WO2004004715A2

WO2004004715A2 - Novel delta opioid receptor ligands

Info

Publication number: WO2004004715A2
Application number: PCT/EP2003/007400
Authority: WO
Inventors: Giulio Dondio; Silvia Macecchini; Luca Francesco Raveglia
Original assignee: Glaxosmithkline Spa
Priority date: 2002-07-09
Filing date: 2003-07-08
Publication date: 2004-01-15
Also published as: AU2003281253A8; WO2004004715A3; AU2003281253A1; GB0215867D0

Abstract

A method for the modulation of conditions associated with the delta opioid receptor, which method comprises the administration to the mammal in need thereof an effective or prophylactic amount of a compound of formula (I): wherein X, Y, Z, R1, and R2 are as defined in the specification; to compounds for use in such a method, to processes for their preparation, and to their use in medicine.

Description

Novel Method and Compounds

The present invention is concerned with a novel method of treatment, to compounds for use in such a method, to processes for their preparation, and to their use in medicine.

The presence of three populations of opioid receptors (mu, delta and kappa) is now well established and documented and all three are reported to be present in the central and peripheral nervous system of many species including man (Lord J.A.H. et al, Nature 1977, 267, 495). Activation of all three opioid receptor subtypes can lead to antinociception in animal models. In particular, studies with peptidic delta agonists have indicated that activation of the delta receptor produces antinociception in rodents, primates and can induce clinical analgesia in man (D. E. Moulin et al. Pain, 1985, 23, 213). Evidence exists that suggest a lesser propensity of delta agonists to cause the usual side-effects associated with mu and kappa activation (Galligan et al, J. Pharm. Exp. Then, 1984, 229. 641).

United States Patents Numbers 5,223,507 and 5,225,417 (G. D. Searle & Co.) disclose bicycle-condensed morphinoid compounds which are said to be delta opioid agonists having therapeutic utility as analgesics agents. International Patent Application Publication Number WO 94/07896 (Toray Ind. Inc.) discloses indole-condensed morphinoid compounds useful as immunosuppressants, anti-allergic and anti- inflammatory agents. WO 97/25531 (SmithKline Beecham S.p.A.) and WO 96/02545 (SmithKline Beecham Farmaceutici S.p.A.) disclose certain heterocycle-condensed morphinoid derivatives as delta opioid receptor agonists and antagonists. WO 97/10216 (SmithKline Beecham S.p.A.), WO 95/04734 (SmithKline Beecham Farmaceutici

S.p.A.), and WO 93/01186 (Dr. Lo Zambeletti S.p.A.) disclose certain hydroisoquinoline derivatives as delta opioid receptor agonists and antagonists. WO 97/10230 (SmithKline Beecham S.p.A.) discloses certain diarylalkenylamines as delta opioid receptor agonists. WO 96/36620 (SmithKline Beecham S.p.A.) discloses certain diaryldiamine derivatives as delta opioid receptor agonists. WO 97/24122, WO 97/24124, WO 98/14192, WO 98/30542, and WO 99/15508 (SmithKline Beecham Corporation) disclose certain pyridylamino derivatives as vitronectin receptor antagonists. WO 97/36901 (Merck & Co. Inc.) discloses certain phenylpyridylamino derivatives as farnesyl-protein transferase inhibitors. WO 95/05366 (Janssen Pharmaceutica N.V.) discloses certain pyridylamino derivatives as vasoconstrictors. EP 0 359 389 (Pfizer Limited) discloses certain pyridylamino derivatives as antiarrhythmic agents. EP 0 699 718 and European Patent EP 0 463 995 (Ciba-Geigy AG) disclose certain pyridylamino derivatives as intermediates in the synthesis of azo dyes. United Kingdom Patent Application GB 1 594 384 (BASF Aktiengesellschaft) discloses certain pyridylamino derivatives as intermediates in the synthesis of azo dyes.

It has now surprisingly been found that certain pyridylamino derivatives are potent delta opioid receptor ligands and hence may modulate conditions associated with this receptor. These compounds may therefore be of potential therapeutic utility for the treatment and/or prophylaxis of pain, rejection in organ transplant and skin graft, allergic and inflammatory responses, brain cell damage, drug and alcohol abuse, gastritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists and antagonists of the delta opioid receptor.

Accordingly, the present invention provides a method for the modulation of conditions associated with the delta opioid receptor, which method comprises the administration to the mammal in need thereof an effective or prophylactic amount of a compound of formula (I):

wherein:

R-j is hydrogen or C-|_ρalkyl, with the proviso that when R-| is C-μgalkyl, then the group R1 R2N- is located at position 4 of the pyridine ring;

R2 is hydrogen;

X is a moiety of formula (XA):

^ / (^CRna^Rnb)n\ /"- (^CRpc^Rpd)p\<^

^Rs (XA)

wherein:

R3 is hydrogen or C-j.galkyl; R_na, R_nD, Rpc an Rpd ^{are eacn} independently hydrogen or Cι_βalkyl;

T is a bond, oxygen, or sulphur; n and p are independently 1-4; with the following proviso: that when T is oxygen or sulphur, then n and p should each be at least 2; or,

X is a moiety of formula (XB):

wherein:

R3« is hydrogen or C-|_galkyl;

Rq_e and Rqf are each independently hydrogen or C<|_6alkyl;

U is a C3.8 cycloalkylene group, which group may optionally be interrupted by one or more heteroatoms; q is 0-3; or,

X is a moiety of formula (XC):

wherein:

V is a C3.8 alkylene chain, which chain may optionally be interrupted by one or more heteroatoms;

R_rg, R_rn, R_sj, and R_sk are each independently hydrogen or C-μρalkyl; W is a bond, oxygen, or sulphur; r and s are independently 0-3; with the following proviso: that when W is oxygen or sulphur, then s is at least 2;

Y is -[O]-, -[S]-, or NR4 where R4 is hydrogen, C-j. alkyl, or Cή_6alkylcarbonyl; Z is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; with the proviso that formula (I) does not include 2-(3-phenoxy)propylamino-3- aminopyridine; or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof.

In a further aspect, the present invention provides a method of treatment and/or prophylaxis of pain, allergic and inflammatory responses, brain cell damage, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists of the delta opioid receptor, which method comprises the administration to the mammal in need thereof an effective or prophylactic amount of a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof. The present invention also provides a method of treatment and/or prophylaxis of Crohn's disease, ulcerative colitis, and irritable bowel syndrome, which method comprises the administration to the mammal in need thereof an effective or prophylactic amount of a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof. In a yet further aspect, the present invention provides a method of treatment and/or prophylaxis of rejection in organ transplant and skin graft, and of drug and alcohol abuse, and of those conditions which customarily can be treated with antagonists of the delta opioid receptor, which method comprises the administration to the mammal in need thereof an effective or prophylactic amount of a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof.

Suitably, the group R-1 R2N- is at position 4 or 5 of the pyridine ring.

Suitably, R-| is hydrogen. Suitably, X is a moiety of formula (XA).

Suitably, X is a moiety of formula (XB).

Suitably, X is a moiety of formula (XC).

Suitably, R3 is hydrogen or methyl.

Suitably, T is a bond or oxygen. Suitably, R_na, R_nD, Rp_C, and Rprj are each hydrogen.

When T is a bond, then suitably n+p = 3 or 4.

When T is other than a bond, then suitably n is 2 and p is 2.

Suitably, R3> is hydrogen.

Suitably, U is a Cβ-cyclomethylene ring. Suitably, Rq_e and Rqf are both hydrogen.

Suitably, q is 1.

Suitably, V is a Cs-methylene chain.

Suitably, W is a bond.

When W is a bond, then suitably, r + s = 2. Suitably, R_rg, R_rn, R_sj, and R_sk are each hydrogen.

Suitably, Y is oxygen.

Examples of aryl groups include phenyl and naphthyl.

Examples of heteroaryl groups include quinolinyl and indolyl.

When Z is substituted phenyl, suitable substituents include up to five, suitably up to three, groups independently selected from RsRsNC^galkylene where R5 and Rg together with the nitrogen atom to which they are attached form a C3..8 heterocyclic aliphatic ring, C-i.galkyl, halo, C^galkoxy, phenyl, carboxy, C-|.galkoxycarbonyl, benzoyl, C^galkylcarbonyl, aminocarbonyl, mono- and di-Cι_galkylaminocarbonyl, Cι_ βalkylcarbonylamino, C<|_galkylcarbonylC-|_6alkyl, hydroxyC-i.βalkyl, and aryloxy; additionally two of the substituents when attached to adjacent carbon atoms of the phenyl ring form a group selected from C3_4alkylene, oxyC<|_2alkyleneoxy, and oxymethylenecarbonyl .

When Z is substituted phenyl, suitable substituents also include up to five, suitably up to three, groups independently selected from RsRgNC-μgalkylene where R5 and Rg together with the nitrogen atom to which they are attached form a C^.Q heterocyclic aliphatic ring, C-j.ρalkyl, halo, C-i.ρalkoxy, phenyl, carboxy, C-|. galkoxycarbonyl, benzoyl, C-i.galkylcarbonyl, aminocarbonyl, mono- and di-C-| _ galkylaminocarbonyl, C^galkylcarbonylamino, C-_|_QalkylcarbonylC-|_6alkyl, hydroxyC-|_ galkyl, and aryloxy.

