Europäisches Patentamt *EP001053238B1* (19) European Patent Office Office européen des brevets (11) EP 1 053 238 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C07D 489/02, C07D 489/04, of the grant of the patent: C07D 489/12, C07D 221/28, 28.12.2005 Bulletin 2005/52 C07D 223/06, C07D 211/32, (21) Application number: 99903533.0 C07D 211/64, C07D 223/14, C07D 221/26, A61K 47/48 (22) Date of filing: 29.01.1999 (86) International application number: PCT/AU1999/000062 (87) International publication number: WO 1999/038869 (05.08.1999 Gazette 1999/31) (54) THERAPEUTIC COMPOUNDS THERAPEUTISCHE VERBINDUNGEN COMPOSES THERAPEUTIQUES (84) Designated Contracting States: • BOURA, Alan, Louis, Arthur, Monash University AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Clayton, VIC 3168 (AU) MC NL PT SE (74) Representative: Towler, Philip Dean (30) Priority: 29.01.1998 AU PP153098 Frank B. Dehn & Co., 21.04.1998 AU PP311498 European Patent Attorneys, 04.08.1998 AU PP504698 179 Queen Victoria Street London EC4V 4EL (GB) (43) Date of publication of application: 22.11.2000 Bulletin 2000/47 (56) References cited: EP-A- 0 004 960 WO-A-95/18186 (73) Proprietors: FR-A- 2 296 420 US-A- 3 341 538 • MONASH UNIVERSITY US-A- 3 928 359 US-A- 4 806 556 Clayton, VIC 3168 (AU) US-A- 5 610 283 • NEURO THERAPEUTICS LIMITED Toorak, Victoria 3142 (AU) • CHEMICAL ABSTRACTS, 117:82892; & CLIN. EXP. PHARMACOL. PHYSIOL., (1992), 19(11), (72) Inventors: pages 17-23, RN 142740-96-3, RN 142740-97-4. • JACKSON, Roy, William Burwood, VIC 3125 (AU) Remarks: • SUBASINGHE, Kamani, Rupika The file contains technical information submitted Glen Waverley, VIC 3150 (AU) after the application was filed and not included in this specification Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 053 238 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 053 238 B1 Description [0001] This invention relates to novel structural analogues and derivatives of compounds with general analgesic or related pharmacological activity. In particular the invention relates to derivatives of opioid compounds, particularly 5 morphine and related compounds. BACKGROUND OF THE INVENTION [0002] A large range of therapeutic compounds is currently used in the treatment of conditions such as allergies, 10 diarrhoea, migraine and other pain conditions, and in the treatment of congestive heart failure. These compounds include compounds with analgesic or related activities, such as anti-tussives, anti-depressants, local anaesthetics, anti-hypertensives, anti-asthmatics, antihistamines, and anti-serotonins. [0003] However, many of the therapeutic compounds of the types enumerated above have undesirable side-effects, such as the respiratory depression caused by opiates. In particular, many drugs which are useful for their action on 15 the peripheral nervous system have undesirable effects in the central nervous system. [0004] Thus opiates are the most powerful analgesics known, but their usefulness is greatly limited by their side- effects, including severe respiratory depression, and ability to induce addiction and physical dependence. [0005] Despite intensive efforts to design analogues of morphine and related opioids which retain the analgesic activity but which do not have a deleterious effect on the central nervous system and the bowel, success has been 20 limited. Structure-activity relationships have been extensively investigated, and a number of features have been widely accepted as essential. See for example "An Introduction to Pharmacology" by J.J. Lewis (E. & S. Livingston Ltd, 1964 Pages 401-407), and "Principles of Drug Action: The Basis of Pharmacology (Ed. W.B. Pratt and P.Taylor; Churchill Livingstone, 3rd edition, 1990, Pages 25-27). In particular, it is generally considered that to retain analgesic activity the group on the tertiary nitrogen should be small, and should preferably be methyl; larger substituents are likely to be 25 opiate receptor antagonists rather than agonists. Thus replacement of the methyl group of morphine by an allyl or cyclopropylmethyl moiety produces an antagonist. Although there are some exceptions to this rule, such as N-amyl- normorphine and N-hexylnormorphine, in general a large substituent will result in antagonist activity. [0006] We have attempted to modify the ability of biologically-active compounds to cross the blood-brain barrier by incorporating a highly polar group into the molecular structure. Thus we have shown that derivatives of the 2N atom 30 of mianserin comprising a guanidino group show H1 and 5-hydroxytryptamine activity, but show no detectable