Macroheterocyclic nucleoside derivatives and their analogues, production and use thereof

Abstract

Nucleosides and nucleotides (nucleos(t)ides) have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with viral infections or cancer. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Therefore nucleos(t)ide are of great interest as promising chemotherapeutic agents, including: 2-deoxy-L-uridine (CAS 31501-19-6), 2-deoxy-D-uridine (CAS 951-78-0), telbivudine (CAS 3424-98-4), zidovudine (AZT, CAS 30516-87-1), trifluridine (CAS 70-00-8), clevudine (CAS 163252-36-6), PSI-6206 (CAS 863329-66-2), 2-(S)-2-chloro-2-deoxy-2-fluorouridine (CAS 1673560-41-2), ND06954 (CAS 114248-23-6), stavudine (CAS 3056-17-5), 5-ethynyltavudine (Festinavir, CAS 634907-30-5), torcitabine (CAS 40093-94-5), ()-beta-D-(2R,4R)-dioxolane-thymine (DOT, 1-((2R,4R)-2-(hydroxymethyl)-1,3-dioxolan-4-yl)-5-methyl-2,4(1H,3H)-pyrimidinedione, CAS No. 127658-07-5), 2-(6-amino-purin-9-yl)-ethanol (CAS 707-99-3), 2-C-methylcytidine (CAS 20724-73-6), PSI-6130 (CAS 817204-33-4), gemcitabine (CAS 95058-81-4), 2-chloro-2-deoxy-2-fluorocytidine (CAS 1786426-19-4), 2,2-dichloro-2-deoxycytidine (CAS 1703785-65-2), 2-C-methylcytidine (CAS 20724-73-6), PSI-6130 (CAS 817204-33-4), lamivudine (3TC, CAS 134678-17-4), emtricitabine (CAS 143491-57-0), 2-deoxyadenosine (CAS 958-09-8), 2-deoxy--L-adenosine (CAS 14365-45-8), 2-deoxy-4-C-ethynyl-2-fluoroadenosine (CAS 865363-93-5), didanosine (CAS 69655-05-6), entecavir (CAS 209216-23-9), FMCA (CAS 1307273-70-6), dioxolane-G (DOG, CAS 145514-01-8), -D-2-deoxy-2-(R)-fluoro-2--C-methylguanosine (CAS No 817204-45-8), abacavir (ABC, CAS 136470-78-5), dioxolane-A (DOA, CAS #145514-02-9), [(2R,4R)-4-(6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2-yl]-methanol (CAS 1446751-04-7), amdoxovir (AMDX, CAS 145514-04-1), (R)-1-(6-amino-purin-9-yl)-propan-2-ol (CAS 14047-28-0), and [(2S,5R)-5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yl]-methanol. Macroheterocyclic nucleoside derivative and its analog of the general formula 1 or general formula 2, a stereoisomer, isotope-enriched analog, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, ##STR00001##
wherein: Ar is aryl or hetaryl; R.sup.1 and R.sup.2 are not necessarily the same substituents selected from H, F, Cl, CH.sub.3, OH; R.sup.3 is H or CH.sub.3; X is oxygen or ethanediyl-1,1 (CCH.sub.2); Y is CH(R.sup.4)(CH.sub.2).sub.k, CH(R.sup.4)(CH.sub.2).sub.mC(O)O(CH.sub.2).sub.n; R.sup.4 is H or CH.sub.3; k has a value from zero to six; m has a value from zero to two; n has a value of one to four; Q is a radical selected from Q1-Q4; ##STR00002##
wherein: R.sup.5 is the substituent selected from H, F, Cl, CH.sub.3, OH; the arrow (.fwdarw.) indicates the location, joined by Q1-Q4.

Claims

1. Macroheterocyclic nucleoside derivative and its analogue of the general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate and solvate thereof, ##STR00038## wherein: Ar is aryl or hetaryl; R.sup.1 and R.sup.2 are not necessarily the same substituents selected from H, F, Cl, CH.sub.3 and OH; R.sup.3 is H or CH.sub.3; X is oxygen or ethanediyl-1,1 (CCH.sub.2); Y is CH(R.sup.4)(CH.sub.2).sub.k or CH(R.sup.4)(CH.sub.2).sub.mC(O)O(CH.sub.2).sub.n; R.sup.4 is H or CH.sub.3; k has a value from zero to six; m has a value from zero to two; n has a value of one to four; Q is a radical selected from Q1-Q4; ##STR00039## wherein: R.sup.5 is the substituent selected from H, F, Cl, CH.sub.3 and OH; the arrow (.fwdarw.) indicates the location, joined by Q1-Q4.

2. The macroheterocyclic nucleoside derivative and its analogue according to claim 1 selected from the group consisting of: (2R,3aS,6S,9S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-6,9-dimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(1/2)), (2R,3aS,6S,9S,11S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-6,9-dimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(1)), (2R,3aS,6S,9S,11R,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-6,9-dimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(2)), (2R,3R,3aR,6S,9S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,6,9-trimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(3/4)), (2R,3R,3aR,6S,9S,11S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,6,9-trimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(3)), (2R,3R,3 aR,6S,9S,11R,13 aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,6,9-trimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(4)), (2R,3R,3aR,10S, 14aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,10-dimethyl-12-oxo-12-phenoxy-octahydro-1,4,8,13-tetraoxa-11-aza-12-phospha-cyclopentacyclotridecene-5,9-dione (1(5/6)), (2R,3R,3aR,10S,12S,14aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,10-dimethyl-12-oxo-12-phenoxy-octahydro-1,4,8,13-tetraoxa-11-aza-12-phospha-cyclopentacyclotridecene-5,9-dione (1(5)), (2R,3R,3aR,10S,12R,14aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,10-dimethyl-12-oxo-12-phenoxy-octahydro-1,4,8,13-tetraoxa-11-aza-12-phospha-cyclopentacyclotridecene-5,9-dione (1(6)), (2S,3aS,11 S,15aR)-2-(2-amino-6-oxo-1,6-dihydro-purin-9-yl)-11-methyl-1-methylene-13-oxo-13-phenoxy-decahydro-4,9,14-trioxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(7/8)), (2S,3aS,11S,13S,15aR)-2-(2-amino-6-oxo-1,6-dihydro-purin-9-yl)-11-methyl-1-methylene-13-oxo-13-phenoxy-decahydro-4,9,14-trioxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(7)), (2S,3S,3aS,11S,13R,15aR)-2-(6-amino-purin-9-yl)-3,11-dimethyl-1-methylene-13-oxo-13-phenoxy-decahydro-4,9,14-trioxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(8)), (2R,3aS,11S,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(9/10)), (2R,3aS,11S,13S,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(9)), (2S,3aR,11S,13R,15aS)-11-methyl-2-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(10)), (2R,3aS,11S,15aR)-2-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(11/12)), (2R,3aS,11 S,13 S,15aR)-2-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(11)), (2S,3R,3aS,11S,13R,15aS)-3-fluoro-11-methyl-2-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(12)), (2R,3R,3aR,11S,5aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,11-dimethyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(13/14)), 2R,3R,3aR,11 S,13 S,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,11-dimethyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(13)), (2R,3R,3aR,11 S,13R,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,11-dimethyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(14)), (2R,3aR,11S,15aR)-2-(4-amino-2-oxo-2H-pyrimidin-1-yl)-3,3-difluoro-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(15/16)), (2R,3 aR,11S,13 S,15aR)-2-(4-amino-2-oxo-2H-pyrimidin-1-yl)-3,3-difluoro-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(15)), (2R,3aR,11 S,13R,15aR)-2-(4-amino-2-oxo-2H-pyrimidin-1-yl)-3,3-difluoro-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(16)), (2R,3R,3aR,12S,16aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12-dimethyl-14-oxo-14-phenoxy-decahydro-1,4,10,15-tetraoxa-13-aza-14-phospha-cyclopentacyclopentadecene-5,11-dione (1(17/18)), (2R,3R,3aR,12S,14S,16aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12-dimethyl-14-oxo-14-phenoxy-decahydro-1,4,10,15-tetraoxa-13-aza-14-phospha-cyclopentacyclopentadecene-5,11-dione (1(17)), (2R,3R,3aR,12S,14R,16aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12-dimethyl-14-oxo-14-phenoxy-decahydro-1,4,10,15-tetraoxa-13-aza-14-phospha-cyclopentacyclopentadecene-5,11-dione (1(18)), (2R,3R,3aR,13S,15S,17aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,13-dimethyl-15-oxo-15-phenoxy-decahydro-1,4,11,16-tetraoxa-14-aza-15-phospha-cyclopentacyclohexadecene-5,12-dione (1(19/20)), (2R,3R,3aR,13S,15S,17aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,13-dimethyl-15-oxo-15-phenoxy-decahydro-1,4,11,16-tetraoxa-14-aza-15-phospha-cyclopentacyclohexadecene-5,12-dione (1(19)), (2R,3R,3aR,13S,15R,17aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,13-dimethyl-15-oxo-15-phenoxy-decahydro-1,4,11,16-tetraoxa-14-aza-15-phospha-cyclopentacyclohexadecene-5,12-dione (1(20)), (2R,3R,3aR,14S,16S,18aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,14-dimethyl-16-oxo-16-phenoxy-dodecahydro-1,4,12,17-tetraoxa-15-aza-16-phospha-cyclopentacycloheptadecene-5,13-dione (1(21/22)), (2R,3R,3aR,14S,16S,18aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,14-dimethyl-16-oxo-16-phenoxy-dodecahydro-1,4,12,17-tetraoxa-15-aza-16-phospha-cyclopentacycloheptadecene-5,13-dione (1(21)), (2R,3R,3aR,14S,16R,18aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,14-dimethyl-16-oxo-16-phenoxy-dodecahydro-1,4,12,17-tetraoxa-15-aza-16-phospha-cyclopentacycloheptadecene-5,13-dione (1(22)), (2R,3R,3aR,15S,17S,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-dodecahydro-1,4,13,18-tetraoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,14-dione (1(23/24)), (2R,3R,3aR,15S,17S,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-dodecahydro-1,4,13,18-tetraoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,14-dione (1(23)), (2R,3R,3aR,15S,17R,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-dodecahydro-1,4,13,18-tetraoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,14-dione (1(24)), (2R,3R,3aR,12S,15S,17S,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12,15-trimethyl-17-oxo-17-phenoxy-decahydro-1,4,9,13,18-pentaoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,10,14-trione (1(25/26)), (2R,3R,3aR,12S,15S,17S,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12,15-trimethyl-17-oxo-17-phenoxy-decahydro-1,4,9,13,18-pentaoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,10,14-trione (1(25)), (2R,3R,3aR,15S,17R,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-decahydro-1,4,8,13,18-pentaoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,9,14-trione (1(26)), (2R,3R,3aR,9S,11S,13aR,15R,16R,16aR,22S,24S,26aR)-2,15-bis(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,16-difluoro-3,9,16,22-tetramethyl-11,24-diphenoxydodecahydro-2H,13H-difuro [3,2-j:3,2-v][1,6,9,13,18,21,3,15,2,14]hexaoxadiazadiphosphacyclotetracosine-5,8,18,21 (6H,9H,19H,22H)-tetrone 11,24-dioxide (1(27)) and (2R,3R,3aR,11S,13S,15aR,17R,18R,18aR,26S,28S,30aR)-2,17-bis(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,18-difluoro-3,11,18,26-tetramethyl-13,28-diphenoxyhexadecahydro-2H,15H-difuro[3,2-1:3,2-z][1,6,11,15,20,25,3,17,2,16]hexaoxadiazadiphosphacyclooctacosine-5,10,20,25(6H,11H,21H,26H)-tetrone 13,28-dioxide (1(28)), or a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate and solvate thereof.