When Z is substituted naphthyl, suitable substituents include up to five, suitably up to three, substituents independently selected from C^galkoxy. When Z is quinolinyl, suitable substituents include up to five, suitably up to three, substituents independently selected from C-|.βalkyl.

Suitably, Z is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, or unsubstituted or substituted quinolinyl.

Favourably, Z is naphthyl, naphthyl substituted with methoxy, quinolinyl, quinolinyl substituted with methyl or ethyl, unsubstituted phenyl, or phenyl substituted with up to three substituents independently selected from the group consisting of (N- piperidyl)methyl, methyl, chloro, methoxy, phenyl, methoxycarbonyl, benzoyl, acetyl, N,N-diethylaminocarbonyl, acetamido, f-butyl, 3-oxo-but-1-yl, and 1-(2-hydroxy)ethyl, additionally two of the substituents when attached to adjacent carbon atoms of the phenyl ring form a group selected from methylenedioxy, butylene, and oxymethylenecarbonyl.

More favourably, Z is naphthyl, quinolinyl, unsubstituted phenyl, or phenyl substituted with up to three substituents independently selected from the group consisting of (N-piperidyl)methyl, methyl, chloro, methoxy, phenyl, methoxycarbonyl, benzoyl, acetyl, N,N-diethylaminocarbonyl, acetamido, f-butyl, 3-oxo-but-1-yl, and 1-(2- hydroxy)ethyl.

There exists a sub-group of compounds falling wholly within formula (I), being of formula (IA):

wherein:

Rl , R2, X, Y, and Z are as defined in formula (I), with the following provisos; that when R-i is hydrogen, X is a moiety of formula (XA) as hereinbefore defined wherein R3 is C^alkyl, T is a bond, R_na, R_nD, Rp_C, and Rprj are each hydrogen, n+p = 2-4, and Y is oxygen or NR4 where R4 is Ci^alkyl, then Z is not C-|_ 4alkylcarbonylaminophenyl; and that when R-j is hydrogen, X is a moiety of formula (XC) as hereinbefore defined wherein V is a C4_5alkylene group, W is a bond, R_rg, R_rn, R_sj, and R_s|< are each hydrogen, r+s = 0-2, and Y is oxygen or NR4 where R4 is C-]_4alkyl, then Z is not C-μ 4alkylcarbonylaminophenyl.

The compounds of formula (IA) are considered to be novel. Accordingly, in a further aspect, the invention provides a compound of formula (IA) or a derivative thereof. There exists a sub-group of compounds falling wholly within formula (I), being of formula (IB):

wherein:

R-j , R2, X, and Y are as defined in formula (I);

Z is unsubstituted phenyl or phenyl substituted with up to five, suitably up to three, groups independently selected from C-|.galkyl, halo, C-|_galkoxy, phenyl, carboxy, Cι_galkoxycarbonyl, benzoyl, C<ι_galkylcarbonyl, aminocarbonyl, mono- and di-C<ι_ galkylaminocarbonyl, Cι_galkylcarbonylamino, Cι_galkylcarbonylC-|_galkyl, hydroxyC-i. galkyl, and aryloxy; additionally two of the substituents when attached to adjacent carbon atoms of the phenyl ring form a group selected from C3_4alkylene, oxyCι_ 2alkyleneoxy, and oxymethylenecarbonyl. with the following provisos; that when R-j is hydrogen, X is a moiety of formula (XA) as hereinbefore defined wherein R3 is C- galkyl, T is a bond, R_na, R_nD, Rp_C, and Rpd are each hydrogen, n+p = 2-4, and Y is oxygen or NR4 where R4 is C^alkyl, then Z is not C-μ 4alkylcarbonylaminophenyl; and that when R-_j is hydrogen, X is a moiety of formula (XC) as hereinbefore defined wherein V is a C4_5alkylene group, W is a bond, R_rg, R_rn, R_sj, and R_Sk are each hydrogen, r+s = 0-2, and Y is oxygen or NR4 where R4 is C^alkyl, then Z is not Cι_ 4alkylcarbonylaminophenyl.

The compounds of formula (IB) are considered to be novel. Accordingly, in a further aspect, the invention provides a compound of formula (IB) or a derivative thereof.

There exists a sub-group of compounds falling wholly within formula (I), being of formula (IC):

wherein:

R-j , R2, X, and Y are as defined in formula (I);

Z is unsubstituted phenyl or phenyl substituted with up to five, suitably up to three, groups independently selected from C-j .galkyl, halo, Cι_galkoxy, phenyl, carboxy, C-|_galkoxycarbonyl, benzoyl, C-|_galkylcarbonyl, aminocarbonyl, mono- and di-C<_|_ galkylaminocarbonyl, Cι_galkylcarbonylamino, C-ι_galkylcarbonylCι .galkyl, hydroxyC-j. galkyl, and aryloxy; with the following provisos; that when R<| is hydrogen, X is a moiety of formula (XA) as hereinbefore defined wherein R3 is C-^alkyl, T is a bond, R_na, R_n , Rp_C> and Rprj are each hydrogen, n+p = 2-4, and Y is oxygen or NR4 where R4 is C-^alkyl, then Z is not C-j. 4alkylcarbonylaminophenyl; and that when R-j is hydrogen, X is a moiety of formula (XC) as hereinbefore defined wherein V is a C4_5alkylene group, W is a bond, R_rg, R_rn, R_sj, and R_sk are each hydrogen, r+s = 0-2, and Y is oxygen or NR4 where R4 is C^alkyl, then Z is not C-j. 4alkylcarbonylaminophenyl.

The compounds of formula (IC) are considered to be novel. Accordingly, in a further aspect, the invention provides a compound of formula (IC) or a derivative thereof. The compounds of formulae (I), (IA), (IB) and (IC) may contain chiral atoms and/or multiple bonds and therefore may exist in more than one stereoisomeric form. It will be understood that the present invention extends to all such forms, including enantiomers and diastereoisomers, including geometric isomers, as well as to mixtures thereof including racemic modifications.

Suitable derivatives of the compounds of the invention are pharmaceutically acceptable derivatives. Suitable derivatives of the compounds of the invention include salts and solvates. Suitable pharmaceutically acceptable derivatives include N-oxides, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates. Suitable pharmaceutically acceptable salts include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2- hydroxyethylamine, bis-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N- benzyl-β-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline. Suitable pharmaceutically acceptable salts also includes pharmaceutically acceptable acid addition salts, such as those provided by pharmaceutically acceptable inorganic acids or organic acids. Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable inorganic acids includes the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and hydroiodide. Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable organic acids includes the acetate, tartrate, maleate, fumarate, malonate, citrate, succinate, lactate, oxalate, benzoate, ascorbate, methanesulphonate, -ketoglutarate and α-glycerophosphate. Suitable pharmaceutically acceptable solvates include hydrates.

The N-oxides of certain compounds of formula (I) wherein R-j is hydrogen are also ligands of the delta opioid receptor. Preferably, the compounds of formula (I) are not N-oxides.

As used herein, the term "aryl" includes mono- and bicyclic carbocyclic aromatic groups, for example phenyl and naphthyl.

As used herein, the term "heteroaryl" includes mono- and bicyclic aromatic groups, one or both rings each being interrupted by one or more heteroatoms, for example quinolinyl and indolyl.

As used herein, the term "heteroatom" includes sulphur, oxygen, and nitrogen.

As used herein, the term "halo" includes fluoro, chloro, bromo, and iodo.

Suitable substituents for any aryl group, unless hereinbefore defined, include one or more substituents independently selected from the group consisting of heterocyclylalkyl, alkyl, halo, aryloxy, alkoxy, aryl, carboxy, alkoxycarbonyl, arylcarbonyl, alkylcarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonylalkyl, hydroxyalkyl, hydroxy, and heterocyclyl.

Suitable substituents for any heteroaryl group include one or more substituents independently selected from the group consisting of heterocyclylalkyl, alkyl, halo, alkoxy, aryl, carboxy, alkoxycarbonyl, arylcarbonyl, alkylcarbonyl, aminocarbonyl, mono- and di- alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonylalkyl, hydroxyalkyl, hydroxy, and heterocyclyl.

As used herein, the term "heterocyclyl" includes cyclic aliphatic groups interrupted by one or more heteroatoms.

A further aspect of the invention provides a process for the preparation of a compound of formulae (IA), (IB) or (IC), wherein R-j is hydrogen, which process comprises the reaction of a compound of formula (II):

wherein:

X, Y and Z are as hereinbefore defined and M can be either oxygen or a lone pair of electrons; with a suitable reducing agent to produce a compound of formulae (IA), (IB) or (IC), wherein R^ is hydrogen, and thereafter carrying out one or more of the following optional steps:

(i) converting a compound of formulae (IA), (IB) or (IC) wherein R-j is hydrogen, to another compound of formulae (IA), (IB) or (IC) wherein R-j is hydrogen, respectively; (ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed. Preferably, when the nitro group is at position 4, then M is oxygen. The reduction process may suitably be carried out in two ways; Process (A) or Process (B). Process (A)

In general, a mixture of the compound of formula (II), a suitable catalyst, and a suitable hydrogen transfer reagent in a suitable protic solvent is stirred at a suitable temperature, generally an elevated temperature, over a suitable reaction time providing a suitable rate of formation of the desired product. A suitable catalyst is palladium on carbon. Suitable hydrogen transfer reagents are cyclohexene, 1,4-cyclohexadiene, formic acid and salts of formic acid such as potassium formate or ammonium formate.

