WO2004089881A1

WO2004089881A1 - New sulfonyl derivatives of aminonaphtols

Info

Publication number: WO2004089881A1
Application number: PCT/SE2004/000574
Authority: WO
Inventors: Yevgeni Besidski; Jan-Erik Nyström
Original assignee: Astrazeneca Ab
Priority date: 2003-04-14
Filing date: 2004-04-13
Publication date: 2004-10-21
Also published as: WO2004089877A1

Abstract

The present invention relates to new compounds of formula I, [Chemical formula should be inserted here. Please see paper copy] wherein R1, R2, R3, R4 and R5 are as defined as in formula I, or salts, solvates or solvated salts thereof, a process for their preparation, pharmaceutical compositions containing said compounds and to the use of said compounds in therapy. The compounds are vanilloid receptor 1 (VR1) inhibitors and are useful in the treatment of a number of different disorders, for example acute and chronic neuropathic and inflammatory pain.

Description

NEW SULFONYL DERIVATIVES OF AMLNONAPHTOLS

FIELD OF THE INVENTION

The present invention relates to a new class of compounds, to pharmaceutical compositions containing said compounds and to the use of said compounds in therapy. The present invention further relates to a process for the preparation of said compounds.

BACKGROUND OF THE INVENTION

Pain sensation in mammals is due to the activation of the peripheral terminals of a specialized population of sensory neurons known as nociceptors. Capsaicin, the active ingredient in hot peppers, produces sustained activation of nociceptors and; also produces a ^• dose-dependent pain sensation in humans. Cloning of the vanilloid receptor 1 (VRl or TRPV1) demonstrated that VRl is the molecular target for capsaicin and its analogues. (Caterina,M.J., Schumacher,M.A., et.al. Nature (1997) v.389 p 816-824). Functional studies using VRl indicate that it is also activated by noxious heat , tissue acidification) and other inflammatory mediators (Tominaga,M., Caterina,MJ. et.al. Neuron (1998) v.21, p.531-543). Expression of VRl is also regulated after peripheral nerve damage of the type that leads to neuropathic pain. These properties of VRl make it a highly relevant target for pain and for diseases involving inflammation. While agonists of the VRl receptor can act as analgesics through nociceptor destruction, the use of agonists, such as capsaicin and its analogues, is limited due to their pungency, neurotoxicity and induction of hypothermia. Instead, agents that block the activity of VRl should prove more useful. Antagonists would maintain the analgesic properties, but avoid pungency and neurotoxicity side effects.

Compounds with VRl inhibitor activity are believed to be of potential use for the treatment and/or prophylaxis of disorders such as pain, especially that of inflammatory or traumatic origin such as arthritis, ischaemia, cancer, fibromyalgia, low back pain and post-operative pain (Walker et al J Pharmacol Exp Ther. (2003) Jan;304(l):56-62). In addition to this visceral pains such as chronic pelvic pain, cystitis, including interstitial cystitis, irritable bowel syndrome (IBS), pancreatitis and the like, as well as neuropathic pain such as sciatia, diabetic neuropathy, HIV neuropathy, multiple sclerosis, and the like (Walker et al ibid, Rashid et al J Pharmacol Exp Ther. (2003) Mar;304(3):940-8), are potential pain states that could be treated with VRl inhibitonThese compounds are also believed to be potentially useful for inflammatory disorders like asthma, cough, inflammatory bowel disease (IBD) (Hwang and Oh Curr Opin Pharmacol (2002) Jun;2(3):235-42). Compounds with VRl blocker activity are also useful for itch and skin diseases like psoriasis and for gastro-esophageal reflux disease (GERD), emesis, cancer, urinary incontinence and hyperactive bladder (Yiangou et al BJU Int (2001) Jun;87(9):774-9, Szallasi Am J Clin Pathol (2002) 118: 110-21). VRl inhibitors are also of potential use for the treatment and/or prophylaxis of the effects of exposure to VRl activators like capsaicin or tear gas, acids or heat (Szallasi ibid). A further portential use relates to the treatment of tolerance to VRl activators.

