AU2003266841A1 - Amidine compounds - Google Patents

Description

WO 2004/033458 PCT/AU2003/001329 AMIDINE COMPOUNDS This invention relates to novel derivatives of compounds with opiate receptor agonist or antagonist 5 activity, such as analgesic or related pharmacological activity. In particular, the invention relates to derivatives of morphine-like opioid compounds in which an amidine group of a particular structure is linked to the tertiary nitrogen atom of the morphine-like opioid. 10 BACKGROUND OF THE INVENTION A range of therapeutic compounds are currently used in the treatment of conditions such as allergies, 15 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, anti 20 histamines, and anti-serotonins. 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 25 on the peripheral nervous system have undesirable effects in the central nervous system. Thus opiates are the most powerful analgesics known, but their usefulness is greatly limited by their side-effects, including severe respiratory depression, and 30 ability to induce addiction and physical dependence. 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 35 limited. 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 WO 2004/033458 PCT/AU2003/001329 -2 molecular structure. Thus we have shown that derivatives of the 2N atom of mianserin comprising a guanidino group show H, and 5-hydroxytryptamine activity, but show no detectable activity in the central nervous system. In 5 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). 10 In our International patent application No. PCT/AU99/00062 (W099/38869), we showed that compounds obtained by linking a highly charged group to the tertiary nitrogen atom of a morphine-like opioid via a spacer group not only have reduced central side-effects, but retain 15 activity at desired peripheral receptors. We believe that this is a result of the decreased lipophilicity of the compounds, and their resulting decreased ability to penetrate the blood-brain barrier. In particular, those compounds which show activities at opioid receptors 20 retained broad analgesic activity, contrary to the previously accepted state of the art, which teaches that the analgesic effects of morphine-like opioids are mediated from the CNS. The selectivity of these compounds for peripheral opioid receptors not only makes them useful 25 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. We have now surprisingly found that a particular range of compounds of a new structure have remarkably high 30 analgesic activity, accompanied by reduced toxicity. These compounds also have the desired decreased ability to penetrate the blood-brain barrier. SUMMARY OF THE INVENTION 35 In a first aspect, the invention provides a compound of formula I WO 2004/033458 PCT/AU2003/001329 -3 NR YN-X-(NH),-C R' in which YN is a morphine-like opioid radical; X is - a direct bond, 5 - an optionally substituted, branched, straight-chained or cyclic alkylene having from 1 to 6 carbon atoms, optionally containing one or two heteroatoms in the alkyl chain, or 10 - an optionally substituted, branched or straight-chained alkenylene having from 4 to 10 carbon atoms; R and R' are independently hydrogen, alkyl, substituted alkyl, alkene, substituted alkene, alkyne, 15 substituted alkyne, aryl, substituted aryl, heterocycle, substituted heterocycle or cyano; and n is 0 when X is said direct bond, or n is 1 when X is said alkylene or alkenylene; or a pharmaceutically acceptable salt, hydrate, 20 solvate, pharmaceutically acceptable derivative, pro-drug, tautomer and/or isomer thereof. Preferably R is H, alkyl, phenyl, substituted phenyl, heterocycle or substituted heterocycle. Preferably R' is H, alkyl, substituted alkyl, 25 phenyl, substituted phenyl, heterocycle or substituted heterocycle. It is preferred that at least one of R and R' is not H. It is more preferred that R' is not H. Preferably, at each instance, the heterocycle or 30 substituted heterocycle is heteroaromatic or substituted heteroaromatic, respectively. Preferably the substituent on the aryl or heteroaryl group is a C 1

-

6 alkyl group such as methyl or WO 2004/033458 PCT/AU2003/001329 ethyl, haloalkyl (including di- and tri- haloalkyls, such as trifluromethyl), hydroxy, amino, alkoxy, haloalkoxy, cyano, nitro, alkylthio, thiol, a salt or ester of a phosphorous-containing acid (such as phosphate or 5 phosphite) or halo. Where the alkyl, alkenyl or alkynyl groups referred to above are substituted, the preferred substituents are aryl, substituted aryl, heteroaromatic, substituted heteroaromatic, haloalkyl (including di- and 10 tri- haloalkyls, such as trifluromethyl), hydroxy, amino, alkoxy, haloalkoxy, nitro, alkylthio, thiol, cyano or halo. Most preferably, in the case of R' being aryl or alkyl substituted with aryl, the preferred substituents on the aryl group (when aryl is substituted) are one or more 15 selected from alkyl, halo, alkoxy, hydroxy, nitro, cyano, a salt or ester of a phosphorous-containing acid (such as phosphate or phosphite) and alkyl thio. According to one embodiment, X is said alkylene and n is 1. 20 Preferably, the radical YN- is a radical of Formula II or Formula III: N RRe O Re Ra Rd II wherein: 25 Ra is H, C 1

-

4 alkyl, C 1

-

4 alkanoyl, C 1 4 carboxyalkyl, or an 0 protecting group; WO 2004/033458 PCT/AU2003/001329 -5 Rb is H, OH, protected hydroxy, Ci- 4 alkanoyloxy or C 1

.

4 alkoxy; or, when C6 does not have a double bond to C7, and does not have an endoetheno or endoethano bridge to C14, Rb may be =0 or =CH 2 ; 5 Rc is H, OH or protected hydroxy; Rd is H or Ci-4 alkyl; Re is H, CN, C 1

-

4 alkanoyl, Ci- 4 alkoxycarbonyl, C2-8 alkenyl, -cRg 10 OH in which R is H, alkyl, aryl, or alkaryl, and Rl is CI-S alkyl, C 2

-

6 alkenyl, C 2 -6alkynyl, each of these three groups being optionally substituted by aryl, or RI is substituted 15 aryl (the substituent(s) on the aryl group being chosen from halo, alkyl, Ci- 4 alkoxy, haloalkyl), tetrahydrofuranyl, Ci-4 alkoxy; wherein the oxygen between C4 and C5 may or may not be present, as represented by the broken lines; wherein the 20 brackets around the group between C6 and C14 represents that the group may or may not be present, and when present the group may be an endoetheno or an endoethano bridge, as represented by the broken line; and wherein the dashed line between C6, C7, C8 and C14 represents that there is 25 or are either zero, one or two double bonds, with the one double bond being either between C6 and C7, or C7 and C8, and the two double bonds being between C6 and C7, and C8 and C14; WO 2004/033458 PCT/AU2003/001329 -6 N III wherein Rh is H or C 1

-

4 alkyl; 5 R 1 is H, OH, C 1

-

4 alkanoyl or Ci- 4 alkyl; Ri is H, OH, C 1

_

4 alkoxy, C1-4 alkanoyl, C 1

.

4 alkanoyloxy; C 1 -4 carboxyalkyloxy or protected hydroxy; and Rk is H, OH, or protected hydroxy; and wherein the two dashed lines represent that the two 10 bonds may be both present or both absent. In one embodiment of the invention, the radical YN- is a radical of formula II. Preferably, the radical YN- is a radical of a compound selected from the group consisting of morphine, 15 codeine, heroin, ethylmorphine, 0-carboxymethylmorphine, 0-acetylmorphine, hydrocodone, hydromorphone, oxymorphone, oxycodone, dihydrocodeine, thebaine, metopon, etorphine, acetorphine, ketobemidone, ethoheptazine, diprenorphine (M5050), buprenorphine, phenomorphan, levorphanol, 20 pentazocine, eptazocine, metazocine, dihydroetorphine and dihydroacetorphine. Preferably the radical YN- is a radical of morphine, codeine, buprenorphine or diprenorphine.

WO 2004/033458 PCT/AU20031001329 -7 Particularly preferred compounds are as follows: HO" 0. NCHCHCHNH<N KRS-6-41 HO 0 NCH 2

CHCH

2 NH< KRS-6-51 HO"

NCHCHCH

2 NHC h KRS-6-48 Ho"" 0 KRS-6-71 HO 9. NPh

NCH

2

CH

2

CH

2 NH/ ,--Ph

H/~

WO 2004/033458 PCT/AU2003/001329 HO NPh

NCH

2

CH

2

CH

2 NHC

CHCH

2

CH

3 HO HO NH/ NPh

NCH

2

CH

2

CH

2 NH

'CH

2 Ph HO HO F N

NCH

2

CH

2

CH

2 NHC CH2CH3 HO z

NCH

2

CH

2

CH

2 NHC N "-CH2CH2CH3 HO\\\.\\ Z = alkyl, halo, alkoxy, hydroxy, cyano, nitro, alkyl thio. 5 In a second aspect, the invention provides a process for the preparation of a compound of formula I defined above which includes the step of reacting a precursor for the radical YN- or YN-X-NH- with a precursor for the radical WO 2004/033458 PCT/AU2003/001329 -9 NR C R' in which YN-, X, R, R', R" and n are as defined in formula I. 5 The reaction preferably includes the step of reacting YN-H or YN-X-NH 2 with a compound of formula NR R"O-C R' in which R and R' are as defined for the compound of formula I, and R'' is alkyl, substituted alkyl, aryl or 10 substituted aryl, to form a compound of Formula I. According to a third aspect, the invention provides a pharmaceutical or veterinary composition comprising a compound according to formula I, together with a pharmaceutically or veterinarily acceptable 15 carrier. According to a fourth aspect, the invention provides a method of treatment and/or prophylaxis of a condition or symptom that is inhibited, reduced or alleviated by opioid receptor activation, comprising 20 administering a therapeutically effective amount of the compound of formula I to a subject in need thereof. Preferably, the method involves the treatment and/or prophylaxis of pain in the peripheral nervous system with comparably less or no activity on the central nervous 25 system. According to a fifth aspect, the invention provides a method of inducing analgesia, comprising the step of administering an effective amount of a compound of formula I to a subject in need of such treatment.