Suitable protic solvents are /so-propyl alcohol and ethyl alcohol. Suitable reaction temperatures include those in the range 50-100°C. A suitable reaction time is 24-48 hours. The product is isolated by filtration and purified by conventional means, for example chromatography. Conventional methods of heating may be employed, for example electric heating mantles.

In a preferred aspect, a mixture of the compound of formula (II), ethyl alcohol, and 10% palladium on charcoal in cyclohexene is stirred at 65°C for 40 hours. The reaction mixture is then filtered on a Celite pad, evaporated to dryness and the residue purified by flash chromatography to yield the compound of formulae (IA), (IB) or (IC) wherein R-j is hydrogen.

Process (B)

In general, a mixture of the compound of formula (II) and iron in a suitable organic acid is stirred at a suitable temperature, generally an elevated temperature, over a suitable reaction time providing a suitable rate of formation of the desired product. A suitable organic acid is acetic acid. Suitable reaction temperatures include those in the range 50-100°C. A suitable reaction time is 1-5 hours. The product is isolated by conventional means such as quenching, filtration and extraction with a suitable organic solvent. The reaction is suitably quenched with water, basified with a suitable aqueous base, and extracted with a suitable organic solvent. A suitable aqueous base is aqueous sodium hydroxide solution. A suitable organic solvent is dichloromethane. The product is purified by conventional means, for example chromatography. Conventional methods of heating may be employed, for example electric heating mantles. In a preferred aspect, a mixture of compound of formula (II), iron powder and acetic acid is heated at 80°C for 2 hours. The reaction is then quenched with water, basified with 40% aqueous sodium hydroxide solution, filtered on a Celite pad, and extracted with dichloromethane. The organic layer is then washed with water, dried and the solvent removed by evaporation. The crude material is then purified by flash chromatography to yield the compound of formulae (IA), (IB) or (IC) wherein R-j is hydrogen.

Process (B) is most preferably used when Z is substituted aryl or substituted heteroaryl wherein the substituents include halo.

Compounds of formula (II) wherein Y is oxygen or sulphur may be prepared according to Process (C) or Process (D). Process (C) Compounds of formula (II) wherein Y is oxygen or sulphur may be obtained by reaction of a compound of formula (111):

wherein:

M is as defined in formula (II), X is as defined in formulae (IA), (IB) or (IC), and L is a leaving group; with a compound of formula (IV):

\A-T-Z ₍|v)

wherein:

Y' is oxygen or sulphur and Z is as defined in formulae (IA), (IB) or (IC), in the presence of a suitable base. An example of a leaving group, L, is an alkane sulphonate such as methane sulphonate. An example of a suitable base is a hindered base i.e. a base which will not act as a competing nucleophile, for example a tertiary amine.

In general, a solution of the compound of formula (III) and the compound of formula (IV) in a suitable solvent is stirred at a suitable temperature over a suitable reaction time, in the presence of a suitable base, to produce the compound of formula (II). The compound of formula (II) is generally isolated by filtration of the reaction mixture, removal of the solvent followed by purification by conventional means. A suitable solvent is acetonitrile. Suitable temperatures are those in the range 30-50°C. Suitable reaction times are those in the range 12-96 hours. A suitable base is 1 ,5,7- triazabicyclo[4.4.0]dec-5-ene bound to polystyrene cross-linked with 2% divinylbenzene (PTBD). A suitable workup entails filtration, sequential washing of the residue with acetonitrile, methanol, then dichloromethane and evaporation of the filtrate to yield the crude compound of formula (II). The compound of formula (II) may then be purified by flash chromatography or used without further purification. Conventional methods of heating may be employed, such as electric heating mantles. In a preferred aspect, a solution of the compound of formula (III) and an excess of the compound of formula (IV) in acetonitrile is stirred at 40°C for 48 hours in the presence of an excess of 1 ,5,7-triazabicyclo[4.4.0]dec-5-ene bound to polystyrene cross-linked with 2% divinylbenzene (PTBD). The reaction mixture is then filtered and the residue washed sequentially with acetonitrile, methanol, and dichloromethane. The solvent is removed from the filtrate by evaporation to yield the crude compound of formula (II). The crude compound may be purified by flash chromatography or used without further purification. Compounds of formula (III) wherein L is an alkane sulphonate group may be prepared from compounds of formula (V):

wherein:

X is as defined in formulae (IA), (IB) or (IC) and M is as defined in formula (II), by reaction with an alkane sulphonyl halide in the presence of a base.

In general, a solution of the compound of formula (V), an alkane sulphonyl halide, and a suitable base in a suitable solvent is stirred at a suitable temperature under an inert atmosphere over a suitable period of time. A suitable alkane sulphonyl halide is methane sulphonyl chloride. A suitable base is a hindered base i.e. a base which will not compete with the leaving group as a nucleophile, for example a tertiary amine. A suitable solvent is an alkyl halide. Suitable temperatures are those in the range 0-30°C. A suitable inert atmosphere is an atmosphere of nitrogen. Suitable reaction times are those in the range 2-24 hours. The compound of formula (III) is isolated by conventional means such as quenching, isolation and washing of the organic layer, and removal of the organic solvent. The crude compound of formula (III) may be purified by conventional means such as chromatography and trituration. In a preferred aspect, a solution of the compound of formula (V) and ethyl di-/so- propylamine in dichloromethane under an atmosphere of nitrogen is cooled to 0°C, and a solution of methane sulphonyl chloride in dichloromethane is added dropwise, maintaining the temperature below 10°C. The reaction mixture is then allowed to warm to room temperature and stirred for 3 hours. The reaction mixture is then quenched with water, washed with 10% citric acid, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulphate, and evaporated to dryness. The crude compound of formula (III) is then purified by flash chromatography and, optionally, triturated with di-/so-propyl ether. Process (D) The compound of formula (V) is reacted directly with the compound of formula

(IV) to give a compound of formula (II) in a reaction of the Mitsunobu type as described in Organic Reactions, 1992, 42, 335-656 and Synthesis, 1981, 1-28. The reaction is mediated by the complex formed between diethyl azodicarboxylate (DEAD) or di-/so- propyl azodicarboxylate (DIAD) and triphenylphosphine or triphenylphosphine supported on polystyrene, and is conducted in an aprotic solvent, such as tetrahydrofuran, dichloromethane, or dimethylformamide.

In general, a mixture of the compound of formula (V), the compound of formula (IV), triphenylphosphine or polymer-bound triphenylphosphine, and di-/^'so-propyl azodicarboxylate in a suitable solvent, is stirred under a suitable inert atmosphere at a suitable temperature over a suitable reaction time. A suitable solvent is tetrahydrofuran, dimethylformamide, or a mixture of dichloromethane and tetrahydrofuran. A suitable inert atmosphere is an atmosphere of nitrogen. Suitable temperatures are those in the range 0-30°C. Suitable reaction times are those in the range 2-24 hours. The product is isolated by conventional means including filtration if polymer supported triphenylphosphine was utilised, washing of the residue, and then evaporation of the filtrate; or evaporation to dryness of the reaction mixture if non-supported triphenylphosphine was used. The crude compound of formula (II) may then be purified by conventional means such as flash chromatography or used without further purification. Conventional methods of heating and cooling may be employed such as ice/salt baths and electric heating mantles.

In a preferred aspect, a mixture of the compound of formula (V), the compound of formula (IV), and polymer-bound triphenylphosphine in dichloromethane is stirred under an atmosphere of nitrogen at ambient temperature for one hour. The reaction mixture is then cooled to 0°C and a solution of di-/so-propyl azodicarboxylate in dichloromethane added dropwise. The reaction mixture is stirred at room temperature for 8 hours, the resin removed by filtration and the residue washed with dichloromethane. The filtrate is evaporated to dryness and the compound of formula (II) thus obtained either purified by flash chromatography or utilised without further purification.

Compounds of formula (IV) are known and are commercially available. Compounds of formula (V) are known compounds or may be synthesised according to known methods, for example those disclosed in WO 98/30542 (SmithKline Beecham Corporation), wherein 2-chloro-4-nitropyridine-N-oxide (Jain P.C., Chatterjee S.K., Anand N. Indian Journal of Chemistry 1966, 403), 2-chloro-3-nitropyridine (commercially available), 2-chloro-5-nitropyridine (commercially available), or 2-bromo-6- nitropyridine (Den Hertog H.J. and Street J.W. Reel. Trav. Chim. Pays-Bas. 1969, 1391) is reacted with a compound of formula (VI):

H— X— OH (VI)

wherein:

X is as defined in formulae (IA), (IB) or (IC) and the hydrogen atom is attached to the nitrogen atom of moiety X, in the presence of sodium bicarbonate and te/f-amyl alcohol, at reflux, for a suitable reaction time. The reaction is then diluted with dichloromethane, the insoluble material is removed by filtration and the filtrate evaporated to dryness in vacuo. The crude compound of formula (V) thus obtained is then purified by flash chromatography. Suitable reaction times are those in the range 1- 5 hours.