Prior art

There are many properties of a compound that are of importance in determining its suitability as a drag product. Of high importance is the interaction of the compound at the target protein and its pharmacokinetic profile, i.e. its ability to access the target protein in sufficient quantity for a sufficient duration of time to have the desired therapeutic effect. The object of the present invention is to provide novel aminonaphthol derivatives with surprisingly improved characteristics, carrying other substituents on the naphtyl ring as previously described.

WO 03/014064 discloses phenyl-naphtyl urea derivatives having a vanilloid receptor antagonistic activity. The compounds of the present invention differ from those disclosed in WO 03/014064 in that the naphtyl ring is substituted by a sulphonyloxy group.

We have found that the mentioned change in the substitution pattern has led to dramatic improvements with regard to pharmocokinetic profile. DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is to provide compounds exhibiting an inhibitory activity at vanilloid receptor 1 (VRl).

The present invention provides a compound of formula I

R¹ is R¹²S0₂;

R² is NHR¹³ orCHR⁷NR⁸R⁹;

R is H;

R R⁴⁴ aanndd R⁵ are independently selected .from the group consisting of H, halo, nitro and

COR⁷;

R and R are independently selected from the group consisting of H, Cι_-4alkyl, arylCo_-6alkyl, heteroarylC₀.₆alkyl and a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, whereby the aryl or heterocyclic ring may be fused with a 5 or 6 membered ring and said aryl and 5 or 6 membered ring may be optionally substituted by one or more A, or R⁸ and R⁹ form together a 5, 6 or 7 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, which may be fused with a 5 or 6 membered ring and said heterocyclic ring and 5 or 6 membered ring may be optionally substituted by one or more A; R¹² is Cι_-4alkyl, C_1-6haloalkyl or NR¹⁶R¹⁷;

R¹³ is C_2-8alkyl, heteroarylCo_-6alkyl or arylCo-ealkyl, whereby any aryl or heteroaryl may be substituted by one or more A;

R and R are independently selected from the group consisting of H, C_1- alkyl and Cι- haloalkyl; A is halo, nitro, CHO, CN, OR⁷, COR¹⁴, R¹⁴, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkylC_0-6alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, Co_-6alkylNR¹⁴R¹⁵, OC_1-6alkylNR¹⁴R¹⁵, CO₂R¹⁴, CONR¹⁴R¹⁵, NR¹⁴(CO)R¹⁵, O(CO)R¹⁴, COR¹⁴, SR¹⁴, (SO₂)NR¹⁴R¹⁵, (SO)NR¹⁴R¹⁵, SO₃R¹⁴, SO₂R¹⁴, SOR¹⁴ or a 5 or 6 membered heterocyclic saturated or partially saturated heterocyclic ring containing one or more heteroatoms independently selected from N, O or S; and

R⁷, R¹⁴ and R¹⁵ are independently selected from the group consisting of H, C_1-4alkyl, heteroarylCo_-6alkyl and arylC_0-6alkyl; or salts, solvates or solvated salts thereof.

One embodiment of the invention relates to the compound of formula I wherein

R¹ is R¹²S0₂;

R² is NHR¹³;

R³, R⁴ and R⁵ are H; ^: R¹² is C_1-4alkyl or NR¹⁶R¹⁷;

R⁷ is C_1-4alkyl; ^{' •} ! ^{' •}

R¹³ is C_2-8alkyl, heteroarylCo_-6alkyl or arylC_0-6alkyl, whereby any aryl or heteroaryl may be substituted by one or more A;

1 f. 17 R R¹⁶ aanndd R R are independently selected from the group consisting of H and Cι_-4alkyl; and A is OR⁷.

Another embodiment of the invention relates to the compound of formula I wherein R¹ is R¹²S0₂; R¹² is _-4alkyl or NR¹⁶R¹⁷; and

R¹⁶ and R¹⁷ are independently selected from the group consisting of H, methyl, ethyl and propyl.

In a further embodiment of the invention R¹⁶ and R¹⁷ are both H or both methyl.

