Alkynylamino-nucleotides

Claim 2

An alkynylamino-nucleotide having the structure: Nuc--C.tbd.C--R.sub.1 --NR.sub.2 R.sub.3 wherein R 1 is a diradical moiety of 1-20 atoms, R 2 and R 3 are, independently, H, C 1 -C 4 alkyl or a protecting group, and Nuc is R 4 -Het having the structure ##STR16## Z is H or NH 2 , and R 4 is ##STR17## wherein R 5 is H, PO 3 H 2 , P 2 O 6 H 3 , P 3 O 9 H 4 or salts thereof, and (i) when R 7 ═R 8 ═H, then R 6 ═H, OH, F, N 3 or NH 2 ; or (ii) when R 7 ═H and R 8 ═OH, then R 6 ═H or OH; or (iii) when R 7 ═OH and R 8 ═H, then R 6 ═OH.

Claim 3

The alkynylamino-nucleotide of claim 1 wherein R 1 is straight chained C 1 -C 10 alkylene moiety.

Claim 4

The alkynylamino-nucleotide of claim 1 wherein R 1 is --CH 2 .

Claim 5

The alkynylamino-nucleotide of claim 1 wherein R 2 is H and R 3 is H or a protecting group.

Claim 6

The alkynylamino-nucleotide of claim 1 wherein R 4 is a chain-terminating sugar.

Claim 7

A labeled alkynylamino-nucleotide having the structure: Nuc--C.tbd.C--R.sub.1 --NR.sub.2 R.sub.3 wherein R 1 is a diradical moiety of 1-20 atoms. R 2 is H, C 1 -C 4 alkyl or a protecting group, and Nuc is R 4 -Het having the structure ##STR18## Z is H or NH 2 , and R 4 is ##STR19## wherein R 5 is H, PO 3 H 2 , P 2 O 6 H 3 , P 3 O 9 H 4 or (i) when R 7 ═R 8 ═H, then R 6 ═H, OH, R, N 3 or NH 2 ; or (ii) when R 7 ═H and R 8 ═OH, then R 6 ═H or OH; or (iii) when R 7 ═OH and R 8 ═H, then R 6 ═OH, and R R 3 is a reporter group.

Claim 8

A labeled alkynylamino-nucleotide having the structure: Nuc--C.tbd.C--R.sub.1 --NR.sub.2 R.sub.3 wherein R 1 is a diradical moiety of 1-20 atoms. R 2 is H, C 1 -C 4 alkyl or a protecting group, and Nuc is R 4 -Het having the structure ##STR18## Z is H or NH 2 , and R 4 is ##STR19## wherein R 5 is H, PO 3 H 2 , P 2 O 6 H 3 , P 3 O 9 H 4 or (i) when R 7 ═R 8 ═H, then R 6 ═H, OH, R, N 3 or NH 2 ; or (ii) when R 7 ═H and R 8 ═OH, then R 6 ═H or OH; or (iii) when R 7 ═OH and R 8 ═H, then R 6 ═OH, and R R 3 is a reporter group.

Claim 9

The labeled alkynlamino-nucleatide of claim 6 wherein R 3 is a fluorescent group.

Claim 10

A process for preparing 2-thioalkoxy-6-alkoxy-7-iodo-7-deazapurines wherein 2-thioalkoxy-7-deazapurines are reacted with N-iodosuccinimide for the regioselective introduction of iodine at the 7-position and obtaining the 7-iodo regioisomer.

Claim 11

A process for preparing 2-thioalkoxy-6-alkoxy-7-iodo-7-deazapurines wherein 2-thioalkoxy-7-deazapurines are reacted with N-iodosuccinimide for the regioselective introduction of iodine at the 7-position and obtaining the 7-iodo regioisomer.

