The present invention is concerned with the besylate salts of substituted nitrogen-containing six- membered amino-heterocycles and analogues and derivatives thereof, which are useful as therapeutic compounds, particularly in the treatment of pain and other conditions ameliorated by the modulation of the function of the vanilloid-1 receptor (VRl).

The pharmacologically active ingredient of chilli peppers has been recognised for some time to be the phenolic amide capsaicin. The application of capsaicin to mucous membranes or when injected intradermally, causes intense burning- like pain in humans. The beneficial effects of topical administration of capsaicin as an analgesic is also well established. However, understanding of the underlying molecular pharmacology mediating these responses to capsaicin has been a more recent development.

The receptor for capsaicin, termed the vanilloid VRl receptor, was cloned by Caterina and colleagues at UCSF in 1997 (Nature, 398:816, 1997). VRl receptors are cation channels that are found on sensory nerves that innervate the skin, viscera, peripheral tissues and spinal cord. Activation of VRl elicits action potentials in sensory fibres that ultimately generate the sensation of pain. Importantly the VRl receptor is activated not only by capsaicin but also by acidic pH and by noxious heat stimuli. It is also sensitized by a number of inflammatory mediators and thus appears to be a polymodal integrator of painful stimuli.

The prototypical VRl antagonist is capsazepine (Walpole et al., J. Med. Chem., 37:1942, 1994) - VRl IC ₅₀ of 42OnM. A novel series of sub-micromolar antagonists has also been reported recently (Lee et al, Bioorg. Med. Chem., 9:1713, 2001), but these reports provide no evidence for in vivo efficacy. A much higher affinity antagonist has been derived from the 'ultra-potent' agonist resiniferatoxin. Iodo-resiniferatoxin (Wahl et al, MoI. Pharmacol, 59:9, 2001) is a nanomolar antagonist of VRl but does not possess properties suitable for an oral pharmaceutical. This last is also true of the micromolar peptoid antagonists described by Garcia -Martinez (Proc. Natl. Acad. ScI, USA, 99:2374, 2002). WO-A- 0208221 has described a novel series of VRl antagonists, which are stated to show efficacy in a number of animal models. We herein describe another novel series of VRl modulators. These comprise predominantly VRl antagonists but encompass VRl partial antagonists and VRl partial agonists. Such compounds have been shown to be efficacious in animal models of pain.

Related compounds are disclosed in WO-A -03099284 (Amgen Inc.). There is no disclosure of compounds in which Y is quinoline or isoquinoline. Preferred compounds of the present invention have improved pharmacokinetics with lower clearance and thus improved half- life. The compounds used in the present invention are described in WO 05/047279 (Merck & Co.,

Inc.) hereby incorporated by reference.

The present invention provides compounds of formula I:

Y-J-L-Z

(D wherein:

L is NR ¹ , O, S or CH ₂ ; J is a six-membered heterocycle containing one, two or three nitrogen atoms which is unsubstituted or substituted with up to three substituents, depending on the number of nitrogen atoms present, chosen independently from: halogen; hydroxy; nitro; cyano; isonitrile; C ₃ . ₇ cycloa]kyl; C^alkyl; C ₂ - ₆ alkenyl; C ₂ _ ₆ alkynyl; C^alkoxy; C ₃ . ₇ cycloalkoxy; hydroxyC^alkyl; aminoCi_ ₆ alkyl; C _1-6 alkoxycarbonyl; haloC _1-6 alkyl; haloC _1-6 alkoxy; -NR ² R ³ ; -CONR ² R ³ ; -S(O) _n C ₁ ^alkyl; -S(O) _n NR ² R ³ ; -NHCOR ¹ ; -NHS(O) _n C ₁ . ₆ alkyl; -COH, carboxy;

-(CH ₂ ) _P NR ² R ³ ; O(CH ₂ )^R ² R ³ ; -(CH ₂ ) _p Q; -O(CH ₂ ) _P Q; and phenyl, a five-membered heterocyclic ring containing one, two, three or four heteroatoms chosen from O, N and S, at most one heteroatom being O or S, or a six-membered heterocyclic ring containing one, two or three nitrogen atoms , wherein this substituent is unsubstituted or substituted by one, two or three groups chosen from halogen, hydroxy, nitro, cyano, isonitrile, Ci_ ₆ alkyl, C^alkoxy, haloQ^alkyl, haloC ₁ . ₂ alkoxy, -NR ² R ³ , -CONR ² R ³ , -S(O) _n NR ² R ³ , -NHCOR ¹ , NHS(O) _n R ¹ , -COH, CO ₂ H and -S(O) _n C ₁ . ₆ alkyl; when J is substituted by hydroxy, tautomerism may occur, in which case any nitrogen atom ortho or para to the resulting carbonyl group may be substituted as defined above;

Q is phenyl, a five-membered heterocyclic ring containing one, two, three or four heteroatoms chosen from O, N and S, at most one heteroatom being O or S, or a six-membered heterocyclic ring containing one, two or three nitrogen atoms, optionally substituted by halogen, C^alkyl or haloC ₁ . ₄ alkyl; wherein J is substituted at positions meta to each other by L and Y; Y is naphthalene or a fused 9- or 10-membered heteroaromatic system containing a six- membered heterocyclic ring, as defined above, or a phenyl ring, or a six-membered nitrogen-containing partially saturated ring, fused either to a six-membered heterocyclic ring as defined above or to a five- membered heterocyclic ring as defined above, Y being unsubstituted or substituted with one, two or three groups independently chosen from halogen, hydroxy, cyano, nitro, isonitrile, C^alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, haloQ.ealkyl, hydroxyCi_ ₆ alkyl, aminoC^alkyl, C^alkoxy, Ci_ ₆ alkylthio, haloC^alkoxy, -NR ² R ³ , -CONR ² R ³ , -S(O) _n NR ² R ³ , -(CH ₂ ) _p NR ² R ³ , -NHCOR ¹ , NHS(O) _n R ¹ , -COH, -CO ₂ H and C^alkoxycarbonyl;

