Phosphoramidite derivatives of macrocycles

• US 5,837,866 A
• Filed: 05/23/1997
• Issued: 11/17/1998
• Est. Priority Date: 09/21/1994
• Status: Expired due to Fees

• Current Assignee: Pharmacyclics Incorporated (Abbvie Incorporated), Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated), Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Sessler, Jonathan L., Magda, Darren, Crofts, Shaun P.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/862,778
• Time in Patent Office: 543 Days
• Field of Search: 540/145, 540/472, 536/17.1, 536/17.3, 536/17.4
• US Class Current: 540/145
• CPC Class Codes: A61K 47/546 Porphyrines; Porphyrine with an expanded ring system, e.g. texaphyrine
• 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

Abstract

The invention is directed to phosphoramidite derivatives of macrocycles, such as porphyrins and expanded porphyrins, including sapphyrins and texaphyrins. The phosphoramidite derivatives are useful as intermediates in the preparation of macrocycle-oligonucleotide conjugates.

Claims

1. A phosphoramidite derivative of an expanded porphyrin.

2. A phosphoramidite derivative of a sapphyrin.

3. A phosphoramidite derivative of a sapphyrin, said derivative having the following formula III:

##STR8## wherein, each of R¹ -R¹⁰ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkyl, hydroxyalkyl, glycol, polyglycol, thiol, alkyl thiol, aminoalkyl, carboxyalkyl, alkoxyalkyl, aryloxyalkyl, alkyloxycarbonyl, aryloxycarbonyl, CHO--, an ether group, a ketone group, carboxyl, phosphate, phosphonate, sulfate, phosphate-substituted alkyl, phosphonate-substituted alkyl, sulfate-substituted alkyl, phosphoramidityl, alkylphosphoramidityl, alkoxyphosphoramidityl, the group --(CH₂)_t --O--W where W is hydrogen or a protecting group and t is an integer less than or equal to 10, or the group --(CH₂)_x --A--(CH₂)_y --B, where A is CH₂, O, S, NH or NR¹¹, where R¹¹ is alkyl, alkenyl, alkynyl, halo, haloalkyl, hydroxyalkyl, glycol, polyglycol, thiol, alkyl thiol, aminoalkyl, carboxyalkyl, alkoxyalkyl, aryloxyalkyl, alkyloxycarbonyl, aryloxycarbonyl, CHO--, an ether group a ketone group, carboxyl phosphate, phosphonate, sulfate, phosphate-substituted alkyl, phosphonate-substituted alkyl, or sulfate-substituted alkyl, COO, CONH, CSNH, or CONR¹¹ ;

B is selected from the values of A, aryl, silyl, siloxy, aminoaryl, amino, amidoaryl, sugar, sugar derivative, polysaccharide, metal chelating group, alkylating agent, steroid, steroid derivative, amino acid, peptide, or polypeptide; and

each of x and y is independently an integer of less than or equal to 10 or are zero;

with the proviso that one of R¹ -R¹⁰ is phosphoramidityl, alkylphosphoramidityl, or alkoxyphosphoramidityl.

4. A phosphoramidite derivative of a sapphyrin according to claim 3 wherein one of R¹ -R¹⁰ is alkylphosphoramidityl or alkoxyphosphoramidityl, and the others of R¹ -R¹⁰ are independently alkyl, hydroxyalkyl or the group --(CH₂)_t --O--W.

5. A phosphoramidite derivative of a sapphyrin according to claim 3 wherein one of R¹ -R¹⁰ is alkylphosphoramidityl where the alkyl of the alkylphosphoramidityl has from one to ten carbon atoms.

6. A phosphoramidite derivative of a sapphyrin according to claim 5 wherein the alkyl of the alkylphosphoramidityl has from three to six carbon atoms.

7. A phosphoramidite derivative of a sapphyrin according to claim 3 wherein one of R¹ -R¹⁰ is alkoxyphosphoramidityl where the alkoxy of the alkoxyphosphoramidityl has from one to ten carbon atoms.

8. A phosphoramidite derivative of a sapphyrin according to claim 7 wherein the alkoxy of the alkoxyphosphoramidityl has from three to six carbon atoms.

9. A phosphoramidite derivative of a sapphyrin having the following formula:

##STR9## wherein, n is zero or an integer less than or equal to 10;

z is an integer less than or equal to 10; and

each of R¹ -R³ and R⁵ -R¹⁰ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkyl, hydroxyalkyl, glycol, polyglycol, thiol, alkyl thiol, aminoalkyl, carboxyalkyl, alkoxyalkyl, aryloxyalkyl, alkyloxycarbonyl, aryloxycarbonyl, CHO--, an ether group, a ketone group, carboxyl, phosphate, phosphonate, sulfate, phosphate-substituted alkyl, phosphonate-substituted alkyl, sulfate-substituted alkyl, the group --(CH₂)_t --O--W where W is hydrogen or a protecting group and t is an integer less than or equal to 10, or the group --(CH₂)_x --A--(CH₂)_y --B, where A is CH₂, O, S, NH or NR¹¹, where R¹¹ is alkyl, alkenyl, alkynyl, halo, haloalkyl, hydroxyalkyl, glycol, polyglycol, thiol, alkyl thiol, aminoalkyl, carboxyalkyl, alkoxyalkyl, aryloxyalkyl, alkyloxycarbonyl, aryloxycarbonyl, CHO--, an ether group, a ketone group, carboxyl, phosphate, phosphonate, sulfate, phosphate-substituted alkyl, phosphonate-substituted alkyl, or sulfate-substituted alkyl, COO, CONH, CSNH, or CONR¹¹ ;

B is selected from the values of A, aryl, silyl, siloxy, aminoaryl, amino, amidoaryl, sugar, sugar derivative, polysaccharide, metal chelating group, alkylating agent, steroid, steroid derivative, amino acid, peptide, or polypeptide; and

each of x and y is independently an integer of less than or equal to 10 or are zero.

10. A phosphoramidite derivative of a sapphyrin according to claim 9 where each of R¹ -R³, R⁵, R⁶ and R⁸ -R¹⁰ is independently alkyl;

and R⁷ is alkyl, hydroxyalkyl or the group --(CH₂)_t --O--W.

11. A phosphoramidite derivative of a sapphyrin according to claim 9, having the following formula:

##STR10## wherein, n is zero or an integer less than or equal to 10 and z is an integer less than or equal to 6.

12. A phosphoramidite derivative of a porphyrin.