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Claims for Patent: 5,648,379

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Claims 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): Von Itzstein; Laurence Mark (North Fitzroy, AU), Wu; Wen-Yang (Mount Waverley, AU), Van Phan; Tho (Carnegie, AU), Danylec; Basil (Box Hill, AU), Jin; Betty (Mount Waverly, AU), Colman; Peter Malcolm (East Melbourne, AU), Varghese; Joseph Noozhumurry (Brunswick, AU)
Assignee: Biota Scientific Management Pty., Ltd. (Melbourne, AU)
Application Number:08/325,074
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;

R.sup.1 denotes COOH, P(O)(OH).sub.2, NO.sub.2,SOOH, SO.sub.3 H, tetrazol, CH.sub.2 CHO, CHO or CH(CHO).sub.2,

R.sup.2 denotes H, OR.sup.6, F, Cl, Br, CN, NHR.sup.6, SR.sup.6 or CH.sub.2 X, wherein X is NHR.sup.6, halogen or OR.sup.6 and

R.sup.6 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 NO.sub.2 group, an NH.sub.2 group or a COOH group,

R.sup.3 and R.sup.3' are the same or different, and each denotes hydrogen, CN, NHR.sup.6, N.sub.3, SR.sup.6, .dbd.N--OR.sup.6, OR.sup.6, guanidino, ##STR23## R.sup.4 denotes NHR.sup.6, SR.sup.6, OR.sup.6, COOR.sup.6, NO.sub.2, C(R.sup.6).sub.3, CH.sub.2 COOR.sup.6, CH.sub.2 NO.sub.2 or CH.sub.2 NHR.sup.6, and

R.sup.5 denotes CH.sub.2 YR.sup.6, CHYR.sup.6 CH.sub.2 YR.sup.6 or CHYR.sup.6 CHYR.sup.6 CH.sub.2 CN CHYR.sup.6 CHYR.sup.6 CH.sub.2 YR.sup.6, where Y is O, S, NH or H, and successive Y moieties in an R.sup.5 group are the same or different,

and pharmaceutically acceptable salts or derivatives thereof,

provided that in general formula (I)

(i) when R.sup.3 or R.sup.3' is OR.sup.6 or hydrogen, and A is oxygen or sulphur, then said compound cannot have both

(a) an R.sup.2 that is hydrogen and

(b) an R.sup.4 that is O-acyl or NH-acyl, and

(ii) R.sup.6 represents a covalent bond when Y is hydrogen, and that in general formula (Ia),

(i) when R.sup.3 or R.sup.3' is OR.sup.6 or hydrogen, and A is nitrogen, then said compound cannot have both

(a) an R.sup.2 that is hydrogen, and

(b) an R.sup.4 that is NH-acyl, and

(ii) R.sup.6 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 R.sup.3 is hydrogen or R.sup.3' and R.sup.3' is --N.sub.3, --CN, --CH.sub.2 NH.sub.2, or --N.R.sup.8.R.sup.9 ;

R.sup.8 and R.sup.9 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).NH.sub.2, --CH.sub.2.COOH, --CH.sub.2 --CH.sub.2 --OH or --CH.sub.2.CH.(R.sup.10) (R.sup.11) ,

R.sup.10 and R.sup.11 may be the same or different, and each denotes oxygen or R.sup.12 N.dbd., and

R.sup.12 denotes hydrogen, --OH, --OCH.sub.3, --NH.sub.2, or (CH.sub.3).sub.2 N--

or a pharmaceutically acceptable salt or derivative thereof.

3. A compound as claimed in claim 1 wherein R.sup.3 is NHR.sup.6.

4. A compound as claimed in claim 1 wherein R.sup.3 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-e nopyranosonate;

Sodium 5-acetamido-4-amino-2,3,4,5-tetradeoxy-D-glycero-talo-non-2-enopyranosonat e; (4-epi-amino-Neu4Ac2en);

Methyl 5-acetamido-7,8,9-tri-O-acetyl-4-N,N-diallylamino-2,3,4,5-tetradeoxy-D-gly cero-D-galacto-non-2-enopyranosonate (4-N,N-diallylamino-Neu5,7,8,9Ac.sub.4 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-Neu5,7,8,9Ac.sub.4 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-azidoNeu5,7,8,9Ac.sub.4 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 comprising

administration 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;

R.sup.1 denotes COOH, P(O)(OH).sub.2, NO.sub.2, SOOH, SO.sub.3 H, tetrazol, CH.sub.2 CHO, O or CH(CHO).sub.2,

R.sup.2 denotes H, OR.sup.6, F. Cl, Br, CN, NHR.sup.6, SR.sup.6 or CH.sub.2 X, wherein X is NHR.sup.6, halogen or OR.sup.6 and

R.sup.6 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 NO.sub.2 group, an NH.sub.2 group or a COOH group,

R.sup.3 and R.sup.3' are the same or different, and each denotes hydrogen, CN, NHR.sup.6, N.sub.3, SR.sup.6, .dbd.N--OR.sup.6, OR.sup.6, guanidino ##STR27## R.sup.4 denotes NHR.sup.6, SR.sup.6, OR.sup.6, COOR.sup.6, NO.sub.2, C(R.sup.6).sub.3, CH.sub.2 COOR.sup.6, CH.sub.2 NO.sub.2 or CHYR.sup.6- CHYR.sup.6 CH.sub.2 CN CH.sub.2 NHR.sup.6, and

R.sup.5 denotes CH.sub.2 YR.sup.6, CHR.sup.6 CH.sub.2 YR.sup.6 or CHYR.sup.6 CHYR.sup.6 CH.sub.2 YR.sup.6, where Y is O, S, NH or H, and successive Y moieties in an R.sup.5 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 R.sup.1, R.sup.2, R.sup.4 and R.sup.5 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 R.sup.3b is (alk).sub.x NR.sup.6b R.sup.7b, CN or N.sub.3 where alk is an unsubstituted or substituted methylene,

x is 0 or 1

R.sup.6b is hydrogen, C.sub.1-6 alkyl, aryl, aralkyl, amidine, NR.sup.7b R.sup.8b or an unsaturated or saturated ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur,

R.sup.7b is hydrogen, C.sub.1-6 alkyl, or allyl;

R.sup.8b is hydrogen or C.sub.1-6 alkyl and R.sup.4b is NNHCOR.sup.9b where R.sup.9b is hydrogen, substituted or unsubstituted C.sub.1-4 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-enopyrano sonic 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-enopy ranosonic 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 R.sup.4B 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 R.sup.3 is NHR.sup.6.

24. A compound as claimed in claim 3 wherein R.sup.3 is NMR.sup.6.
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