Z is phenyl, naphthyl, a six-membered heterocyclic ring containing one, two, or three nitrogen atoms or a five-membered heterocyclic ring containing one, two, three or four heteroatoms chosen from O, N and S, at most one heteroatom being O or S, Z being unsubstituted or substituted with one, two or three substituents independently chosen from halogen, hydroxy, cyano, nitro, isonitrile, C^alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, ImIoC ₁ _ ₆ alkyl, hydroxyC^alkyl, aminoCuβalkyl, Ci. ₆ alkoxy, C^alkylthio, halod. ₆ a]koxy, -NR ² R ³ , -CONR ² R ³ , -S(O) _n NR ² R ³ , -NHCOR ¹ , -NHS(O) _n R ¹ , -COH, -CO ₂ H and C^alkoxycarbonyl; each R ¹ is H or C^alkyl;

each R ² and R ³ is chosen from H and Ci ₆ alkyl, or R ² and R ³ , together with the nitrogen atom to which they are attached, may form a 4-6 membered ring optionally containing an oxygen atom or a further nitrogen atom, which ring is optionally substituted by Ci_ ₆ alkyl or Q; each n is 0, 1 or 2; each p is 1, 2, 3 or 4; q is 2, 3 or 4; as the besylate salt.

L is preferably NR ¹ , particularly NH.

L may be CH ₂ or NR ¹ . J is preferably unsubstituted or substituted by one or two substituents. Most preferably J is unsubstituted or monosubstituted. J may be disubstituted.

J is thus preferably an unsubstituted or substituted pyrimidine, pyrazine, pyridazine or triazine. Pyrimidine is particularly favoured. J may be pyridine, which is unsubstituted or substituted, such as unsubstituted pyridine. Substituents on J are preferably chosen independently from halogen, hydroxy, nitro, cyano,

Ci_ ₄ alkyl, C ₂ _ ₄ alkenyl, C ₂ _ ₄ alkynyl, Ci_ ₄ alkoxy, Ci_ ₄ cycloalkoxy, hydroxyCi_ ₄ alkyl, aminoCi_ ₄ alkyl, haloC^alkyl, haloC^alkoxy, C^alkoxycarbonyl, -NR ² R ³ , C^alkylthio, Q, CH ₂ Q, OCH ₂ Q, - (CH ₂ ) _p NR ² R ³ , -CONR ² R ³ and -CO ₂ H. Substituents on J may be chosen independently from halogen, hydroxy, nitro, cyano, C^alkyl, C ₂ _ ₄ alkenyl, C ₂ _ ₄ alkynyl, C^alkoxy, hydroxyC^alkyl, aminoC^alkyl, haloC^alkyl, haloC^alkoxy, C^alkoxycarbonyl, -NR ² R ³ , -(CH ₂ ) _P NR ² R ³ , -CONR ² R ³ and -CO ₂ H. In particular substituents are independently chosen from halogen, hydroxy, nitro, amino, Ci_ ₄ alkyl, haloCi ₄ alkyl, C _{3 5} cycloalkyl and Ci ₄ alkoxy. Thus substituents can be chosen from chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro, amino, tertiarybutyl, hydroxymethyl, 2,6-dimethylmorpholino, bromo, methylthio, cyano, 2-methylpyrrolidino, morpholino, trifluoromethoxy, hydroxy, N-phenylpiperazinyl, 2,2,2-trifluoroethyl, morpholinomethyl, imidazomethyl, cyclopropylmethoxy, pyridomethoxy, morpholinoethoxy and tetrazolyl. Most preferably any substituents are chosen from chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro and amino.

More preferably any substituents are independently chosen from halogen, hydroxy, nitro, amino, Ci_ ₄ alkyl and Ci. ₄ alkoxy. Most preferably the substituent is fluoro, methyl, methoxy, nitro or amino.

Particular embodiments of J are pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, pyrimidin-4-yl, pyridazin-4-yl, l,3,5-triazin-2-yl, 5-methoxypyrimidin-4-yl, 5-methylpyrimidin-4-yl, 5-fluoropyrimidin- 4-yl, 2-methoxypyrimidin-4-yl, 2-methylpyrimidin-4-yl, 5-nitropyrimidin-4-yl and 5-aminopyrimidin-4- yl. Further particular embodiments of J are 5-tertiarybutylpyrimidin-4-yl, 2-trifluoromethylpyrimidin-4- yl, 2-hydroxymethylpyrimidin-4-yl, (cis-2,6-dimethy]moφholin-4-yl)methylpyrimidin-4-yl, 5- bromopyrimidin-4-yl, 2-methylthio-5-methylpyrimidin-4-yl, 2-cyano-5-methylpyrimidin-4-yl, 2-(2- methylpyrrolidin- l-yl)-5-methylpyrimidin-4-yl, 2-(morpholin-4-yl)-5-methylpyrimidin-4-yl, 2-(2,2,2-

trifluoroethoxy)-5-methylpyrimidin-4-yl, 2-methyl-5-aminopyrimidin-4-yl, 2-hydroxypyrimidin-4-yl, 2- cyanopyrimidin-4-yl, 2-(morpholin-4-yl)pyrimidin-4-yl,

2-( l-phenylpiperazin-4-yl)pyrimidin-4-yl, 2-(2,2,2-trifluoroethyl)pyrimidin-4-yl, 2-methyltriazin-4-yl, 2- tertiarybutyl-5-methylpyrimidm-4-yl, 2-(moφho]in-4-ylmethyl)pyrimidin-4-yl, 2-(imidazol-l- ylmethyl)pyrimidm-4-yl, 2-isopropyl-5-methylpyrimidm-4-yl, 2-methylthiopyrimidin-4-yl, 2- cyclopropylmethoxypyrimidin-4-yl, 2-(pyridine-3-ylmethoxyl)pyrimidin-4-yl, 2-trifluoromethyl-5- methylpyrimidin-4-yl, 2-(morpholin-4-ylethoxy)pyrimidin-4-yl and 2-(tetrazoH-yl)pyrimidin-4-yl. For the avoidance of doubt the preceding lists indicate the position of attachment to L.

J may also be 2-chloropyrimidin-4-yl, 5-trifluoromethylpyridin-4-yl, 5-ethylpyrimidin-4-yl, 2- cyclopropyl-5-methylpyrimidm-4-yl, 5-isopropylpyrimidin-4-yl or pyridin-4-yl. p can be one or two.

Q can be pyridyl or phenyl. Q can be unsubstituted.

