SPRUSON 8( FERGUSON AUSTRALIA PATENTS ACT 1990 PATENT REQUEST: STANDARD PATENT I/We, the Applicant(s)/Nominated Person(s) specified below, request I/We be granted a patent for the invention disclosed in the accompanying standard complete specification. [70,71] Appiicant(s)/Nomhated Person(s): Ciba-Geigy AG, incorporated in Switzerland, of Klybeckstrasse 141, 4002 Basle, SWITZERLAND [54] Invention Title: Dinucleotide and Oligonucleotide Analogues [72] Inventor(s): Anthony David Baxter, Eric Keith Baylis, Stephen Paul Collingwood, Roger John Taylor, Alain De Mesmaeker and Chantal • * ■ · Schmi t • · · · • · · V • · • · [74] Address for service in Australia: • · · • · · Spruson & Ferguson, Patent Attorneys • · 0 · • · Level 33 St Martins Tower • β · e · 31 Market Street • · · • · Sydney New South Wales Australia (Code SF) • · 9 0 Details of Basic Application (s): [31] Appl’n No(s): [33] Country: [32] Application Date: • · · · • · · · 9304618.3 GB 6 March 1993 • · · e e · · • · ® BasicApplicant(s): Ciba-Geigy AG DATED this FOURTH day of MARCH 1994 Ciba-Geigy AG By: istered Patent Attorney IRN: 264314 INSTR CODE: 52739 S 044420 040394 5845/3 SPRUSON & FERGUSON Australia Patents Act 1990 Notice Of Entitlement I, John David O'Connor, of 31 Market Street, Sydney, New South Wales, 2000, Australia, Patent Attorney for the Applicant/Nominated Person in respect of an application entitled: Dinucleotide and Oligonucleotide Analogues state the following:- The Applicant/Nominated Person has entitlement from the actual inventors as follows:- The Applicant/Nominated Person is the assignee of the actual inventors. The Applicant/Nominated Person is the applicant of the basic application listed on the Patent ,····, Request. • · · · ·> · · · ’••’I The basic application listed on the Patent Request is the first application made in a Convention Country in respect of the invention. Dated 1 March 1994 John David O'Connor • · « · • · · · • · · · IRN: 264314 INSTR CODE: 52739 IN LIBUI03169 GSA 1 of 5 AU9457590 (12) PATENT ABRIDGMENT (11) Document No. AU-B-57590/94 (19) AUSTRALIAN PATENT OFFICE (10) Acceptance no. 675104 (54) Title DINUCLEOTIDE AND OLIGONUCLEOTIDE ANALOGUES International Patent Classification(s) (51)5 C07F 009/32 A61K031/70 C07F 009/44 C07H 021/04 (21) Application No. : 57590/94 (22) Application Date : 04.03.94 (30) Priority Data (31) Number (32) Date (33) Country 9304618 06.03.93 GB UNITED KINGDOM (43) Publication Date : 08.09.94 (44) Publication Date of Accepted Application : 23.01.97 (71) Applicant(s) CIBA-GEIGY AG (72) Inventor(s) ANTHONY DAVID BAXTER; ERIC KEITH BAYLIS; STEPHEN PAUL COLLINGWOOD; ROGER JOHN TAYLOR, ALAIN DE MESMAEKER; CHANTAL SCHMIT (74) Attorney or Agent SPRUSON & FERGUSON , GPO Box 3898, SYDNEY NSW 2001 (56) Prior Art Documents AU 15497/92 C07F9/165 WO 91/15499 (57) Claim A dinucleotide analogue of formula where . ./2 (11) AU--B-57590/94 -2­ (10) 675104 B1 and B2 are each independently a monovalent nucleoside base radical; R1 is R’a or Z; R’a, R2, R3 and R4 are each independently hydrogen, halogen or hydroxy; R5 is R5a or Z; R6 is hydrogen or R6a; R7 is hydrogen, alkyl-N,N-dialkyIphosphoramidyl or R7a, R8 is R8a or Z, or the indicated R7O and R8 together