3. A pharmaceutical composition comprising the compound according to claim 1 or 2 and a pharmaceutically acceptable medium.

4. A process for preparing the compounds according to claim 1 by cyclization of acid of general formula 3 or 16 and if necessary division of the latter on the stereoisomers ##STR00040## wherein: Ar, R.sup.1, R.sup.2, R.sup.3, X, Y, and Q are as defined above.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) One embodiment of the present invention is a novel macroheterocyclic nucleoside derivative and its analogue of the general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof,

(2) ##STR00009##
wherein: Ar is aryl or hetaryl; R.sup.1 and R.sup.2 are not necessarily the same substituents selected from H, F, Cl, CH.sub.3, OH; R.sup.3 is H or CH.sub.3; X is oxygen or ethanediyl-1, 1 (CCH.sub.2); Y is CH(R.sup.4)(CH.sub.2).sub.k, CH(R.sup.4)(CH.sub.2).sub.mC(O)O(CH.sub.2).sub.n; R.sup.4 is H or CH.sub.3; k has a value from zero to six; m has a value from zero to two; n has a value of one to four; Q is a radical selected from Q1-Q4;

(3) ##STR00010##
wherein: R.sup.5 is the substituent selected from H, F, Cl, CH.sub.3, OH; the arrow (.fwdarw.) indicates the location, joined by Q1-Q4.

(4) More preferred macroheterocyclic nucleoside derivatives and its analogue are: (2R,3aS,6S,9S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-6,9-dimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(1/2)), (2R,3aS,6S,9S,11R,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-6,9-dimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(2)), (2R,3aS,6S,9S,11R,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-6,9-dimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(2)), (2R,3R,3aR,6S,9S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,6,9-trimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(3/4)), (2R,3R,3aR,6S,9S,11S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,6,9-trimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(3)), (2R,3R,3aR,6S,9S,11R,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,6,9-trimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(4)), (2R,3R,3aR,10S,14aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,10-dimethyl-12-oxo-12-phenoxy-octahydro-1,4,8,13-tetraoxa-11-aza-12-phospha-cyclopentacyclotridecene-5,9-dione (1(5/6)), (2R,3R,3aR,10S,12S,14aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,10-dimethyl-12-oxo-12-phenoxy-octahydro-1,4,8,13-tetraoxa-11-aza-12-phospha-cyclopentacyclotridecene-5,9-dione (1(5)), (2R,3R,3aR,10S,12R,14aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,10-dimethyl-12-oxo-12-phenoxy-octahydro-1,4,8,13-tetraoxa-11-aza-12-phospha-cyclopentacyclotridecene-5,9-dione (1(6)), (2S,3aS,11S,15aR)-2-(2-amino-6-oxo-1,6-dihydro-purin-9-yl)-11-methyl-1-methylene-13-oxo-13-phenoxy-decahydro-4,9,14-trioxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(7/8)), (2S,3aS,11S,13S,15aR)-2-(2-amino-6-oxo-1,6-dihydro-purin-9-yl)-11-methyl-1-methylene-13-oxo-13-phenoxy-decahydro-4,9,14-trioxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(7)), (2S,3S,3aS,11S,13R,15aR)-2-(6-amino-purin-9-yl)-3,11-dimethyl-1-methylene-13-oxo-13-phenoxy-decahydro-4,9,14-trioxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(8)), (2R,3aS,11S,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(9/10)), (2R,3aS,11S,13S,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(9)), (2S,3aR,11S,13R,15aS)-11-methyl-2-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(10)), (2R,3aS,11S,15aR)-2-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(11/12)), (2R,3aS,11S,13S,15aR)-2-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(11)), (2S,3R,3aS,11S,13R,15aS)-3-fluoro-11-methyl-2-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(12)), (2R,3R,3aR,11S,5aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,11-dimethyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(13/14)), 2R,3R,3aR,11S,13S,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,11-dimethyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(13)), (2R,3R,3aR,11S,13R,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,11-dimethyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(14)), (2R,3aR,11S,15aR)-2-(4-amino-2-oxo-2H-pyrimidin-1-yl)-3,3-difluoro-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(15/16)), (2R,3aR,11S,13S,15aR)-2-(4-amino-2-oxo-2H-pyrimidin-1-yl)-3,3-difluoro-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(15)), (2R,3aR,11S,13R,15aR)-2-(4-amino-2-oxo-2H-pyrimidin-1-yl)-3,3-difluoro-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(16)), (2R,3R,3aR,12S,16aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12-dimethyl-14-oxo-14-phenoxy-decahydro-1,4,10,15-tetraoxa-13-aza-14-phospha-cyclopentacyclopentadecene-5,11-dione (1(17/18)), (2R,3R,3aR,12S,14S,16aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12-dimethyl-14-oxo-14-phenoxy-decahydro-1,4,10,15-tetraoxa-13-aza-14-phospha-cyclopentacyclopentadecene-5,11-dione (1(17)), (2R,3R,3aR,12S,14R,16aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12-dimethyl-14-oxo-14-phenoxy-decahydro-1,4,10,15-tetraoxa-13-aza-14-phospha-cyclopentacyclopentadecene-5,11-dione (1(18)), (2R,3R,3aR,13S,15S,17aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,13-dimethyl-15-oxo-15-phenoxy-decahydro-1,4,11,16-tetraoxa-14-aza-15-phospha-cyclopentacyclohexadecene-5,12-dione (1(19/20)), (2R,3R,3aR,13S,15S,17aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,13-dimethyl-15-oxo-15-phenoxy-decahydro-1,4,11,16-tetraoxa-14-aza-15-phospha-cyclopentacyclohexadecene-5,12-dione (1(19)), (2R,3R,3aR,13S,15R,17aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,13-dimethyl-15-oxo-15-phenoxy-decahydro-1,4,11,16-tetraoxa-14-aza-15-phospha-cyclopentacyclohexadecene-5,12-dione (1(20)), (2R,3R,3aR,14S,16S,18aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,14-dimethyl-16-oxo-16-phenoxy-dodecahydro-1,4,12,17-tetraoxa-15-aza-16-phospha-cyclopentacycloheptadecene-5,13-dione (1(21/22)), (2R,3R,3aR,14S,16S,18aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,14-dimethyl-16-oxo-16-phenoxy-dodecahydro-1,4,12,17-tetraoxa-15-aza-16-phospha-cyclopentacycloheptadecene-5,13-dione (1(21)), (2R,3R,3aR,14S,16R,18aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,14-dimethyl-16-oxo-16-phenoxy-dodecahydro-1,4,12,17-tetraoxa-15-aza-16-phospha-cyclopentacycloheptadecene-5,13-dione (1(22)), (2R,3R,3aR,15S,17S,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-dodecahydro-1,4,13,18-tetraoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,14-dione (1(23/24)), (2R,3R,3aR,15S,17S,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-dodecahydro-1,4,13,18-tetraoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,14-dione (1(23)), (2R,3R,3aR,15S,17R,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-dodecahydro-1,4,13,18-tetraoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,14-dione (1(24)), (2R,3R,3aR,12S,15S,17S,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12,15-trimethyl-17-oxo-17-phenoxy-decahydro-1,4,9,13,18-pentaoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,10,14-trione (1(25/26)), (2R,3R,3aR,12S,15S,17S,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12,15-trimethyl-17-oxo-17-phenoxy-decahydro-1,4,9,13,18-pentaoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,10,14-trione (1(25)), (2R,3R,3aR,15S,17R,19aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-decahydro-1,4,8,13,18-pentaoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,9,14-trione (1(26)), (2R,3R,3aR,9S,11S,13aR,15R,16R,16aR,22S,24S,26aR)-2,15-bis(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,16-difluoro-3,9,16,22-tetramethyl-11,24-diphenoxydodecahydro-2H,13H-difuro[3,2-j:3,2-v][1,6,9,13,18,21,3,15,2,14]hexaoxadiazadiphosphacyclotetracosine-5,8,18,21(6H,9H,19H,22H)-tetrone 11,24-dioxide (1(27)), (2R,3R,3aR,11S,13S,15aR,17R,18R,18aR,26S,28S,30aR)-2,17-bis(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,18-difluoro-3,11,18,26-tetramethyl-13,28-diphenoxyhexadecahydro-2H,15H-difuro[3,2-1:3,2-z][1,6,11,15,20,25,3,17,2,16]hexaoxadiazadiphosphacyclooctacosine-5,10,20,25(6H,11H,21H,26H)-tetrone 13,28-dioxide (1(28)), or a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof.

(5) ##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##

(6) New macroheterocyclic nucleoside derivatives and their analogues of the general formula 1 or general formula 2 are undoubtedly of interest in particular as drug candidates for the treatment of hepatitis C. For example, macroheterocycle 1(13) is more stable (T.sub.1/2>24 h) in the simulated gastric fluid (SFG) and the human S9 fraction (T.sub.1/2>12.4 h) than Sovaldi, for which the T.sub.1/2=15 h in SGF environment and T.sub.1/2>1.8 h in Human S9 fraction.

(7) Macroheterocycle 1(13) also shows higher C.sub.max=341 ng/ml metabolite of PSI-352707 [E. Murakami et al. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem. 2010, 285 (45), 34337-34347] in plasma of rats (SD rats, 10 mg/kg p.o.) than under the same conditions shows Sovaldi, for which C.sub.max=154 ng/ml metabolite PSI-352707, with the same time (1 h) to achieve a comparable C.sub.max and enter values T.sub.1/2=1.80 h and T.sub.1/2=1.75 h, respectively, for Macroheterocycle 1(13) and Sovaldi. In rat liver Cmax of PSI-352707 is comparable for macroheterocycle 1(13) and Sovaldi, respectively C.sub.max=1578 ng/ml and C.sub.max=1702 ng/ml. Meanwhile macroheterocycle 1(13) has a more acceptable value T.sub.max=0.25 h and T.sub.1/2=1.9 h than Sovaldi, for which T.sub.max=0.50 h and T.sub.1/2=1.3 h.

(8) Dosage, Administration, and Use

(9) The subject of the present invention is a pharmaceutical composition comprising one or more of macroheterocyclic nucleoside derivatives of general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, optionally in combination with a pharmaceutically acceptable excipient, carrier, additive, diluent, and equivalent medium for the treatment of viral infections and/or neoplastic diseases in mammals.

(10) The compounds of general formula 1 or 2 may be formulated in a wide variety of oral administration dosage forms and carriers, oral administration can be in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions. Compounds of the present invention are efficacious when administered by suppository administration, among other routes of administration. The most convenient manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the severity of the disease and the patient's response to the antiviral and anticancer medication.

(11) A macroheterocyclic nucleoside derivatives of general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as suspensions, emulsions, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration. A typical preparation will contain from about 5% to about 95% active compound or compounds (w/w). The term preparation or dosage form is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.

(12) The term excipient as used herein refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. The compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.

(13) Solid form preparations include powders, tablets, pills, capsules, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

(14) Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs and aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.

(15) The macroheterocyclic nucleoside derivative of general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.