Y is thus preferably an unsubstituted or substituted quinoline, quinazoline, quinoxaline, phthalazine, isoquinoline, cinnoline, naphthyridine, indole, indazole, benzimidazole, benzothiazole, benzoxazole, imidazopyridine, imidazopyridazine, imidazopyrimidine, pyrazolopyridine, pyrazolopyridazine, pyrazolopyrimidine or triazolopyridine. Y may be substituted benzimidazole attached to J via the benzene portion. Y may be quinoxaline attached to L via the benzene portion. Y may be naphthyridine such as 1,8-naphthyridine or 1,5-naphthyridine. Y is most preferably an unsubstituted or substituted quinoline or isoquinoline, particularly a quinoline. Substituents on Y are preferably independently chosen from halogen, hydroxy, cyano, nitro, amino, C^alkyl, C ₂ . ₄ alkenyl, C ₂ ^alkynyl, haloC^alkyl, hydroxyC^alkyl, aminoC^alkyl, C^alkoxy and haloCi ₄ alkoxy. Particular substituents are hydroxy, halogen, Ci ₄ alkyl and haloCi ₄ alkyl such as hydroxy, fluorine, methyl, ethyl and trifluoromethyl. The substituents can be halogen, d_ ₄ alkyl and haloC^alkyl such as fluorine, methyl and trifluoromethyl. Y is preferably unsubstituted or substituted with one or two substituents. More preferably Y is unsubstituted or monosubstituted. Y may be naphthalene or a fused 10-membered heteroaromatic ring. Y is generally a fused 10-membered heteroaromatic system.

Particular values of Y include quinolin-8-yl, quinoline -7-yl, 3-methylquinolin-7-yl, quinolin-5-yl, quinolin-6-yl, 6-fluoroquinolin-7-yl, 8-fluoroquinolin-7-yl, 6-trifluoromethylquinolin-7-yl, 8- fluoroquinolin-7-yl and isoquinolin-7-yl. Further particular values of Y include 8-ethylquinolin-7-yl, 1,8- naphthyridin-7-yl, 4-trifluoromethylquinolin-7-yl, 5-fluoroquinolin-7-yl, l,5-naphthyridin-7-yl, 1-methyl- lH-benzimidazol-5-yl, lH-benzimidazol-6-yl, 3-fluoroquinolin-7-yl, 4-hydroxyquinolin-7-yl and quinoxalin-6-yl.

Z is preferably a six-membered ring such as pyridazinyl, phenyl or pyridyl preferably phenyl or pyridyl Z is preferably monosubstituted, particular para to the attachment to L. Particular embodiments of Z include 4-trifluoromethylphenyl, 3-trifluoromethylpyrid-6-yl and 2-trifluoromethylpyrid-5-yl. Further embodiments include 4-trifluoromethoxyphenyl and 2-fluoro- 4-trifluoromethylphenyl. Yet further embodiments include 3-trifluoromethylpyridazin-6-yl and 3-fluoro-5-trifluorcmethylpyridin-2-yl.

Substituents on Z are preferably independently chosen from halogen, amino, Ci ₄ alkyl, haloC^alkyl, hydroxyC^alkyl, aminoC^alkyl, C^alkoxy and haloCi_ ₄ alkoxy. Particular substituents are haloCi_ ₄ alkyl such as trifluoromethyl.

Z may be substituted by halogen, haloC^alkyl or haloC ₁ . ₄ alkoxy. Thus Z may be substituted by trifluoromethyl, rrifluoromethoxy or fluorine.

Each R ¹ is preferably hydrogen or Ci_ ₄ alkyl such as methyl. R ¹ is particularly hydrogen.

Each R ² and R ³ is preferably independently hydrogen or C^alkyl such as methyl. R ² and R ³ are preferably hydrogen. R ² and R ³ may form a piperidine, piperazine or morpholine ring, R ² and R ³ may then be substituted by C^alkyl, phenyl or pyridyl, particularly when they form a piperazine ring. A particularly preferred subclass of compounds is of formula Ia:

Y-J-NH-Z

(Ia) wherein: Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from hydroxy, halogen, 1IaIoC ₁ _ ₄ alkyl, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, haloCi_ ₄ alkoxy, nitro and amino;

J is pyridine, pyridazine, pyrazine, pyrimidine or triazine optionally substituted with one or two substituents independently chosen from hydroxy, halogen, haloCi_ ₄ alkyl, Ci_ ₄ alkyl, C ₃ . ₅ cycloalkyl, CV ₄ alkoxy, hydroxyCi_ ₄ alkyl, cyano, hydroxy, C^cycloalkoxy, C^alkylthio, haloQ^alkoxy, nitro, Q, (CH ₂ ) _p Q, -NR ² R ³ , -(CH ₂ ) _p NR ² R ³ and -O(CH ₂ ) _P NR ² R ³ ; wherein J is substituted at positions meta to each other by NH and Y; and Z is phenyl or pyridyl optionally substituted with one or two substituents independently selected from halogen, haloCi_ ₄ alkyl, Ci. ₄ alkyl, d. ₄ alkoxy, ImIoC ₁ . ₄ alkoxy, nitro and amino;

Q is phenyl, a five-membered heterocyclic ring containing one, two, three or four heteroatoms chosen from O, N and S, at most one heteroatom being O or S, or a six-membered heterocyclic ring containing one, two or three nitrogen atoms, optionally substituted by C^alkyl; each R ² and R ³ is chosen from H and Ci_ ₄ alkyl, or R ² and R ³ , together with the nitrogen atom to which they are attached, may form a six-membered ring optionally containing an oxygen atom or a further nitrogen atom, which ring is optionally substituted by Ci_ ₄ alkyl or Q; p is 1, 2 or 3; as the besylate salt. In one embodiment:

Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from halogen, haloCi_ ₄ alkyl, C^alkyl, C^alkoxy, haloCi_ ₄ alkoxy, nitro and amino; J is pyridine, pyridazine, pyrazine, pyrimidine or triazine optionally substituted with one or two substituents independently chosen from halogen, haloQ^alkyl, C^alkyl, C ₃ . ₅ cycloalkyl, C^alkoxy, nitro and amino; wherein J is substituted at positions meta to each other by NH and Y; and

Z is phenyl or pyridyl optionally substituted with one or two substituents independently selected from halogen, haloCi_ ₄ alkyl, d. ₄ alkyl, d. ₄ alkoxy, ImIoC ₁ . ₄ alkoxy, nitro and amino; as the besylate salt.