denote an isopropylidenedioxy group; R5a and R8a are each independently hydrogen, halogen, hydroxy, -OR10, -OCOR10 or silyloxy substituted by three C]-C15 hydrocarbyl groups; R6a and R7a are each independently a Cj-Cjq aliphatic radical, a C6-C]5 aromatic radical, a C7-C30 araliphatic radical, -COR11, -SO2R11 or silyl substituted by three Cj-C^ hydrocarbyl groups; R9 is hydrogen, a Cj-Cg aliphatic radical, a C3-C8 cycloaliphatic radical, a Cg-C^ aromatic radical, a C7’C13 araliphatic radical, an alkali metal ion or an ammonium ion; R10 and R11 are each independently a ΟΓΟ10 aliphatic radical, a C3-C8 cycloaliphatic radical, a Cg-C15 aromatic radical or a C7-C]g araliphatic radical; Rx and Ry are independently hydrogen, halogen, hydroxy, a Ci-C10 alkyl, C2-Ci0 alkenyl, C3-C8 cycloalkyl, C6-C15 aryl, C7-C16 aralkyl, CpC^ alkoxy, C2-C10 alkenoxy, Cg-Cjo aryioxy or C7-C16 aralkyloxy group, which is substituted or unsubstituted, or -OCORZ; Rz is a substituted or unsubstituted C]-C10 alkyl, C2-C10 alkenyl, C3-C8 cycloalkyl, C6-C15 aryl or C7-Cig aralkyl group; and Z is C6-C10 aryloxythiocarbonyloxy, the C6-C10 aryl group being substituted or unsubstituted. ./3 (11) AU-B-57590/94 -3- 675104(10) 25. A compound of Formula O ... .„ Rm_P_C-C-0^B11 1 1 Ro2 ORg R4 Ry )-----\ R7O Rsa where R3, R4, R7, Rg, R9, Rx, Ry and B2 are as defined in claim 1 and Rm is hydrogen or a protecting group, provided that Rx and Ry are not both hydrogen. 29. A pharmaceutical composition comprising as active ingredient a dinucleotide analogue according to any one of claims 1 to 10, 26 or 28, an oligonucleotide incorporating at least one unit derived therefrom or an oligonucleotide according to any one of claims 19 or 21 to 24, - 1- FL/6-19470/A/MA2080 Dinucleotide and Oligonucleotide Analogues This invention relates to compounds which are dinucleotide analogues, their preparation and to oligonucleotide analogues incorporating units derived therefrom. For several years there has been interest in structural analogues of natural oligonucleotides because of their utility as anti-sense probes for inhibiting gene expression in biological systems and as pharmaceuticals in the treatment of viruses such as influenza, herpes and HIV, and in the treatment of cancer. Amongst the analogues of recent interest are those in which the groups linking the sugar moieties of oligonucleotides are modified by the replacement of the 31 and 51 oxy linkages by other linking groups. WO 91/15499 describes oligonucleotides of formula .. where B is a nucleic acid base; A is -O- or -CH2-; X and Z are each -0-., -S-, -NH- or • β · 9 .·*:·. -CH2- where X and Z may be the. same or different; V and W are =0, =S, =Se, -NH2, alkoxy, -OH or -SH, where V and W may be the same or different in a monomer unit; L is -H or a partner of a bonding pair; C is -OR where R is an alkyl, alkenyl or alkynyl group . * ’ * ’ · optionally substituted by one or more halogen, cyano, carboxy, hydroxy, nitro and/or mercapto radical"; and n is any integer. 