Claims for Patent: 5,648,379

Summary for Patent: 5,648,379

Title:	Derivatives and analogues of 2-deoxy-2,3-didehydro-n-acetyl neuraminic acid and their use as antiviral agents
Abstract:	Derivatives and analogues of 2-deoxy-2,3-didehydro-N-acetyl neuraminic acid, pharmaceutical formulations thereof, methods for their preparation and their use in the treatment of viral infections, in particular influenza, are described.
Inventor(s):	Laurence Mark Von Itzstein, Wen-Yang Wu, Tho Van Phan, Basil Danylec, Betty Jin, Peter Malcolm Colman, Joseph Noozhumurry Varghese
Assignee:	Biota Scientific Management Pty Ltd
Application Number:	US08/325,074
Patent Claims:	1. A compound of formula (I) or formula (Ia) ##STR22## where in general formula (I), A is oxygen, carbon or sulphur, and in general formula (Ia), A is nitrogen or carbon;R1 denotes COOH, P(O)(OH)2, NO2,SOOH, SO3 H, tetrazol, CH2 CHO, CHO or CH(CHO)2, R2 denotes H, OR6, F, Cl, Br, CN, NHR6, SR6 or CH2 X, wherein X is NHR6, halogen or OR6 and R6 is hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; an allyl group or an unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an NO2 group, an NH2 group or a COOH group, R3 and R3' are the same or different, and each denotes hydrogen, CN, NHR6, N3, SR6, ═N--OR6, OR6, guanidino, ##STR23## R4 denotes NHR6, SR6, OR6, COOR6, NO2, C(R6)3, CH2 COOR6, CH2 NO2 or CH2 NHR6, and R5 denotes CH2 YR6, CHYR6 CH2 YR6 or CHYR6 CHYR6 CH2 CN CHYR6 CHYR6 CH2 YR6, where Y is O, S, NH or H, and successive Y moieties in an R5 group are the same or different, and pharmaceutically acceptable salts or derivatives thereof, provided that in general formula (I)(i) when R3 or R3' is OR6 or hydrogen, and A is oxygen or sulphur, then said compound cannot have both(a) an R2 that is hydrogen and (b) an R4 that is O-acyl or NH-acyl, and (ii) R6 represents a covalent bond when Y is hydrogen, and that in general formula (Ia), (i) when R3 or R3' is OR6 or hydrogen, and A is nitrogen, then said compound cannot have both(a) an R2 that is hydrogen, and (b) an R4 that is NH-acyl, and (ii) R6 represents a covalent bond when Y is hydrogen. 2. A compound as claimed in claim 1 wherein the compound is a compound of formula (II) ##STR24## wherein R3 is hydrogen or R3' and R3' is --N3, --CN, --CH2 NH2, or --N.R8.R9 ;R8 and R9 are the same or different, and each denotes hydrogen, a linear or cyclic alkyl group of 1 to 6 carbon atoms, an acyl or substituted acyl group of 1 to 6 carbon atoms, --C. (NH).NH2, --CH2.COOH, --CH2 --CH2 --OH or --CH2.CH.(R10) (R11) , R10 and R11 may be the same or different, and each denotes oxygen or R12 N═, and R12 denotes hydrogen, --OH, --OCH3, --NH2, or (CH3)2 N-- or a pharmaceutically acceptable salt or derivative thereof. 3. A compound as claimed in claim 1 wherein R3 is NHR6. 4. A compound as claimed in claim 1 wherein R3 is ##STR25## 5. A compound as claimed in claim 1 and selected from the group consisting of:Sodium 5-acetamido-4-azido-2,3,4,5-tetradeoxy-D-galacto-non-2-enopyranosonate (4-Azido-Neu5Ac2en); Sodium 5-acetamido-4-N,N-diallylamino-2,3,4,5-tetra deoxy-D-glycero-D-galacto-non-2-enopyranosonate; Sodium 5-acetamido-4-N-allylamino-2,3,4,5-tetra-deoxy-D-glycero-D-galacto-non-2-enopyranosonate; Sodium 5-acetamido-4-amino-2,3,4,5-tetradeoxy-D-glycero-talo-non-2-enopyranosonate; (4-epi-amino-Neu4Ac2en); Methyl 5-acetamido-7,8,9-tri-O-acetyl-4-N,N-diallylamino-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosonate (4-N,N-diallylamino-Neu5,7,8,9Ac4 2en1Me); Sodium 5-acetamido-4-N,N-diallylamino-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosonate; Methyl 5-acetamido-7,8,9-tri-O-acetyl-4-N-allylamino-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosonate (4-N-allylamino-Neu5,7,8,9Ac4 2en1Me); Sodium 2,-3-dideoxy-D-glycero-D-galacto-non-2-enopyranosonate; and Methyl5-acetamido-7,8,9-tri-O-acetyl-4-azido-2,3,4,5-tetradeoxy-D-glycero-D-talo-non-2-enopyranosonate (4-epi-azidoNeu5,7,8,9Ac4 2en1Me). 6. A pharmaceutical formulation comprising a compound of formula (I) or (Ia) as defined in claim 1 or a pharmaceutically acceptable salt or derivative thereof, together with a pharmaceutically acceptable carrier therefor. 7. A pharmaceutical formulation as claimed in claim 6 wherein the formulation is adapted for intranasal administration. 