Compounds of formula (VI) are commercially available or are prepared according to literature procedures (Powell, J.; James, N.; Smith, S.J. Synthesis 1986, 338). Compounds of formula (II) wherein Y is NR4 are prepared by reaction of 2- chloro-4-nitropyridine-N-oxide (Jain, P.C.; Chatterjee, S.K.; Anand, N. Indian Journal of Chemistry 1966, 403) or 2-chloro-3-nitropyridine (commercially available) or 2-chloro-5- nitropyridine (commercially available) or 2-bromo-6-nitropyridine (Den Hertog, H.J.; Street, J.W. Reel. Trav. Chim. Pays-Bas. 1969, 1391) with a compound of formula (VII):

H— X— Y"-Z _(VN)

wherein: X and Z are as defined in formula (IA), (IB) or (IC) and Y" is NR4, wherein R4 is as defined in formulae (IA), (IB) or (IC), in the presence of sodium bicarbonate and tert- amyl alcohol, at reflux, for a suitable reaction time. Suitable reaction times are those in the range 1-5 hours. The reaction is then diluted with dichloromethane, the insoluble material removed by filtration and the filtrate evaporated to dryness in vacuo. The crude compound of formula (II) wherein Y is NR4 is then purified by flash column chromatography or may be utilised without further purification.

Compounds of formula (VII) are known, commercially available compounds or are prepared according to procedures described in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.

A further aspect of the invention provides a process for the preparation of a compound of formulae (IA), (IB) or (IC) wherein R-j is C-j .galkyl, which process comprises the reaction of a compound of formula (VIII):

wherein:

R-j' is C-j .galkyl and R2, X, Y, and Z are as defined in formulae (IA), (IB) or (IC), with a suitable reducing agent to produce a compound of formulae (IA), (IB) or (IC) wherein R-j is C-j .galkyl, and thereafter carrying out one or more of the following optional steps:

(i) converting a compound of formulae (IA), (IB) or (IC) wherein R-j is C-j .galkyl to another compound of formulae (IA), (IB) or (IC) respectively wherein R-j is C-j .galkyl;

(ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed. The reduction may be carried out according to Process (A) or Process (B) as hereinbefore described. Process (B) is most preferably used when Z is substituted aryl or substituted heteroaryl wherein the substituents include halo.

Compounds of formula (VIII) may be prepared by reacting a compound of formula (IX):

wherein: X, Y, and Z are as defined in formulae (IA), (IB) or (IC), with a compound of formula (X):

R_fR₂NH ....

wherein:

R-j- is as defined in formula (VIII) and R2 is as defined in formulae (IA), (IB) or (IC), utilising the synthetic procedures described in Pohl R., Prutianov V., and Smrckova-Voltrova S. Collect. Czech. Chem. Commun. 1995, 1170; and Chambers R.D., Hall C.W., Hutchinson J., and Millar R.W. J. Chem. Soc. Perkin Trans. 1 1998, 1705.

Compounds of formula (IX) are prepared according to the analogous synthetic procedure described for the preparation of compounds of formula (II).

Compounds of formula (X) are known, commercially available compounds or are prepared according to procedures described in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.

Compounds of formula (I) wherein R-| is hydrogen, X is a moiety of formula (XA) as hereinbefore defined wherein R3 is C-j galkyl, T is a bond, R_na, R_nD, Rp_C, and Rpd are each hydrogen, n+p = 2-4; Y is oxygen or NR4 where R4 is C-j galkyl, and Z is C-j. 4alkylcarbonylaminophenyl, and compounds of formula (I) wherein R-j is hydrogen, X is a moiety of formula (XC) as hereinbefore defined wherein V is a C-4_5 alkylene group, W is a bond, R_rg, R_rn, R_sj, and R_s^ are each hydrogen, r+s = 0-2; Y is oxygen or NR4 where R4 is C-j galkyl, and Z is C-j_4alkylcarbonylaminophenyl may be prepared according to procedures described in EP 0 359 389. Compounds of formulae (I), (IA), (IB) and (IC) may be converted into their pharmaceutically acceptable salts by reaction with the appropriate organic or mineral acids. Solvates of the compounds of formulae (I), (IA), (IB) and (IC) may be formed by crystallisation or recrystallisation from the appropriate solvent. For example, hydrates may be formed by crystallisation or recrystallisation from aqueous solutions, or solutions in organic solvents containing water. Salts or solvates of the compounds of formulae (I), (IA), (IB) and (IC) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates.

Accordingly, salts or solvates of compounds of formula (IA), (IB) and (IC) also form an aspect of this invention.

As previously mentioned herein, certain pyridylamino derivatives are potent delta opioid receptor ligands.

Accordingly, the present invention provides the use of a compound of formula (I), or a derivative thereof, as a ligand of the delta opioid receptor.

In a further aspect, the invention provides the use of a compound of formula (I), or a derivative thereof, as an agonist of the delta opioid receptor. In yet a further aspect, the invention provides the use of a compound of formula

(I), or a derivative thereof, as an antagonist of the delta opioid receptor.

As previously mentioned herein, compounds of formulae (I) and (IA), (IB) or (IC) may be useful in the treatment and/or prophylaxis of pain, allergic and inflammatory responses, brain cell damage, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists of the delta opioid receptor. As also previously mentioned herein, the compounds of formulae (1) and (IA), (IB) or (IC) may be useful in the treatment and/or prophylaxis of Crohn's disease, ulcerative colitis and irritable bowel syndrome. As also previously mentioned herein, compounds of formulae (I) and (IA), (IB) or (IC) may be useful in the treatment and/or prophylaxis of rejection in organ transplant and skin graft, and of drug and alcohol abuse, and of those conditions which customarily can be treated with antagonists of the delta opioid receptor.

Accordingly the present invention also provides a compound of formulae (IA), (IB) or (IC), or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

In a further aspect, the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, as an agonist of the delta opioid receptor for the treatment and/or prophylaxis of pain, allergic and inflammatory responses, brain cell damage, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists of the delta opioid receptor. In a yet further aspect, the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, as an agonist of the delta opioid receptor for the treatment and/or prophylaxis of Crohn's disease, ulcerative colitis or irritable bowel syndrome, and of those conditions which customarily can be treated with agonists of the delta opioid receptor. In yet a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, as an antagonist of the delta opioid receptor for the treatment and/or prophylaxis of rejection in organ transplant and skin graft, and of drug and alcohol abuse, and of those conditions which customarily can be treated with antagonists of the delta opioid receptor.

As previously mentioned herein, N-oxides of certain compounds of formula (I) wherein R-j is hydrogen are also ligands of the delta opioid receptor.

Accordingly, there is provided the use of an N-oxide of a compound of formula (I), wherein R-j is hydrogen, as a ligand of the delta opioid receptor.

In a further aspect, there is provided the use of an N-oxide of a compound of formula (I), wherein R-j is hydrogen, as an agonist of the delta opioid receptor.

In yet a further aspect, there is provided the use of an N-oxide of a compound of formula (I), wherein R-j is hydrogen, as an antagonist of the delta opioid receptor. In still a further aspect, the present invention provides the use of a compound of formulae (IA), (IB) or (IC), or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, for the treatment and/or prophylaxis of pain, allergic and inflammatory responses, brain cell damage, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists of the delta opioid receptor. In a yet further aspect, the present invention also provides the use of a compound of formula (IA), (IB) or (IC) or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, for the treatment and/or prophylaxis of Crohn's disease, ulcerative colitis or irritable bowel syndrome. In yet a further aspect, the present invention provides the use of a compound of formulae (IA), (IB) or (IC), or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, for the treatment and/or prophylaxis of rejection in organ transplant and skin graft, and of drug and alcohol abuse, and of those conditions which customarily can be treated with antagonists of the delta opioid receptor. The present invention further provides a pharmaceutical composition comprising a compound of formulae (IA), (IB) or (IC), or a pharmaceutically acceptable derivative or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of pain, allergic and inflammatory responses, brain cell damage, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists of the delta opioid receptor. The present invention further provides for the use of a compound of formula (I), or a pharmaceutically acceptable derivative or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of Crohn's disease, ulcerative colitis, irritable bowel syndrome.

The present invention further provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of rejection in organ transplant and skin graft, and of drug and alcohol abuse, and of those conditions which customarily can be treated with antagonists of the delta opioid receptor.

Such a medicament, or a composition of this invention, may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner. Preferably, a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such preparations may be in a pack form accompanied by written or printed instructions. The suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration. The compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient. Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories. The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.

Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients. Compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

The compounds of this invention may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, antioxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multidose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.

The compounds of this invention may also be administered by inhalation, via the nasal or oral routes. Such administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant. Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles. Preferably, the compound particle size is from about 2 to 10 microns.

A further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation. A preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient. For a constant rate of percutaneous absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.

As mentioned above, the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg. The composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 50 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.

No unacceptable toxicological effects are expected with compounds of the invention when administered in accordance with the invention.

The following Examples illustrate the invention, but do not limit it in any way.

