanine or 2-naphthylalanine, optionally possessing protective groups, in their D or L form, or, optionally,

E and G are linked together via an alkyl chain --(CH₂)_q --,

K can be --CO--, --SO₂ -- or --CH₂ --,

L can be a carrier system, reporter ligand, a solubility-mediating group or hydrogen,

M can, independently of L, be a carrier system, reporter ligand, a solubility-mediating group or hydrogen,

m can be 0, 1, 2 or 3,

n can be 0, 1, 2 or 3,

p can be 0 or 1,

q can be 0, 1 or 2, and

s can assume values of between 3 and 20.

3. A compound of the formula (I) according to claim 1 in which

A represents --(CH₂)_n -- or --CO--,

B represents all natural nucleobases or halogenated precursors thereof, optionally substituted on the amino groups by protective groups selected from the group consisting of acetyl, trifluoroacetyl, trichloroacetyl, benzoyl, phenylacetyl, benzyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl or (9-fluorenyl)methoxycarbonyl, or other protective groups which are customary in peptide and nucleic acid chemistry, or possessing free amino groups,

D represents --(CO)_p --,

E and G, independently of each other, represent --CHR--, where

R represents H or a residue of a natural or unnatural amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, phenylalanine, tyrosine, histidine, tryptophan, lysine, ornithine, asparagine, aspartic acid, glutamine, glutamic acid, arginine, proline, hydroxyproline, sarcosine, dehydroalanine or dehydro-α

-aminobutyric acid, optionally possessing protective groups, in their D or L form, or, optionally,

E and G are linked together via an alkyl chain --(CH₂)_q --,

K is --CO--,

L can be a carrier system, reporter ligand, a solubility-mediating group or hydrogen,

M can, independently of L, be a carrier system, reporter ligand, a solubility-mediating group or hydrogen,

m can be 0, 1 or 2,

n can be 0, 1, 2 or 3,

p can be 0 or 1,

q can be 0 or 1, and

s can assume values of between 3 and 18.

4. A compound according to claim 1, containing the radical of 4-tert-butyloxycarbonylamino-N-[(thymin-1-yl)acetyl]-L-cis-proline.

5. A compound according to claim 1, containing the radical of N-[(N⁴ -benzoylcytosin-1-yl)acetyl]-4-tert-butyloxycarbonylamino-L-cis-proline.

6. A compound according to claim 1, containing the radical of 4-tert-butyloxycarbonylamino-N-[(thymin-1-yl)-acetyl]-L-trans-proline.

7. A compound according to claim 1, containing the radical of 4-tert-butyloxycarbonylamino-N-[(N⁶ -benzyloxycarbonyl-adenin-9-yl)-acetyl]L-cis-proline.

8. A compound according to claim 1, containing the radical of 4-tert-butyloxycarbonylamino-N-[(N⁶ -benzyloxycarbonyl-adenin-9-yl )acetyl]-L-trans-proline.

9. A compound according to claim 1, containing the radical of 4-tert-butyloxycarbonylamino-N-[(N⁴ -benzyloxycarbonyl-cytosin-1-yl)-acetyl]-L-trans-proline.

10. A compound selected from the group consisting of

4-tert-butyloxycarbonylamino-N-[(thymin-1-yl)acetyl]-L-cis-proline,

N-[(N⁴ -benzoylcytosin-1-yl)acetyl]-4-tert-butyloxycarbonylamino-L-cis-proline,

4-tert-butyloxycarbonylamino-N-[(thymin-1-yl)-acetyl]-L-trans-proline,

4-tert-butyloxycarbonylamino-N-[(N⁶ -benzyloxycarbonyl-adenin-9-yl)-acetyl]-L-cis-proline,

4-tert-butyloxycarbonylamino-N-[(N⁶ -benzyloxycarbonyl-adenin-9-yl)acetyl]-L-trans-proline, and

4-tert-butyloxycarbonylamino-N-[(N⁴ -benzyloxycarbonyl-cytosin-1-yl)-acetyl]-L-trans-proline.

11. A compound according to claim 10, wherein such compound is 4-tert-butyloxycarbonylamino-N-[(thymin-1-yl)acetyl]-L-cis-proline.

12. A compound according to claim 10, wherein such compound is N-[(N⁴ -benzoylcytosin-1-yl)acetyl]-4-tert-butyloxycarbonylamino-L-cis-proline.

13. A compound according to claim 10, wherein such compound is 4-tert-butyloxycarbonylamino-N-[(thymin-1-yl)-acetyl]-L-trans-proline.

14. A compound according to claim 10, wherein such compound is 4-tert-butyloxycarbonylamino-N-[( N⁶ -benzyloxycarbonyl-adenin-9-yl)-acetyl]L-cis-proline.

15. A compound according to claim 10, wherein such compound is 4-tert-butyloxycarbonylamino-N-[(N⁶ -benzyloxycarbonyl-adenin-9yl)acetyl]-L-trans-proline.

16. A compound according to claim 10, wherein such compound is 4-tert-butyloxycarbonylamino-N-[(N⁴ -benzyloxycarbonyl-cytosin-1-yl)-acetyl]-L-trans-proline.