In another embodiment Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from halogen, haloC^alkyl, C^alkyl, C^alkoxy, haloCi_ ₄ alkoxy, nitro and amino;

J is pyridazine, pyrazine, pyrimidine or triazine optionally substituted with one or two substituents independently chosen from halogen, haloC ₁ . ₄ alkyl, Q^alkyl, C ₁ ^aIkOXy, haloCi. ₄ alkoxy, nitro and amino; wherein J is substituted at positions meta to each other by NH and Y;

Z is phenyl or pyridyl optionally substituted with one or two substituents independently selected from halogen, hak>Ci_ ₄ alkyl, Q^alkyl, C ₁ ^aIk oxy, haloC^alkoxy, nitro and amino; as the besylate salt.

Y is particularly quinoline or isoquinoline and is unsubstituted or monosubstituted. Preferred substituents include hydroxy, trifluoromethyl, fluorine, methyl and ethyl such as fluoro and methyL Y may be quinoline.

J can be unsubstituted, monosubstituted or disubstituted with substituents preferably chosen from chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro, amino, tertiarybutyl, hydroxymethyl, 2,6- dime thy lmorpholino, bromo, methylthio, cyano, 2-methylpyrrolidino, morpholino, trifluoromethoxy, hydroxy, N-phenylpiperazinyl, 2,2,2-trifluoroethyl, morpholinomethyl, imidazomethyl, cyclopropylmethoxy, pyridomethoxy, morpholinoethoxy and tetrazolyl. The substituents are preferably chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro and amino.

J is preferably unsubstituted or monosubstituted with fluorine, methoxy, methyl, amino or nitro. J is preferably pyrimidine. J may be pyridine. J may be triazine. Z is preferably monosubstituted at a position para to the point of attachment to NH. Z may be substituted by F, CF ₃ or OCF ₃ . The substituent is preferably CF ₃ .

Particularly preferred are compounds of formula Ia in which:

Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from halogen, haloCi_ ₄ alkyl, Q^alkyl, C^alkoxy, haloCi_ ₄ alkoxy, nitro and amino; J is pyrimidine optionally substituted with one or two substituents independently chosen from halogen, haloCi_ ₄ alkyl, Ci. ₄ alkyl, C ₃ . ₅ cycloalkyl, d_ ₄ alkoxy, ImIoC ₁ . ₄ alkoxy, nitro and amino; wherein J is substituted at positions meta to each other by NH and Y; and Z is pyridyl substituted at at least the position para to the point of attachment to NH by CF ₃ or OCF ₃ and which is optionally further substituted by halogen; as the besylate salt.

Particular embodiments of Y, J and Z are described above. Particular embodiments of the invention include the besylate salts of: 4-quinolin-8- y 1-N- [4-trifluoromethylphenyl]pyrimidin - 2-amine ;

6-quinolm-8-yl-N-[4-trifluoromethylphenyl]pyrazm-2-amine;

5-quinolin-8-yl-N-[4-trifluoromethylphenyl]pyridazin-3-am me;

6-quinolin-8-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-am ine;

6-quinolm-7-yl-N-[Φtrifluoromethylphenyl]pyrazin-2-amine ; 4-quinolin-7- y 1-N- [4-trifluoromethylphenyl]pyrimidin - 2-amine ;

6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidm-4-ami ne;

5-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyridazin-3-am me;

6-quinolin-7-yl-N-[5-trifluoromethylpyridin-2-yl]pyrimidi n-4-amine;

6-quinolin-7-yl-N-[6-trifluoromethylpyridin-3-yl]pyrimidi n-4-amine; 5-methoxy-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimid in-4-amme;

5-methy]-6-qumolin -7-y 1-N- [4-trifluoromethylphenyl]pyrimidin - 4-amine ;

5-fluoro-6- quinolin-7- y 1-N- [4-trifluoromethylphenyl]pyrimidin - 4-amine ;

2-methoxy-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyri midin -4-amine;

2-methy]-6-quinolin -7-y 1-N- [4-trifluoromethylphenyl]pyrimidin - 4-amine ; 6-( 3-methylquinolin -7-yl) -N- [4-trifluoromethylphenyl]pyrimidin -4-amine;

6-quinolm-5-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-ami ne;

6-quinolm-6-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-ami ne;

6-(2-methylquinolin-7-yl)-N-[4-trifluoromethylphenyl]pyri midin -4-amine;

6-( 6-fluoroquinolin -7-yl) -N- [4-trifluoromethylphenyl]pyrimidin-4-amine; 6-( 8-fluoroquinolin -7- yl) -N- [4-trifluoromethylphenyl]pyrimidin - 4-amine ;

N-[4-(trifluoromethyl)phenyl]-6-[6-trifluoromethylquinoli n-7-yl]pyrimidin -4-amine;

6-(8-methylquinolin-7-yl)-N-[4-trifluoromethylphenyl]pyri midin -4-amine;

5-fluoro-6-(8-methylquinolin-7-yl)-N-[4-trifluoromethylph enyl]pyrimidin -4-amine;

6-isoquinolin-7- yl-N- [4-trifluoromethylphenyl]pyrimidin-4-amine; 6-quinolin-8- y 1-N- [4-trifluoromethylphenyl]pyridazin -4-amine ;

4-quinolm-8-yl-N-[4-trifluoromethylphenyl] -l,3,5-triazin-2-amine;

5-nitro-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimi din-4-amine; and

6-quinolin-7-yl-N ⁴ -[4-trifluoromethylphenyl]pyrimidine-4,5-diamine. Further particular embodiments include the besylate salts of: 6-( 8-fluoroquinolin-7- yl) -5-methyl-N- [5-trifluoromethylpyridin -2- yl]pyrimidin-4-amine ;

6-( 8-fluoroquinolin -7-yl) -5-methyl-N- [4-trifluoromethylphenyl]pyrimidin - 4-amine ;

5-methoxy-2-methy]-6-quinolin- 7-y l-N-[4-trifluoromethylphenyl]pyrimidin -4-amine;

2-methy]-6-(8-methylquinolin-7-yl)-N-[4-trifluoromethylph enyl]pyrimidin-4-amine;

