5' O [(N ACYL)AMIDOPHOSPHATE] AND 5' O [(N ACYL)AMIDOTHIOPHOSPHATE] AND 5' O [(N ACYL)AMIDODITHIOPHOSPHATE] AND 5' O [(N ACYL)AMIDOSELENOPHOSPHATE] DERIVATIVES OF NUCLEOSIDES AND PROCESSES FOR THE MANUFACTURE THEREOF
First Claim
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1. 5′
- -O-[(N-acyl)amidophosphate]- and 5′
-O-[(N-acyl)amidothiophosphate]- and 5′
-O-[(N-acyl)amidodithiophosphate]- and 5′
-O-[(N-acyl)amidoselenophosphate]- derivatives of nucleosides of general formula 1 wherein A1 represents a fluorine atom or azide or hydroxyl group, A2 represents a hydrogen atom, B1 represents an adenine, 2-chloroadenine, 2-fluoroadenine, 2-bromoadenine, 2-iodoadenine, hypoxanthine, guanine, cytosine, 5-fluorocytosine, 5-bromocytosine, 5-iodocytosine, 5-chlorocytosine, azacytosine, thymine, 5-fluorouracil, 5-bromouracil, 5-iodouracil, 5-chlorouracil, 5-(2-bromovinyl)uracil or 2-pyrimidione moiety, W1 represents an oxygen or carbon atom or a methylidene group, W2 represents a carbon atom or A1, A2 and W2 jointly represent a sulphur or oxygen atom, Z1 represents a hydrogen or fluorine atom or hydroxyl group, Z2 represents a hydrogen or fluorine atom or hydroxyl or methyl group, or Z1 with Z2 jointly represent a fluoromethylene group, or A1, A2, Z1 and Z2 jointly represent a double bond, X represents an oxygen, sulphur or selenium atom, Y represents an oxygen or sulphur atom, R1 represents a simple alkyl or aryl group with 1-6 carbon atoms or a moiety of a primary amino acid amide.
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Abstract
The subject of the invention includes 5′-O-[(N-acyl)amidophosphate]- and 5′-O-[(N-acyl)amidothiophosphate]- and 5′-O-[(N-acyl)amidodithiophosphate]- and 5′-O-[(N-acyl)amidoselenophosphate]- derivatives of nucleosides.
54 Citations
15 Claims
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1. 5′
- -O-[(N-acyl)amidophosphate]- and 5′
-O-[(N-acyl)amidothiophosphate]- and 5′
-O-[(N-acyl)amidodithiophosphate]- and 5′
-O-[(N-acyl)amidoselenophosphate]- derivatives of nucleosides of general formula 1 wherein A1 represents a fluorine atom or azide or hydroxyl group, A2 represents a hydrogen atom, B1 represents an adenine, 2-chloroadenine, 2-fluoroadenine, 2-bromoadenine, 2-iodoadenine, hypoxanthine, guanine, cytosine, 5-fluorocytosine, 5-bromocytosine, 5-iodocytosine, 5-chlorocytosine, azacytosine, thymine, 5-fluorouracil, 5-bromouracil, 5-iodouracil, 5-chlorouracil, 5-(2-bromovinyl)uracil or 2-pyrimidione moiety, W1 represents an oxygen or carbon atom or a methylidene group, W2 represents a carbon atom or A1, A2 and W2 jointly represent a sulphur or oxygen atom, Z1 represents a hydrogen or fluorine atom or hydroxyl group, Z2 represents a hydrogen or fluorine atom or hydroxyl or methyl group, or Z1 with Z2 jointly represent a fluoromethylene group, or A1, A2, Z1 and Z2 jointly represent a double bond, X represents an oxygen, sulphur or selenium atom, Y represents an oxygen or sulphur atom, R1 represents a simple alkyl or aryl group with 1-6 carbon atoms or a moiety of a primary amino acid amide.