activity in the central nervous system. In contrast, a compound in which the 2N atom of mianserin was substituted with a urea group still showed pronounced central nervous system activity (Jackson et al; Clin. Ex. Pharmacol. Physiol., 1992 19 17-23 and our U.S. Patent No. 5,049,637). [0007] Naltrexamine and oximorphamine have been modified by incorporation of groups which are zwitterionic at 35 biological pH in order to restrict access to the central nervous system (Botros et al; J. Med. Chem., 1989 32 2068-2071, and Portoghese, U.S. Patent No. 4,730,048). In US-4,730,048 the zwitterionic group was added at C6. Some of these analogues were full agonists, and one was a strong antagonist. [0008] A bis(t-butyldimethylsiloxy)-substituted compound in which a guanidino derivative was attached to the nitrogen via a 3 carbon spacer chain was found to show no opioid activity at µ-receptors in isolated guinea-pig ileum (Jackson 40 et al, 1992). This suggested that such compounds would not have the desired activity. FR 2,296,420 discloses zwitte- rionic sulphate derivatives of morphine. [0009] WO 95/18186 discloses complex ammimide derivatives of a range of compounds including some opioids. [0010] US 5,610,283 discloses antigen (protein or polypeptide) derivatives of opioids for use in immunoassay proc- esses. 45 [0011] EP 0004960 discloses derivatives of certain opioids having an oxygen-containing substitutent on the nitrogen atom thereof. [0012] US 3,928,359 discloses certain aromatic ring-containing derivatives of normorphine and norcodeine. [0013] US 3,341,538 discloses certain derivatives 2,6-methano-3-benzazocines containing no spacer groups. [0014] Clin. Exp. Pharmacol. Physiol. (1992), 19(a) pp1723 discloses attempts to modify opioids to act on peripheral 50 nervous system, with no success. [0015] US 4,806,556 discloses opiate derivatives containing uncharged groups on the opidd nitrogen atom, and a 6-(R'NH-) or 6-(R"N=) group. [0016] Therefore there is a need for therapeutic compounds which have less activity within the central nervous sys- tem, thus having fewer undesirable side-effects, whilst at the same time having greater specificity of action on peripheral 55 physiological mechanism. We have found that several compounds with the general formula outlined below not only have reduced central side-effects, but retain activity at desired peripheral receptors. In particular, those compounds which show activities at opioid receptors retain broad analgesic activity, contrary to current orthodoxy which teaches that the analgesic effects of opioids are mediated from the CNS. Their selectivity for peripheral opioid receptors not 2 EP 1 053 238 B1 only makes them useful for the treatment of pain without sedative or addictive effects, but also may make them useful for treatment of AIDS and related immune deficiency diseases. SUNIMARY OF THE INVENTION 5 [0017] In its broadest aspect, the invention provides an opioid compound of general formula I: YN-X-[amidine or guanidine group] I 10 in which YN is an organic residue obtained by removal of the group on the nitrogen atom of an opioid, the position of said nitrogen atom being that position which corresponds to position 17 of morphine, and X is a spacer group; or a pharmaceutically acceptable salt thereof, in which the opioid from which the organic residue YN- is derived 15 is selected from the group consisting of morphine, codeine, heroin, ethylmorphine, O-carboxymethylmorphine, O- acetylmorphine, hydrocodone, hydromorphone, oxymorphone, oxycodone, dihydrocodeine, thebaine, metopon, etor- phine, acetorphine, ketobemidone, ethoheptazine, diprenorphine (M5050), buprenorphine, phenomorphan, levorpha- nol, pentazocine, eptazocine, metazocine, O,O-di-(tert-butyldimethylsilyl)-morphine, O,O-di-(tert-butyl-dimethylsilyl)- normorphine, dihydroetorphine and dihydroacetorphine; 20 but not including the bisulphate salt of 3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-(N-aminoimi- nomethylaminopropyl)morphinan. [0018] For the purposes of this specification, the term "opioid compound" is to be taken to mean a compound struc- turally related to morphine. The opioid compound preferably, but not necessarily, has opioid agonist or antagonist activity at opioid receptors. 25 [0019] The spacer can be any spacer group of dimensions approximately equivalent to an alkyl chain of 1 to 6 carbon atoms, and may for example be a straight or branched alkyl chain of 1 to 6 carbon atoms or an alkenyl or alkynyl chain of up to 6 carbon atoms, which may optionally be substituted. The spacer may also comprise a cyclic