(16) The macroheterocyclic nucleoside derivative of general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate

(17) The subject of the invention is directed to a use of the macroheterocyclic nucleoside derivative represented by formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, in the manufacture of a medicament for the treatment of viral and cancerous diseases. It is contemplated that the compound of the use of the macroheterocyclic nucleoside derivative represented by formula 1 or general formula 2 in the manufacture of a medicament for the treatment of any of the antiviral and anticancer conditions disclosed herein can be any of the compounds of the formulas 1(1)-1(26), 2(1), and 2(2), a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, either alone or in combination with another compound of the present invention. A medicament includes, but is not limited to, any one of the compositions contemplated of the present invention.

(18) The term medicament means a substance used in a method of treatment and/or prophylaxis of a subject in need thereof, wherein the substance includes, but is not limited to, a composition, a formulation, a dosage form, and the like, comprising the phosphoramidate macroheterocycle of formula 1 or general formula 2.

(19) The subject of the present invention is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering a therapeutically effective amount of the macroheterocyclic nucleoside derivative represented by formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof to the subject.

(20) The subject of the present invention is also directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering a therapeutically effective of at least two or more different macroheterocyclic nucleoside derivatives falling within the scope of the compound represented by formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof to the subject.

(21) The subject of the present invention is also directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises alternatively or concurrently administering a therapeutically effective of at least two macroheterocyclic nucleoside derivatives falling within the scope of the compound represented by formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof to the subject.

(22) The term subject means a mammal, which includes, but is not limited to, cattle, pigs, sheep, chicken, turkey, buffalo, llama, ostrich, dogs, cats, and humans, preferably the subject is a human. It is contemplated that in the method of treating a subject thereof of the sixth embodiment can be any of the compounds contemplated in any of the aspects of the first, second, and third embodiments or those specifically recited in the tables above, either alone or in combination with another compound of the present invention.

(23) The term therapeutically effective amount as used herein means an amount required to reduce symptoms of the disease in an individual. The dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved. For oral administration, a daily dosage of between about 0.1 and about 10 g, including all values in between, per day should be appropriate in monotherapy and/or in combination therapy. A preferred daily dosage is between about 0.1 and about 7 g per day, more preferred 0.2 and about 5.0 g per day. Generally, treatment is initiated with a large initial loading dose to rapidly reduce or eliminate the virus following by a decreasing the dose to a level sufficient to prevent resurgence of the infection. One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.

(24) The subject of the present invention is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering to the subject a therapeutically effective of a compound represented by formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, and a therapeutically effective amount of another antiviral agent; wherein the administration is concurrent or alternative. It is understood that the time between alternative administration can range between 1-24 hours, which includes any sub-range.

(25) Examples of another antiviral agents include, but are not limited to: HCV NS3 protease inhibitors Examples of another antiviral agents include, but are not limited to: HCV NS3 protease inhibitors, HCV NS4 inhibitors (see US US 20140296136, U.S. Pat. Nos. 8,987,195, 7,973,040, US 2012214783); HCV NS4 inhibitors (see EP1497282); HCV NS3/NS4 inhibitors (EP 2364984); HCV NS5A inhibitors (Shingo Nakamoto et al. Hepatitis C virus NSSA inhibitors and drug resistance mutations. World J Gastroenterol. 2014 Mar. 21; 20(11): 2902-2912 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961994/); A. V. Ivachtchenko et al. Discovery of Novel Highly Potent Hepatitis C Virus NS5A Inhibitor (AV4025). J. Med. Chem. 2014, 57, 7716-7730; Pat. Appl. U.S. Ser. No. 14/845,333); toll-like receptor agonists (see WO 2015023958, WO 2012097012); and other inhibitors (see WO 2014106019, WO 2014033176, WO 2014033170, WO 2014033167, WO 2013006394, US 20090163545).

(26) More preferred is a pharmaceutical composition, which together with the novel macroheterocyclic nucleoside derivative represented by formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, further includes an antiviral or anticancer drug in therapeutically effective amounts.

(27) More preferred is a pharmaceutical composition, which together with the macroheterocyclic nucleoside derivative represented by formula 1 and general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, further comprises a therapeutically effective amount the HCV NS5A ingibitor the selected from the group of Daclatasvir (Daklinza, BMS790052) [Belema, M. et al. J. Med. Chem. 57, 1643-1672, 2014, WO 2008/021927, WO 2008/021928, WO-2008/021936. https://en.wikipedia.org/wiki/Daclatasvir;], Ombitasvir (ABT-267) [DeGoey, et al. J Med. Chem. 57, 2047-2057, 2014, WO 2010/144646], GS-5885[ ], Velpatasvir (GS-5816) [Everson G. T. et al. Sofosbuvir with Velpatasvir in Treatment-Naive Noncirrhotic Patients with Genotype 1 to 6 Hepatitis C Virus Infection: A Randomized Trial. Ann. Intern. Med. 2015, 163(11), 818-826. doi: 10.7326/M15-1000. Epub 2015 Nov. 10. www.medkoo.com/products/9855], Odalasvir (ACH-3102) [U.S. Pat. No. 8,809,313. http://en.wikipedia.org/wiki/Odalasvir] and Elbasvir (MK-8742) [Coburn, C. A. et al. ChemMedChem. 8, 1930-1940, 2013, WO 2012/040923, WO 2012/041014], Hepavivir (AV-4025) [Ivachtchenko, A. V. et al. J. Med. Chem. 57, 7716-7730, 2014, WO 2012/074437, http://allachem.com/wp-content/uploads/2013/08/hcv-AV4025-082413.doc], AV-4067 and AV-4084 [Pat. Appl. U.S. Ser. No. 14/845,333.], AVI-4056 and AVI-4058 [Pat. Appl. US 15221613].

(28) The subject of the present invention is directed to a method of treatment of viral and cancerous diseases in a subject in need thereof said method comprises alternatively or concurrently administering a therapeutically effective of a compound represented by general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, and another antiviral or anticancer agent to the subject. It is understood that the time between alternative administration can range between 1-24 hours, which includes any sub-range in between.

(29) The subject of the present invention is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering to the subject a therapeutically effective of at least one compound represented by general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, and a therapeutically effective amount of another antiviral or anticancer agent; wherein the administration is concurrent or alternative. It is understood that the time between alternative administration can range between 1-24 hours, which includes any sub-range in between.

(30) It is contemplated that the another antiviral agent includes, but is not limited to interferon-, interferon-, pegylated interferon-, ribavirin, levovirin, viramidine, another nucleoside HCV polymerase inhibitor, a HCV non-nucleoside polymerase inhibitor, a HCV protease inhibitor, a HCV helicase inhibitor or a HCV fusion inhibitor, and a HBV DNA polymerase inhibitor and a HIV-1 reverse transcriptase (RT) inhibitor. When the active compound or its derivative or salt are administered in combination with another antiviral or anticancer agent the activity may be increased over the parent compound. When the treatment is combination therapy, such administration may be concurrent or sequential with respect to a compound represented by general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof Concurrent administration as used herein thus includes administration of the agents at the same time or at different times. Administration of two or more agents at the same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent.

(31) It will be understood that references herein to treatment extend to prophylaxis as well as to the treatment of existing conditions. Furthermore, the term treatment of a viral infection, as used herein, also includes treatment or prophylaxis of a disease or a condition associated with or mediated by viral infection, or the clinical symptoms thereof.

(32) Process for Preparation

(33) The subject of the present invention is a process for preparing the macroheterocyclic nucleoside derivative represented by general formula 1 and general formula 2 by cyclization of acid of general formula 3 (Scheme 1) and if necessary division of the latter on the stereoisomers.

(34) ##STR00021##
wherein: 1-3, and a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof; Ar, R.sup.1, R.sup.2, R.sup.3, R.sup.4, X, Y, and Q are as defined above.

(35) Acids of general formula 3 can be obtained (Scheme 2) by reacting a corresponding chlorophosphorylamino derivative of general formula 8, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, with compound of general formula 12, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, followed by removal of the benzyl and Cbz groups by catalytic hydrogenation of the resulting benzyl ethers of general formula 13, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, and if necessary division of the latter on the stereoisomers.

(36) ##STR00022##
wherein: 3-13 and a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof; Ar, R.sup.1, R.sup.2, R.sup.3, X, Y, and Q are as defined above.

(37) Macroheterocyclic nucleoside derivative represented by general formula 1 or general formula 2 can be obtained starting from the acid of general formula 16 and if necessary division of the latter on the stereoisomers. The acid of general formula 16, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, can be obtained starting from the nucleoside of general formula 14 (Scheme 3).

(38) ##STR00023##
wherein: 14-16 and a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof; Ar, R.sup.1, R.sup.2, R.sup.3, X, Y, and Q are as defined above.

(39) For obtain certainly (S) and (R) phosphoric enantiomer of the macrocycles 1 and 2 (1(P.sup.(S)), 2(P.sup.(S)), 1(P.sup.(R)), 2(P.sup.(R))) are using an appropriate (S) and (R) phosphoric enantiomers of corresponding acids of general formula 19(P(.sup.S)) or 19(P(.sup.R)) (Scheme 4).

(40) ##STR00024##
wherein: 1(P.sup.(S-)), 2(P.sup.(S-)), 1(P.sup.(R-)), 2(P.sup.(R-)), and a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof; Ar, R.sup.1, R.sup.2, R.sup.3, X, Y, and Q are as defined above.

(41) The acids 19(P.sup.(S)), 19(P.sup.(R)) are prepared by reaction of chlorides 8 with pentafluorophenol (Scheme 4). The resulting reaction phosphoric enantiomeric mixtures 17 is separated into individual phosphoric enantiomers 17(P.sup.(S)) and 17(P.sup.(R)) by crystallization from a suitable solvent or by chromatography. Reaction of the last compounds with the nucleosides 12 gives compounds 18(P.sup.(S)), 18(P.sup.(R)), which is hydrogenated catalytically to give acids 19(P.sup.(S)), 19(P.sup.(R)).

(42) ##STR00025##
wherein: 1(P.sup.(S-)), 2(P.sup.(S-)), 1(P.sup.(R-)), and 2(P.sup.(R-)), 8, 17, 17(P.sup.(S-)), 17(P.sup.(R)), 18(P.sup.(S-)), 18(P.sup.(R)), 19(P.sup.(S- )), 19(P.sup.(R)), and a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof; Ar, R.sup.1, R.sup.2, R.sup.3, X, Y, and Q are as defined above.

(43) The present disclosure will now be described in connection with certain embodiments, which are not intended to limit its scope. On the contrary, the present disclosure covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include specific embodiments, will illustrate one practice of the present disclosure, it being understood that the examples are for the purposes of illustration of certain embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.

EXAMPLES

Example 1. General Procedure for Preparing Tert-Butoxycarbonylamino)-Propanoates 6a-g

(44) ##STR00026##

(45) To a solution 2.606 g (14.5 mmol) of benzyl L-lactate (4) and 2.764 g (14.6 mmol) of N-Boc-1-alanine (5a) in 100 ml of DCM at 0 C. were added DMAP (0.353 g, 2.9 mmol) and DCC (3.044 g, 14.7 mmol). The reaction was stirred for 15 h at rt and filtered. The precipitate was washed with ether, the combined filtrate was rotovapped and purified by column chromatography on silica gel (hexane: EtOAc 4:1) to give 4.7 g (92%) of 5)-((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-(tert-butoxycarbonylamino)propanoate (6a) as a viscous colorless oil. 1H NMR (DMSO-d.sub.6, 400 MHz) : 7.36 (m, 6H), 5.15 (s, 2H), 5.12 (m, 1H), 4.04 (m, 1H), 1.43 (d, J=7.2 Hz, 3H), 1.37 (s, 9H), 1.23 (t, J=7.2 Hz, 3H).