- -O-[(N-acyl)amidophosphate]- and 5′
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2. The process for the manufacture of 5′
- -O-[(N-acyl)amidophosphate]- and 5′
-O-[(N-acyl)amidothiophosphate]- and 5″
-O-[(N-acyl)amidodithiophosphate]- and 5′
-O-[(N-acyl)amidoselenophosphate]- derivatives of nucleosides of general formula 1 wherein A1 represents a fluorine atom or azide or hydroxyl group, A2 represents a hydrogen atom, B1 represents an adenine, 2-chloroadenine, 2-fluoroadenine, 2-bromoadenine, 2-iodoadenine, hypoxanthine, guanine, cytosine, 5-fluorocytosine, 5-bromocytosine, 5-iodocytosine, 5-chlorocytosine, azacytosine, thymine, 5-fluorouracil, 5-bromouracil, 5-iodouracil, 5-chlorouracil, 5-(2-bromovinyl)uracil or 2-pyrimidione moiety, W1 represents an oxygen or carbon atom or a methylidene group, W2 represents a carbon atom or A1, A2 and W2 jointly represent a sulphur or oxygen atom, Z1 represents a hydrogen or fluorine atom or hydroxyl group, Z2 represents a hydrogen or fluorine atom or hydroxyl or methyl group, or Z1 with Z2 jointly represent a fluoromethylene group, or A1, A2, Z1 and Z2 jointly represent a double bond, X represents an oxygen, sulphur or selenium atom, Y represents an oxygen or sulphur atom, R1 represents a simple alkyl or aryl group with 1-6 carbon atoms or a moiety of a primary amino acid amide characterized in that a nucleoside of general formula 2 wherein A2, W1 are as above, A3 represents a fluorine atom or azide or protected hydroxyl group, W2 represents a carbon atom or A2, A3 and W2 jointly represent a sulphur atom, B2 represents an adenine, 2-chloroadenine, 2-fluoroadenine 2-bromoadenine, 2-iodoadenine, hypoxanthine, guanine or cytosine moiety of formulas 3, 4, 5 wherein Z5 represents a hydrogen atom or a known exoamine blocking group, Z6 represents a hydrogen atom or a chlorine, fluorine, bromine or iodine atom, Z7 represents a hydrogen atom or fluorine, chlorine, bromine or iodine atom or B2 represents a thymine moiety, an azacytosine moiety or a 5-fluorouracil, 5-chlorouracil, 5-bromouracil, 5-iodouracil, 5-(2-bromovinyl)uracil or 2-pyrimidione moiety, and Z3 represents a hydrogen or fluorine atom or a protected hydroxyl group, Z4 represents a hydrogen or fluorine atom, a protected hydroxyl group or a methyl group or Z3 and Z4 jointly represent a fluoromethylene group or A2, A3, Z3, Z4 jointly represent a double bond, is condensed with a compound of general formula 6, wherein R2, R3, R4 and R5 each represent a hydrogen atom, simple alkyl or aryl with 1-6 carbon atoms, R6 represents an aromatic or non-aromatic 5- or 6-membered heterocyclic ring with 1-3 heteroatoms selected from a group consisting of an oxygen atom, nitrogen atom and sulphur atom, wherein the aryl or heterocyclic groups may be substituted with 1, 2 or 3 substituents independently selected from a group consisting of alkyl, halogen atom, CHF2, CF3, alkoxyl, halogenoalkoxyl, alkylthio group or R6 represents alkyl or phenyl or cycloalkyl which may be substituted with 1, 2 or 3 substituents independently selected from a group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkenyloxyl, alkynoxyl, cycloalkyl, cycloalkenyl, cycloalkyloxyl, cycloalkenyloxyl, phenyl and halogen atom, and the phenyl may be substituted with 1-5 halogen atoms and/or 1-3 substituents independently selected from a group consisting of an alkyl, halogenoalkyl, alkoxyl, halogenoalkoxyl, alkylthio group or halogenoalkylthio group, wherein the phenylamide group may be condensed with a saturated or unsaturated 5- or 6-membered ring which may be substituted with one or more alkyl groups and/or possibly containing a heteroatom selected from a group consisting of an oxygen atom, a nitrogen atom and a sulphur atom, or R6 represents a moiety of a primary amino acid amide of general formula 7 wherein R7 represents an amino acid side chain, R8 represents a hydrogen atom or a known amino acid alpha-amine-blocking group, X represents an oxygen, sulphur or selenium atom, Y represents an oxygen or sulphur atom;