8. A method for the treatment of a mammal including man suffering from a viral infection comprisingadministration of a compound of formula (I) or formula (Ia) ##STR26## where in general formula (I), A is oxygen, carbon or sulphur, and in general formula (Ia), A is nitrogen or carbon; R1 denotes COOH, P(O)(OH)2, NO2, SOOH, SO3 H, tetrazol, CH2 CHO, O or CH(CHO)2, R2 denotes H, OR6, F. Cl, Br, CN, NHR6, SR6 or CH2 X, wherein X is NHR6, halogen or OR6 and R6 is hydrogen; an accyl group having 1 to 4 carbon atoms; a linear or cyclicc alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; an allyl group or an unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an NO2 group, an NH2 group or a COOH group, R3 and R3' are the same or different, and each denotes hydrogen, CN, NHR6, N3, SR6, ═N--OR6, OR6, guanidino ##STR27## R4 denotes NHR6, SR6, OR6, COOR6, NO2, C(R6)3, CH2 COOR6, CH2 NO2 or CHYR6- CHYR6 CH2 CN CH2 NHR6, and R5 denotes CH2 YR6, CHR6 CH2 YR6 or CHYR6 CHYR6 CH2 YR6, where Y is O, S, NH or H, and successive Y moieties in an R5 group are the same or different, or a pharmaceutically acceptable salt or derivative thereof. 9. A method for the treatment of a mammal including man suffering from a viral infection which comprises the step of administering to said mammal an effective amount of a compound of formula (I) or (Ia) as defined in claim 1. 10. A method as claimed in claim 9 wherein the viral infection is influenza. 11. A method as claimed in claim 8 wherein the infection is by a respiratory virus. 12. A method as claimed in claim 8 wherein the active ingredient is administered to the respiratory tract. 13. A method as claimed in claim 8 wherein the active ingredient is administered intranasally. 14. A method for the preparation of a compound of formula (I) as defined in claim 1 which comprises the steps of(A) reaction of a compound, of formula (III) ##STR28## wherein R1, R2, R4 and R5 are as defined in claim 1 and OL is a leaving group, with a nucleophile; or (B) interconversion of one compound of formula (I) to another compound of formula (I), and if necessary or desired, subjecting the resulting compound to one or two further reactions comprising:(i) removing any protecting groups; (ii) converting a compound of formula (I) or a salt thereof into a pharmaceutically acceptable salt thereof. 15. A method for the treatment of a mammal including man suffering from a viral infection comprising administration of an effective amount of a compound of formula (Ib) ##STR29## wherein R3b is (alk)x NR6b R7b, CN or N3 where alk is an unsubstituted or substituted methylene,x is 0 or 1 R6b is hydrogen, C1-6 alkyl, aryl, aralkyl, amidine, NR7b R8b or an unsaturated or saturated ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, R7b is hydrogen, C1-6 alkyl, or allyl; R8b is hydrogen or C1-6 alkyl and R4b is NNHCOR9b where R9b is hydrogen, substituted or unsubstituted C1-4 alkyl or aryl, or a pharmaceutically acceptable salt or derivative thereof. 16. A method as claimed in claim 15 wherein the infection is a viral respiratory infection. 17. A method as claimed in claim 16 wherein the viral infection is influenza. 18. A method as claimed in claim 15 wherein the active ingredient is administered to the respiratory tract. 19. A method as claimed in claim 15 wherein the compound is administered intranasally. 20. A method as claimed in claim 15 wherein the compound is 5-acetamido-4-amino-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosonic acid or a pharmaceutically acceptable salt thereof. 21. A method as claimed in claim 15 wherein the compound is 5-acetamido-4-guanidino-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosonic acid or a pharmaceutically acceptable salt thereof. 22. A method for the preparation of a compound of formula (Ib) as defined in claim 15 which comprises the steps of:(A) reaction of a compound, of formula (IIIb) ##STR30## wherein R4B is defined in claim 15 and OL is a leaving group, or a protected derivative of said compound, with a nucleophile; or (B) interconversion of one compound of formula (Ib) to another compound of formula (Ib) and necessary subjecting the resulting compound to one or two further reactions comprising:(i) removing any protecting groups; (ii) converting a compound of formula (Ib) or salt thereof into a pharmaceutically acceptable salt thereof. 23. A compound as claimed in claim 2 wherein R3 is NHR6. 24. A compound as claimed in claim 3 wherein R3 is NMR6.