16 17

In yet another embodiment of the invention R is H and R is methyl or ethyl. In yet a further embodiment of the invention R¹ is H and R¹⁷ is ethyl.

One embodiment of the invention relates to the compound of formula I wherein the group O-R¹ is a residue of sulfamic acid, ethylsulfamic acid dimethylsulfamic acid or methanesulfonic acid. In another embodiment of the invention relates to the compound of formula I wherein R³, R⁴ and R⁵ are H.

A further embodiment of the invention relates to the compound of formula I wherein

R² is NHR¹³;

R¹³ is C_2-8alkyl, heteroarylCo-θalkyl or arylC_0-6alkyl, whereby any aryl or heteroaryl may be substituted by one or more A; and

A is halo, nitro, CHO, CN, OR⁷, COR¹⁴, R¹⁴, R¹⁴R¹⁵, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_0-6alkylC_3-6cycloalkyl, C_1-4haloalkyl, OC_1-4haloalkyl, C_0-6alkylNR¹⁴R¹⁵,

OCι_-6alkylNR¹⁴R¹⁵, C0₂R¹⁴, CONR¹⁴R¹⁵, NR¹⁴(CO)R¹⁴, O(CO)R¹⁴, COR¹⁴, SR¹⁴,

(SO₂)NR¹⁴R¹⁵, (SO)NR¹⁴R¹⁴, SO₃R¹⁴, S0₂R¹⁴, SOR¹⁴or a 5 or 6 membered heterocyclic saturated or partially saturated heterocyclic ring containing one or more heteroatoms independently selected from N, O or S.

1 ^

In a further embodiment of the invention R is aryl or arylC_1-4alkyl substituted by one or more A.

In yet another embodiment of the invention R¹³ is benzyl or benzylC_1-4alkyl substituted by one or more A. In one embodiment of the invention R is benzyl or benzylmethyl, substituted by one or more OR⁷; wherein R⁷ is methyl, ethyl or propyl. In another embodiment of the invention R⁷ is methyl or ethyl.

In a further embodiment of the invention R¹³ is benzyl or benzylmethyl substituted by one or more methoxy.

Another embodiment of the invention relates to the compound of formula I wherein R is methoxy-benzyl-ureido or dimethoxyphenyl-ureido. In another embodiment R¹³ is para substituted. In a further embodiment R¹³ is meta disubstituted.

Another embodiment of the invention relates to compounds selected from the group consisting of sulfarnic acid 8-[3-(3,5-dimethoxyphenyl)-ureido]-naphthalen-2-yl ester, sulfamic acid 8-[3-(4-methoxy-benzyl)-ureido]-naphthalen-2-yl ester, ethylsulfamic acid 8-[3-(3,5-dimethoxyphenyl)-ureido]-naphthalen-2-yl ester, ethylsulfamic acid 8-[3-(4-methoxybenzyl)-ureido]-naphthalen-2-yl ester, dimethylsulfamic acid 8-[3-(3,5-dimethoxy-phenyl)-ureido]-naphthalen-2-yl ester, methanesulfonic acid 8-[3-(3,5-dimethoxyphenyl)-ureido]-naphthalen-2-yl ester, and methanesulfonic acid 8-[3-(4-methoxybenzyl)-ureido]-naphthalen-2-yl ester, or salts, solvates or solvated salts thereof.

Listed below are definitions of various terms used in the specification and claims to describe the present invention.

For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the other definitions for that group.

For the avoidance of doubt it is to be understood that in this specification 'Cι_-6' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.

In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i- hexyl or t-hexyl. The term Cι_-3alkyl having 1 to 3 carbon atoms may be methyl, ethyl, n- propyl or i-propyl.

In this specification, unless stated otherwise, the term "cycloalkyl" refers to an optionally substituted, saturated cyclic hydrocarbon ring system. The term "C_3-7cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In this specification, unless stated otherwise, the term "alkenyl" includes both straight and branched chain alkenyl groups. The term C₂-₆alkenyl having 2 to 6 carbon atoms and one or two double bonds, may be, but is not limited to vinyl, allyl, propenyl, butenyl, crotyl, pentenyl, or hexenyl. A butenyl group may for example be, buten-2-yl, buten-3-yl or buten-4-yl.