(46) Similarly prepared were: (S)-3-(benzyloxy)-3-oxopropyl 2-(tert-butoxycarbonylamino)propanoate (6b)yield 97%, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.36 (m, 5H), 7.24 (d, J=7.6 Hz, 1H), 5.12 (s, 2H), 4.32 (p, J=6.0 Hz, 1H), 4.22 (p, J=6.0 Hz, 1H), 3.95 (p, J=7.2 Hz, 0.9H), 3.87 (m, 0.1H), 2.73 (t, J=6.0 Hz, 2H), 1.37 (s, 8H), 1.32 (brs, 1H), 1.17 (d, J=7.2 Hz, 3H); (S)-benzyl 4-(2-(tert-butoxycarbonylamino)propanoyloxy)butanoate (3c)yield 96%, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.36 (m, 5H), 7.26 (d, J=7.6 Hz, 1H), 5.09 (s, 2H), 4.06 (m, 2H), 3.97 (m, 1H), 2.45 (t, J=7.6 Hz, 2H), 1.84 (p, J=6.8 Hz, 2H), 1.36 (s, 8H), 1.31 (brs, 1H), 1.22 (d, J=7.2 Hz, 3H); (S)-benzyl 5-(2-(tert-butoxycarbonylamino)propanoyloxy)pentanoate (3d)yield 99%, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 7.36 (m, 5H), 7.23 (d, J=7.2 Hz, 1H), 5.08 (s, 2H), 4.01 (m, 3H), 2.39 (m, 2H), 1.59 (m, 4H), 1.37 (s, 8H), 1.32 (brs, 1H), 1.22 (d, J=7.2 Hz, 3H); (S)-benzyl 6-(2-(tert-butoxycarbonylamino)propanoyloxy)hexanoate (3e)yield 99%, .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.37 (m, 5H), 5.13 (s, 2H), 5.05 (brs, 1H), 4.30 (m, 1H), 4.13 (m, 2H), 2.39 (t, J=7.2 Hz, 2H), 1.68 (m, 4H), 1.46 (s, 8.4H), 1.44 (brs, 0.6H), 1.40 (m, 2H), 1.38 (d, J=7.2 Hz, 3H); (5)-benzyl 7-(2-(tert-butoxycarbonylamino)propanoyloxy)heptanoate (3f)yield 99%, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.35 (m, 5H), 7.23 (d, J=7.6 Hz, 1H), 5.08 (s, 2H), 4.00 (m, 3H), 2.34 (t, J=7.2 Hz, 2H), 1.54 (m, 4H), 1.37 (s, 8H), 1.33 (brs, 1H), 1.28 (m, 4H), 1.22 (d, J=7.2 Hz, 3H). (S)-benzyl 8-(2-(tert.-butoxycarbonylamino)propanoyloxy)octanoate (3 g)yield 99%, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 7.36 (m, 5H), 7.23 (d, J=7.2 Hz, 1H), 5.08 (s, 2H), 4.00 (m, 3H), 2.34 (t, J=7.2 Hz, 2H), 1.53 (m, 4H), 1.37 (s, 8H), 1.33 (brs, 1H), 1.26 (m, 6H), 1.22 (d, J=7.2 Hz, 3H).

Example 2. General Procedure for Preparing 2-aminopropanoate Hydrochlorides 7a-g

(47) ##STR00027##

(48) To a solution 4.7 g (13.4 mmol) of (5)-((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-(tert-butoxycarbonylamino)propanoate (6a) in 40 ml of dioxane 40 ml of 3N HCl in dioxane was added. The solution was stirred for 15 h at rt and rotovapped to afford (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-aminopropanoate hydrochloride (7a) quantitatively as a viscous colorless oil which slowly crystallized. LC-MS (ESI) 252 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 8.63 (brs, 3H), 7.38 (m, 5H), 5.26 (q, J=7.2 Hz, 1H), 5.19 (m, 2H), 4.15 (q, J=7.2 Hz, 1H), 1.48 (d, J=7.2 Hz, 3H), 1.42 (d, J=7.2 Hz, 3H).

(49) Similarly prepared were: (S)-3-(benzyloxy)-3-oxopropyl 2-aminopropanoate hydrochloride (7b)LC-MS (ESI) 252 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 8.56 (brs, 3H), 7.37 (m, 5H), 5.13 (s, 2H), 4.43 (m, 1H), 4.33 (m, 1H), 4.01 (m, 1H), 2.80 (t, J=6.0 Hz, 2H), 1.34 (d, J=7.2 Hz, 3H); (S)-benzyl (2-aminopropanoyloxy)butanoate hydrochloride (7c)LC-MS (ESI) 266(M+H).sup.+; (S)-benzyl 5-(2-aminopropanoyloxy)pentanoate hydrochloride (7d)LC-MS (ESI) 280 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 8.60 (brs, 3H), 7.36 (m, 5H), 5.09 (s, 2H), 4.15 (m, 2H), 4.04 (m, 1H), 2.41 (m, 2H), 1.63 (m, 4H), 1.41 (d, J=7.2 Hz, 3H); (S)-benzyl 6-(2-aminopropanoyloxy)hexanoate hydrochloride (7e)LC-MS (ESI) 294 (M+H).sup.+; (S)-benzyl 7-(2-aminopropanoyloxy)heptanoate hydrochloride (7f)LC-MS (ESI) 308(M+H).sup.+, .sup.1H NMR (D.sub.2O, 400 MHz) : 7.27 (m, 5H), 5.00 (s, 2H), 4.11 (m, 3H), 2.25 (t, J=7.2 Hz, 2H), 1.51 (m, 4H), 1.48 (d, J=7.6 Hz, 3H), 1.19 (m, 4H); (S)-benzyl 8-(2-aminopropanoyloxy)octanoate hydrochloride (7 g)LC-MS (ESI) 322 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 8.54 (brs, 3H), 7.36 (m, 5H), 5.08 (s, 2H), 4.14 (m, 2H), 4.05 (m, 1H), 2.35 (t, J=7.2 Hz, 2H), 1.56 (m, 4H), 1.41 (d, J=7.2 Hz, 3H), 1.28 (m, 6H).

Example 3. General Procedure for Preparing 2-chloro(phenoxy)phosphorylamino)-propanoates 8a-g

(50) ##STR00028##

(51) A solution 3.035 g (10.5 mmol) of (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-aminopropanoate hydrochloride (7a) and phenyl dichlorophosphate (1.575 ml, 10.5 mmol) were dissolved in 40 ml of DCM and cooled to 78 C. A solution of triethylamine (2.86 mL, 21 mmol) in 10 mL of DCM was added dropwise and the resulted mixture was stirred at 78 C. for 1 h and then allowed to warm up to rt. The mixture was rotovapped and the residue was treated with benzene. The precipitate was filtered off and the filtrate was subjected to dry flash chromatography on dry silica gel (washed with MeCN, EtOAc, toluene, hexane) eluting with hexane: EtOAc 2:1 to give 3.8 g (85%) of S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-(chloro(phenoxy)phosphorylamino)propanoate (8a) as a colourless oil. .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.37 (m, 7H), 7.27 (m, 3H), 5.24 (m, 1H), 5.19 (m, 2H), 4.25 (m, 2H), 1.55 (m, 6H).

(52) Similarly prepared were: (2S)-3-(benzyloxy)-3-oxopropyl 2-(chloro(phenoxy)phosphorylamino)-propanoate (8b)yield 65%, .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.37 (m, 7H), 7.26 (m, 3H), 5.16, 5.17 (2s, 2H), 4.49 (m, 2H), 4.20 (m, 2H), 2.75 (q, J=5.6 Hz, 2H), 1.45, 1.46 (2d, J=7.2 Hz, 3H); benzyl 4-((S)-2-(chloro(phenoxy)phosphorylamino)propanoyloxy)butanoate (8c)yield 49%, .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.37 (m, 7H), 7.27 (m, 3H), 5.15 (2s, 2H), 4.32 (m, 1H), 4.24 (q, J=6.4 Hz, 2H), 4.18 (m, 1H), 2.48 (m, 2H), 2.05 (m, 2H), 1.51 (2d, J=7.2 Hz, 3H); benzyl 5-((S)-2-(chloro(phenoxy)phosphorylamino)propanoyloxy)pentanoate (8d)yield 61%, .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.37 (m, 7H), 7.27 (m, 3H), 5.14 (2s, 2H), 4.34 (m, 1H), 4.20 (m, 2H), 4.16 (m, 1H), 2.42 (m, 2H), 1.74 (m, 4H), 1.51, 1.52 (2d, J=7.2 Hz, 3H); benzyl 6-((S)-2-(chloro(phenoxy)phosphorylamino)propanoyloxy)hexanoate (8e)yield 22%, .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.37 (m, 7H), 7.28 (m, 3H), 5.13 (2s, 2H), 4.31 (m, 1H), 4.21 (m, 1H), 4.18 (q, J=6.8 Hz, 2H), 2.38 (m, 2H), 1.70 (m, 4H), 1.51, 1.52 (2d, J=7.2 Hz, 3H), 1.42 (m, 2H); benzyl 74(5)-2-(chloro(phenoxy)phosphorylamino)propanoyloxy)heptanoate (8f)yield 75%, .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.37 (m, 7H), 7.27 (m, 3H), 5.13 (s, 2H), 4.33 (m, 1H), 4.17 (m, 3H), 2.37, 2.38 (2t, J=7.4 Hz, 2H), 1.67 (m, 4H), 1.52, 1.53 (2d, J=7.2 Hz, 3H), 1.37 (m, 4H); benzyl 8-((S)-2-(chloro(phenoxy)phosphorylamino)propanoyloxy)octanoate (8 g)yield 72%; .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.37 (m, 7H), 7.27 (m, 3H), 5.13 (s, 2H), 4.31 (m, 1H), 4.19 (m, 3H), 2.36, 2.37 (2t, J=7.4 Hz, 2H), 1.65 (m, 4H), 1.52, 1.53 (2d, J=7.2 Hz, 3H), 1.34 (m, 6H).

Example 4. General Procedure for Preparing 1-((2R, 3R, 4R, 5R)-5-((tert-butyldimethylsilyloxy)methyl)-4-hydroxy-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-diones (10a,b)

(53) ##STR00029##

(54) To a solution 1.3 g (5 mmol) of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (9a) in 10 mL of pyridine was added tert-butylchlorodimethylsilane (866 mg, 5.75 mmol) at 0-5 C. followed by an addition of 1-methylimidazole (0.399 mL, 5 mmol). The mixture was stirred for 3 h, then 3 mL of methanol was added and stirred for 1 h more. The mixture was rotovapped, dissolved in DCM, washed with 5% citric acid solution, with brine, dried over Na.sub.2SO.sub.4 and rotovapped to afford 1-((2R,3R,4R,5R)-5-((tert-butyldimethylsilyloxy)methyl)-3-fluoro-4-hydroxy-3-methyl-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (10a) with quantitative yield. LC-MS (ESI) 375 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 11.51 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 6.00 (d, J=18.8 Hz, 1H), 5.73 (d, J=6.8 Hz, 1H), 5.54 (dd, J.sub.1=8.0 Hz, J.sub.2=2.4 Hz, 1H), 4.02 (dd, J.sub.1=12.0 Hz, J.sub.2=1.2 Hz, 1H), 3.89 (m, 1H), 3.80 (m, 2H), 1.27 (d, J=22.4 Hz, 3H), 0.90 (s, 9H), 0.10 (d, J=2.4 Hz, 6H).