WO 2004/033458 PCT/AU2003/001329 - 10 According to a sixth aspect, the invention provides the use of a compound of formula I in the manufacture of a medicament for the treatment and/or prophylaxis of a condition or symptom that is inhibited, 5 reduced or alleviated by opioid receptor activation. Again, the condition or symptom is preferably pain. The present invention also provides a compound of formula I for use in the treatment and/or prophylaxis of a condition or symptom that is inhibited, reduced or 10 alleviated by opioid receptor activation, such as pain. The present invention further provides use of a compound for formula I as an analgesic. The present invention further provides a method of reducing the central nervous system activity of a 15 morphine-like opioid, comprising the step of linking the nitrogen atom of the morphine-like opioid to the radical NR // -X (NH)n--C in which X, R, R' and n are as defined above. 20 DETAILED DESCRIPTION OF THE INVENTION A number of terms of the art are used in this specification and the claims, and they are described below 25 for complete understanding of the scope of the invention. The word "comprising" means "including but not limited to", and the word "comprises" has a corresponding meaning. The term "aryl" refers to single, polynuclear, 30 conjugated and fused residues of aromatic hydrocarbons preferably having 6 to 20 carbon atoms, such as phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl, naphthyl, anthryl and the like.

WO 2004/033458 PCT/AU2003/001329 - 11 The term "alkyl" refers to a straight chain, branched, mono- or poly-cyclic saturated hydrocarbon chain, preferably having from 1 to 10 carbon atoms, most preferably 1 to 6 carbon atoms such as methyl, ethyl, n 5 propyl, isopropyl, n-butyl, secondary butyl, tert-butyl, n-hexyl, n-heptyl, n-octyl, n- decyl, n-dodecyl, 2 ethyldodecyl, tetradecyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise indicated. In some instances, the alkyl groups are said 10 to be C1_4 alkyl groups. When this term is used either alone or in a compound word such as "optionally substituted C 1

-

4 alkoxy", this term refers to straight chained, branched or cyclic hydrocarbon groups having from 1 to 4 carbon atoms. Illustrative of such alkyl groups 15 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl and tert-butyl. The term "alkenyl" refers to a straight chain branched, mono- or poly-cyclic unsaturated hydrocarbon chain, preferably having from 2 to 10 carbon atoms, most 20 preferably 2 to 6 carbon atoms such as vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl, 1-pentenyl, 1 hexenyl, 3-hexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, 1 nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3 butadienyl, 1-4,pentadienyl, 1,3-hexadienyl, 1,4 25 hexadienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like, unless otherwise indicated. The term "alkynyl" refers to a straight chain, branched, mono- or poly-cyclic unsaturated hydrocarbon chain, preferably having from 2 to 10 carbon atoms, most 30 preferably 2 to 6 carbon atoms such as ethynyl, 1 propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2 pentynyl, 3-pentynyl, 4-pentynyl,2-hexynyl,3-hexynyl,4 hexynyl, 5-hexynyl, 10-undecynyl, 4-ethyl-l-octyn-3-yl, 7 dodecynyl, 9-dodecynyl, 10-dodecynyl, 3-methyl-l-dodecyn 35 3-yl, 2-tridecynyl, 11-tridecynyl, 3-tetradecynyl, 7 hexadecynyl, 3-octadecynyl and the like, unless otherwise indicated.

WO 2004/033458 PCT/AU2003/001329 - 12 The terms "alkylene", "alkenylene" and "alkynylene" are the divalent radical equivalents of the terms "alkyl", "alkenyl" and "alkynyl", respectively. The two bonds connecting the alkylene, alkenylene or 5 alkynylene to the adjacent groups may come from the same carbon atom or different carbon atoms in the divalent radical. The term "heterocycle" refers to a cyclic alkyl, alkenyl or alkynyl group of from 1 to 12 carbon atoms 10 containing at least one heteroatom selected from oxygen, nitrogen and sulphur. Examples include unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 15 triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocyclic groups 20 containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic 25 group containing an oxygen atom, such as, pyranyl or furyl; unsaturated 3 to 6-membered hetermonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic 30 group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoxazolyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; 35 unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; WO 2004/033458 PCT/AU2003/001329 - 13 unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl or thiadiazolyl; saturated 3 to 6-membered heteromonocyclic group 5 containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolidinyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl heteroatom 10 selected from oxygen, nitrogen and sulphur. The term "heteraromatic" refers to any of the unsaturated heterocyclic compounds defined above which are also aromatic. Suitable substituents include halo, alkyl, 15 alkene, alkyne, aryl, heterocyclic, haloalkyl, haloalkene, haloalkyne, acyl, acyloxy, hydroxy, amino, substituted amino groups such as NHacyl, alkylamino, cyano, nitro, thio, alkylthio, carboxy, sulphonic acid, sulphoxides, sulphonamides, quaternary ammonium groups and alkoxy 20 groups such as methoxy, alkenyloxy, alkynyloxy haloalkoxy, haloalkenyloxy, haloalkynyloxy and are preferably F, Cl, hydroxy, C 1 6 alkoxy, Ca 6 alkylamino or carboxy. Halo will be understood to mean Cl, F, Br or I. The term "optionally substituted" refers to a 25 group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, 30 nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, 35 alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, WO 2004/033458 PCT/AU2003/001329 - 14 mercapto, alkylthio, benzylthio, acylthio, phosphorus containing groups and the like. In some instances in this specification, where substituents may be present, preferred substituents have been mentioned. 5 Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist appropriate for the protection of the group in question, and may be introduced by conventional methods. 10 Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group 15 with minimum disturbance of groups elsewhere in the molecule. Examples of hydroxyl protecting groups include lower alkyl groups (eg. t-butyl), lower alkenyl groups (eg. allyl); lower alkanoyl groups (eg. acetyl); lower 20 alkoxycarbonyl groups (eg. t-butoxycarbonyl); lower alkenyloxycarbonyl groups (eg. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg. benzoyloxycarbonyl, p methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (eg. 25 trimethylsilyl, t-butyldimethylsilyl) and aryl lower alkyl (eg. benzyl) groups. An acetyl group is preferred. Methods appropriate for removal of hydroxy protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups 30 such as p-nitrobenzyloxycarbonyl, hydrogenation and for groups such as o-nitrobenzyloxycarbonyl, photolytically. The term "morphine-like opioid" is used herein in its broadest sense and refers to any compounds, natural or synthetic, having a morphine-like action. The term 35 encompasses morphine and its natural and semisynthetic derivatives, together with other chemical classes of drugs with pharmacological actions similar to those of morphine.