In this specification, unless stated otherwise, the term "alkynyl" includes both straight and branched chain alkynyl groups. The term C₂-₆alkynyl having 2 to 6 carbon atoms and one or two trippel bonds, may be, but is not limited to etynyl, propargyl, pentynyl or hexynyl. A butynyl group may for example be, butyn-3-yl or butyn-4-yl.

In this specification, unless stated otherwise, the term "5, 6 or 7 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S" or includes both heteroaromatic rings and heterocyclic rings that are saturated or unsaturated. Examples of such heterocyclic rings may be, but is not limited to imidazolidinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrrolidinyl or tetrahydropyranyl.

In this specification, unless stated otherwise, the term "5 or 6 membered saturated or partially saturated heterocyclic ring containing one or more heteroatoms independently selected from N, O or S," may be, but is not limited to morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrrolidinyl or tetrahydropyranyl.

In this specification, unless stated otherwise, the terms "5, 6 or 7 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, which may be fused with a 5 or 6 membered ring", or "arylC₀.₆alkyl, heteroarylCo-₆alkyl and a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, whereby the aryl or heterocyclic ring may be fused with a 5 or 6 membered ring" includes both aromatic, heteroaromatic rings and heterocyclic rings that are saturated or unsaturated. Examples of such rings may be, but are not limited to, indoline, indole, indolizine, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzothiazole, purine, quinoline, quinolizine, isoquinoline, quinozoline, quinoxaline, naphthalene, indene, azulene, oxindole, cinnoline, chroman or isochroman. In this specification, unless stated otherwise, the terms "aryl" and "heteroaryl" refer to an optionally substituted monocyclic hydrocarbon unsaturated aromatic ring system. Examples of "aryl" may be, but are not limited to, phenyl or naphthalenyl.

Examples of "heteroaryl" may be, but are not limited to, furan, thiophene, pyrrole, triazole, pyrazole, pyridazine, pyrimidine, pyrazine, triazine or pyran.

In this specification, unless stated otherwise, the terms "arylalkyl" and "heteroarylalkyl" refer to a substituent that is attached via the alkyl to an aryl group.

In this specification, unless stated otherwise, the terms "halo" and "halogen" may be fluoro, iodo, chloro or bromo.

In this specification, unless stated otherwise, the term "haloalkyl" means an alkyl group as defined above, which is substituted with halo. The term "C_1-6haloalkyl" may be, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or bromopropyl. The term

may be, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.

The present invention relates to the use of compounds of formula I as hereinbefore defined as well as to the salts, solvates or solvated salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I. A suitable pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid-addition salt, for example an inorganic or organic acid. In addition, a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base. Other pharmaceutically acceptable salts and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18 Edition, Mack Publishing Co., (1990)). Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomeric and geometric isomers.

The invention also relates to any and all tautomeric forms of the compounds of formula I.

Methods of Preparation

Another aspect of the present invention provides processes for preparing compounds of formula I, or salts, solvates or solvated salts thereof.

Throughout the following description of such processes it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, (1999). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, "Advanced Organic Chemistry", March 4^th ed. McGraw Hill (1992) or "Organic Synthesis", Smith, McGraw Hill, (1994) The term "room temperature" shall mean, unless otherwise specified, a temperature between 16 and 25 °C.

Another embodiment of the invention relate to a process for the preparation of the

1 17 compounds of formula I, wherein R to R , are defined as in formula I, comprising;

(H) (HI) (la) wherein R³, R¹² and R¹³ are defined as hereinbefore, and whereby an urea of formula LI is treated with an sulfonyl chloride of formula HI to obtain a compound of formula la. This reaction may be performed in any manner known to the skilled man in the art. The reaction may be carried out in a solvent including halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane or tertiary amides such as N- methylpyrrolidine, dimethylformamide and dimethylaceta ide or aromatic and heteroaromatic compounds such as benzene, toluene, xylene, pyridine and lutidine or ethers such as ethyl ether, tetrahydrofuran and dioxan.