the condensation is carried out in anhydrous organic solvents in the presence of condensation activators, and after reaction completion the amino acid alpha-amine-blocking group, the 2′
- and 3′
-hydroxyl blocking groups and the nucleoside exoamine blocking groups are removed using methods known in the art. - View Dependent Claims (3, 4, 5, 6, 7, 8)
- -O-[(N-acyl)amidophosphate]- and 5′
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9. The process for the manufacture of 5′
- -O-[(N-acyl)amidophosphate]- and 5′
-O-[(N-acyl)amidothiophosphate]- and 5′
-O-[(N-acyl)amidodithiophosphate]- and 5′
-O-[(N-acyl)amidoselenophosphate]-derivatives of nucleosides of general formula 1 wherein A1 represents a fluorine atom or azide or hydroxyl group, A2 represents a hydrogen atom, B1 represents an adenine, 2-chloroadenine, 2-fluoroadenine, 2-bromoadenine, 2-iodoadenine, hypoxanthine, guanine, cytosine, 5-fluorocytosine, 5-bromocytosine, 5-iodocytosine, 5-chlorocytosine, azacytosine, thymine, 5-fluorouracil, 5-bromouracil, 5-iodouracil, 5-chlorouracil, 5-(2-bromovinyl)uracil or 2-pyrimidione moiety, W1 represents an oxygen or carbon atom or a methylidene group, W2 represents a carbon atom or A1, A2 and W2 jointly represent a sulphur or oxygen atom, Z1 represents a hydrogen or fluorine atom or hydroxyl group, Z2 represents a hydrogen or fluorine atom or hydroxyl or methyl group, or Z1 with Z2 jointly represent a fluoromethylene group, or A1, A2, Z1 and Z2 jointly represent a double bond, X represents an oxygen, sulphur or selenium atom, Y represents an oxygen or sulphur atom, R1 represents a simple alkyl or aryl group with 1-6 carbon atoms or a moiety of a primary amino acid amide characterized in that the reagents used in the condensation include primary carboxylic amides of general formula R6CONH2 wherein R6 is as above or amino acid amides with moieties of general formula 7 wherein R7 and R8 are as above with nucleoside derivatives of general formula 8 wherein A2, A3, B2, R2, R3, R4, R5, W1, W2, Z3, Z4 are as above, X represents an oxygen, sulphur or selenium atom and Y represents an oxygen or sulphur atom;
the condensation is carried out in anhydrous organic solvents in the presence of condensation activators, and after reaction completion the amino acid alpha-amine-blocking groups, the 2′
- and 3′
-hydroxyl blocking groups and the nucleoside exoamine blocking groups are removed using methods known in the art. - View Dependent Claims (10, 11, 12, 13, 14, 15)
- -O-[(N-acyl)amidophosphate]- and 5′
Specification
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Current AssigneeP Centrum Badan Milekularnychi Makromolekularnych
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Original AssigneeP Centrum Badan Milekularnychi Makromolekularnych
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InventorsKaczmarek, Renata, Korczynski, Dariusz, Pieta, Katarzyna, Baraniak, Janina, Wasilewska, Ewa, Stec, Wojciech J.
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Application NumberUS12/444,774Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current536/26.800CPC Class CodesA61P 31/12 AntiviralsA61P 35/00 Antineoplastic agentsC07F 9/65586 at least one of the hetero ...C07F 9/65616 containing the ring system ...