WO 2004/033458 PCT/AU2003/001329 - 15 Compounds in these groups have agonistic (including competitive or partial agonistic) activity on at least one of the opiate receptors. Hence, these compounds variably have the capacity to produce analgesia, respiratory 5 depression, gastrointestinal spasm and/or morphine-like physical dependence. Groups of compounds in this class include morphinans (in which the C7 to C8 double bond is a single bond, and optionally the ether oxygen between positions 4 and 5 is removed), the morphinones and 10 dihydromorphinones (in which the OH at C6 is replaced with =0, and optionally the C7 to C8 double bond is a single bond, and also optionally the ether oxygen between C4 and C5 is not present), the Diels-Alder adducts of thebaine (in which there is an endoetheno bridge between C6 and 15 C14, or an endoethano bridge between C6 and C14, and optionally a C7 substitution), benzomorphans (in which the cycloalkene ring and the tetrahydrofuran rings are absent) and phenylpiperidines. Such compounds are well known in the art; see for example "The Pharmacological Basis of 20 Therapeutics" (ed. A.G. Gilman et al; 7 th edition, 1985, chapter 22). It will be clearly understood that all of the compounds set out in Table 1 of PCT/AU99/00062 are suitable for use in the invention. The radical form of the morphine-like opioid is 25 constituted by the morphine-like opioid with the atom or group on the nitrogen of the morphine-like opioid removed. Structurally, the morphine-like opioid radicals include the radicals of formulae II and III defined above. The radicals encompassed by the structure of 30 Figure II may be divided into a number of groups: (a) the morphine derivatives in which there is a single double bond between C7 and C8 (or C6 and C8, as in the case of pseudocodeine), and there is no bridging group between C6 and C14; 35 (b) the morphinan derivatives in which there are no double bonds between any of C6, C7, C8 and C14, and no bridging group between C6 and C14, (including one WO 2004/033458 PCT/AU2003/001329 - 16 subclass in which Rb is H, and another in which Rb is

=CH

2 ); (c) the morphinone derivatives, in which Rb is =0, and there is no bridging group between C6 and C14 5 (including the subclass of dihydromorphinones, in which there are also no double bonds between any of C6, C7, C8 and C14); and (d) the thebaine derivatives (Diels-Alder adducts of thebaine), in which there is an endoetheno or an 10 endoethano bridge between C6 and C14 (including the particularly important subclass where Re is (figure)). The radicals encompassed by the structure of Figure III may be divided into a number of groups including: 15 (e) the benzomorphan derivatives, in which the bonds represented by the broken lines are present; and (f) the phenylpiperidines, in which the bonds represented by the broken lines are not present (including the significant subclass in which Ri is C 1

.

4 alkanoyl). 20 For the synthesis of the compounds of formula I, the precursors for radical components are utilised. A precursor for a radical is either: - a compound containing the radical coupled to a functional group that is removed during 25 reaction to couple the radical to another radical; or - a compound from which the radical is formed by chemical rearrangement during the reaction, with removal of an atom or group from the 30 compound. For the first type of precursor, suitable functional groups depend on the reaction being conducted, and may for instance be hydrogen, an amine, halogen, alcohol, and so forth. 35 It will be appreciated by those skilled in the art that the compounds of formula I may be modified to provide pharmaceutically acceptable derivatives thereof at WO 2004/033458 PCT/AU2003/001329 - 17 any of the functional groups in the compounds of formula I. Of particular interest as such derivatives are compounds modified at the carboxyl function, hydroxyl functions or at the guanidino or amino groups. Thus 5 compounds of interest include C 1 -alkyl esters, such as methyl, ethyl, propyl or isopropyl esters, aryl esters, such as phenyl, benzoyl esters, and C 1 6 acetyl esters of the compounds of formula I. Consequently, the term "pharmaceutically acceptable derivative" means any 10 pharmaceutically acceptable salt, ester or salt of such ester of a compound of formula I or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula I or a biologically active metabolite or residue thereof. 15 Pharmaceutically acceptable salts of the compounds of formula I include those derived from pharmaceutically acceptable cations, inorganic and organic acids and bases. Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations 20 such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; 25 or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic, toluenesulphonic, 30 benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Some of the acids mentioned above such as oxalic acid, while not in themselves pharmaceutically acceptable, may be useful 35 in the preparation of salts useful as intermediates in obtaining compounds of the invention and their pharmaceutically acceptable acid addition salts.