Catalysts such as tertiary amines like triethylamine, N-methylmorpholine and ethyl diisopropylamine may also be used.

The temperature should suitably be between -60 and 30°C and the reaction time between 1 and 40 h. The starting compounds of formula II can be synthesized by treatment of 8- isocyanatonaphthalen-2-ol with an appropriate amine or by treatment of 8-amino-2- naphthole with an appropriate isocyanate or amine according to the published procedure in Honma, Teruki; Hayashi, Kyoko et.al. J.Med.Chem. (2001) v.44; 26; p. 4615 - 4627.

Pharmaceutical composition

According to one embodiment of the present invention there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of formula I, or salts, solvates or solvated salts thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

The composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream or for rectal administration e.g. as a suppository.

In general the above compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers. Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man, are approximately 0.01 to 250 mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration. The typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician.

Examples of pharmaceutical composition

The following illustrate representative pharmaceutical dosage forms containing a compound of formula I, or salts, solvates or solvated salts thereof, (hereafter compound X), for preventive or therapeutic use in mammals:

The above compositions may be obtained by conventional procedures well known in the pharmaceutical art. Medical use

Surprisingly, it has been found that the compounds according to the present invention are useful in therapy. The compounds of formula I, or salts, solvates or solvated salts thereof, as well as their corresponding active metabolites, exhibit a high degree of potency and selectivity for individual vanilloid receptor 1 (VRl) groups. Accordingly, the compounds of the present invention are expected to be useful in the treatment of conditions associated with excitatory activation of vanilloid receptor 1 (VRl). The compounds may be used to produce an inhibitory effect of VRl in mammals, including man.

VRl are highly expressed the peripheral nervous system and in other tissues. Thus, it is expected that the compounds of the invention are well suited for the treatment of

VRl mediated disorders. . . .. . ^• . ,

The compounds of formula I are expected to be suitable for the treatment of acute and chronic pain, acute and chronic neuropathic pain and acute and chronic inflammatory pain.

Examples of such disorder may be selected from the group comprising arthritis, fibromyalgia, low back pain, post-operative pain, visceral pains like chronic pelvic pain, cystitis, including interstitial cystitis, bowel syndrome (TBS), pancreatitis, ischeamic, sciatia, diabetic neuropathy, multiple sclerosis, HIV neuropathy, asthma, cough and inflammatory bowel disease (IBD).

Further relevant disorders may be selected from the group comprising gastro-esophageal reflux disease (GERD), psoriasis, cancer, emesis, urinary incontinence and hyperactive bladder.

Other relevant disorders are related to respiratory diseases and may be selected from the group comprising asthma, chronic obstructive lung disease and emphysema, lung fibrosis and interstitial lung disease. The VRl inhibitor(s) may be administrated by either an oral or inhaled route. The respiratory disease may be an acute and chronic illness and may be related to infection(s) and/or exposure to environmental pollution and/or irritants. The compounds of formula I may also be used as antitoxin to treat (over-) exposure to VRl activators like capsaicin, tear gas, acids or heat. Regarding heat, there is a potential use for VRl antagonists in (sun-) burn induced pain, or inflammatory pain resulting from bran injuries. The compounds may further be used for treatment of tolerance to VRl activators.

One embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, in therapy.

Another embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of VRl mediated disorders.

A further embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of acute and chronic pain disorders.

Yet another embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of acute and chronic neuropathic pain.

Yet a further embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of acute and chronic inflammatory pain.

One embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of arthritis, fibromyalgia, low back pain, post-operative pain, visceral pains like chronic pelvic pain, cystitis, IBS, pancreatitis or ischeamic.

Another embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of sciatia, diabetic neuropathy, multiple sclerosis or HIV neuropathy. A further embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of asthma, cough, IBD, psoriasis, gastro-esophageal reflux disease (GERD), psoriasis, cancer, emesis, urinary incontinence or hyperactive bladder.