N-[2-fluoro-4-trifluoromethylphenyl]-5-methoxy-6-quinolin -7-ylpyrimidin -4-amine; 5-methoxy-6-quinolin-7-yl-N-[4-trifluoromethoxyphenyl]pyrimi din-4-amine;

5-methy]-6-(8-methylquinolin-7-yl)-N-[4-trifluoromethylph enyl]pyrimidin-4-amine;

5-methy]-6-(8-methylquinolin-7-yl)-Ν-[5-trifluoromethylp yridin-2-yl]pyrimidin -4-amine;

6-quinolin-7-yl-5-trifluoromethy]-N-[4-trifluoromethylphe nyl]pyrimidin-4-amine;

5-ethy l-6-quinolin-7-y 1-N- [4-trifluoromethylphenyl]pyrimidin -4-amine ;

5-ethy l-6-quinolm-7-y 1-N- [5-trifluoromethylpyridin-2-yl]pyrimidin -4-amine ;

5-methy]-6-qumolin-7-yl-N-[5-trifluoromethylpyridin-2-yl] pyrimidin-4-amine;

2-cyclopropyl-5-methy]-6-qumolm-7-yl-N-[5-trifluoromethyl pyridm- 2- yl]pyrimidin- 4-amine; 2-cyclopropyl- 5-methyl-6- quinolin-7- yl-N- [4-trifluoromemylphenyl]pyrimidin^4-amine;

5-isopropy]-6-quinolin-7-yl-N-[5-trifluoromethylpyridin-2 -yl]pyrimidm -4-amine;

6-( 6-fluoroquinolin -7- yl) -5-methyl-N- [5-trifluoromethylpyridin -2- yl]pyrimidin - 4-amine;

6-( 6-fluoroquinolin -7- yl) -5-methyl-N- [4-trifluoromethylphenyl]pyrimidin - 4-amine ;

5-fluoro-6-(8-methylquinolin-7-yl)-N-[5-trifluoromethylpy ridin-2-yl]pyrimidin-4-amine; N-(2-quinolm-7-ylpyridm-4-yl)-5-trifluoromethylpyridm-2-amin e;

2-quinolin-7- y 1-Ν- [4-trifluoromethylphenyl]pyridin -4-amine ;

5-chloro-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrim idin-4-amme; and

5-chloro-6-quinolin-7-yl-N-[5-trifluoromethylpyridin-2-yl ]pyrimidin -4-amine.

Further preferred embodiments include the besylate salts of: 5-fert-butyl-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyri midin -4-amine;

5-ferϊ-buty]-6-quinolin-7-yl-N-[5-trifluoromethylpyridm- 2-yl]pyrimidm -4-amine;

6-(8-ethylquinolin-7-yl)-N-[4-trifluoromethylphenyl]pyrim idin -4-amine;

6-(8-ethylquinolin-7-yl)-N-[5-trifluoromethylpyridin-2-yl ]pyrimidin -4-amine;

6-(8-ethylquinolin-7-yl)-5-methyl-N-[4-trifluoromethylphe nyl]pyrimidin-4-amine; 6-(8-ethylquinolin-7-yl)-5-methyl-N-[5-trifluoromethylpyridi n-2-yl]pyrimidm-4-amine;

N-[2-fluoro-4-trifluoromethylphenyl]-5-methy]-6-quinolin- 7-ylpyrimidin-4-amine;

6-( 8-methylquinolin -7-yl) - 2-trifluoromethyl-N- [4-trifluoromethylphenyl] pyrimidin-4-amine ;

6-( 8-methylquinolin -7-yl) - 2-trifluoromethyl-N- [5-trifluoromethylpyridin-2-yl]pyrimidin -4-amine ; 2-methoxymethyl-5-methy]-6-quinolin-7-yl-N-[5-trifluoromethy lpyridin-2-yl]pyrimidm-4-amine;

5-fluoro-6-(8-fluoroquinolin-7-yl)-Λ^-[4-tτifluoromethy lphenyl]pyrimidin-4-amine;

5-fluoro-6-(8-fluoroquinolin -7- yl) -N- [5-trifluoromethylpyridin -2- yl]pyrimidin- 4-amine ;

Λf-(5-methyt6-quinolm-7-ylpyrimidin-4-yl)-6-trifluoromet hylpyridazm-3-amine;

6-(l,8-naphthyridin-2-yl)-Λ ^r -[4-trifluoromethylphenyl]pyrimidin-4-amine; 5-methy]-6-quinolin-8-yl-N-[4-trifluoromethylphenyl]pyrimidi n-4-amine;

5-methy]-6-quinolin-8-yl-N-[5-trifluoromethylpyridin-2-yl ]pyrimidm-4-amine;

N- [4-trifluoromethylphenyl] -6- [ 4-trifluoromethylquinolin -7-yl]pyrimidin- 4-amine ;

5-methy]-Λ ^r -[4-trifluoromethylphenyl]-6-[4-trifluoromethylquinoli n-7-yl]pyrimidin -4-amine;

5-methyk/V- [5-trifluoromethylpyridin-2-yl] -6- [4-trifluoromethy]quinolin-7-yl]pyrimidin -4-amine ; 6-quinolin-7-yl-Λ' ⁴ -[5-trifluoromethylpyridin-2-yl]pyrimidine-4,5-diamine ;

N-[3-fluoro-5-trifluoromethylpyridin-2-yl]-5-methyl-6-qui nolin-7-ylpyrimidm-4-amine;

(5-methyl-4-qumolin-7-yl-6-{5-trifluoromethylpyridin-2-yl amino}pyrimidin-2-yl)methanol;

2-[(c^-2,6-dimethylmoφholm-4-yl)methyl]-5-methyl-6-quinolin -7-yl-Λ ^r -[5-trifluoromethylpyridin-2- yl]pyrimidin -4-amine ;

5-methyl-6-(l,8-naphthyridm-2-yl)-N-[4-trifluoromethylphe nyl]pyrimidin-4-amine;

5-methy]-6-(l,8-naphthyridm-2-yl)-N-[5-trifluoromethylpyr idin-2-yl]pyrimidm-4-amine; 5-isopropyl-6-( 1 ,8-naphthyridin-2-yl) -N- [4-trifluoromethylphenyl]pyrimidin-4-amme;