(55) Similarly prepared were: 1-((2R, 4S, 5R)-5-((tert-butyldimethylsilyloxy)methyl)-4-hydroxy-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (10b). From 2-deoxyuridine. LC-MS (ESI) 343 (M+H).sup.+. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.31 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 6.14 (t, J=6.8 Hz, 1H), 5.57 (dd, J.sub.1=8.0 Hz, J.sub.2=2.0 Hz, 1H), 5.29 (d, J=4.4 Hz, 1H), 4.20 (m, 1H), 3.77 (m, 3H), 2.15 (m, 1H), 2.05 (m, 1H), 0.87 (s, 9H), 0.07 (s, 6H).

Example 5. General Procedure for Preparing Benzyl (2R, 3R, 4R, 5R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl carbonates (11a,b)

(56) ##STR00030##

(57) To a solution 1.935 g (5.17 mmol) of 1-((2R,3R,4R,5R)-5-((tert-butyldimethylsilyloxy)methyl)-3-fluoro-4-hydroxy-3-methyl-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (10a) and DMAP (1.263 g, 10.34 mmol) in 50 mL of DCM was added dropwise benzyl chloroformate (1.107 mL, 7.75 mmol) at 0-5 C. Then the reaction mixture was warmed to room temperature and stirred overnight, then washed with 5% citric acid solution and brine. After drying over Na.sub.2SO.sub.4 and rotovapping benzyl (2R,3R,4R,5R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-3-yl carbonate (11a) was used for the next step without additional purification. Yield quantitative. LC-MS (ESI) 509 (M+H).sup.+. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 11.56 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.39 (m, 5H), 6.04 (d, J=18.8 Hz, 1H), 5.62 (d, J=8.0 Hz, 1H), 5.21 (s, 2H), 5.14 (m, 1H), 4.18 (d, J=9.2 Hz, 1H), 4.18 (dd, J.sub.1=12.0 Hz, J.sub.2=2.4 Hz, 1H), 3.77 (dd, J.sub.1=12.0 Hz, J.sub.2=3.2 Hz, 1H), 1.33 (d, J=22.8 Hz, 3H), 0.86 (s, 9H), 0.08 (d, J=3.2 Hz, 6H).

(58) Similarly prepared were benzyl (2R,3S,5R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl carbonate (11b)LC-MS (ESI) 477 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 11.37 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.39 (m, 5H), 6.13 (dd, J.sub.1=8.0 Hz, J.sub.2=6.0 Hz, 1H), 5.63 (dd, J.sub.1=8.0 Hz, J.sub.2=2.0 Hz, 1H), 5.17 (s, 2H), 5.14 (m, 1H), 4.14 (m, 1H), 3.80 (m, 2H), 2.43 (m, 1H), 2.27 (m, 1H), 0.87 (s, 9H), 0.07 (s, 6H).

Example 6. General Procedure for Preparing Benzyl (2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-yl carbonates (12a,b)

(59) ##STR00031##

(60) To a solution 2.62 g (5.15 mmol) of benzyl (2R,3R,4R,5R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-3-yl carbonate (11a) in 50 mL of DCM was added Et.sub.3N.3HF (4.21 mL, 25.75 mmol) and the mixture was stirred for 24 h. The mixture was washed with water, dried over Na.sub.2SO.sub.4, diluted with 50 ml of toluene and rotovapped to a volume of about 30 mL. The precipitated product was filtered off, washed with hexane and dried. Yield of benzyl (2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-2-(hydroxymethyl)-4-methyl-tetrahydrofuran-3-yl carbonate (12a) is 1.715 g (84%). LC-MS (ESI) 395 (M+H).sup.+. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 11.53 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.40 (m, 5H), 6.05 (d, J=19.2 Hz, 1H), 5.72 (d, J=8.0 Hz, 1H), 5.36 (brs, 1H), 5.22 (m, 2H), 5.12 (dd, J.sub.1=20.0 Hz, J.sub.2=8.4 Hz, 1H), 4.12 (m, 1H), 3.80 (m, 1H), 3.61 (m, 1H), 1.33 (d, J=23.2 Hz, 3H).

(61) Similarly prepared were benzyl (2R, 3S, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-yl carbonate (12b). Yield 80%. LC-MS (ESI) 363 (M+H).sup.+. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.34 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.39 (m, 5H), 6.15 (dd, J.sub.1=8.8 Hz, J.sub.2=6.0 Hz, 1H), 5.67 (dd, J.sub.1=8.0 Hz, J.sub.2=2.0 Hz, 1H), 5.19 (m, 2H), 5.17 (s, 2H), 4.07 (m, 1H), 3.62 (m, 2H), 2.37 (m, 1H), 2.29 (m, 1H).

Example 7. General Procedure for Preparing (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-((((2R,3R,4R,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoates (13a-i)

(62) ##STR00032##

(63) To a solution 197 mg (0.5 mmol) of benzyl (2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-2-(hydroxymethyl)-4-methyl-tetrahydrofuran-3-yl carbonate (8a) and 330 mg (0.75 mmol) (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-(chloro(phenoxy)phosphorylamino)-propanoate (12a) in 10 ml of acetonitrile was added N-methylimidazole (0.159 mL, 1 mmol) and the mixture was stirred for 18 h then quenched with 0.2 mL of methanol. The solvent was rotovapped, the residue was dissolved in DCM, washed with 3% citric acid and brine, dried over Na.sub.2SO.sub.4, rotovapped subjected to column chromatography on silica gel (hexane: EtOAc 2:3) to give 364 mg (93%) of (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-((((2R,3R,4R,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate (13a) as colourless glassy solid. LC-MS (ESI) 784 (M+H).sup.+.

(64) Similarly prepared were: (S)-3-(benzyloxy)-3-oxopropyl 2-((((2R,3R,4R,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate (13b)yield 88%, LC-MS (ESI) 784 (M+H).sup.+; benzyl 445)-2-((((2R,3R,4R,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)-phosphorylamino)propanoyloxy)butanoate (13c)yield 81%, LC-MS (ESI) 798 (M+H).sup.+; benzyl 5-((S)-2-((((2R,3R,4R,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy)pentanoate (13d)yield 84%, LC-MS (ESI) 812 (M+H).sup.+; benzyl 6-((S)-2-((((2R,3R,4R,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy) phosphorylamino)propanoyloxy)hexanoate (9e)yield 85%, LC-MS (ESI) 826 (M+H).sup.+; benzyl 7-((S)-2-((((2R,3R,4R,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy)heptanoate (9f)yield 80%, LC-MS (ESI) 840 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 11.57 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.36 (m, 12H), 7.18 (m, 3H), 6.07 (m, 2H), 5.63 (t, J=8.6 Hz, 1H), 5.20 (m, 3H), 5.07 (s, 2H), 4.31 (m, 3H), 3.97 (m, 2H), 3.84 (m, 1H), 2.31, 2.32 (2t, J=7.2 Hz, 2H), 1.49 (m, 4H), 1.34 (d, J=22.8 Hz, 3H), 1.23 (m, 7H); benzyl 8-((S)-2-(4(2R,3R,4R,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)-phosphorylamino)propanoyloxy)octanoate (13 g)yield 83%, LC-MS (ESI) 854 (M+H).sup.+; (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-(((2R,3S,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate (13 h)yield 70%, LC-MS (ESI) 752 (M+H).sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 11.38 (s, 1H), 7.59, 7.62 (2d, J=8.4 Hz, 1H), 7.37 (m, 12H), 7.19 (m, 3H), 6.15 (m, 2H), 5.57 (m, 1H), 5.18 (m, 1H), 5.17 (s, 2H), 5.15 (s, 2H), 5.07 (m, 1H), 4.24 (m, 3H), 3.94 (m, 1H), 2.36 (m, 1H), 2.23 (m, 1H), 1.40, 1.41 (2d, J=6.8 Hz, 3H), 1.23, 1.25 (2d, J=7.2 Hz, 3H); benzyl 4((S)-2-((((2R,3S,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino) propanoyloxy)butanoate (13i)yield 81%, LC-MS (ESI) 766 (M+H).sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 11.39 (s, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.36 (m, 12H), 7.18 (m, 3H), 6.12 (m, 2H), 5.54, 5.61 (2dd, J.sub.1=8.0 Hz, J.sub.2=2.0 Hz, 1H), 5.18 (m, 1H), 5.17 (s, 2H), 5.07, 5.08 (2s, 2H), 4.24 (m, 3H), 4.03 (m, 2H), 3.86 (m, 1H), 2.43 (t, J=7.2 Hz, 2H).

Example 8. General Procedure for Preparing S)-2-((S)-2-(4(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxy-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino) propanoyloxy)propanoic acid (3a-i)

(65) ##STR00033##

(66) A solution 364 mg (0.46 mmol) of compound 13a in 20 ml of EtOAc was stirred with 40 mg of 10% Pd/C under hydrogen for 12 h. The resulted solution was filtered through a celite and rotovapped to afford 260 mg (100%) of S)-2-((S)-2-(4(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy) propanoic acid (3a). LC-MS (ESI) 560 (M+H).sup.+. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 13.00 (brs, 1H), 11.51 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 7.21 (m, 3H), 6.14 (m, 1H), 6.03 (m, 1H), 5.55 (m, 1H), 4.89 (m, 1H), 4.40 (m, 1H), 4.25 (m, 1H), 4.02 (m, 1H), 3.87 (m, 2H), 1.37, 1.38 (2d, J=7.2 Hz, 3H), 1.26 (m, 6H).

(67) Similarly prepared were: 3-((S)-2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy) propanoic acid (3b)LC-MS (ESI) 560 (M+H).sup.+; 4-((S)-2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy) phosphorylamino)propanoyloxy)butanoic acid (3c)LC-MS (ESI) 574 (M+H).sup.+; 5-((S)-2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy)pentanoic acid (3d)LC-MS (ESI) 588 (M+H).sup.+; 6-((S)-2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy)-hexanoic acid (3e)LC-MS (ESI) 602 (M+H).sup.+; 7-((S)-2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino) propanoyloxy)heptanoic acid (3f)LC-MS (ESI) 616 (M+H).sup.+; 7-((S)-2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy) (phenoxy)phosphorylamino)propanoyloxy)-octanoic acid (3 g)LC-MS (ESI) 630 (M+H).sup.+; (S)-2-((S)-2-((((2R,3S,5R)-3-hydroxy-5-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy)propanoic acid (3H)LC-MS (ESI) 542 (M+H).sup.+; 4-((S)-2-((((2R,3S,5R)-3-hydroxy-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy)butanoic acid (3i). LC-MS (ESI) 556 (M+H).sup.+.