Yet another embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of interstitial cystitis and pain related to interstitial cystitis.

Yet a further embodiment of the invention relates to the use of the compound of formula I as hereinbefore defined, for the treatment of respiratory diseases selected from the group comprising asthma, chronic obstructive lung disease and emphysema, lung fibrosis and interstitial lung disease.

One embodiment of the invention relates to the use of the compound of formula I as hereinbefore defined, in the manufacture of a medicament for treatment of VRl mediated disorders and for treatment of acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic inflammatory pain and any other disorder mentioned above.

Another embodiment of the invention relates to a method of treatment of VRl mediated disorders and acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic inflammatory pain and any other disorder mentioned above, comprising administrering to a mammal, including man in need of such treatment, a therapeutically effective amount of the compounds of formula I, as hereinbefore defined.

A further embodiment of the invention relates to a pharmaceutical composition comprising a compound of formula I as hereinbefore defined, for use in treatment of VRl mediated disorders and for treatment of acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic inflammatory pain and any other disorder mentioned above. In the context of the present specification, the term "therapy" and "treatment" includes prevention and prophylaxis, unless there are specific indications to the contrary. The terms "treat", "therapeutic" and "therapeutically" should be construed accordingly.

In this specification, unless stated otherwise, the term "inhibitor" and "antagonist" mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the ligand.

The term "disorder", unless stated otherwise, means any condition and disease associated with vanilloid receptor activity.

Non- Medical use

In addition to their use in therapeutic medicine, the compounds of formula I, or salts, solvates or solvated salts thereof, are. also useful as pharmacological tools in the development and standardisation of in vitro said in vivo test systems for the evaluation of the effects of inhibitors of VRl related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.

Examples

The invention will now be illustrated by the following non-limiting examples.

General methods All starting materials are commercially available or earlier described in the literature. The 1H NMR spectra were recorded on Brucker at 400 MHz. The mass spectra were recorded utilising electrospray (LC-MS; LC: Waters 2790, column XTerra MS C₈ 2.5 μm 2.1X30 mm, buffer gradient H₂O+0.1%TFA:CH₃CN+0.04%TFA, MS: micromass ZMD// ammonium acetate buffer) ionisation techniques. Example 1

Sulfamic acid 8-[3-(3,5-dimethoxyphenyl)-ureido]-naphthalen-2-yl ester

A. l-(3,5-Dimethoxyphenyl)-3-(7-hydroxynaphthalen-l-yl)-urea

To a solution of 8-amino-2-naphthole (159 mg, 1 mmol) in dry 1,4-dioxan (2 ml) a 5 solution of 3,5-dimethoxyphenyl isocyanate (1.1 mmol) in dry 1,4-dioxan (1 ml) was added. The mixture was stirred at room temperature overnight. Methanol (2 ml) was added and the volatiles were removed in vacuum. The residue was chromatographed on a short column packed with silica gel, using a mixture of hexane and ethyl acetate as an eluent to yield the title compound (290 mg, 86%). MW (calcd.): 338.37, MW (found) [M+l]: 339; lo IH NMR (400 MHz, DMSO-d6) δ ppm 3.75 (s, 6H), 6.15 (t, J=1.8 Hz, IH), 6.72 (d, J=1.8 Hz, 2H), 7.13 (dd, J=2.0, 8.8 Hz, IH), 7.23 (t, J=7.9 Hz, IH), 7.32 (d, J=2.0 Hz, IH), 7.54 (d, J=8.8 Hz, IH), 7.79 (t, J= 8.8 Hz, 2H), 8.41 (br.s, IH), 9.00 (br.s, IH), 9.79 (s, IH).

B. Sulfamoyl chloride

Formic acid (1.35 mg) was added dropwise under argon to chlorosulfonyl isocyanate (4.2 • is g) at 5-10°C. The mixture was stirred vigorously at room temperature until the bubbling ceased and solidification occurred (—1 h). Toluene was added and the solution was filtered and concentrated in vacuum to yield sulfamoyl chloride as white solid powder.