Description 1

3-(4-Nitro-1 -oxypyridin-2-ylamino)propan-1 -ol 2-Chloro-4-nitropyridine-1 -oxide (Jain, P.C.; Chatterjee, S.K.; Anand, N. Indian Journal of Chemistry 1966, 403) (4.1 g, 23.5 mmol), 3-aminopropan-1-ol (3.6 mL, 47.0 mmol) and NaHCO₃ (9.9 g, 117.5 mmol) were dissolved in tert-amyl alcohol (35 mL) and heated to 90 °C for 45 minutes. The reaction mixture was then allowed to warm to room temperature, diluted with CH₂CI₂ (85 mL) filtered and evaporated to dryness. The crude material thus obtained was purified by gradient flash column chromatography on 230- 400 mesh silica gel, utilising a mixture of EtOAc/MeOH 90:10 as starting eluent, and a mixture of EtOAc/MeOH 70:30 as final eluent, to yield 4.4 g of the title compound. IR, ¹H nmr spectra and mass spectra were consistent with the assigned structure. C₈HnN₃O₄ MW = 213.20

Description 2

2-[2-(4-Nitro-1-oxypyridin-2-ylamino)ethoxy]ethanol

2-Chloro-4-nitropyridine-1-oxide (Jain, P.C.; Chatterjee, S.K.; Anand, N. Indian Journal of Chemistry 1966, 403) (3.0 g, 17.2 mmol), 2-(2-aminoethoxy)ethanol (3.0 g, 28.7 mmol) and NaHCO₃ (2.8 g, 34.4 mmol) were dissolved in tert-amyl alcohol (30 mL) and heated to 90 °C for 1 hour. The reaction mixture was then allowed to warm to room temperature, diluted with CH₂CI₂ (70 mL) filtered and evaporated to dryness. The crude material thus obtained was purified by flash column chromatography on 230-400 mesh silica gel, utilising as eluent a mixture of EtOAc/MeOH 95:5 to yield 3.6 g of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assigned structure.

Description 3 4-Nitro-2-[4-(2-hydroxy)ethyl]piperidin-1-yl-1-oxypyridine

2-Chloro-4-nitropyridine-1-oxide (Jain, P.C.; Chatterjee, S.K.; Anand, N. Indian Journal of Chemistry 1966, 403) (2.0 g, 11.5 mmol), 2-piperidin-4-ylethanol (2.0 mL, 15.5 mmol) and NaHCO₃ (1.9 g, 23.0 mmol) were dissolved in tert-amyl alcohol (30 mL) and heated to 90 °C for 1 hour. The reaction mixture was then allowed to warm to room temperature and filtered. After dilution with EtOAc (10 mL) and Et₂O (3 mL) the desired compound precipitated and was recovered by suction filtration to yield 3.0 g of the title compound as a red solid. IR, ¹H nmr spectra and mass spectra were consistent with the assigned structure. C₁₂H₁₇N₃O₄ MW = 267.29

Description 4 3-(5-Nitropyridin-2-ylamino)propan-1-ol

2-Chloro-5-nitropyridine (5.0 g, 31.5 mmol), 3-aminopropan-1-ol (4.8 mL, 63.1 mmol) and NaHCO₃ (13.2 g, 157.1 mmol) were dissolved in tert-amyl alcohol (40 mL) and heated to 90 °C for 2 hours. The reaction mixture was then allowed to warm to room temperature, diluted with CH₂CI₂ (100 mL) filtered and evaporated to dryness. The crude material thus obtained was purified by trituration with Et₂O to yield 6.2 g of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assigned structure. CβHnNaOa MW = 197.19

Description 5

3-(3-Nitropyridin-2-ylamino)propan-1-ol

2-Chloro-3-nitropyridine (5.0 g, 31.5 mmol), 3-aminopropan-1-ol (4.8 mL, 63.1 mmol) and NaHCO₃ (13.2 g, 157.1 mmol) were dissolved in tert-amyl alcohol (40 mL) and heated to 90 °C for 2 hours. The reaction mixture was then allowed to warm to room temperature, diluted with CH₂CI₂ (100 mL) filtered and evaporated to dryness. The crude material thus obtained was purified by trituration with pentane to yield 6.2 g of the title compound.

QjHnNsOs MW = 197.19

Description 6

3-[Methyl-(4-nitro-1 -oxypyridin-2-yl)amino]propan-1 -ol

According to the same procedure of Description 1 except substituting 3- methylaminopropan-1-ol (Powell, J.; James, N.; Smith, S.J. Synthesis 1986, 338) for 3- aminopropan-1-ol.

C₉H₁₃N₃O₄ MW = 227.22

Description 7 4-(4-Nitro-1-oxypyridin-2-ylamino)butan-1-ol

According to the same procedure of Description 1 except substituting 4-aminobutan-1-ol for 3-aminopropan-1-ol.

IR, ¹H nmr spectra and mass spectra were consistent with the assigned structure. C₉H₁₃N₃O₄ MW = 227.22

Description 8 (+)-frans-[2-(4-Nitro-1-oxypyridin-2-ylamino)cyclohexyl]methanol According to the same procedure of Description 1 except substituting (±)-trans (2- aminocyclohexyl)methanol for 3-aminopropan-1-ol.

C₁₂H₁₇N₃O₄ MW = 267.29

Description 9

(R,S)-4-Nitro-2-[2-(2-hydroxyethyI]piperidin-1-yl]-1 oxypyridine

According to the same procedure of Description 1 except substituting (R,S)-2-piperidin-

2-ylethanol for 3-aminopropan-1-ol. IR, ¹H nmr spectra and mass spectra were consistent with the assigned structure.

C₁₂H₁₇N₃O₄ MW = 267.29

It is considered that the compounds on the following list are novel and accordingly these compounds form a further aspect of the invention:

2-[2-(4-Nitro-1-oxypyridin-2-ylamino)ethoxy]ethanol; 4-nitro-2-[4-(2-hydroxy)ethyl]piperidin-1 -yl-1 -oxypyridine;

3-[methyl-(4-nitro-1 -oxypyridin-2-yl)amino]propan-1 -ol;

4-(4-nitro-1 -oxypyridin-2-ylamino)butan-1 -ol;

(+)-frans-[2-(4-nitro-1-oxypyridin-2-ylamino)cyclohexyl]methanol, and;

(R,S)-4-nitro-2-[2-(2-hydroxyethyl]piperidin-1-yl]-1 oxypyridine.

PROCESS C Description 10 2-[3-(Naphthalen-2-yloxy)propylamino]-4-nitro-1 -oxypyridine

3-(4-Nitro-1-oxypyridin-2-ylamino)propan-1-ol (compound of Description 1 , 0.5 g, 2.3 mmol) was suspended under nitrogen atmosphere in CH₂CI₂ (25 mL); triethylamine (TEA, 0.36 mL, 2.6 mmol) was added and the reaction mixture was cooled to 0 °C. Methanesulfonyl chloride (0.2 mL, 2.6 mmol) dissolved in CH₂CI₂ (5 mL) was added dropwise maintaining the temperature between 0 and 5 °C, then the reaction mixture was allowed to warm to room temperature and stirred for additional 4 hours. After quenching with water, the organic layer was extracted and washed with 10% citric acid, sat. sol. NaHCO₃ and brine; the organic layer was dried over MgSO , filtered and evaporated to dryness. The residue was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 95:5 as starting eluent, and a mixture of EtOAc/MeOH 90:10 as final eluent, to yield 517 mg of the mesylate derivative of 3-(4-nitro-1-oxypyridin-2-ylamino)propan-1-ol. This mesylate derivative (0.25 g, 0.86 mmol), naphthalen-2-ol (0.198 g, 1.37 mmol) and 1 ,5,7- triazabicyclo[4.4.0]dec-5-ene bound to polystyrene cross-linked with 2% divinylbenzene (PTBD, 0.899 g, 2.34 mmol) were suspended in CH₃CN (3.5 mL) and stirred at room temperature for 22 hours. The resin was filtered off and washed with CH₃CN and CH₂CI₂ and the combined filtrates were evaporated in vacuo to dryness. The crude material thus obtained was purified by flash column chromatography on 230-400 mesh silica gel, utilising as eluent a mixture of hexane/EtOAc 30:70, and then was triturated with

/Pr₂O/Et₂O to yield 110 mg of the title compound.

IR, H nmr spectra and mass spectra were consistent with the assigned structure.

C₁₈H₁₇N₃O₄ MW = 339.35 Description 10 is an example of the coupling step performed utilising Process C.