WO 2004/033458 PCT/AU2003/001329 - 18 The term "pro-drug" is used herein in its broadest sense to include those compounds which are converted in vivo to compounds of Formula I. The term "tautomer" is used herein in its 5 broadest sense to include compounds of Formula I which are capable of existing in a state of equilibrium between two isomeric forms. Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound. 10 The term "isomer" is used herein in its broadest sense and includes structural, geometric and stereo isomers. As the compound of Formula I have one or more chiral centres, it is capable of existing in enantiomeric forms. 15 Some compounds of the invention are optically active, and it will be clearly understood that both racemic mixtures and isolated stereoisomers are within the scope of the invention. A method of separating enantiomers of mianserin-like compounds with a guanidino-type 20 substituent is disclosed in our International patent application No.PCT/AU98/00807 (W099/16769), and could be used with the compounds of the invention. Other methods of resolution for amino compounds are summarised in Chapter 7, Separation of Stereoisomers. Resolution. Racemisation, 25 pages 297-421 of E.L. Eliel, S.H. Wilen and L.N. Mander, Stereochemisty of Organic Compounds, Wiley-Interscience, New York, 1994. The compositions of the present invention comprise at least one compound of Formula I together with 30 one or more pharmaceutically acceptable carriers and optionally other therapeutic agents. Each carrier, diluent, adjuvant and/or excipient must be pharmaceutically "acceptable" in the sense of being compatible with the other ingredients of the composition 35 and not injurious to the subject. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including WO 2004/033458 PCT/AU2003/001329 - 19 subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods 5 include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, 10 diluents, adjuvants and/or excipients or finely divided solid carriers or both, and then if necessary shaping the product. The compounds of the present invention may be used to treat a condition or symptom that is inhibited, 15 reduced or alleviated by opioid receptor activation. This refers to conditions or symptoms that are associated with one or more of the nervous system, vascular system, gastrointestinal system, pulmonary system and heart. Examples of such conditions are pain, pulmonary edema and 20 diarrhoea. It will be understood that the brain and spinal cord are CNS organs which lie principally inside (central to) the blood brain barrier. Accordingly, an agent with "reduced or no CNS activity" will act primarily with cells 25 or tissues of the body which lie outside (peripheral to) the blood brain barrier. The specificity for "reduced or no CNS activity" may be a result of the inhibition of the passage of the agent from the circulation across the blood brain barrier into the CNS. 30 The term "subject" as used herein refers to any animal having a disease or condition which requires treatment with a pharmaceutically-active agent. The subject may be a mammal, preferably a human, or may be a domestic or companion animal. While it is particularly 35 contemplated that the compounds of the invention are suitable for use in medical treatment of humans, it is also applicable to veterinary treatment, including WO 2004/033458 PCT/AU2003/001329 - 20 treatment of companion animals such as dogs and cats, and domestic animals such as horses, ponies, donkeys, mules, llama, alpaca, pigs, cattle and sheep, or zoo animals such as primates, fields, canids, bovids, and ungulates. 5 Suitable mammals include members of the Orders Primates, Rodentia, Lagomorpha, Cetacea, Carnivora, Perissodactyla and Artiodactyla. Members of the Orders Perissodactyla and Artiodactyla are particularly preferred because of their similar biology and economic importance. 10 For example, Artiodactyla comprises approximately 150 living species distributed through nine families: pigs (Suidae), peccaries (Tayassuidae), hippopotamuses (Hippopotamidae), camels (Camelidae), chevrotains (Tragulidae), giraffes and okapi (Giraffidae), deer 15 (Cervidae), pronghorn (Antilocapridae), and cattle, sheep, goats and antelope (Bovidae). Many of these animals are used as feed animals in various countries. More importantly, many of the economically important animals such as goats, sheep, cattle and pigs have very similar 20 biology and share high degrees of genomic homology. The Order Perissodactyla comprises horses and donkeys, which are both economically important and closely related. Indeed, it is well known that horses and donkeys interbreed. 25 As used herein, the term "therapeutically effective amount" is meant an amount of a compound of the present invention effective to yield a desired therapeutic response, for example, to induce analgesia. The specific "therapeutically effective amount" 30 will, obviously, vary with such factors as the particular condition being treated, the physical condition of the subject, the type of subject being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the 35 structure of the compound or its derivatives. The compounds of the present invention may additionally be combined with other medicaments to provide WO 2004/033458 PCT/AU2003/001329 - 21 an operative combination. It is intended to include any chemically compatible combination of pharmaceutically active agents, as long as the combination does not eliminate the activity of the compound of formula I. It 5 will be appreciated that the compound of the invention and the other medicament may be administered separately, sequentially or simultaneously. Methods and pharmaceutical carriers for preparation of pharmaceutical compositions are well known 10 in the art, as set out in textbooks such as Remington's Pharmaceutical Sciences, 20th Edition, Williams & Wilkins, Pennsylvania, USA. As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent or 15 vehicle for delivering the compound of formula I to the subject. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Each carrier must be pharmaceutically "acceptable" in the sense of being compatible with other ingredients of 20 the composition and non injurious to the subject. The compound of formula I may be administered orally, topically, or parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and 25 vehicles. The term parenteral as used herein includes subcutaneous injections, aerosol for administration to lungs or nasal cavity, intravenous, intramuscular, intrathecal, intracranial, injection or infusion techniques. 30 The present invention also provides suitable topical, oral, and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compounds of the present invention may be administered orally as tablets, aqueous or oily 35 suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use may contain one or more agents selected from WO 2004/033458 PCT/AU2003/001329 - 22 the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. Suitable sweeteners include sucrose, lactose, glucose, 5 aspartame or saccharin. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry 10 flavouring. Suitable preservatives include sodium benzoate, vitamin E, alphatocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable 15 time delay agents include glyceryl monostearate or glyceryl distearate. The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. 20 These excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or 25 acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer 30 period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Coating may also be performed using techniques described in the U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for control 35 release. The compound of formula I as well as the pharmaceutically-active agent useful in the method of the WO 2004/033458 PCT/AU2003/001329 - 23 invention can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time independently or together. Administration may be intravenously, intraarterial, intraperitoneally, 5 intramuscularly, subcutaneously, intracavity, transdermally or infusion by, for example, osmotic pump. For in vitro studies the agents may be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue. 10 Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic 15 esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated 20 Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, anti-microbials, anti-oxidants, chelating agents, 25 growth factors and inert gases and the like. Generally, the terms "treating", "treatment" and the like are used herein to mean affecting a subject or tissue to obtain a desired pharmacologic and/or physiologic effect. The effect may be the alteration of 30 the perception of nociceptive stimuli. The effect may be prophylactic in terms of completely or partially preventing a sensation, condition, symptom or disease, and/or may be therapeutic in terms of a partial or complete removal of a sensation, condition or symptom, or 35 cure of a disease. In the context of analgesia, the term "treating" covers the treatment of, or prevention of, the sensation of pain. "Treating" as used herein in any other WO 2004/033458 PCT/AU2003/001329 - 24 context covers any treatment of, or prevention of, condition, symptom or disease in a vertebrate, a mammal, particularly a human, and includes: (a) preventing the condition, symptom or disease from occurring in a subject 5 that may be predisposed to the condition, symptom or disease, but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving or ameliorating the effects of the disease, i.e., cause regression of the effects of the 10 disease. The invention includes various pharmaceutical compositions useful for ameliorating a sensation (such as pain) or disease. The pharmaceutical compositions according to one embodiment of the invention are prepared 15 by bringing a compound of formula I, analogues, derivatives or salts thereof, or combinations of compound of formula I and one or more pharmaceutically-active agents into a form suitable for administration to a subject using carriers, excipients and additives or 20 auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, 25 such as sterile water, alcohols, glycerol and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers. Preservatives include antimicrobial, anti oxidants, chelating agents and inert gases. Other pharmaceutically acceptable carriers include aqueous 30 solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington's Pharmaceutical Sciences, 20th ed. Williams and Wilkins (2000) and The British National Formulary 43rd ed. (British Medical Association and Royal 35 Pharmaceutical Society of Great Britain, 2002; http://bnf.rhn.net), the contents of which are hereby incorporated by reference. The pH and exact concentration WO 2004/033458 PCT/AU2003/001329 - 25 of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See Goodman and Gilman's The Pharmacological Basis for Therapeutics (7th ed., 1985). 5 The pharmaceutical compositions are preferably prepared and administered in dose units. Solid dose units may be tablets, capsules and suppositories. For treatment of a subject, depending on activity of the compound, manner of administration, nature and severity of the 10 disorder, age and body weight of the subject, different daily doses can be used. Under certain circumstances, however, higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out both by single administration in the form of an individual 15 dose unit or else several smaller dose units and also by multiple administration of subdivided doses at specific intervals. The pharmaceutical compositions according to the invention may be administered locally or systemically in a 20 therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease and the weight and general state of the subject. Typically, dosages used in vitro may provide useful guidance in the amounts useful for in situ administration 25 of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of the cytotoxic side effects. Various considerations are described, e.g., in Langer, Science, 249: 1527, (1990). Formulations for oral use may be in the form of hard 30 gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as 35 peanut oil, liquid paraffin or olive oil. Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the WO 2004/033458 PCT/AU2003/001329 - 26 manufacture of aqueous suspension. Such excipients may be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and 5 gum acacia; (2) dispersing or wetting agents which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long chain 10 aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene 15 oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous 20 suspension. This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also a sterile injectable solution or suspension in a non 25 toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are 30 conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. 35 Compounds of formula I may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and WO 2004/033458 PCT/AU2003/001329 - 27 multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds of formula I may also be presented 5 for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions include those adapted for: (a) oral administration, external application, for example 10 drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue; (b) parenteral administration for example by subcutaneous, 15 intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced in the udder via the teat; (c) topical applications, e.g. as a cream, ointment or 20 spray applied to the skin; or (d) intravaginally, e.g. as a pessary, cream or foam. Dosage levels of the compound of formula I of the present invention are of the order of about 0.5 mg to about 20 mg per kilogram body weight, with a preferred 25 dosage range between about 0.5 mg to about 10 mg per kilogram body weight per day (from about 5 mg to about 3 g per patient per day, but in the case of palliative care patients about 5 g to about 10 g per patient per day). The amount of active ingredient that may be combined with 30 the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain about 5 mg to ig of an active compound with an appropriate and convenient 35 amount of carrier material which may vary from about 5 to 95 percent of the total composition. Dosage unit forms will generally contain between from about 5 mg to 500 mg WO 2004/033458 PCT/AU2003/001329 - 28 of active ingredient. Optionally the compounds of the invention are administered in a divided dose schedule, such that there are at least two administrations in total in the schedule. 5 Administrations are given preferably at least every two hours for up to four hours or longer; for example the compound may be administered every hour or every half hour. In one preferred embodiment, the divided-dose regimen comprises a second administration of the compound 10 of the invention after an interval from the first administration sufficiently long that the level of active compound in the blood has decreased to approximately from 5-30% of the maximum plasma level reached after the first administration, so as to maintain an effective content of 15 active agent in the blood. Optionally one or more subsequent administrations may be given at a corresponding interval from each preceding administration, preferably when the plasma level has decreased to approximately from 10-50% of the immediately-preceding maximum. 20 It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of 25 administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. EXAMPLES 30 The invention will now be described in detail by way of reference only to the following non-limiting examples and drawings. Example 1 Preparation of precursors YN-X-NH 2 where X is 35 straight chain alkylene WO 2004/033458 PCT/AU2003/001329 - 29 Methods of synthesis of amine precursors of compounds containing a straight-chained alkyl group as the spacer group "X" are disclosed in PCT/AU99/00062, the full disclosure of which is incorporated into this document by 5 reference. This method yields the precursor compound YN(CH)nNH 2 . One example is provided below. Example la Preparation of 3,6-bis(t-butyldimethyl siloxy)-7,8-didehydro-4,5-epoxy-17-(2 10 cyanoethyl)morphinan Ref: J.A.Bell and C. Kenworthy, Synthesis, 650-652, 1971. 3,6-Bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5 epoxymorphinan (0.26 g, 0.52 mmol) was dissolved in 15 absolute ethanol (3 mL) and acrylonitrile (0.07 ml, 1.0 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure to give a white solid (0.26 g, 90% yield). 20 Example lb Preparation of 3,6-bis(t butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy 17-(aminopropyl)morphinan A solution of 3,6-bis(t-butyldimethylsiloxy)-7,8 25 didehydro-4,5-epoxy-17-(2-cyanoethyl)morphinan (200 mg, 0.36 mmol) in dry ethyl ether (5 ml) was added dropwise to a suspension of lithium aluminum hydride (0.13 g, 3.6 mmol) in dry ethyl ether (5 ml). After stirring for 3 h at room temperature the reaction mixture was added wet 30 ether followed by 10% sodium hydroxide (1.5 ml). The solution was filtered, and the white precipitate was washed with ether. The ether layer was evaporated under reduced pressure to give the amine as a clear liquid (yield = 0.2 g, 99%).

WO 2004/033458 PCT/AU2003/001329 - 30 Example 2 Preparation of precursors YN-X-NH 2 where X is branched chain alkylene Examples la and 1b are repeated using the following readily available compounds in place of acrylonitrile, to 5 yield the corresponding amine precursor YN-X-NH 2 in which X is the corresponding branched chain alkyl.