4 • · · 9 • · · 9 ·"'*· No compounds of the above formula where X and Z are each -CH2- are disclosed in WO -2- 91/15499 and there is no suggestion as to how such compounds might be prepared. The preparation of oligonucleodde analogues in which both the 31 oxy linkage and the 51 oxy linkage are replaced by carbon linkages has remained a significant problem. A method for the preparation of such oligonucleotide analogues has now been found. The resulting novel compounds have good stability towards nuclease hydrolysis and good hybridisation properties, facilitating their use as anti-sense probes and as pharmaceuticals for the treatment of viruses such as influenza, herpes and HIV. Accordingly, the present invention provides a dinucleotide analogue of formula I • · · · • · • · · · • · o · • 0 · • · · • e · · • · • · · · e • · o e · · 9 · · · where B1 and B2 are each independently a monovalent nucleoside base radical; • · · · • · · * • · · · 0 · · R1 is RJa or Z, RJa, R2, R3 and R4 are each independently hydrogen, halogen or hydroxy; • · · · 0 · • · · e R5 is R5a or Z; R6 is hydrogen or R6a; -3- R7 is hydrogen, alkyl-N.N-dialkylphosnhoramidyl or R7a, R8 is R8a or Z, or the indicated R7O and R8 together denote an isopropylidenedioxy group; R5a and R8a are each independently hydrogen, halogen, hydroxy, -OR10, -OCOR10 or silyloxy substituted by three CpC^ hydrocarbyl groups; R6a and R7a are each independently a CrCi0 aliphatic radical, a C6-C]5 aromatic radical, a C7-C3Q araliphatic radical, -COR11, -SO2Rn or silyl substituted by three CpC^ hydrocarbyl groups; R9 is hydrogen, a CrC8 aliphatic radical, a C3-C8 cycloaliphatic radical, a C6-C15 aromatic radical, C7-C13 araliphatic radical, an alkali metal ion or an ammonium ion; R10 and R11 are each independently a Cj-Cjq aliphatic radical, a C3-C8 cycloaliphatic radical, a C6-C15 aromatic radical or a C7-C]6 araliphatic radical; Rx and Ry are independently hydrogen, halogen, hydroxy, a CrC10 alkyl, C2-C10 akenyl, C3-C8 cycloalkyl, C6-C15 aryl, C-j-C^ aralkyl, CpC^ alkoxy, C2-C10 alkenoxy, Cg-Cio aryloxy or C7-C16 aralkyloxy group, which is substituted or unsubstituted, or -OCORZ; Rz is a substituted or unsubstituted Q-Qq alkyl, C2-C10 alkenyl, C3-C8 cycloalkyl, C6-C15 aryl or C7-C16 aralkyl group; and a · a a * ’····* Z is C6-C10 aryloxythiocarbonyloxy, the C6-C10 aryl group being substituted or a a a a *··’ · unsubstituted. • · · •a · ·a ·a • · ' • ” t Generally, in compounds of formula I, • · · · R5 and R8 are each independently hydrogen, fluorine, chlorine, hydroxy, Cj-C10 alkoxy, C2-C10 alkenoxy, C6-C15 aryloxy, C7-C16 aralkyloxy, -OCOR10 or silyloxy substituted by , three Ci-C15 hydrocarbyl groups; a a a a • · 0 · • · a · a a · *' * R6a and R7a are each i..dependently a substituted or unsubstituted Cj-Cjq alkyl, C2-C10 .. .. alkenyl, C6-C15 aryl or C7-C30 aralkyl group, -COR11, -SO2Rn or silyl substituted by a a a three CpCjs hydrocarbyl groups; a a ” * ’ R9 is hydrogen, substituted or unsubstituted Cj-C8 alkyl, C3-C8 cycloalkyl, C6-C15 aryl or . C7-Ci3 aralkyl, an alkali metal ion or an ammonium ion; and a a a a a a a a a a ’ R10 and R11 are each independently substituted or unsubstituted C]-C10 alkyl, C2-C10 -4- alkenyl, C3-C8 cycloalkyl, C6-C15 aryl or C7-C16 aralkyl. The compounds of formula I may be in the form of one of the possible isomers, for example as a diastereomer, an optical isomer, a racemate or a mixture thereof.