5-tert-buty]-6-( 1 ,8-naphthyridin-2-yl) -N- [4-trifluoromethylphenyl]pyrimidin-4-amine;

6-(5-fluoroquinolin -7- yl) -5-methy 1-N- [5-trifluoromethylpyridin -2- yl]pyrimidin - 4-amine;

5-methyl-6-(l,5-naphthyridm-3-yl)-N-[4-trifluoromethylphe nyl]pyrimidm-4-amine;

5-methyl-6-(l,5- naphthyridin - 3 - yl) -N- [5-trifluoromethylpyridin - 2-y 1] pyrimidin-4-amine ; 5-methy ]-6-( 1- methyl- lH-benzimidazol-5-yl) -N- [4-trifluoromethyl phenyl]pyrimidin-4-amine ;

6-(l//-benzimidazo]-6-yl)-N-[4-trifluoromethylphenyl]pyri midin-4-amine;

5-bromo-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimi din -4-amine;

5-methy]-2-methylthio-6-qumolin-7-yl-N-[4-trifluoromethyl phenyl]pyrimidin -4-amine; 5-methy ]-4-quinolin -7-y 1- 6- { 4-trifluoromethylphenylamino } pyrimidine -2-carbonitrile ;

6-( 3-fluoroquinolin -7- yl) -5-methy 1-N- [5-trifluoromethylpyridin -2- yflpyrimidin - 4-amine;

5-methy]-2-(2-methylpyrrolidin-l-yl)-6-quinolin-7-yl-N-[5 - trifluoromethylpyridin-2-yl]pyrimidin-4- amine;

5-methyl-2-morpholin-4-yl-6-quinolin-7-yl-N-[5-trifluorom ethylpyridm-2-yl]pyrimidin-4-amme; 5-methy]-6-quinolin-7-yl-2-(2,2,2-trifluoroethoxy)-N-[5-trif luoromethylpyridm-2-yl]pyrimidin-4-amine;

7-(5-methy 1-6- { 5-trifluoromethylpyridin-2-ylamino }pyrimidin-4-yl)quinolin-4-ol;

5-5-methyl-6-{ 5-trifluoromethylpyridin-2-ylamino}pyrimidin-4-ylquinolin-4- ol;

2-methy]-6-quinolin-7-yl-N ⁴ -[4-trifluoromethylphenyl]pyrimidine-4,5-diamine;

4-quinolin-7-yl-6-{4-trifluoromethylphenylamino}pyrimidin -2-ol; 2-chloro-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidi n-4-amine;

2-morpholin-4-yl-6-quinolin-7-yl-N-[4-trifluoromethylphen yl]pyrimidin-4-amine;

2-(4-phenylpiperazin-l-yl)-6-quinolin-7-yl-N-[4-trifluoro methylphenyl]pyrimidin-4-amine;

6-quinolin-7-yl-N ² -(2,2,2-trifluoroethyl)-Λ' ⁴ -[4-trifluoromethylphenyl]pyrimidine-2,4-diamine;

4-methy]-6-quinolin-7-yl-N-[4-trifluoromethylphenyl] -l,3,5-triazm-2-amine; 2-( 1 , 1 - dimethylethyl) -5-methy l-6-quinolin-7-y 1-N- [4-trifluoromethy lphenyl] pyrimidin-4-amine;

5-methy]-6-quinolin-5-yl-N-[5-trifluoromethylpyridin-2-yl ]pyrimidm-4-amine;

2-(morpholin -4- ylmethyl)-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimid in -4-amine;

(4-quinolin-7-yl-6-{ 4-trifluoromethylphenylamino}pyrimidin-2-yl)methanol; 2-( lH-imidazol- 1 - ylmethyl) - 6-quinolin - 7-y l-N-4-trifluoromethylphenyl]pyrimidin -4-amine;

2-isopropyl-5-methyl- 6-quinolin-7-y 1-N- [4-trifluoromethyl phenyl]pyrimidin-4-amine;

2-methylthio-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]p yrimidin-4-amine;

4-quinolin-7-yl-6-{4-trifluoromethylphenylamino}pyrimidin e-2-carbonitrile;

2-cyclopropylmethoxy-6-quinolin-7-yl-N-[4-trifluoromethylphe nyl]-pyrimidin-4-amine;

2-(pyridin-3-ylmethoxy)-6-quinolm-7-yl-N-[4-trifluorometh ylphenyl]-pyrimidm-4-ainine;

2-(2-morpho]in-4-ylethoxy)-6-quinolin-7-yl-N-[4-trifluoro methylphenyl]-pyrimidin-4-amine;

6-quinolin-7-yl-2-( l//-tetrazol-5-yl)-N-[4-trifluoromethylphenyl] -pyrimidin-4-amine trifluoroacetic acid salt;

6-quinolin-7-yl-2-trifluoromethy]-N-[4-trifluoromethylphe nyl]-pyrimidm-4-amme;

6-quinoxalin-6-yl-N-[4-trifluoromethylphenyl]pyrimidin-4- amine;

5-methyl-6-quinoxalm-6-yl-N-[4-trifluoromethylphenyl]pyri midm-4-amine;

5-methy]-6-qumolin-7-yl-2-trifluoromethy]-Ν-[4-trifluoro methylphenyl]pyrirriidin-4-amine; 5-methy]-2-methylthio-6-qumolin-7-yl-N-[5-trifluoromethylpyr idm-2-yl]pyrimidm-4-amine;

5-methy]-2- methylsulfony]-6-quinolin-7-y 1-N- [4-trifluoromethylphenyl]pyrimidin-4-amine ;

5-methy]-2-methylsulfony]-6-quinolm-7-yl-N-[5-trifluorome thylpyridm-2-yl]pyrimidm-4-amine; and

2-methylsulfony]-6-quino]in-7-yl-N-[4-trifluoromethylphen yl]pyrimidin-4-amine.