Example 9. Procedure for Preparing (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-((S)-(perfluorophenoxy)(phenoxy)phosphorylamino)propanoate (17a)

(68) ##STR00034##

(69) To a solution 6.247 g (14.7 mmol) of (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-(chloro(phenoxy)phosphorylamino)propanoate (8a) in 70 mL of anhydrous DCM was added dropwise a solution 2.7 g (14.7 mmol) of pentafluorophenol and triethylamine (1.99 mL, 14.7 mmol) in 20 mL of DCM at 0 C. The mixture was stirred at rt for 15 h and rotovapped. The residue was treated with 150 mL of toluene, the solution was filtered and rotovapped again. The residue was treated with 100 mL of 4:1 hexane/EtOAc. After 1 h the precipitate was filtered, washed with hexane and recrystallized from 100 mL of 4:1 Hexane/EtOAc to afford 2.766 g (33%) of (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-((S)-(perfluorophenoxy)(phenoxy)phosphorylamino)propanoate (17a) as a white solid. LC-MS (ESI) 574 (M+H).sup.+, .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.36 (m, 7H), 7.25 (m, 3H), 5.19 (m, 3H), 4.27 (m, 1H), 3.89 (m, 1H), 1.54 (d, J=7.2 Hz, 3H), 1.49 (d, J=7.2 Hz, 3H).

Example 10. Procedure for Preparing Benzyl 4-((S)-2-((S)-(perfluorophenoxy)(phenoxy)phosphorylamino)propanoyloxy)butanoate (17b)

(70) ##STR00035##

(71) To a solution 5.8 g (13.2 mmol) of benzyl 4-((S)-2-(chloro(phenoxy)phosphorylamino)propanoyloxy)butanoate (8b) in 70 mL of anhydrous DCM was added a solution 2.43 g (13.2 mmol) of pentafluorophenol and triethylamine (1.84 mL, 13.2 mmol) in 10 mL of dichloromethane at 0 C. The mixture was stirred at rt for 15 h and rotovapped. The residue was treated with 150 mL of toluene, the solution was filtered and rotovapped again. The residue was treated with 100 mL of hexane. After 1 h the formed precipitate was filtered, washed with hexane and air-dried. The product was washed with water and air-dried. Benzyl 4-((S)-2-((S)-(perfluorophenoxy)(phenoxy)phosphorylamino)propanoyloxy)butanoate (17b) was obtained as a white solid, 5.8 g, 75%. LC-MS (ESI) 588 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3, 400 MHz) : 7.36 (m, 7H), 7.24 (m, 3H), 5.14 (s, 2H), 4.19 (m, 3H), 3.97 (m, 1H), 2.45 (t, J=7.2 Hz, 2H), 2.02 (m, 2H), 1.47 (d, J=6.8 Hz, 3H).

Example 11. General Procedure for Preparing Compounds 18aP(S), 18cP(S) and 18iP(S)

(72) ##STR00036##

(73) To a solution 789 mg (2 mmol) of benzyl (2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-2-(hydroxymethyl)-4-methyl-tetrahydrofuran-3-yl carbonate (12a) in 40 mL of THF under Ar was added tert-butylmagnesium chloride 1M solution in THF (4.2 mL, 4.2 mmol) and the mixture was stirred for 0.5 h at rt. A solution 0.63 g (1.1 mmol) of (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-((S)-(perfluorophenoxy)(phenoxy)phosphorylamino)propanoate (17a) in 5 ml of THF was added by syringe and the mixture was stirred overnight under Ar at rt. The reaction mixture was quenched with 1 mL of methanol, rotovapped, the residue was dissolved in DCM, washed with 5% citric acid, saturated NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and rotovapped. The desired product was separated by column chromatography on silica gel (hexane: EtOAc 1:1, 1:2, 0:1). Yield of (S)((S)-1-(benzyloxy)-1-oxopropan-2-yl) 2-((S)-(((2R,3R,4R,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate (18aP.sup.(S)) is 700 mg (44%). LC-MS (ESI) 784 (M+H).sup.+.

(74) Similarly prepared were: benzyl 4-((S)-2-((S)-(((2R,3R,4R,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy)butanoate (18cP.sup.(S))yield 69%, LC-MS (ESI) 798 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 11.55 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.37 (m, 12H), 7.17 (m, 3H), 6.08 (dd, J.sub.1=12.8 Hz, J.sub.2=10.4 Hz, 1H), 6.01 (m, 1H), 5.62 (d, J=8.0 Hz, 1H), 5.20 (m, 3H), 5.08 (s, 2H), 4.34 (m, 1H), 4.27 (m, 2H), 4.03 (m, 2H), 3.86 (m, 1H), 2.42 (t, J=7.6 Hz, 2H), 1.82 (p, J=6.8 Hz, 2H), 1.34 (d, J=23.2 Hz, 3H), 1.22 (d, J=7.2 Hz, 3H); benzyl 4-((S)-2-((((2R,3S,5R)-3-(benzyloxycarbonyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydro furan-2-yl)methoxy) (phenoxy)phosphorylamino)propanoyloxy)butanoate (18iP.sup.(S))yield 94%, LC-MS (ESI) 766 (M+H).sup.+.

Example 12. General Procedure for Preparing Compounds 19aP(S), 19cP(S) and 19iP(S)

(75) ##STR00037##

(76) A solution 700 mg (0.9 mmol) of compound 18aP.sup.(S) in 25 ml of EtOAc was stirred with 70 mg of 10% Pd/C under hydrogen for 12 h. The resulted solution was filtered through a celite and rotovapped to afford 499 mg (100%) of (S)-2-((S)-2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy)propanoic acid (19aP.sup.(S)). LC-MS (ESI) 560 (M+H).sup.+.

(77) Similarly prepared were: 4((S)-2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)pho sphorylamino) propanoyloxy)butanoic acid (19cP.sup.(S))LC-MS (ESI) 574 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) : 12.11 (s, 1H), 11.50 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.37 (m, 2H), 7.30 (m, 3H), 6.07 (dd, J.sub.1=12.8 Hz, J.sub.2=10.4 Hz, 1H), 6.01 (m, 1H), 5.83 (d, J=8.0 Hz, 1H), 5.54 (dd, J.sub.1=8.0 Hz, J.sub.2=2.0 Hz, 1H), 4.37 (m, 1H), 4.24 (m, 1H), 4.02 (m, 3H), 3.86 (m, 2H), 2.27 (t, J=7.2 Hz, 2H), 1.77 (p, J=6.8 Hz, 2H), 1.25 (d, J=22.4 Hz, 3H), 1.25 (d, J=7.2 Hz, 3H); 4-((S)-2-((((2R,3S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoyloxy)butanoic acid (19iP.sup.(S))LC-MS (ESI) 542 (M+H).sup.+.

Example 13. General Procedure for Preparing Macroheterocyclic Nucleoside Derivative and their Analogue of the General Formula (1) or (2)

(78) Cyclization of the acids 10a-i, 19aP.sup.(S), 19cP.sup.(S), and 19iP.sup.(S) (general procedure). To a solution 0.5 mmol of the acid 10a-i, 19aP.sup.(S), 19cP.sup.(S), or 19iP.sup.(S) and HATU (209 mg, 0.55 mmol) in 10 mL of dry MeCN was added DIPEA (0.218 mL, 1.25 mmol) and the mixture was stirred for 24 h. The solution was rotovapped, dissolved in DCM, washed with 5% citric acid solution, with brine, rotovapped and subjected to column chromatography on silica gel (hexane: EtOAc 1:3-1:4). Corresponding macroheterocyclic nucleoside derivative and their analogue of the general formula 1 or 2 is prepared in the form of mixtures or individual enantiomers. Mixtures of enantiomers 1 and 2 were separated by crystallization from a suitable solvent or by chromatography. (2R,3aS,6S,9S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-6,9-dimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(1/2)), LC-MS (ESI) 510 (M+H).sup.+. (2R,3aS,6S,9S,11S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-6,9-dimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(1)), LC-MS (ESI) 510 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.33 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 7.22 (m, 2H), 7.19 (m, 1H), 6.16 (m, 2H), 5.62 (d, J=8.0 Hz, 1H), 5.06 (m, 1H), 4.92 (q, J=7.0 Hz, 1H), 4.26 (m, 1H), 4.16 (m, 2H), 3.88 (m, 1H), 2.62 (m, 1H), 2.36 (m, 1H), 1.47 (d, J=7.2 Hz, 3H), 1.32 (d, J=7.2 Hz, 3H). (2R,3aS,6S,9S,11R,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-6,9-dimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(2)), LC-MS (ESI) 510 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.32 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.40 (m, 2H), 7.22 (m, 3H), 6.34 (dd, J.sub.1=15.2 Hz, J.sub.2=9.6 Hz, 1H), 6.13 (dd, J.sub.1=8.0 Hz, J.sub.2=2.8 Hz, 1H), 5.59 (d, J=8.0 Hz, 1H), 5.02 (q, J=8.0 Hz, 1H), 4.92 (q, J=6.8 Hz, 1H), 4.44 (m, 1H), 4.05 (m, 1H), 3.91 (m, 1H), 3.75 (m, 1H), 2.66 (m, 1H), 2.37 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.24 (d, J=6.8 Hz, 3H). (2R,3R,3aR,6S,9S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,6,9-trimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(3/4)), LC-MS (ESI) 542 (M+H).sup.+. (2R,3R,3aR,6S,9S,11S,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,6,9-trimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(3)), LC-MS (ESI) 542 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.56 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.41 (m, 2H), 7.22 (m, 3H), 6.42 (dd, J.sub.1=14.8 Hz, J.sub.2=9.2 Hz, 1H), 6.16 (brs, 0.5H), 5.67 (d, J=8.0 Hz, 1H), 5.29 (brs, 0.5H), 4.98 (q, J=6.8 Hz, 1H), 4.44 (m, 1H), 4.24 (m, 2H), 3.78 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 1.36 (d, J=24.0 Hz, 3H), 1.27 (d, J=6.8 Hz, 3H). (2R,3R,3aR,6S,9S,11R,13aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,6,9-trimethyl-11-oxo-11-phenoxy-hexahydro-1,4,7,12-tetraoxa-10-aza-11-phospha-cyclopentacyclododecene-5,8-dione (1(4)), LC-MS (ESI) 542 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.47 (s, 1H), 7.46 (s, 1H), 7.36 (m, 2H), 7.22 (m, 2H), 7.18 (m, 1H), 6.18 (m, 2H), 6.05 (d, J=4.8 Hz, 1H), 5.11 (m, 0.5H), 4.98 (m, 0.5H), 4.91 (m, 2H), 4.22 (m, 3H), 3.99 (m, 1H), 3.91 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 1.36 (d, J=24.0 Hz, 3H), 1.27 (d, J=6.8 Hz, 3H). (2R,3R,3aR,10S,14aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,10-dimethyl-12-oxo-12-phenoxy-octahydro-1,4,8,13-tetraoxa-11-aza-12-phospha-cyclopentacyclotridecene-5,9-dione (1(5/6)), LC-MS (ESI) 542 (M+H).sup.+. (2R,3R,3aR,10S,12S,14aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,10-dimethyl-12-oxo-12-phenoxy-octahydro-1,4,8,13-tetraoxa-11-aza-12-phospha-cyclopentacyclotridecene-5,9-dione (1(5)), LC-MS (ESI) 542 (M+H).sup.+. (2S,3aS,11S,15aR)-2-(2-amino-6-oxo-1,6-dihydro-purin-9-yl)-11-methyl-1-methylene-13-oxo-13-phenoxy-decahydro-4,9,14-trioxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(7/8)), LC-MS (ESI) 556 (M+H).sup.+.