Claim 12

A process of preparing 7-(3-amino-1-propynyl)2',3'-dideoxyguanosine 5'-triphosphate comprising the steps of: (A) reacting 6-methoxy-2-methylthio-7-deazapurine with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-ribofuranose in presence of sodium hydride; (B) hydrolyzing the ester product 9 of step (A) under basic condition to diol 10; (C) protecting the 5-OH position in diol 10 with a trityl group; (D) removing the 3-OH group by reducing an intermediate thionocarbonate with a tin hydride reducing agent; (E) treating the dideoxydeazapurine 12 resulting from step (D) with N-iodosuccinimide to form the 7-iodo derivative 13; (F) reacting compound 13 with sodium thiocresolate in hexamethylphosphoramide to form the 7-deazapurin-6-one 14; (G) treating compound 14 successively with meta-chloroperoxybenzoic acid and ammonia to obtain the 7-deazaguanosine 15; (H) coupling N-propargyltrifluoroacetamide to the deprotected 7-iodo compound 16 to obtain 7-(3-trifluoroacetamido-1-propynyl)-2',3'-dideoxy-7-deazaguanosine; and (I) reacting the product of step (H) sequentially with phosphorous oxychloride and pyrophosphate to convert it to the 5'-triphosphate followed by deprotection.

Claim 13

A process of preparing 7-(3-amino-1-propynyl)2',3'-dideoxyguanosine 5'-triphosphate comprising the steps of: (A) reacting 6-methoxy-2-methylthio-7-deazapurine with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-ribofuranose in presence of sodium hydride; (B) hydrolyzing the ester product 9 of step (A) under basic condition to diol 10; (C) protecting the 5-OH position in diol 10 with a trityl group; (D) removing the 3-OH group by reducing an intermediate thionocarbonate with a tin hydride reducing agent; (E) treating the dideoxydeazapurine 12 resulting from step (D) with N-iodosuccinimide to form the 7-iodo derivative 13; (F) reacting compound 13 with sodium thiocresolate in hexamethylphosphoramide to form the 7-deazapurin-6-one 14; (G) treating compound 14 successively with meta-chloroperoxybenzoic acid and ammonia to obtain the 7-deazaguanosine 15; (H) coupling N-propargyltrifluoroacetamide to the deprotected 7-iodo compound 16 to obtain 7-(3-trifluoroacetamido-1-propynyl)-2',3'-dideoxy-7-deazaguanosine; and (I) reacting the product of step (H) sequentially with phosphorous oxychloride and pyrophosphate to convert it to the 5'-triphosphate followed by deprotection.

Claim 14

A process for preparing 6-chloro-7-iodo-7-deazapurines wherein 6-chloro-7-deazapurines are reacted with iodine monochloride for the regioselective introduction of iodine at the 7-position and obtaining the 7-iodo regioisomer.

Claim 15

A process for preparing 6-chloro-7-iodo-7-deazapurines wherein 6-chloro-7-deazapurines are reacted with iodine monochloride for the regioselective introduction of iodine at the 7-position and obtaining the 7-iodo regioisomer.

Claim 16

An improved method for preparing alkynylaminonucleotides by coupling iodo-nucleotides having an iodine atom attached to a carbon atom within the heterocyclic base with terminal alkynyl amines using a bis(triphenylphosphine)palladium dichloride/cuprous iodide catalyst, the improvement comprising the use of a tetrakis(triphenylphosphine)palladium(O)/cuprous iodide catalyst.

Claim 17

An improved method for preparing alkynylaminonucleotides by coupling iodo-nucleotides having an iodine atom attached to a carbon atom within the heterocyclic base with terminal alkynyl amines using a bis(triphenylphosphine)palladium dichloride/cuprous iodide catalyst, the improvement comprising the use of a tetrakis(triphenylphosphine)palladium(O)/cuprous iodide catalyst.

Claim 18

7-Iodo-nucleotides having the structure: ##STR20## Z is H or NH 2 , and R 4 is ##STR21## wherein R 5 is H, PO 3 H 2 , P 2 O 6 H 3 , P 3 O 9 H 4 or salts thereof, and (i) when R 7 ═R 8 ═H, then R 6 ═H, OH, R, N 3 or NH 2 ; or (ii) when R 7 ═H and R 8 ═OH, then R 6 ═H or OH; or (iii) when R.sub. ═OH and R 8 ═H, then R 6 ═OH.

Claim 19

7-Iodo-nucleotides having the structure: ##STR20## Z is H or NH 2 , and R 4 is ##STR21## wherein R 5 is H, PO 3 H 2 , P 2 O 6 H 3 , P 3 O 9 H 4 or salts thereof, and (i) when R 7 ═R 8 ═H, then R 6 ═H, OH, R, N 3 or NH 2 ; or (ii) when R 7 ═H and R 8 ═OH, then R 6 ═H or OH; or (iii) when R.sub. ═OH and R 8 ═H, then R 6 ═OH.