Particular embodiments include: 7-(5-methyl-6- { 5-trifluoromethylpyridin-2-ylamino]pyrimidin-4-yl)quinoliniu m benzenesulfonate;

7-(2-cyclopropyl-5-methyl-6-{5-trifluoromethylpyridin-2-y ]amino}pyrimidin-4-yl)quinolinium benzenesulfonate;

7-(2-cyclopropyl-5-methyl-6-{4-trifluoromethylphenykmino} pyrimidin-4-yl)quinolinium benzenesulfonate; 7-(5-isopropyl-6-{5-trifluoromethylpyridin-2-y]amino}pyrimid m-4-yl)quinolmium benzenesulfonate;

6-fluoro-7-(5-methy]-6-{ 5-trifluoromethylpyridin-2-y]amino}pyrimidin-4-yl)quinolmium benzenesulfonate; and

6-fluoro-7-(5-methy]-6-{ 4-trifluoromethylpheny]ammo}pyrimidin-4-yl)quinolinium benzenesulfonate.

As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i- propyl, n-butyl, s -butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. "Alkylthio" shall be construed in an analogous manner. Examples of

"C ₃ . ₇ cycloalkyl" groups are cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl and methylcyclopropyl groups. As used herein, the term "hydroxyC^alkyl" means a C^alkyl group in which one or more (in particular 1 to 3, and especially 1) hydrogen atoms have been replaced by hydroxy groups. Particularly preferred are hydroxyC _1-3 alkyl groups, for example, CH ₂ OH, CH ₂ CH ₂ OH, CH(CH ₃ )OH or C(CH ₃ ) ₂ OH, and most especially CH ₂ OH. "AminoC ₁ . ₆ alkyl" shall be construed in an analogous manner.

As used herein, the terms "haloC^alkyl" and "ImIoC ₁ _ ₆ alkoxy" means a C^alkyl or Ci_ ₆ alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. Preferred are fluoroCi_ ₆ alkyl and HUOTOC ₁ . ₆ alkoxy groups, in particular, fluoroQj alkyl and fluoroC^ alkoxy groups, for example, CF ₃ , CH ₂ CH ₂ F, CH ₂ CHF ₂ , CH ₂ CF ₃ ,

OCF ₃ , OCH ₂ CH ₂ F, OCH ₂ CHF ₂ or OCH ₂ CF ₃ , and most especially CF ₃ and OCF ₃ .

As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is acetylene or propargyl.

When used herein, the term "halogen" means fluorine, chlorine, bromine and iodine. The most preferred halogens are fluorine and chlorine, especially fluorine.

When used herein, the term "Ci_ ₆ alkoxycarbonyl" denotes a Ci_ ₆ alkoxy radical attached via the oxygen atom thereof to a carbonyl (C=O) radical thus forming a C^alkoxycarbonyl or haloC^alkoxycarbonyl radical. Suitable examples of such esterified carboxy groups include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

Examples of 6-membered heterocycles are pyridine, pyrimidine, pyrazine, pyridazine and triazine.

Examples of 5-membered heterocycles are thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, oxadiazole, thiadiazole and tetrazole.

"Heterocyclic" in the above is interchangeable with "heteroaromatic".

The salts may be formed by conventional means, such as by reacting the free base form of the compound of formula I with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.

The present invention also includes within its scope N-oxides of the compounds of formula I above. In general, such N-oxides may be formed on any available nitrogen atom. The N-oxides may be formed by conventional means, such as reacting the compound of formula I with oxone in the presence of wet alumina. The present invention includes within its scope prodrugs of the compounds of formula I above.

In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the

"parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.

The present invention includes within its scope solvates of the compounds of formula for example, hydrates.

The compounds according to the invention may have one or more asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, the compounds of formula I may also exist in tautomeric forms and the invention includes within its scope both mixtures and separate individual tautomers.

The present invention further provides pharmaceutical compositions comprising one or more compounds of formula I in association with a pharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices, suppositories, creams or gels; for oral, parenteral, intrathecal, intranasal, sublingual, rectal or topical administration, or for administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Favoured unit dosage forms contain from 1 to 500 mg, for example 1, 5, 10, 25, 50, 100, 300 or 500 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of painful conditions such as those listed below, a suitable dosage level is about 1.0 mg to 15 g per day, preferably about 5.0 mg to I g per day, more preferably about 5 mg to 500 mg per

day, especially 10 mg to 100 mg per day. The compounds may be administered on a regimen of 1 to 4 times per day.

It will be appreciated that the amount of a compound of formula I required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the conditbn being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.

The invention further provides a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, for use in treatment of the human or animal body. Preferably, said treatment is for a condition which is susceptible to treatment by modulation (preferably antagonism) of VRl receptors. The compounds of the present invention will be of use in the prevention or treatment of diseases and conditions in which pain and/or inflammation predominates, including chronic and acute pain conditions. Such conditions include rheumatoid arthritis; osteoarthritis; post-surgical pain; musculo¬ skeletal pain, particularly after trauma; spinal pain; myofascial pain syndromes; headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain; ear pain; episiotomy pain; burns, and especially primary hyperalgesia associated therewith; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, pain associated with cystitis and labour pain, chronic pelvic pain, chronic prostatitis and endometriosis; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; itching conditions including pruritis, itch due to hemodialysis, and contact dermatitis; pain (as well as broncho-constriction and inflammation) due to exposure (e.g. via ingestion, inhalation, or eye contact) of mucous membranes to capsaicin and related irritants such as tear gas, hot peppers or pepper spray; neuropathic pain conditions such as diabetic neuropathy, chemotherapy- induced neuropathy and post-herpetic neuralgia; "non-painful" neuropathies; complex regional pain syndromes; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage, low back pain, sciatica and ankylosing spondylitis; gout; scar pain; irritable bowel syndrome; inflammatory bowel disease; urinary incontinence including bladder detrusor hyper-reflexia and bladder hypersensitivity; respiratory diseases including chronic obstructive pulmonary disease (COPD), chronic bronchitis, cystic fibrosis, asthma and rhinitis, including allergic rhinitis such as seasonal and perennial rhinitis, and non-allergic rhinitis; autoimmune diseases; and immunodeficiency disorders. In particular conditions that can be treated or prevented by the compounds of the present invention include respiratory diseases such as chronic obstructive pulmonary disease (COPD); chronic bronchitis; cystic fibrosis; asthma; and rhinitis, including allergic rhinitis such as seasonal and perennial rhinitis, non-allergic rhinitis and cough. The compounds of the present invention may also be useful in the treatment of depression. They may also be used to treat gastro- oesophageal reflux disease (GERD), particularly the pain associated with GERD.