Following the same procedure described in Description 10 and starting from the appropriate compounds of formula (V), transforming them into the corresponding compounds of formula (III) and reacting them with the appropriate compounds of formula (IV) the following compounds of formula (II) were prepared (hereinafter referred to as List A):

4-Nitro-2-[3-(3-piperidin-1-ylmethylphenoxy)propylamino]-1-oxypyridine;

4-nitro-2-[3-(4-methylphenoxy)propylamino]-1 -oxypyridine;

4-nitro-2-[3-(2-chlorophenoxy)propylamino]-1 -oxypyridine;

4-nitro-2-[3-(4-methoxyphenoxy)propylamino]-1 -oxypyridine; 4-nitro-2-[3-(3-methoxycarbonylphenoxy)propylamino]-1 -oxypyridine;

4-nitro-2-[3-(3-benzoylphenoxy)propylamino]-1 -oxypyridine;

4-nitro-2-[3-(3-methylphenoxy)propylamino]-1 -oxypyridine;

4-nitro-2-[3-(3-methoxyphenoxy)propylamino]-1 -oxypyridine;

4-nitro-2-[3-[4-(3-oxobutyl)phenoxy]propylamino]-1 -oxypyridine; 4-nitro-2-[2-[2-(biphenyl-3-yloxy)ethoxy]ethylamino]-1 -oxypyridine;

4-nitro-2-[2-[2-(3-methoxycarbonylphenoxy)ethoxy]ethylamino]-1 -oxypyridine;

4-nitro-2-[2-[2-(3-benzoylphenoxy)ethoxy]ethylamino]-1 -oxypyridine;

4-nitro-2-[2-[2-(3-methylcarbonylphenoxy)ethoxy]ethylamino]-1 -oxypyridine;

4-nitro-2-[2-[2-(3-methylphenoxy)ethoxy]ethylamino]-1-oxypyridine; 4-nitro-2-[2-[2-(3-methoxyphenoxy)ethoxy]ethylamino]-1 -oxypyridine;

4-nitro-2-[2-[2-(4-te/τ-butylphenoxy)ethoxy]ethylamino]-1 -oxypyridine;

(+)-f.rat7s-4-nitro-2-[2-(biphenyl-3-yloxymethyl)cyclohexylamino]-1-oxypyridine;

(±)-t.rans-4-nitro-2-[2-(3-benzoylphenoxymethyl)cyclohexylamino]-1 -oxypyridine;

(+)-f.rans-4-nitro-2-[2-(3-methylcarbonylphenoxymethyl)cyclohexylamino]-1 -oxypyridine; (+)-frans-4-nitro-2-[2-(3-methoxyphenoxymethyl)cyclohexylamino]-1-oxypyridine;

(±)-f.rat7s-4-nitro-2-[2-(4-acetylaminophenoxymethyl)cyclohexylamino]-1 -oxypyridine;

(±)-frans-4-nitro-2-[2-(4-tert-butylphenoxymethyl)cyclohexylamino]-1-oxypyridine;

4-nitro-2-[3-[3-(2-hydroxyethyl)phenoxy]propylamino]-1-oxypyridine;

4-nitro-2-[4-[2-(biphenyl-3-yloxy)ethyl]piperidin-1-yl]-1-oxypyridine; 4-nitro-2-[4-[2-(3-methoxycarbonylphenoxy)ethyl]piperidin-1 -yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(3-benzoylphenoxy)ethyl]piperidin-1-yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(3-methylcarbonylphenoxy)ethyl]piperidin-1-yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(3-methylphenoxy)ethyl]piperidin-1-yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(3-methoxyphenoxy)ethyl]piperidin-1-yl]-1 -oxypyridine; 4-nitro-2-[4-[2-[3-(2-hydroxyethyl)phenoxy]ethyl]piperidin-1 -yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(4-diethylaminocarbonyl-2-methoxyphenoxy)ethyl]piperidin-1-yl]-1- oxypyridine; 4-nitro-2-[4-[2-(4-acetylaminophenoxy)ethyljpiperidin-1-yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(4-tert-butylphenoxy)ethyl]piperidin-1-yl]-1-oxypyridine;

4-nitro-2-[4-[2-(quinolin-6-yloxy)ethyl]piperidin-1-yl]-1 -oxypyridine, and;

4-nitro-2-[4-[2-[4-(3-oxobutyl)phenoxy]ethyl]piperidin-1-yl]-1 -oxypyridine.

IR, ¹H nmr spectra and mass spectra for all the above compounds were consistent with the assigned structures.

It is considered that 2-[3-(naphthalen-2-yloxy)propylamino]-4-nitro-1 -oxypyridine and the compounds of List A are novel and accordingly these compounds form a further aspect of the invention.

PROCESS D Description 11 4-Nitro-2-(3-phenoxypropylamino)-1 -oxypyridine

A solution of di-/so-propyl azodicarboxylate (DIAD, 1.5 mL, 7.7 mmol) in THF (8 mL) was added dropwise at 0°C and under inert atmosphere to a solution of phenol (530 mg, 5.6 mmol), 3-(4-nitro-1-oxypyridin-2-ylamino)propan-1-ol (compound of Description 1 , 1.0 g,

4.7 mmol) and triphenylphosphine (2.0 g, 7.6 mmol) in DMF (18 mL). The reaction mixture was stirred at 0 °C for 10 minutes and then allowed to warm to room temperature and stirred at room temperature for 23 hours. After evaporation to dryness, the residue was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising EtOAc as starting eluent, and a mixture of EtOAc/MeOH 97:3 as final eluent, to yield 630 mg of the title compound as an orange solid.

C₁₄H₁₅N₃O₄ MW = 289.29 Description 11 is an example of the coupling step performed utilising Process D.

Following the same procedure described in Description 11 and starting from the appropriate compounds of formula (IV) and of formula (V) the following compounds of formula (II) were prepared (hereinafter referred to as List B):

4-Nitro-2-[methyl-(3-phenoxypropyl)amino]-1 -oxypyridine; 4-nitro-2-[3-(biphenyl-3-yloxy)propylamino]-1 -oxypyridine;

4-nitro-2-[3-(3-methylcarbonylphenoxy)propylamino]-1 -oxypyridine;

4-nitro-2-[3-(4-diethylaminocarbonyl-2-methoxyphenoxy)propylamino]-1 -oxypyridine;

4-nitro-2-(4-phenoxybutylamino)-1 -oxypyridine;

4-nitro-2-[2-[2-[4-(3-oxobutyl)phenoxy]ethoxy]ethylamino]-1-oxypyridine; 4-nitro-2-[3-[4-(2-methoxycarbonylethyl)phenoxy]propylamino]-1 -oxypyridine, and;

5-nitro-2-(3-phenoxypropylamino)pyridine.

It is considered that 4-nitro-2-(3-phenoxypropylamino)-1 -oxypyridine and the compounds of List B are novel and accordingly these compounds form a further aspect of the invention. Description 12 4-Nitro-2-[3-(4-acetylaminophenoxy)propylamino]-1 -oxypyridine

DIAD (131 mg, 0.65 mmol) was added under inert atmosphere to a solution of N-(4- hydroxyphenyl)acetamide (74 mg, 0.49 mmol), 3-(4-nitro-1-oxypyridin-2-ylamino)propan- 1-ol (compound of Description 1 , 86 mg, 0.41 mmol) and polymer bound triphenylphosphine (216 mg, loading 3 mmol/g, 0.65 mmol) in CH₂CI₂ (5 mL). The reaction mixture was stirred at room temperature overnight, then the resin was filtered off and washed with CH₂CI₂ and MeOH. The combined filtrates were evaporated in vacuo to dryness to yield the crude title compound which was used in the following reaction without further purification.

C₁₆Hι₈N₄O₅ MW = 346.34

Description 12 is an example of the coupling step performed utilising Process D and polymer bound triphenylphosphine. Following the same procedure described in Description 12 and starting from the appropriate compounds of formula (IV) and of formula (V) the following compounds of formula (II) were prepared (hereinafter referred to as List C):

4-Nitro-2-[3-(4-tert-butylphenoxy)propylamino]-1 -oxypyridine;

4-nitro-2-[3-(quinolin-6-yloxy)propylamino]-1-oxypyridine; 4-nitro-2-[2-[2-(4-diethylaminocarbonyl-2-methoxyphenoxy)ethoxy]ethylamino]-1- oxypyridine;

4-nitro-2-[2-[2-(4-acetylaminophenoxy)ethoxy]ethylamino]-1 -oxypyridine;

4-nitro-2-[2-[2-(quinolin-6-yloxy)ethoxy]ethylamino]-1 -oxypyridine;

4-nitro-2-[2-(2-phenoxyethoxy)ethylamino]-1 -oxypyridine; (R,S)-4-nitro-2-[2-(2-phenoxyethyl)piperidin-1 -yl]-1 -oxypyridine;

4-nitro-2-[4-(3-phenoxypropyl)piperidin-1 -yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(3,4-dimethoxyphenoxy)ethyl]piperidin-1-yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(benzo(1 ,3)dioxol-5-yloxy)ethyl]piperidin-1 -yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(quinolin-4-yloxy)ethyl]piperidin-1-yl]-1 -oxypyridine; 4-nitro-2-[4-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]piperidin-1-yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(benzofuran-3-one-6-yloxy)ethyl]piperidin-1-yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(4-methoxynaphthalen-1-yloxy)ethyl]piperidin-1-yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(quinolin-5-yloxy)ethyl]piperidin-1-yl]-1 -oxypyridine;

4-nitro-2-[4-[2-(2-methylquinolin-4-yloxy)ethyl]piperidin-1 -yl]-1 -oxypyridine; and 4-nitro-2-[4-[2-(8-ethylquinolin-4-yloxy)ethyl]piperidin-1 -yl]-1 -oxypyridine.