CH

2 =C-CN CHH CH3CH 2 CN

CH

3 CN CH=C methacrylonitrile crotononitrile cis-pent-2-ene nitrile CN

CH

3 0 P CH=CH CH=CWCN 3-phenylacrylonitrile methoxy acrylonitrile 10 Example 3 Preparation of precursors YN-X-NH 2 where X is branched chain alkylene As an alternative to Example 2, precursors

YN-X-NH

2 are prepared by reaction of the demethylated 15 opioid with a-aminoacids yielding an amide, which can be reduced to an amine containing a branch chain with one carbon atom in the spacer. A wide variety of a-aminoacids are commercially available. opioid-NH + HO 2

C-CH-NH

2 a opioid-N-C-CHNH 2 R OR LiALH 4 opioid-N-CH 2

-CHNH

2

R

WO 2004/033458 PCT/AU2003/001329 - 31 As another alternative to Example 2, S-aminoacids (eg. 3-aminobutanoic acid) are used to produce compounds with a branched chain group with three carbon atoms in the main chain. 5 opioid-NH + HO 2

C-CH

2

-CH-NH

2 : opioid-N-CH 2

CH

2 -CrHNH 2 I CH 3 CH3 Example 4 Preparation of precursors YN-X-NH 2 where X is alkenylene

NH

2

-(CH

2 )n-CHO HO-(CH 2 )n-Br Protecting PPh 3 Group

PG-NH-(CH

2 )n-CHO + HO-(CH2)n-PPh 3 Bf

PG-NH-(CH

2 )

(CH

2 )n-OH 1. brominate 2.OPIOID

PG-NH-(CH

2 )

'(CH

2 )n-N-OPIOID 3. Deprotection

H--N-(CH

2 )

(CH

2 )n-N-OPIOID 10 WO 2004/033458 PCT/AU2003/001329 - 32 The method disclosed in Albeck, A. et al, Tetrahedron, 2000, 56, 1505-1516, is used to prepare the compound containing the protected amino group at one end and hydroxy group at the other end illustrated in the 5 scheme set out above. This compound is then brominated (step 1) using the method and conditions specified in D. Poirier et al, Tet. Lett., Vol 35, 7, 1051, 1995. The brominated product is reacted with the opioid using the conditions and methods set out in one of the following 10 three references: 1. NaOH/isopropanol - Limanov, V.E., Myazina, N.V. Zh, Prikl Khim. 1988, 61(10), 2365-8. 2. KOH/triethyl amine - Mohri, K. Suzuki, K, Usui M, Isobe, K, Tsuda, Y. Chemical & Pharmaceutical Bulletin 15 1995, 43 (1), 159-61. 3. CsOH - Salvatore, R. Nagle, A. Schmidt, S. Jung, K. Organic Letters, 1999, 1(12), 1893-96. Thereafter, the amine is deprotected following the method and conditions outlined in Albeck et al, to 20 yield YN-X-NH 2 in which X is an alkenylene. Example 5 Preparation of precursors YN-X-NH 2 where X is ether-containing alkylene 25 Standard chemical reactions can be used in the sequence outlined below to prepare precursor YN-X-NH 2 in which X is an ether-containing alkylene. The individual reactions are conducted in standard conditions for the 30 given types of reactions.

WO 2004/033458 PCT/AU2003/001329 - 33 YNH + Br OH OH or" n = 1,2,-- n=1,2, or YNH + CO2E 3 YCO 2 Et Reduction YN OH YNOH 1. NaH NH YN - YN"'nNH 2. n= 1,2,-- Br NH2 n = 1,2,- An alternative route for the synthesis of the 5 precursor YN-X-NH 2 in which X is an ether-containing alkylene is outlined below. Again, each individual reaction is of a standard class of reaction. Alternatively 0 0 YN + Br O OH 3 YN O OH or TsO either Mitsunobu or Diethylene glycol OH -OTs o N 3

NH

2 YN O

NH

2 WO 2004/033458 PCT/AU2003/001329 - 34 Example 6 Preparation of subject amidines from YN-X-NH 2 or YN-H. Once the precursor YN-X-NH 2 has been synthesised by one of the methods outlined above (or 5 below), the amidine is synthesised by reacting the amine

YN-X-NH

2 with the appropriate imidate. The conditions for this reaction are as set forth in Sandler, S. R., Karo, W. Imidates in Organic Chemistry; Academic Press, New York, 1972, Chapter 8, Vol 3, pages 268-300. This is 10 illustrated in the following reaction scheme with the ethyl imidate: NR NR

YN-X-NH

2 + C 2

H

5 0 - YN-X-NH R' R' Using this procedure, the following compounds are prepared from the given starting materials: 15 Opioid Imidate Product Morphine HO NH C2H 0

.NCH

2 CHCHNH CH

C

2 HH3 G H 3 HOd", KRS-6-41 20 Morphine NPh HO

C

2

H

5 0

CH

3

NCH

2

CH

2

CH

2 NHC HO" KRS-6-51 WO 2004/033458 PCT/AU20031001329 - 35 Oploid Imidate Amidine NPh H

C

2

H

5 0 Ok NCH2OH 2

H

2 NH/N P 4 C 2

H

5 H

'CH

2 CH, KRS-6-48 Morphine HO N 0 NHC 2

C

2 H CHCH 3 C,, 1C 2

H

5 0 2

H

5 NHCHN CH 2

CH

3 KCRS-6-7 1 Morphine HO NPh 0 2

H

5 0 /NPh Ph NCHCHOHNHC Ph HOe Morphine HO C2 H5 0 h 4 CH 2

CH

2

CH

3 01NPh

NCH

2

CH

2

CH

2 NH/

CH

2

CH

2 I

HO

WO 2004/033458 PCT/AU20031001329 -36 op 1 o Id Imidate Amidine Morphine HO NPh

C

2

H

5 0 01. 7 NPh 4 CH 2 Ph

NCH

2

OH

2 OHNH CHP H/ 5 Morphine HO F aF 0 N NCHZCHCH 2 NH /2,

O-H

2 CH, 0 2

H

5 0 CAH He~ Morphine 10 HO 100 t h a .a l N ,H NCH 2

H

2

CH

2 NH/ ' T H G 2 H 15 CH2CH2CH3 20 Z= alylhalo, alkoxy, hydroxy, cyano, nitro, alkyl WO 2004/033458 PCT/AU2003/001329 - 37 Example 7 Synthesis of (5a, 6a)-7, 8-didehydro-4, 5 epoxy-17-((N-phenylpropionamidino)-propyl)morphinan, 3, 6 diol (KRS-6-48) 5 HO O. NPh

NCH

2

CH

2

CH

2 NHC

CH

2

CH

3 HO KRS-648 Preparation of 3, 6-bis(t-butyldimethylsiloxy) -7,8 didehydro-4, 5-epoxy-17- ( (N-phenylpropionamidino) 10 propyl)morphinan. Ethyl N-phenylpropanimidate was prepared according to the procedure disclosed in Sandler and Karo (1972) (see Example 6 for full reference). A solution of freshly prepared 15 ethyl N-phenylpropanimidate (89 mg, 0.539 mmol) in acetonitrile (1 ml) was added to a solution of 3, 6-bis (t-butyldimethylsiloxy) -7, 8-didehydro-4, 5-epoxy-17- (3 aminopropyl)morphinan (200 mg, 0.359 mmol) in acetonitrile (1 ml) and methanol (1 ml) and was stirred 20 overnight at room temperature under N 2 . The reaction mixture was evaporated to dryness and the crude residue was purified by column chromatography on silica gel using methylene chloride/ methanol/ ammonium hydroxide 9:1:0.1 to give the protected amidine as a white solid ( 0.148 g, 25 60 % yield). Preparation of (5a, 6a)-7, 8-didehydro-4, 5-epoxy-17-((N phenylpropionamidino)-propyl)morphinan, 3, 6-diol (KRS-6 48) WO 2004/033458 PCT/AU2003/001329 - 38 3, 6-bis (t-butyldimethylsiloxy) -7, 8-didehydro-4, 5-epoxy 17- ( (N-phenylpropionamidino) -propyl) -morphinan (143 mg, 0.208 mmol) in methanol (10 ml) was added ammonium 5 fluoride (0.08 g, 2.08 mmol) and the reaction mixture was stirred overnight at room temperature under N 2 . The reaction mixture was evaporated to dryness and the crude was purified by column chromatography on silica gel using methylene chloride/methanol/ammonium hydroxide 9:2:0.2 to 10 give the amidine as a white solid (82 mg, 85% yield). M.P. 188-190 0 C (HCl salt) Example 8 Synthesis of (5a, 6a)-7, 8-didehydro-4, 5 15 epoxy-17-(3-acetamidinopropyl)morphinan, 3, 6-diol (KRS-6 41) HO

NCH

2

CH

2

CH

2 NHC CHs HO KRS-6-41 20 Preparation of 3, 6-bis (t-butyldimethylsiloxy) -7,8 didehydro-4, 5-epoxy-17-(3-acetamidinopropyl)morphinan. A solution of ethyl acetimidate hydrochloride (0.037 g, 0.295 mol) and 3,6-bis(t-butyldimethylsiloxy)-7,8 25 didehydro-4,5-epoxy-17-(3-aminopropyl)morphinan (150 mg, 0.269 mmol) in acetonitrile (1 ml) and methanol (1 ml) was stirred at room temperature for 3 days. The reaction mixture was evaporated to dryness and the crude residue was chromatographed on silica gel using methylene 30 chloride/ methanol/ ammonium hydroxide 9:2:0.2 as the WO 2004/033458 PCT/AU2003/001329 - 39 eluent to give the protected amidine. (0.139 g, 86 % yield) Preparation of (5a, 6az)-7,8-didehydro-4,5-epoxy-17-(3 5 acetamidinopropyl)morphinan, 3, 6-diol (KRS-6-41) The protected amidine was deprotected using ammonium fluoride in methanol using the same procedure described in Example 7 to give KRS-6-41 as a white solid (74 mg, 86 % 10 yield) M.P. 156- 160"C. Example 9 Synthesis of (5a, 6t) -7,8-didehydro-4,5 epoxy-17 - ( (N-phenylacetamidino) -propyl)morphinan, 3, 6-diol (KRS-6-51) 15 HO ONPh -. NCH 2

CH

2

CH

2 NHC CH3 H& KRS-6-51 (5a, 6at)-7, 8-didehydro-4, 5-epoxy-17-((N phenylacetamidino)-propyl)morphinan, 3,6-diol (KRS-6-51) 20 was prepared following the procedure detailed in Example 7 using ethyl N-phenylacetimidate which was prepared according to Sandler and Karo (1972). M.P. 120 0

C.