(79) (2S,3aS,11S,13S,15aR)-2-(2-amino-6-oxo-1,6-dihydro-purin-9-yl)-11-methyl-1-methylene-13-oxo-13-phenoxy-decahydro-4,9,14-trioxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(7)), LC-MS (ESI) 556 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.53 (s, 1H), 7.40 (m, 3H), 7.27 (m, 2H), 7.20 (m, 1H), 6.27 (dd, J.sub.1=14.8 Hz, J.sub.2=11.6 Hz, 1H), 6.08 (d, J=20.0 Hz, 1H), 5.26 (brs, 1H), 5.10 (brs, 1H), 4.40 (m, 2H), 4.29 (m, 1H), 4.20 (m, 2H), 3.65 (m, 1H), 2.57 (m, 2H), 2.05 (m, 1H), 1.96 (m, 1H), 1.29 (d, J=22.8 Hz, 3H), 1.21 (d, J=7.2 Hz, 3H). (2S,3S,3aS,11S,13R,15aR)-2-(6-amino-purin-9-yl)-3,11-dimethyl-1-methylene-13-oxo-13-phenoxy-decahydro-4,9,14-trioxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(8)), LC-MS (ESI) 556 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.56 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.39 (m, 2H), 7.21 (m, 3H), 6.17 (t, J=7.2 Hz, 1H), 6.08 (d, J=20.0 Hz, 1H), 5.62 (d, J=8.0 Hz, 1H), 5.40 (m, 1H), 4.35 (m, 3H), 4.20 (m, 2H), 3.80 (m, 1H), 2.62 (m, 2H), 2.07 (m, 1H), 1.90 (m, 1H), 1.30 (d, J=22.8 Hz, 3H), 1.18 (d, J=7.2 Hz, 3H). (2R,3aS,11S,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(9/10)), LC-MS (ESI) 524 (M+H).sup.+. (2R,3aS,11S,13S,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-11-methyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(9)), LC-MS (ESI) 524 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.32 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 7.24 (m, 2H), 7.19 (m, 1H), 6.19 (dd, J.sub.1=14.4 Hz, J.sub.2=11.2 Hz, 1H), 6.13 (dd, J.sub.1=6.8 Hz, J.sub.2=6.0 Hz, 1H), 5.43 (d, J=8.0 Hz, 1H), 5.30 (m, 1H), 4.38 (m, 1H), 4.14 (m, 3H), 4.03 (m, 1H), 3.64 (m, 1H), 2.55 (m, 1H), 2.44 (m, 2H), 2.29 (m, 1H), 1.99 (m, 2H), 1.21 (d, J=6.8 Hz, 3H). (2S, 3aR,11S,13R,15aS)-11-methyl-2-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(10)), LC-MS (ESI) 524 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.36 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 7.20 (m, 3H), 6.14 (t, J=6.8 Hz, 1H), 6.05 (t, J=10.8 Hz, 1H), 5.64 (d, J=8.0 Hz, 1H), 5.33 (m, 1H), 4.35 (m, 1H), 4.21 (m, 2H), 4.11 (m, 2H), 3.80 (m, 1H), 2.47 (m, 3H), 2.29 (m, 1H), 2.02 (m, 1H), 1.89 (m, 2H), 1.13 (d, J=6.8 Hz, 3H). (2R,3R,3aR,11S,5aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,11-dimethyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(13/14)), LC-MS (ESI) 556 (M+H).sup.+. (2R, 3R, 3aR, 11S, 13S, 15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,11-dimethyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(13)), LC-MS (ESI) 556 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.53 (s, 1H), 7.40 (m, 3H), 7.27 (m, 2H), 7.20 (m, 1H), 6.27 (dd, J.sub.1=14.8 Hz, J.sub.2=11.6 Hz, 1H), 6.08 (d, J=20.0 Hz, 1H), 5.26 (brs, 1H), 5.10 (brs, 1H), 4.40 (m, 2H), 4.29 (m, 1H), 4.20 (m, 2H), 3.65 (m, 1H), 2.57 (m, 2H), 2.05 (m, 1H), 1.96 (m, 1H), 1.29 (d, J=22.8 Hz, 3H), 1.21 (d, J=7.2 Hz, 3H).

(80) (2R,3R,3aR,11S,13R,15aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,11-dimethyl-13-oxo-13-phenoxy-octahydro-1,4,9,14-tetraoxa-12-aza-13-phospha-cyclopentacyclotetradecene-5,10-dione (1(14)), LC-MS (ESI) 556 (M+H).sup.+. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.56 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.39 (m, 2H), 7.21 (m, 3H), 6.17 (t, J=7.2 Hz, 1H), 6.08 (d, J=20.0 Hz, 1H), 5.62 (d, J=8.0 Hz, 1H), 5.40 (m, 1H), 4.35 (m, 3H), 4.20 (m, 2H), 3.80 (m, 1H), 2.62 (m, 2H), 2.07 (m, 1H), 1.90 (m, 1H), 1.30 (d, J=22.8 Hz, 3H), 1.18 (d, J=7.2 Hz, 3H). (2R,3R,3aR,12S,16aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12-dimethyl-14-oxo-14-phenoxy-decahydro-1,4,10,15-tetraoxa-13-aza-14-phospha-cyclopentacyclopentadecene-5,11-dione (1(17/18)), LC-MS (ESI) 560 (M+H).sup.+. (2R,3R,3aR,12S,14S,16aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12-dimethyl-14-oxo-14-phenoxy-decahydro-1,4,10,15-tetraoxa-13-aza-14-phospha-cyclopentacyclopentadecene-5,11-dione (1(17)), LC-MS (ESI) 560 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.55 (s, 1H), 7.54 (brs, 1H), 7.40 (m, 2H), 7.22 (m, 3H), 6.21 (dd, J.sub.1=14.4 Hz, J.sub.2=10.4 Hz, 1H), 6.05 (brs, 1H), 5.43 (brs, 1H), 5.28 (brs, 1H), 4.48 (m, 1H), 4.39 (m, 1H), 4.17 (m, 2H), 4.09 (m, 1H), 3.80 (m, 1H), 2.58 (m, 1H), 2.42 (m, 1H), 1.83 (m, 1H), 1.72 (m, 1H), 1.65 (m, 2H), 1.29 (d, J=22.8 Hz, 3H), 1.20 (d, J=6.8 Hz, 3H). (2R,3R,3aR,12S,14R,16aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,12-dimethyl-14-oxo-14-phenoxy-decahydro-1,4,10,15-tetraoxa-13-aza-14-phospha-cyclopentacyclopentadecene-5,11-dione (1(18)), LC-MS (ESI) 560 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.55 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 7.19 (m, 3H), 6.11 (brs, 1H), 6.01 (m, 1H), 5.69 (d, J=8.0 Hz, 1H), 5.21 (brs, 1H), 4.43 (m, 1H), 4.28 (m, 2H), 4.09 (m, 2H), 3.86 (m, 1H), 2.66 (m, 1H), 2.30 (m, 1H), 1.85 (m, 1H), 1.69 (m, 2H), 1.51 (m, 1H), 1.32 (d, J=22.8 Hz, 3H), 1.14 (d, J=7.2 Hz, 3H). (2R,3R,3aR,13S,15S,17aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,13-dimethyl-15-oxo-15-phenoxy-decahydro-1,4,11,16-tetraoxa-14-aza-15-phospha-cyclopentacyclohexadecene-5,12-dione (1(19/20)), LC-MS (ESI) 584 (M+H).sup.+. (2R,3R,3aR,13S,15S,17aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,13-dimethyl-15-oxo-15-phenoxy-decahydro-1,4,11,16-tetraoxa-14-aza-15-phospha-cyclopentacyclohexadecene-5,12-dione (1(19)), LC-MS (ESI) 584 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.56 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.37 (m, 2H), 7.19 (m, 3H), 6.05 (m, 2H), 5.58 (d, J=8.0 Hz, 1H), 5.28 (brs, 1H), 4.35 (m, 1H), 4.26 (m, 2H), 4.19 (m, 1H), 4.01 (m, 1H), 3.86 (m, 1H), 2.47 (m, 2H), 1.61 (m, 4H), 1.35 (m, 2H), 1.30 (d, J=22.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H). (2R,3R,3aR,13S,15R,17aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,13-dimethyl-15-oxo-15-phenoxy-decahydro-1,4,11,16-tetraoxa-14-aza-15-phospha-cyclopentacyclohexadecene-5,12-dione (1(20)), LC-MS (ESI) 584 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.55 (s, 1H), 7.49 (d, J=6.8 Hz, 1H), 7.41 (m, 2H), 7.28 (m, 2H), 7.21 (m, 1H), 6.19 (dd, J.sub.1=15.2 Hz, J.sub.2=10.4 Hz, 1H), 6.08 (d, J=19.6 Hz, 1H), 5.31 (d, J=6.8 Hz, 1H), 5.17 (brs, 1H), 4.50 (m, 1H), 4.38 (m, 2H), 3.95 (m, 2H), 3.82 (m, 1H), 2.48 (m, 2H), 1.61 (m, 4H), 1.27 (d, J=19.2 Hz, 3H), 1.24 (m, 2H), 1.14 (d, J=6.8 Hz, 3H). (2R,3R,3aR,14S,16S,18aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,14-dimethyl-16-oxo-16-phenoxy-dodecahydro-1,4,12,17-tetraoxa-15-aza-16-phospha-cyclopentacycloheptadecene-5,13-dione (1(21/22)) LC-MS (ESI) 598 (M+H).sup.+. (2R,3R,3aR,14S,16S,18aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,14-dimethyl-16-oxo-16-phenoxy-dodecahydro-1,4,12,17-tetraoxa-15-aza-16-phospha-cyclopentacycloheptadecene-5,13-dione (1(21)), LC-MS (ESI) 598 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.55 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.37 (m, 2H), 7.17 (m, 3H), 6.04 (m, 2H), 5.63 (d, J=8.0 Hz, 1H), 5.31 (brs, 1H), 4.36 (m, 1H), 4.29 (m, 2H), 4.18 (m, 1H), 4.00 (m, 1H), 3.84 (m, 1H), 2.45 (t, J=6.0 Hz, 2H), 1.70 (m, 1H), 1.57 (m, 3H), 1.34 (m, 4H), 1.31 (d, J=22.8 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H). (2R,3R,3aR,14S,16R,18aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,14-dimethyl-16-oxo-16-phenoxy-dodecahydro-1,4,12,17-tetraoxa-15-aza-16-phospha-cyclopentacycloheptadecene-5,13-dione (1(22)), LC-MS (ESI) 598 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.54 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.39 (m, 2H), 7.24 (m, 2H), 7.19 (m, 1H), 6.16 (dd, J.sub.1=14.4 Hz, J.sub.2=10.0 Hz, 1H), 6.05 (m, 1H), 5.47 (d, J=7.6 Hz, 1H), 5.29 (brs, 1H), 4.39 (m, 1H), 4.33 (m, 1H), 4.19 (m, 1H), 4.13 (m, 1H), 4.01 (m, 1H), 3.78 (m, 1H), 2.47 (m, 2H), 1.68 (m, 1H), 1.62 (m, 3H), 1.34 (m, 4H), 1.28 (d, J=22.8 Hz, 3H), 1.19 (d, J=6.8 Hz, 3H). (2R,3R,3aR,15S,17S,19aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-dodecahydro-1,4,13,18-tetraoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,14-dione (1(23/24)), LC-MS (ESI) 612 (M+H).sup.+. (2R,3R,3aR,15S,17S,19aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-dodecahydro-1,4,13,18-tetraoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,14-dione (1(23)), LC-MS (ESI) 612 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.55 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.36 (m, 2H), 7.19 (m, 3H), 6.05 (m, 2H), 5.48 (d, J=8.0 Hz, 1H), 5.25 (brs, 1H), 4.33 (m, 4H), 3.92 (m, 1H), 3.84 (m, 1H), 2.44 (m, 2H), 1.58 (m, 4H), 1.30 (m, 6H), 1.28 (d, J=22.8 Hz, 3H), 1.19 (d, J=6.8 Hz, 3H). (2R,3R,3aR,15S,17R,19aR)-2-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-fluoro-3,15-dimethyl-17-oxo-17-phenoxy-dodecahydro-1,4,13,18-tetraoxa-16-aza-17-phospha-cyclopentacyclooctadecene-5,14-dione (1(24)), LC-MS (ESI) 612 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.54 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 7.21 (m, 3H), 6.10 (dd, J.sub.1=14.4 Hz, J.sub.2=9.6 Hz, 1H), 6.04 (m, 1H), 5.52 (d, J=8.0 Hz, 1H), 5.24 (brs, 1H), 4.32 (m, 2H), 4.23 (m, 2H), 3.96 (m, 1H), 3.80 (m, 1H), 2.44 (m, 2H), 1.59 (m, 4H), 1.31 (m, 6H), 1.28 (d, J=22.8 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H). (2R,3R,3aR,9S,11S,13aR,15R,16R,16aR,22S,24S,26aR)-2,15-Bis(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,16-difluoro-3,9,16,22-tetramethyl-11,24-diphenoxydodecahydro-2H,13H-difuro[3,2-j:3,2-v][1,6,9,13,18,21,3,15,2,14] hexaoxadiazadiphosphacyclotetracosine-5,8,18,21(6H,9H,19H,22H)-tetrone 11,24-dioxide (2(1)), LC-MS (ESI) 1055. (2R,3R,3aR,11S,13S,15aR,17R,18R,18aR,26S,28S,30aR)-2,17-bis(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,18-difluoro-3,11,18,26-tetramethyl-13,28-diphenoxyhexadecahydro-2H,15H-difuro[3,2-1:3,2-z][1,6,11,15,20,25,3,17,2,16]hexaoxadiazadiphosphacyclooctacosine-5,10,20,25(6H,11H,21H,26H)-tetrone 13,28-dioxide (2(2)), LC-MS (ESI) 1111 (M+H).sup.+, .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.55 (s, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.38 (m, 4H), 7.22 (m, 4H), 7.19 (m, 2H), 6.15 (dd, J.sub.1=14.0 Hz, J.sub.2=10.0 Hz, 2H), 6.03 (m, 2H), 5.57 (d, J=8.0 Hz, 2H), 5.28 (brs, 2H), 4.37 (m, 2H), 4.28 (m, 2H), 4.17 (m, 4H), 4.07 (m, 2H), 3.85 (m, 2H), 2.53 (m, 4H), 1.88 (m, 4H), 1.30 (d, J=22.8 Hz, 6H), 1.23 (d, J=7.2 Hz, 6H).