It is considered that 4-nitro-2-[3-(4-acetylaminophenoxy)propylamino]-1- oxypyridine and the compounds of List C are novel and accordingly these compounds form a further aspect of the invention. Description 13

4-Nitro-2-[4-(3-hydroxy)propyl]piperidin-1 -yl-1 -oxypyridine

According to the same procedure of Description 3 except substituting 3-piperidin-4- ylpropanol for 2-piperidin-4-ylethanol. IR, ¹H nmr spectra and mass spectra were consistent with the assigned structure. C₁₃H₁₉N₃O₄ MW = 281.31

PROCESS A Example 17 4-Amino-2-[3-(quinolin-6-yloxy)propylamino]pyridine

4-Nitro-2-[3-[(quinolin-6-yloxy)propyl]amino]-1-oxypyridine (122 mg, 0.36 mmol) was dissolved in EtOH (5 mL); 10% Pd/C (50 mg) and cyclohexene (804 uL, 8.1 mmol) were added and the reaction mixture was heated at 65 °C for 38 hours, then was filtered and evaporated in vacuo to dryness. The crude compound thus obtained was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of CH₂CI₂/MeOH/30%NH₄OH 95:5:0.5 as starting eluent, and a mixture of CH₂CI₂/MeOH/30%NH₄OH 80:20:0.5 as final eluent, to yield 25 mg of the title compound. Mass spectrum was consistent with the assigned structure (see Table 2) C₁₇Hι₈N₄O MW = 294.36

From the same flash column chromatography a by-product (7.8 mg) was isolated and demonstrated to be the N-oxide analogue of the desired compound: 4-amino-2-[3- (quinolin-6-yloxy)propylamino]-1 -oxypyridine. ¹H nmr spectra and mass spectra were consistent with the assigned structure. C₁₇H₁₈N₄O₂ MW = 310.36

Example 22 4-Amino-2-[2-[2-(3-benzoylphenoxy)ethoxy]ethylamino]pyridine

4-Nitro-2-[2-[2-(3-benzoylphenoxy)ethoxy]ethylamino]-1-oxypyridine (465 mg, 1.1 mmol) was dissolved in EtOH (15 mL); 10% Pd/C (100 mg) and cyclohexene (2.3 mL, 22.7 mmol) were added and the reaction mixture was heated at 65 °C for 48 hours, then was filtered and evaporated in vacuo to dryness. The crude compound thus obtained was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of CH₂CI₂/MeOH/30%NH₄OH 95:5:0.5 as starting eluent, and a mixture of CH₂CI₂/MeOH/30%NH₄OH 90:10:1 as final eluent, to yield 125 mg of the title compound. Mass spectrum was consistent with the assigned structure (see Table 2)

Example 40 4-Amino-2-[4-[2-(3-methoxycarbonylphenoxy)ethyl]piperidin-1-yl]pyridine

4-Nitro-2-[4-[2-(3-methoxycarbonyl)phenoxy]ethyl]piperidin-1 -yl-1 -oxypyridine (160 mg, 0.40 mmol) was dissolved in EtOH (5 mL); 10% Pd/C (70 mg) and cyclohexene (922 uL, 9.1 mmol) were added and the reaction mixture was heated at 65 °C for 38 hours, then was filtered and evaporated in vacuo to dryness. The crude compound thus obtained was purified by preparative HPLC (column: Waters - Simmetry C₁₈, 19X100 mm, 5 urn; eluents: A H₂O:CH₃CN:AcONH₄ 95:5:0.1 ; B H₂O:CH₃CN:AcONH₄ 10:90:0.1 ; gradient: 10-100% B in 8 minutes) basified with sat. sol. NaHCO₃, extracted with CH₂CI₂, dried over MgSO₄, filtered and evaporated in vacuo to dryness to yield 8.5 mg of the title compound.

Mass spectrum was consistent with the assigned structure (see Table 2)

Examples 17, 22 and 40 are examples of the reduction step performed utilising

Process A. Following the same procedure described for these Examples and starting from the appropriate compounds of formula (II) the compounds of Examples 1-3, 7-54, 60 and 61 (Table 1 , analytical data reported in Table 2) were prepared. As for Example 17, also in other cases the compounds deriving from a partial reduction of compounds of formula (II), where the nitro group was reduced to NH₂, but the N-oxide was not reduced, could be isolated (in addition to the desired compounds) as by-products of the reaction.

PROCESS B Example 6

4-Amino-2-[3-(naphthalen-2-yloxy)propylamino]pyridine

2-[3-(Naphthalen-2-yloxy)propylamino]-4-nitro-1 -oxypyridine (compound of Description 10, 100 mg, 0.3 mmol) was dissolved in AcOH (3 mL); iron powder (67 mg, 1.2 mmol) was added and the reaction mixture was heated to 80 °C for 2 hours. Then the reaction was diluted with H₂O (7 ml), basified with 40% NaOH and filtered on a celite pad. The filtrate was extracted with CH₂CI₂, evaporated to dryness and the residue was purified by flash column chromatography on 230-400 mesh silica gel, utilising as eluent a mixture of CH₂CI₂/MeOH/30% NH₄OH 94:4:0.4 to yield 43 mg of the title compound. ¹H nmr spectra and mass spectra were consistent with the assigned structure. C₁₈H₁₉N₃O MW = 293.37

Example 6 is an example of the reduction step performed utilising Process B. Following the same procedure described in Example 6 and starting from the appropriate compounds of formula (II) the compounds of Example 4, 5, 55-59, 62 and 63 (Table 1 , analytical data reported in Table 2) were prepared.

Pharmacological Data

The activity of the compounds of the present invention as selective delta ligands is determined in radioligand binding assays using cloned human delta, mu and kappa opioid receptors stably expressed in cell lines as described below. CHO cells were subjected to stable transfection with cDNA encoding the human delta and mu opioid receptors. Clones were grown in suspension culture in serum free media. Selection was performed by growth in the absence of nucleotides. Human kappa opioid receptors were stably expressed in HEK cells. Cells were grown in adhesion in E-MEM supplemented with 10% FBS and 2 mM L-glutamine, G418 was included for selection.

Membranes were prepared as previously described (J. Med. Chem. (1997), 40, 3192 ). The binding of the preferential delta ligand [3H]-[D-Ala2,D-Leu^]-enkephalin (DADLE) was evaluated at its KQ concentration (0.7nM). The binding of the mu ligand [³H]-DAMGO (Eur. J. Pharmacol., 1989, 166, 213) and of the kappa ligand [³H]-U69593 (Excerpta Medica, 1990, 211) were carried out at 0.5 nM. Non specific binding was determined in the presence of 10 μM of naloxone. Binding data were expressed as percentage of inhibition and fitted the following equation: f(x) = 100-X/(IC-5o + X) where X is the cold drug concentration value. The IC50 values obtained were used to calculate the inhibitory constants (Kj) accordingly to the Cheng and Prusoff relation (Biochem. Pharmacol., 1973, 22, 3099).

The delta agonist activity of the compounds of the present invention is determined in the cAMP bioassay in CHO cell lines stably expressing the human delta opioid receptor (h-DOR/CHO).

The most potent compounds described in the present invention showed affinities for the delta receptor ranging from 3 to 300 nM. These compounds also displayed potent delta agonist properties in the cAMP inhibition bioassay. The rat carrageenan plantar test (Pain 1988, 32, 77) and Seltzer test (Pain 1990, 43, 205) were adopted to evaluate the antinociceptive efficacy of the compounds of the present invention.

Table 1

Coupling step Reduction step

Example R1 R2N used used Rι R₂ X R3 or R3' Y No. position

(Process C or D) (Process A or B)

C or D H H R₃ = H

F^

D H H R₃ = H phenyl

D H H R₃ = CH₃ O phenyl

B H H R₃ = H

R p-tolyl

%.

B H H R₃ = H

R^ O o-CI-phenyl

B H H R₃ = H 2-naphtyl

.

H H N R₃ = H p-OMe-phenyl

-

CM

Φ -Ω

-

SI POS; AQA ; solvent: methanol/ spray 3 kV/ skimmer: 20 V/ probe 135 °C; b Εr l; TSQ 700; source 180 °C;70 V;200 uA,

Claims

1. A method for the modulation of conditions associated with the delta opioid receptor, which method comprises the administration to the mammal in need thereof an effective or prophylactic amount of a compound of formula (I):

wherein:

R-j is hydrogen or C-j .galkyl, with the proviso that when R-j is C-j .galkyl, then the group R1R2N- is located at position 4 of the pyridine ring;

R2 is hydrogen;

X is a moiety of formula (XA):

>^ (CR na ^Rnb)rT (^CRpc^Rpd)p\

N

^R* (XA)

wherein:

R₃ is hydrogen or C-j .galkyl;

R_na, R_nD, Rp_C, and Rprj are each independently hydrogen or C-j .galkyl;

T is a bond, oxygen, -CH2-, or sulphur; n and p are independently 0-3; with the following provisos: that when T is a bond, then n + p is at least 2; that when T is oxygen or sulphur, then n and p should each be at least 2, and; that when T is -CH2-, then n + p is at least 1 ; or,

X is a moiety of formula (XB):

wherein:

R₃' is hydrogen or C-j .galkyl;

Rq_Θ and R_qf are each independently hydrogen or C-_j .galkyl; U is a C3_8 cycloalkylene group, which group may optionally be interrupted by one or more heteroatoms; q is 0-3; or,

X is a moiety of formula (XC):

wherein:

V is a C3.3 alkylene chain, which chain may optionally be interrupted by one or more heteroatoms;

R_rα, R_rn, R_sj, and R_sk are each independently hydrogen or C-j .galkyl; W is a bond, oxygen, or sulphur; r and s are independently 0-3;

Y is -[O]-, -[S]-, or NR4 where R4 is hydrogen, C-| .galkyl, or C-j.galkylcarbonyl; Z is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; with the proviso that formula (I) does not include 2-(3-phenoxy)propylamino-3- aminopyridine; or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof.