WO 2004/033458 PCT/AU2003/001329 - 40 Example 10 Synthesis of (5a, 6a)-7, 8-didehydro-4, 5 epoxy-17- ((N- (2-ethylphenyl)propionamidino) propyl)morphinan, 3, 6-diol (KRS-6-71) HO -. NCH 2

CH

2

CH

2 NH CH 2

CH

3 2CH 2

CH

3 HO KRS-6-71 5 Preparation of 3, 6-bis (t-butyl dimethylsiloxy) -7, 8 didehydro-4, 5-epoxy-17- ((N- (2 ethylphenyl )propi onami dino) -propyl ) morphinan. Ethyl N-(2-ethylphenyl)-propanimidate was prepared from 2 10 ethylaniline and triethylorthopropionate. A solution of ethyl-N- (2-ethylphenyl) -propanimidate (0.235 g, 0.0011 mol) in acetonitrile (1.5 ml) was added to a solution of 3, 6-bis (t-butyldimethylsiloxy) -7, 8-didehydro-4, 5-epoxy 1 7 -(3-aminopropyl)morphinan (0.425 g, 0.76 mmol) in 15 acetonitrile (1 ml) and methanol ( 1 ml). The reaction mixture was stirred for 2 days at room temperature under N 2 and evaporated to dryness. The crude was chromatographed on silica gel using methylene chloride/ methanol/ ammonium hydroxide in 9:2:0.2 ratio to give the protected amidine 20 as a thick liquid in 85% yield. Preparation of (5a, 6a) -7, 8-didehydro-4, 5-epoxy-17- ((N- (2 ethyl phenyl )propionamidino) -propyl )morphinan, 3, 6-diol (KRS-6-71) 25 The amidine was deprotected using ammonium fluoride according to the procedure outlined in Example 7 above and purified by column chromatography to give KRS-6-71 as a white solid in 87% yield. M.P. 58-59 0

C.

WO 2004/033458 PCT/AU2003/001329 - 41 Example 11 Synthesis of (5a,6ox)-7,8-didehydro-4,5-epoxy 17- (N- (4-fluorophenyl) propionamidino) -propyl)morphinan, 3,6-diol (KRS-6-98) HO F 0-- NCH 2

CH

2

CH

2 NH CH2CH3 HO KRS-6-98 5 Ethyl -N- (4-fluorophenyl) -propionimidate was prepared from 4-fluoroaniline and triethylorthopropionate. A solution of ethyl-N-(4-fluorophenyl)-propionimidate (0.114 g, 0.584 mmol) in acetonitrile was added to a solution of 10 3,6-bis (t-butylsiloxy)-7,8-didehydro-4,5-epoxy-17-N-(3 aminopropyl)morphinan (250 mg, 0.449 mmol) in acetonitrile (1 mL) and methanol (1 ml). The reaction mixture was stirred at room temperature under N 2 and was monitored by TLC. After stirring for 2 days, the reaction mixture was 15 evaporated to dryness and the crude was chromatographed on silica gel using methylene chloride/ methanol/ ammonium hydroxide in 9: 1:0.1 ratio to give the t butyldimethylsilyl protected amidine. This was deprotected as described in Example 7 to give KRS-6-98 as a white 20 solid in 43% yield. (M.P. 106 0 C) . Example 12 Analgesic Activity of KRS-6-48 Testing on compound KRS-6-48 was carried out 25 under contract by MDS Services - Taiwan Ltd. KRS-6-48 was evaluated for possible analgesic activity in the phenylquinone-induced writhing model in mice (Siegmund et al, 1957). A serial 2-fold dosage variance was used in the test, from 128 mg/kg to 1 mg/kg (8 doses in total). 30 Groups of 3 male or female ICR mice weighing 22±2 g were WO 2004/033458 PCT/AU2003/001329 - 42 employed. Variant doses (1, 2, 4, 8, 16, 32, 64 and 128 mg/kg) of test substances were administered intraperitoneally (IP). A vehicle of 2% Tween 80 in 0.9% NaCl was used for the intraperitoneal injection. The 5 control group received vehicle alone. Phenylquinone (PQ) at dose of 2 mg/kg was injected intraperitoneally 30 minutes (IP) after test substance, and the number of writhes exhibited during the following 5-10 minute period was recorded. A reduction in the number of writhes by 50 10 percent or more ( 50%) relative to the vehicle-treated group indicated possible analgesic activity. KRS-6-48 Very significant activity was found for KRS-6-48 at doses of 128, 64, 32 and 16 mg/kg. These results are 15 summarised in Table 1. KRS-6-48 did not exhibit Straub tail behaviour at any doses. The Straub test is an indicator of CNS activity. In contrast to this finding, in response to morphine at 3 mg/kg, 2 of 3 test animals exhibited the Straub tail phenomenon. This indicates that 20 KRS-6-48 is able to exert an analgesic effect without a central effect on the central nervous system. At 128 mg/kg (IP), 3 or 3 test animals exhibited twitch and muscle relaxation.

WO 2004/033458 PCT/AU2003/001329 - 43 Table 1 Analgesia in the Phenylquinone Writhing Model Treatment Route Dose N No. of Writhings % Inhibition Individual Average Vehicle IP 10m1/kg 1 15 (2% Tween 2 13 80/0.9%NaC1) 3 10 13 -- (KRS-6-48) IP 1mg/kg 1 10 2 20 3 13 14 0 IP 2mg/kg 1 8 2 20 3 10 13 0 IP 4mg/kg 1 10 2 8 3 9 9 31 IP 8mg/kg 1 12 2 4 3 5 7 46 IP 16mg/kg 1 1 2 13 3 4 6 54 IP 32mg/kg 1 0 2 1 3 1 1 92 IP 64mg/kg 1 0 2 0 3 0 0 100 IP 128mg/kg 1 0 2 0 3 0 0 100 Morphine.HC1 IP 3mg/kg 1 0 2 0 3 0 100 5 WO 2004/033458 PCT/AU2003/001329 - 44 Example 13 Analgesic Activity of KRS-6-41, KRS-6-51, and KRS-6-71 5 Testing on compounds KRS-6-41, KRS-6-51, and KRS 6-71 was also carried out under contract by MDS Services Taiwan Ltd. The study was designed to evaluate the effects of the compounds as analgesics in the phenylquinone-induced writhing assay described in detail 10 in Example 10(Siegmund et al, 1957). In each case, a serial 2-fold dosage variance was used in the test, from 128 mg/kg to 1 mg/kg (8 doses in total). Groups of 3 male or female ICR mice weighing 22±2 g were employed. Variant doses (1, 2, 4, 8, 16, 32, 64 15 and 128 mg/kg) of test substances were administered intraperitoneally (IP). A vehicle of 2% Tween 80 in 0.9% NaCl was used for the intraperitoneal injection. The control group received vehicle alone. Phenylquinone (PQ) at dose of 2 mg/kg was injected intraperitoneally 30 20 minutes (IP) after test substance, and the number of writhes exhibited during the following 5-10 minute period was recorded. A reduction in the number of writhes by 50 percent or more (250%) relative to the vehicle-treated group indicated possible analgesic activity. 25 KRS-6-41 After administration by intraperitoneal injection, a moderate level of inhibition of writhing in the mice was found for KRS-6-41 at doses of 32, 16, 8 and 30 4 mg/kg. These results are summarised in Table 2. At the higher doses of 128 mg/kg, 3 of 3 test animals died, and at 64 mg/kg 1 of 3 test animals died. None exhibited Straub tail behaviour, whereas 2 of 3 test animals exhibited Straub tail behaviour with doses of 3mg/kg of 35 morphine HCl. This indicates that KRS-6-41 should exhibit a moderate analgesic effect without a central effect on the central nervous system.