Thus, according to a further aspect, the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of physiological disorders that may be ameliorated by modulating VRl activity.

The present invention also provides a method for the treatment or prevention of physiological disorders that may be ameliorated by modulating VRl activity, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.

According to a further or alternative aspect, the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates.

According to a further alternative aspect, the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of respiratory diseases such as cough.

The present invention also provides a method for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.

The present invention also provides a method for the treatment or prevention of respiratory diseases, such as cough, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.

According to a further aspect of the present invention, it may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition. The compound of formula I and the other pharmacologically active agent(s) may be administered to a patient simultaneously, sequentially or separately. The combination may thus be presented as a unit dosage form, for example a single tablet.

Thus, for example, for the treatment or prevention of pain and/or inflammation, a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, as well as opioid analgesics, especially morphine, NR2B antagonists, bradykinin antagonists, anti-migraine agents, anticonvulsants such as oxcarbazepine and carbamazepine, antidepressants (such as TCAs, SSRIs, SNRIs, substance P antagonists, etc.), spinal blocks, gabapentin, pregabalin and asthma treatments (such as ^-adrenergic receptor agonists or leukotriene D ₄ antagonists (e.g. montelukast).

Specific anti- inflammatory agents include diclofenac, ibuprofen, indomethacin, nabumetone, ketoprofen, naproxen, piroxicam and sulindac, etodolac, meloxicam, rofecoxib, celecoxib, etoricoxib, parecoxib, valdecoxib and tilicoxib. Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl,

meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof. Suitable anti- migraine agents of use in conjunction with a compound of the present invention include CGRP -antagonists, ergotamines or 5-HT ₁ agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan. Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.

In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment of a condition or disease in which pain and/or inflammation predominates.

Compounds of the invention may be prepared as described in WO-A-05047279.

In general, the besylate salts can be prepared by adding benzene sulfonic acid to a solution of the free base of compound I in a solvent, such as an aprotic solvent, such as DMF, generally at a temperature of about 40°C. To enable crystallization to occur a less polar solvent, such as isopropyl acetate, is added, optionally with seeding with the desired crystalline product. The solution is generally aged for about 30 minutes, with further addition of the less polar solvent, followed by further ageing for one or two hours.

The reaction mixture is generally cooled to 20-25°C, further aged for about two hours and finally filtered, optionally washed and then dried to yield the desired product generally in crystalline form. The following Examples illustrate the present invention.

Example 1 7-(5-Methyl-6-{5-trifluoromethylpyridin-2-y]amino]pyrimidin- 4- yDquinolinium benzenesulfonate To a solution of the free base (see Example 41 in WO-A-05047279) in DMF (40 ml) was added benzenesulfonic acid (1.05 eq., 4.3 g, 27.2 mmoi) at 40 ⁰ C. Isopropyl acetate (10 ml) was added into the solution, which was then seeded with the product (10 mg). The solution was aged for 30 min, then more isopropyl acetate (70 ml) was added over 1-2 hours, keeping the internal temperature at ca. 4O ⁰ C. After addition, the batch was cooled to 20-25 ⁰ C, aged for 2 hours, then filtered. The resulting cake was washed with isopropyl acetate (10 rriL), then dried to give the title compound (13.4 g, 95 %). IH NMR (400 MHz, DMSO-d6): δ 10.07 (IH, br s), 9.26 (IH, dd, J=4.8,1.5 Hz), 8.94 (IH, d, J= 8.2 Hz), 8.90 (IH, s), 8.79 (IH, m), 8.38 (IH, d, J=8.6 Hz), 8.36 (IH, m), 8.32 (IH, d, J=8.8 Hz), 8.25 (IH, dd, J=8.9, 2.4 Hz), 8.02 (IH, dd, J= 8.5, 1.6 Hz), 7.97 (IH, dd, J=8.4, 4.8 Hz), 7.64-7.58 (2 H, om), 7.35-7.26 (3H, om), 2.37 (3H, s); m/z (ES ⁺ ) 382 (M+H ⁺ ).

The following compounds can be prepared according to the procedure described in Example 1.

The above specified compounds of the present invention have been tested in the following assay and generally possess an IC ₅₀ < 30OnM and, in the majority of cases, < 200 nM. Other assays, such as electrophysiology using rat VRl expressed in HEK cells measuring activity at various pH levels, can be used.

Determination of in vitro activity

In vitro activity of compounds was measured using one or both of the following assays.

Method 1

CHO cells, stably expressing recombinant rat or human VRl receptors and plated into black-sided 384- well plates, were washed three times with assay buffer (containing Hepes, NaCl ₂ , KCl, MgCt, CaCl ₂ , sucrose, glucose and probenecid, pH 7.4) and then incubated with test compound and 4uM Fluo-3-AM for 60 minutes at room temperature in darkness. Cells were washed three times more to remove excess dye, before being placed, along with plates containing capsaicin and test compounds into a Molecular Devices FLEPR ³⁸⁴ . The FLEPR ³⁸⁴ simultaneously performed automated pharmacological additions and recorded fluorescence emission from Fluo-3. In all experiments, basal fluorescence was recorded, before re-addition of test compounds and subsequent addition of a previously determined concentration of capsaicin that evoked 80% of the maximum response. Inhibition of capsaicin evoked increases in intracellular [Ca ²⁺ ] were expressed relative to wells on the same plate to which an EC80 concentration of capsaicin was added in the absence of test compounds.

Method 2

Antagonists were ranked by absolute efficacy at a single low concentration vs. activation by either pH 5.5 or capsaicin (500 nM) using a medium-throughput electrophysiology assay. TRPVl activity is initially determined using a 5 second application of 500 nM capsaicin. Agonist (either pH 5.5 or capsaicin) is then applied for 5 seconds followed by a 30 second wash period until a stable control response is achieved. Inhibition of the agonist response is determined following applications of a single concentration of test compound and inhibition is monitored using repeated agonist activation in the presence of the compound until a stable inhibition state is achieved (up to a maximum of 10 minutes of application). If a successful recovery was achieved by re-applying a control wash, additional compounds can be tested sequentially. Inhibition effect of the drug is calculated as the sustained maximum current within the 5 second agonist application divided by the control sustained maximum current before the drug had been applied, multiplied by 100 (= % inhibition @ the test concentration).