2. A method of treatment and/or prophylaxis of pain, allergic and inflammatory responses, brain cell damage, gastritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists of the delta opioid receptor, which method comprises the administration to the mammal in need thereof an effective or prophylactic amount of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof.

3. A method of treatment and/or prophylaxis of rejection in organ transplant and skin graft, and of drug and alcohol abuse, and of those conditions which customarily can be treated with antagonists of the delta opioid receptor, which method comprises the administration to the mammal in need thereof an effective or prophylactic amount of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof.

4. A compound of formula (IA):

wherein:

R-j , R2, X, Y, and Z are as defined in formula (I), with the following provisos; that when R-j is hydrogen, X is a moiety of formula (XA) as hereinbefore defined wherein R3 is C^alkyl, T is a bond, R_na, R_nD, Rp_C. and Rpd are each hydrogen, n+p = 2-4, and Y is oxygen or NR4 where R4 is C-]_4alkyl, then Z is not C<|_ 4alkylcarbonylaminophenyl: and that when R-j is hydrogen, X is a moiety of formula (XC) as hereinbefore defined wherein V is a C4_5alkylene group, W is a bond, R_rg, R_m, R_sj, and R_sk are each hydrogen, r+s = 0-2, and Y is oxygen or NR4 where R4 is C-j galkyl, then Z is not C-j. 4alkylcarbonylaminophenyl; or a derivative thereof.

5. A compound of formula (IB):

wherein:

R-j , R2, X, and Y are as defined in formula (I);

Z is unsubstituted phenyl or phenyl substituted with up to five, suitably up to three, groups independently selected from C-j .galkyl, halo, C-j.galkoxy, phenyl, carboxy, C-j.galkoxycarbonyl, benzoyl, C-j.galkylcarbonyl, aminocarbonyl, mono- and di-C-j. galkylaminocarbonyl, C-j.galkylcarbonylamino, C-|.galkylcarbonylC-j .galkyl, hydroxyC-j. galkyl, and aryloxy; additionally two of the substituents when attached to adjacent carbon atoms of the phenyl ring form a group selected from C3_4alkylene, oxyC-j. 2alkyleneoxy, and oxymethylenecarbonyl. with the following provisos: that when R-j is hydrogen, X is a moiety of formula (XA) as hereinbefore defined wherein R3 is C-|_4alkyl, T is a bond, R_na, R_nD, Rp_C. and R_pcj are each hydrogen, n+p = 2-4, and Y is oxygen or NR4 where R4 is C-_j galkyl, then Z is not C-_j. 4alkylcarbonylaminophenyl; and that when R-j is hydrogen, X is a moiety of formula (XC) as hereinbefore defined wherein V is a C4_5alkylene group, W is a bond, R_rg, R_rn, R_Sj, and R_s^ ate each hydrogen, r+s = 0-2, and Y is oxygen or NR4 where R4 is C-j galkyl, then Z is not C-_j. 4alkylcarbonylaminophenyl; or a derivative thereof.

6. A process for the preparation of a compound of formula (IA) as defined in claim 4, but wherein R<| is hydrogen, which process comprises the reaction of a compound of formula (II):

wherein:

X, Y and Z are as hereinbefore defined and M can be either oxygen or a lone pair of electrons, with a suitable reducing agent to produce a compound of formula (IA), wherein R-| is hydrogen, and thereafter carrying out one or more of the following optional steps: (i) converting a compound of formulae (IA) wherein R-j is hydrogen, to another compound of formulae (IA) wherein R<| is hydrogen; (ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed.

7. A process for the preparation of a compound of formula (IA) as defined in claim 4, but wherein R-_j is C-j .galkyl, which process comprises the reaction of a compound of formula (VIII):

wherein:

R-j¹ is C-j .galkyl and R2, X, Y, and Z are as defined in formula (IA), with a suitable reducing agent to produce a compound of formula (IA) wherein R-j is C-j. galkyl, and thereafter carrying out one or more of the following optional steps: (i) converting a compound of formula (IA) wherein R-j is C-j .galkyl to another compound of formula (IA) wherein R-j is C-j .galkyl; (ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed.

8. A process for the preparation of a compound of formula (IB) as defined in claim 5, but wherein R-_| is hydrogen, which process comprises the reaction of a compound of formula (II):

wherein:

X, Y and Z are as hereinbefore defined and M can be either oxygen or a lone pair of electrons, with a suitable reducing agent to produce a compound of formula (IB), wherein R-j is hydrogen, and thereafter carrying out one or more of the following optional steps: (i) converting a compound of formulae (IB) wherein R-j is hydrogen, to another compound of formula (IB) wherein R-j is hydrogen; (ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed.

9. A process for the preparation of a compound of formula (IB) as defined in claim 5, but wherein R-j is C<| .galkyl, which process comprises the reaction of a compound of formula (VIII):

wherein:

R-j' is C-| .galkyl and R2, X, Y, and Z are as defined in formula (IB), with a suitable reducing agent to produce a compound of formulae (IB) wherein R-j is C-j .galkyl, and thereafter carrying out one or more of the following optional steps: (i) converting a compound of formula (IB) wherein R-j is C-j .galkyl to another compound of formula (IB) wherein R-j is C-j .galkyl; (ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed.

10. Use of a compound of formula (I) as defined in claim 1 , or a derivative thereof, as a ligand of the delta opioid receptor.

11. Use of a compound of formula (I) as defined in claim 1 , or a derivative thereof, as an agonist of the delta opioid receptor.

12. Use of a compound of formula (I) as defined in claim 1 , or a derivative thereof, as an antagonist of the delta opioid receptor.

13. A compound of formula (IA) as defined in claim 4, or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

14. A compound of formula (IB) as defined in claim 5, or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

15. Use of a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, as an agonist of the delta opioid receptor for the treatment and/or prophylaxis of pain, allergic and inflammatory responses, brain cell damage, gastritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists of the delta opioid receptor.

16. Use of a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, as an antagonist of the delta opioid receptor for the treatment and/or prophylaxis of rejection in organ transplant and skin graft, and of drug and alcohol abuse, and of those conditions which customarily can be treated with antagonists of the delta opioid receptor.

17. Use of an N-oxide of a compound of formula (I) as defined in claim 1 , but wherein R-| is hydrogen, as a ligand of the delta opioid receptor.

18. Use of an N-oxide of a compound of formula (I) as defined in claim 1 , but wherein R-j is hydrogen, as an agonist of the delta opioid receptor.

19. Use of an N-oxide of a compound of formula (I) as defined in claim 1 , but wherein R-j is hydrogen, as an antagonist of the delta opioid receptor.

20. Use of a compound of formula (IA) as defined in claim 4, or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, for the treatment and/or prophylaxis of pain, allergic and inflammatory responses, brain cell damage, gastritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists of the delta opioid receptor.

21. Use of a compound of formula (IB) as defined in claim 5, or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, for the treatment and/or prophylaxis of pain, allergic and inflammatory responses, brain cell damage, gastritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists of the delta opioid receptor.

22. Use of a compound of formula (IA) as defined in claim 4, or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, for the treatment and/or prophylaxis of rejection in organ transplant and skin graft, and of drug and alcohol abuse, and of those conditions which customarily can be treated with antagonists of the delta opioid receptor.

23. Use of a compound of formula (IB) as defined in claim 5, or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable solvate thereof, for the treatment and/or prophylaxis of rejection in organ transplant and skin graft, and of drug and alcohol abuse, and of those conditions which customarily can be treated with antagonists of the delta opioid receptor.

24. A pharmaceutical composition comprising a compound of formula (IA) as defined in claim 4, or a pharmaceutically acceptable derivative or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a compound of formula (IB) as defined in claim 5, or a pharmaceutically acceptable derivative or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

26. Use of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable derivative or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of pain, allergic and inflammatory responses, brain cell damage, gastritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy, and of those conditions which customarily can be treated with agonists of the delta opioid receptor.

27. Use of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable derivative or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of rejection in organ transplant and skin graft, and of drug and alcohol abuse, and of those conditions which customarily can be treated with antagonists of the delta opioid receptor.

28. A compound selected from the list consisting of: 2-[2-(4-Nitro-1-oxypyridin-2-ylamino)ethoxy]ethanol; 4-nitro-2-[4-(2-hydroxy)ethyl]piperidin-1 -yl-1 -oxypyridine; 3-[methyl-(4-nitro-1 -oxypyridin-2-yl)amino]propan-1 -ol; 4-(4-nitro-1 -oxypyridin-2-ylamino)butan-1 -ol; (+)-t.rans-[2-(4-nitro-1-oxypyridin-2-ylamino)cyclohexyl]methanol, and; (R,S)-4-nitro-2-[2-(2-hydroxyethyl]piperidin-1-yl]-1 oxypyridine.

29. A compound selected from 2-[3-(naphthalen-2-yloxy)propylamino]-4-nitro-1- oxypyridine and the compounds of List A.

30. A compound selected from 4-nitro-2-(3-phenoxypropylamino)-1 -oxypyridine and the compounds of List B.

31. A compound selected from 4-nitro-2-[3-(4-acetylaminophenoxy)propylamino]-1 - oxypyridine and the compounds of List C.