WO 2004/033458 PCT/AU2003/001329 - 45 KRS-6-51 After administration by intraperitoneal injection, significant activity was found for KRS-6-51 at doses of 64 and 32 mg/kg. These results are summarised in 5 Table 3. At doses of 128 mg/kg 21 of the 3 test animals died within 15 minutes, and 2 of the 3 test animals exhibited tremors and edema. None of the test animals exhibited Straub tail behaviour, thus indicating that KRS 6-51 is able to exert an analgesic effect without a 10 central effect on the central nervous system. Morphine HCl, at 3mg/kg produced Straub tail phenomenon in 2 of 3 test animals. KRS-6-51 accordingly compared well against morphine-HCl. 15 KRS-6-71 After administration by intraperitoneal injection, significant activity was found for KRS-6-71 at doses of 128, 64, 32, 16, 8 and 4 mg/kg. These results are summarised in Table 4. None of the test animals exhibited 20 Straub tail behaviour, thus indicating that KRS-6-71 is able to exert an analgesic effect without a central effect on the central nervous system. Morphine-HCl, at 3mg/kg produced Straub tail phenomenon in 2 of 3 test animals. KRS-6-51 accordingly compared very well against morphine 25 HCl.

WO 2004/033458 PCT/AU2003/001329 - 46 Table 2 Analgesia in the Phenylquinone Writhing Model-KRS-6-41 Treatment Route Dose N Number of Writhings % Inhibition Individual Average Vehicle IP 10 ml/kg 1 17 2% Tween 80/0.9% NaCl 2 10 3 12 13 - KRS-6-41 IP 1mg/kg 1 12 2 15 3 14 14 0 IP 2 mg/kg 1 14 2 6 3 22 14 0 IP 4 mg/kg 1 14 2 8 3 15 12 8 IP 8 mg/kg 1 6 2 10 3 14 10 23 IP 16 mg/kg 1 5 2 16 3 6 9 31 IP 32 mg/kg 1 4 2 10 3 11 8 38 IP 64 mg/kg 1 4 2 14 3 died -- - IP 128 mg/kg 1 died 2 died 3 died -- - Morphine IP 3mg/kg 1 0 2 0 3 0 0 100 WO 2004/033458 PCT/AU2003/001329 - 47 Table 3 Analgesia in the Phenylquinone Writhing Model-KRS-6-51 Treatment Route Dose N Number of Writhings % Inhibition Individual Average Vehicle IP 10 ml/kg 1 13 2% Tween 80/0.9% NaC1 2 17 3 15 15 - KRS-6-51 IP 1mg/kg 1 11 2 14 3 12 12 20 IP 2 mg/kg 1 18 2 9 3 7 11 27 IP 4 mg/kg 1 10 2 13 3 7 10 33 IP 8 mg/kg 1 9 2 8 3 8 8 47 IP 16 mg/kg 1 12 2 4 3 7 8 47 IP 32 mg/kg 1 3 2 5 3 7 5 67 IP 64 mg/kg 1 0 2 0 3 0 0 100 IP 128 mg/kg 1 died 2 0 3 0 - - Morphine IP 3mg/kg 1 0 2 0 3 0 0 100 WO 2004/033458 PCT/AU2003/001329 - 48 Table 4 Analgesia in the Phenylquinone Writhing Model-KRS-6-71 Treatment Route Dose N Number of Writhings % Inhibition Individual Average Vehicle IP 10 ml/kg 1 17 2% Tween 80/0.9% NaCl 2 29 3 22 23 - KRS-6-71 IP 1mg/kg 1 24 2 13 3 18 18 22 IP 2 mg/kg 1 2 2 12 3 18 14 39 IP 4 mg/kg 1 16 2 16 3 2 11 52 IP 8 mg/kg 1 0 2 18 3 15 11 52 IP 16 mg/kg 1 13 2 0 70 3 8 7 IP 32 mg/kg 1 6 2 0 3 15 7 70 IP 64 mg/kg 1 0 2 3 3 0 1 96 IP 128 mg/kg 1 0 2 0 3 0 0 100 Morphine IP 3mg/kg 1 0 2 0 3 0 0 100 WO 2004/033458 PCT/AU2003/001329 - 49 Example 14 Analgesic Activity of KRS-6-98 Testing of compound KRS-6-98 was carried out under contract by MDS Pharma Services - Taiwan. The study 5 was essentially the same as that set out in Examples 12 and 13, and was designed to evaluate the effect of the compound as an analgesic in the phenylquinone-induced writhing assay described in detail in Example 10 (Siegmund et al, 1957). 10 A serial two-fold dosage variance was used in the test, from 128 mg/kg to 1 mg/kg (8 doses in total). Twenty six groups of 3 male or female ICR mice weighing 22±2 g were employed. The variant doses of the test substance were administered intraperitoneally (IP). A 15 vehicle of 2% Tween 80 in 0.9% NaCl was used for the intraperitoneal injection. The control group received the vehicle alone. Phenylquinone (PQ) at a dose of 2 mg/kg was injected intraperitoneally 30 minutes (IP) after the test substance, and the number of writhes exhibited during 20 the following 10-15 minute period was recorded. A reduction of the number of writhes by 50% or more ( 50%) relative to the vehicle-treated group indicate a possible analgesic activity. For KRS-6-98, significant activity was found at 25 all dose levels from 128 down to 2 mg/kg. These results are summarised in Table 5. Straub tail behaviour in the test animals was not reported, thus indicating that KRS-6 98 is able to exert an analgesic effect without a central effect on the central nervous system. In view of the 30 morphine-HCL tests reported in relation to other compounds of the invention set out in Example 13, which produced Straub tail phenomenon, this compound compared very well against morphine-HCL. 35 WO 2004/033458 PCT/AU2003/001329 - 50 Table 5 Analgesia in the Phenylquinone Writhing Model-KRS-6-98 Treatment Route Dose N Number of Writhings % Inhibition Individual Average Vehicle IP 10 ml/kg 1 15 2% Tween 80/0.9% NaCl 2 20 3 18 18 - KRS-6-98 IP 1mg/kg 1 12 2 10 3 8 10 44 IP 2 mg/kg 1 7 2 6 3 7 7 61 IP 4 mg/kg 1 10 2 7 3 4 7 61 IP 8 mg/kg 1 6 2 7 3 2 5 72 IP 16 mg/kg 1 3 2 6 3 4 4 78 IP 32 mg/kg 1 0 2 0 3 0 0 100 IP 64 mg/kg 1 0 2 0 3 0 0 100 IP 128 mg/kg 1 0 2 0 3 0 0 100 WO 2004/033458 PCT/AU2003/001329 - 51 Example 15 In Vitro Opiate Receptor Binding Assays To characterise the target specificity of the 5 compounds, KRS-6-41, KRS-6-48 and KRS-6-51 were tested at a concentration of 10pM for their ability to inhibit the binding of a radioligand to human 8-, K-, or p-opiate receptors in vitro using commercially available assays (MDS Pharma Services; assay catalogue numbers 260110, 10 260210 and 260410 respectively). The results of these assays are presented below. Percentage inhibition of radioligand binding to human opioid receptors in vitro by test compounds (10pM) 15 Test compound KRS-6-41 KRS-6-48 KRS-6-51 6-opiate 68 29 37 receptor K-opiate 58 48 54 receptor p-opiate 97 97 97 receptor It will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding, 20 various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification. References cited herein and below and are 25 incorporated herein by this reference. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art WO 2004/033458 PCT/AU2003/001329 - 52 publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country. 5 REFERENCES D'Amour, F.E. and Smith, D.L. A method for determining loss of pain sensation. J. Pharmacol. Exp. Ther. 72: 74 10 79, 1941. Sandler, S.R., Karo W. Imidates in Organic Chemistry; Academic Press, New York, 1972, Chapter 8, vol 3 pages 268-300. 15 Siegmund, E., Cadmus, R. and Lu, G. A method for evaluating both non-narcotic and narcotic analgesics. Proc. Soc. Exp. Biol. Med. 95, 729-731, 1957.

Claims (27)

1. A compound of formula I NR YN-X-(NH)n-C R' 5 (I) in which YN is a morphine-like opioid radical; X is - a direct bond, 10 - a substituted or unsubstituted, branched, straight-chained or cyclic alkylene having from 1 to 6 carbon atoms, optionally containing one or two heteroatoms in the alkyl chain, or 15 - an optionally substituted, branched or straight-chained alkenylene having from 4 to 10 carbon atoms; R and R' are independently hydrogen, alkyl, substituted alkyl, alkene, substituted alkene, alkyne, 20 substituted alkyne, aryl, substituted aryl, heterocycle, substituted heterocycle or cyano; and n is 0 when X is said direct bond, or n is 1 when X is said alkylene or alkenylene; or a pharmaceutically acceptable salt, hydrate, 25 solvate, pharmaceutically acceptable derivative, pro-drug, tautomer and/or isomer thereof.