Example 14

(81) Preparation of a pharmaceutical composition in the form of a tablet. Starch (1600 mg), ground lactose (1600 mg), talc (400 mg), and (2R, 3R, 3aR, 11S, 13S, 15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-cyclopentacyclotetradecene-5,10-dione (1(13)) (1000 mg) were mixed together and pressed into a bar. The resulting bar was comminuted into granules and sifted through a sieve to collect granules of 14-16 mesh. The granules thus obtained were shaped into tablets of a suitable form weighing 100-300 mg each.

Example 15

(82) Preparation of a pharmaceutical composition in the form of capsules. (2R, 3R,3aR, 11S, 13S, 15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-cyclopentacyclotetradecene-5,10-dione (1(13)) and lactose powder were carefully mixed in the ratio 2:1. The resultant powdery mixture was packed into gelatin capsules of a suitable size, 450 mg or 600 mg in each capsule.

Example 16

(83) Preparation of a pharmaceutical composition in the form of capsules. (2R,3R,3aR,11S,13S,15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-cyclopentacyclotetradecene-5,10-dione (1(13)) and AV-4047 or AV-4056, or AV-4058 and lactose powder were carefully mixed in the ratio 4:(0,51):2. The resultant powdery mixture was packed into gelatin capsules of a suitable size, 350 mg or 700 mg in each capsule.

Example 17

(84) Preparation of a pharmaceutical composition in the form of capsules. (2R, 3R, 3aR, 11S, 13S, 15aR)-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-cyclopentacyclotetradecene-5,10-dione (1(13)), Daclatasvir (Daklinza, BMS790052) and lactose powder were carefully mixed in the ratio 4:1:2. The resultant powdery mixture was packed into gelatin capsules of a suitable size, 700 mg in each capsule.

Example 18

(85) Anti-HCV activity (EC.sub.50) and cytotoxicity (CC.sub.50) of prodrugs of general formula 1. The HCV replicon assay was used to determine the antiviral activity of chemotherapeutic agents of general formula 1 (test compounds). Sovaldi (PSI-7977) was used as the reference drug. The test cell line used in the HCV Replicon Assay was the human hepatoma cell line Huh7 incorporating the HCV replicons synthesized by an outside vendor. 96-well plates were seeded with cells at a density of 7.510.sup.3 cells per well in 50 l of assay media. The compound stock solution was made up freshly in an assay medium (DMEM 1, Cellgro; cat. #10-013-CV) as a 2 stock. A total of 11 serial 3-fold dilutions of test compounds were prepared from the 2 stock in the assay media ranging from 20 nM-0.2 pM final concentrations. At least 4 hours after seeding the cells, compound treatment was initiated by adding 50 l of compound dilution to the plates. The final concentrations of compound therefore ranged from 10 nM to 0.1 pM when diluted 1:1 in culture media. The final DMSO concentration was 0.5%. Cells and inhibitors were incubated for 3 days at 37 C./5% CO.sub.2. The media was removed from the plates by gentle tapping. The cells were fixed with 100 l 1:1 acetone: methanol for 1 minute, washed three times with PBS buffer, and then blocked with 150 l/well 10% Fetal Bovine Serum (FBS) in PBS for 1 hour at room temperature. The cells were then washed three times with PBS buffer and incubated with 100 l/well anti-hepatitis C core mAb (Affinity BioReagents; cat. #MA1-080, 1 mg/ml stock diluted 1:4,000 in 10% FBS-PBS) for 2 hours at 37 C. Then, the cells were washed three times with PBS and incubated with 100 l/well HRP-Goat Anti-Mouse antibody (diluted 1:3.500 in 10% FBS-PBS) for 1 hour at 37 C. The cells were then washed three times with PBS and developed with an OPD solution, 100 l/well (1 OPD tablet+12 ml citrate/phosphate buffer+5 l 30% H.sub.2O.sub.2 per plate), for 30 minutes in the dark at room temperature. The reaction was stopped with 2N H.sub.2SO.sub.4 (100 l/well), and the absorbance was measured at A.sub.490 X on a Victor.sup.3 V 1420 Multilabel counter (Perkin Elmer). The EC.sub.50 values were calculated for test compounds from the resulting best-fit equations determined by Xlfit software.

(86) The cytotoxicity of the test compounds was studied in parallel using the same cell line, Huh7. Cell viability was determined using the ATPLite Kit (Perkin-Elmer, Boston, USA), according to manufacturer's instructions. 96-well black/transparent bottom plates were seeded with cells at a density of 7.510.sup.3 cells per well in 50 l medium. After 18 hours, compound treatment was initiated by adding 50 l of compound dilution into the plates. Each compound dilution was tested in triplicates. The cells and inhibitors were then incubated for 96 hours at 37 C./5% CO.sub.2. The plates were washed twice with PBS (0.2 ml/well), and then lysed by adding lysis buffer, 0.05 ml/well (all reagents were included with the ATPLite Kit). After rocking for 5 min on a rocking platform, substrate buffer was added (0.05 ml/well). After additional 5-min incubation, the plates were kept in dark for 10 min, and the luminescence was read using TopCount NXT (Packard, Perkin Elmer). CC.sub.50 values for all test compounds were determined using XLfit 4.1 software.

Example 19

(87) The human liver S9 fraction metabolic stability in human liver microsomal fraction of Macroheterocyclic nucleoside derivative represented by formula 1 and 2 and Sovaldi. Stock solutions of test compounds and PSI-352707 (10 mM) were prepared in DMSO and stored at 20 C. 10- standard solutions of PSI-352707 (10, 8, 5, 2 and 1 M) were prepared by dilution stock solution with water-acetonitrile mixture (1/1, v/v). The reaction mixture was prepared in a total volume of 350.5 L containing 0.1 M potassium phosphate buffer (pH 7.4), 1 mM NADPH, 7 mM G6P, 1.5 U/mL G6PDH, 3.3 mM MgCl.sub.2, 5 mM UDPGA, 122 Ldeionised water and 1 M test compound. The reaction mixture was pre-incubated at 400 rpm, 37 C. The reaction was initiated by adding 1 mg/mL human liver S9 fraction to the reaction mixture and incubated at 400 rpm, 37 C. At the desired times (0, 0.25, 0.5, 1, 2, 4, 6 8, 24 h), 30 L aliquots were taken and the reaction was stopped by adding 180 L acetonitrile containing 200 ng/ml of internal standard (IS, tolbutamide). Precipitation was performed on ice in refrigerator at +4 C. for 15 min. Then samples were centrifuged for 10 min at 3000 rpm. 150 l of the supernatant were taken for LC-MS/MS analysis. To prepare PSI-352707 calibration samples 148 L of supernatant after incubation without test compound were mixed with 2.1 L of corresponding 10-standard solution of PSI-352707.

(88) LC-MS/MS analysis was performed on QTrap 5500 System (AB Sciex) combined with 1290 UPLC System (Agilent). Separation was achieved on BioBasic AX column (502.1 mm, 5, Thermo Scientific). Mobile phase consisted of solvent A (10 mm ammonium formate in water-acetonitrile mixture (7/3, v/v), pH 5.6), and solvent B (1 mM ammonium formate in water-acetonitrile mixture (7/3, v/v), pH 9.8). Elution was performed using step gradient (0-0.4 min 80% B. 0.8-2.0 min 40% B, 2.2-3.0 mm 80% B).

(89) ABSciex QTrap 5500 Source (TurboIonSpray) was operated in negative ionization mode (Source temperature 650 C., Source gas 1 and Source gas 2-65 and 40 psi respectively). PSI-352707 and IS (tolbutamide) were detected in MRM mode by transitions with m/z 410 to 150 for H027-4261 (collision energy 30 kV) and 269/170 for tolbutamide (collision energy 25 kV). Flow rate was 0.5 mL/min, injection volume 1 L. Data analysis and quantitation was performed in Analyst 1.5.2 Software (AB Sciex).