2. The compound of claim 1, wherein R is H, alkyl, phenyl, substituted phenyl, heterocycle or substituted 30 heterocycle. WO 2004/033458 PCT/AU2003/001329 - 54

3. The compound of claims 1 or 2, wherein R' is H, alkyl, substituted alkyl, phenyl, substituted phenyl, heterocycle or substituted heterocycle. 5

4. The compound of any one of claims 1 to 3, wherein at least one of R and R' is not H.

5. The compound of claim 4, wherein R' is not H. 10

6. The compound of any one of claims 1 to 5, wherein the heterocycle or substituted heterocycle is heteroaromatic or substituted heteroaromatic, respectively. 15

7. The compound of any one of claims 1 to 6, wherein the substituent on the aryl or heteroaryl group is a C 1 s alkyl group, haloalkyl, hydroxy, amino, alkoxy, haloalkoxy, cyano, nitro, alkylthio, thiol, a salt or ester of a phosphorous-containing acid or halo. 20

8. The compound of claim 1, wherein one or both of R and R' is substituted, and wherein the substituent or substituents are selected from aryl, substituted aryl, heteroaromatic, substituted heteroaromatic, haloalkyl, 25 hydroxy, amino, alkoxy, haloalkoxy, nitro, alkylthio, thiol, cyano and halo.

9. The compound of claim 1, wherein R' is aryl or alkyl substituted with aryl, in which the aryl group is 30 optionally substituted.

10. The compound of claim 9, wherein said aryl group is substituted by one or more substituents selected from alkyl, halo, alkoxy, hydroxy, nitro, cyano, a salt or 35 ester of a phosphorous-containing acid and alkyl thio. WO 2004/033458 PCT/AU2003/001329 - 55

11. The compound of any one of claims 1 to 10, wherein X is alkylene and n is 1.

12. The compound of any one of claims 1 to 11, 5 wherein the radical YN- is a radical of Formula II or Formula III: N Rc Re Rao Rd Rb I' wherein: Ra is H, C1- 4 alkyl, C1-4 alkanoyl, Ci- 4 carboxyalkyl, or an 0 10 protecting group; R is H, OH, protected hydroxy, Ci-4alkanoyloxy or Cj 4 alkoxy; or, when C6 does not have a double bond to C7, and does not have an endoetheno or endoethano bridge to C14, Rb may be =0 or =CH 2 ; 15 Rc is H, OH or protected hydroxy; R is H or C1-4 alkyl; Re is H, CN, Ci- 4 alkanoyl, C.- 4 alkoxycarbonyl, C 2 -8 alkenyl, / OH in which R is H, alkyl, aryl, or alkaryl, and R9 is Ci-8 20 alkyl, C 2 -- alkenyl, C 2 - 6 alkynyl, each of these three groups being optionally substituted by aryl, or Rg is substituted aryl (the substituent(s) on the aryl group being chosen WO 2004/033458 PCT/AU2003/001329 - 56 from halo, alkyl, C- 4 alkoxy, haloalkyl), tetrahydrofuranyl, C1-4 alkoxy; wherein the oxygen between C4 and C5 may or may not be present, as represented by the broken lines; 5 wherein the brackets around the group between C6 and C14 represents that the group may or may not be present, and when present the group may be an endoetheno or an endoethano bridge, as represented by the broken line; and wherein the dashed line between C6, C7, C8 and C14 10 represents that there is or are either zero, one or two double bonds, with the one double bond being either between C6 and C7, or C7 and C8, and the two double bonds being between C6 and C7, and C8 and C14; N R h R' Ri Rk III wherein 15 Rh is H or Ci_4 alkyl; R' is H, OH, C1-4 alkanoyl or Ci-aalkyl; R is H, OH, C1-4 alkoxy, C1-4 alkanoyl, C1-4 alkanoyloxy; C1_4 carboxyalkyloxy or protected hydroxy; and R is H, OH, or protected hydroxy; 20 and wherein the two dashed lines represent that the two bonds may be both present or both absent.

13. The compound of claim 12, wherein the radical YN is a radical of formula II. 25 WO 2004/033458 PCT/AU2003/001329 - 57

14. The compound of claim 12, wherein the radical YN is a radical of a compound selected from the group consisting of morphine, codeine, heroin, ethylmorphine, 0-carboxymethylmorphine, 0-acetylmorphine, hydrocodone, 5 hydromorphone, oxymorphone, oxycodone, dihydrocodeine, thebaine, metopon, etorphine, acetorphine, ketobemidone, ethoheptazine, diprenorphine (M5050), buprenorphine, phenomorphan, levorphanol, pentazocine, eptazocine, metazocine, dihydroetorphine and dihydroacetorphine. 10

15. The compound of claim 12, wherein the radical YN is a radical of morphine, codeine, buprenorphine or diprenorphine. 15

16. The compound selected from the group consisting of: HO NCH 2 CH 2 CH 2 NH H N '~CH, Ho KRS-6-41 HO 0NPh NCH 2 CH 2 CH 2 NH&' CH 2 CH 3 HO KRS-6-48 HO 0 NPh NCH 2 CH 2 CH 2 NH( CH 3 HO K KRS-6-51 WO 2004/033458 PCT/AU20031001329 - 58 HO 0 NOH 2 GHCH 2 NHf CH 2 CH 3 CH 2 CH 3 HOK KRS-6-71 HO NPh NCH 2 OH 2 CH 2 NH/ HOh HO NCH2CH 2 CHNHC p CH 2 CH 2 CH 3 0 HO NCH 2 OH 2 CH 2 NH I- HP HO WO 2004/033458 PCT/AU2003/001329 - 59 HO F 0N NCH 2 CH 2 CH 2 NHC CH2CH3 5 HO N NCH 2 CH 2 CH 2 NHC CH 2 CH 2 CH 3 HO\\\' wherein Z is selected from alkyl, halo, alkoxy, hydroxy, cyano, nitro, alkyl thio, or a pharmaceutically acceptable salt, hydrate, solvate, pre-drug, tautomer and/or isomer 10 thereof.

17. A process for the preparation of a compound of formula I as defined in claim 1 comprising the step of reacting a precursor for the radical YN- or YN-X-NH- with 15 a precursor for the radical NR R' in which YN-, X, R, R', R'' and n are as defined in claim 1. WO 2004/033458 PCT/AU2003/001329 - 60

18. The process of claim 17, wherein the process includes the step of reacting YN-H or YN-X-NH 2 with a compound of formula NR R"O R' 5 in which R and R' are as defined in claim 1, and R'' is alkyl, substituted alkyl, aryl or substituted aryl, to form a compound of Formula I.

19. A pharmaceutical or veterinary composition 10 comprising a compound of any one of claims 1 to 16, and of a pharmaceutically or veterinarily acceptable carrier.

20. A method of treatment and/or prophylaxis of a condition or symptom that is inhibited, reduced or 15 alleviated by opioid receptor activation, comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 16, or a composition of claim 19 to a subject in need thereof. 20

21. The method of claim 20, wherein the method involves the treatment and/or prophylaxis of pain in the peripheral nervous system with comparably less or no activity on the central nervous system. 25

22. A method of inducing analgesia, comprising the step of administering an effective amount of a compound of any one of claims 1 to 16 or a composition of claim 19 to a subject in need of such treatment. 30

23. Use of a compound of any one of claims 1 to 16 in the manufacture of a medicament for the treatment and/or prophylaxis of a condition or symptom that is inhibited, reduced or alleviated by opioid receptor activation. WO 2004/033458 PCT/AU2003/001329 - 61

24. The use of claim 23, wherein the condition or symptom is pain.

25. A compound of any one of claims 1 to 16 or a 5 composition of claim 19 for use in the treatment and/or prophylaxis of a condition or symptom that is inhibited, reduced or alleviated by opioid receptor activation, such as pain. 10

26. Use of a compound of any one of claims 1 to 16 or a composition of claim 19 as an analgesic.

27. A method of reducing the central nervous system activity of a morphine-like opioid, comprising the step of 15 linking the nitrogen atom of the morphine-like opioid to the radical NR ' X-(NH)n-C R' in which X, R, R' and n are as defined in claim 1. 20 Dated this 9 t" day of October 2003. POLYCHIP PHARMACEUTICALS PTY LTD and MONASH UNIVERSITY 25 By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent and Trade Mark Attorneys of Australia