C. The title compound.

To a solution of l-(3,5-dimethoxyphenyl)-3-(7-hydroxynaphthalen-l-yl)-urea (part A, 100 20 mg) in N-methylpyrrolidine (1 ml) sulfamoyl chloride (part B, 180 mg) was added and the mixture was stirred at room temperature overnight. Brine was added followed by extraction with ethyl acetate (2x20 ml). The organic phase was washed with brine, dried over sodium sulphate and concentrated in vacuum. The residue was chromatographed on a column packed with silica gel using 40 to 60% ethyl acetate in heptane as an eluent to 25 yield the title compound (78%) as white solid powder. MW (calcd.): 417.4, MW (found) [M+l]: 418.1; IH NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 6H), 6.15 (t, J=2.0 Hz, IH), 6.72 (d, J=2.1 Hz, 2H), 7.47 - 7.53 (m, 2H), 7.70 (d, J=8.1 Hz, IH), 7.96 (br.d, IH), 7.99 - 8.08 (m, 4H), 8.69 (br.s, IH), 9.06 (br.s, IH).

30 Example 2

Sulfamic acid 8-[3-(4-methoxy-benzyl)-ureido]-naphthalen-2-yl ester A. l-(7-Hydroxynaphthalen-l-yl)-3-(4-methoxybenzyl)-urea The compound was synthesized from 8-amino-2-naphthole and 4-methoxybenzyl isocyanate according to a procedure described in Example 1, part A. B. The title compound l-(7-Hydroxynaphthalen-l-yl)-3-(4-methoxybenzyl)-urea was treated with sulfamoyl chloride (Example 1, part B) as described in Example 1, part C to yield the title compound (75%). MW (calcd.): 401.4, MW (found) [M+l]: 402.2; IH NMR (400 MHz, methanol- d4) δ ppm 1.13 (t, J=6.4 Hz, 3H), 3.18 (q, J=7.2 Hz, 2H), 3.74 (s, 3H), 4.32 (s, 2H), 6.81 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 7.33 (dd, J=2.5, 8.7 Hz, IH), 7.4 (t, 7.7 Hz, IH), 7.6 (d, J=8.6 Hz, IH), 7.68 (d, J=7.6 Hz, IH), 7.80 (d, J=8.6 Hz, IH), 7.81 (br.s, IH).

Example 3

Ethylsulfamic acid 8-[3-(3,5-dimethoxyphenyl)-ureido]-naphthalen-2-yl ester

A. N-Ethylsulfamoyl chloride

Sulfuryl chloride (4 mmol) was added to ethylamine hydrochloride (2 mmol). The mixture was stirred at 70-75°C for 12 h. Diisopropyl ether was added, the turbid solution was filtered and concentrated in vacuum to yield crude N-ethyl sulfamoyl chloride which was used in the next step without further purification.

B. The title compound was synthesized from l-(3,5-dimethoxyphenyl)-3-(7- hydroxynaphthalen-l-yl)-urea (Example 1, part A) and N-ethylsulfamoyl chloride according to the procedure described in Example 1, part C. MW (calcd.): 445.5, MW (found) [M+l]: 446.3; IH NMR (400 MHz, methanol-d4) δ ppm 1.10 (t, J=7.3 Hz, 3H), 3.18 (q, J=7.2 Hz, 2H), 3.72 (s, 6H), 6.11 (t, J=1.7Hz, IH), 6.66 (d, 1=1.6 Hz, 2H), 7.33 (dd, J=2.5, 8.6 Hz, IH), 7.42 (t, J=8.1 Hz, IH), 7.61 (d, J=8.1 Hz, IH), 7.75 - 7.86 (m, 3H).

Example 4

Ethylsulfamic acid 8-[3-(4-methoxybenzyl)-ureido]-naphthalen-2-yl ester The title compound was synthesized from l-(7-hydroxynaphthalen-l-yl)-3-(4- methoxybenzyl)-urea (Example 2, part A) and N-ethyl sulfamoyl chloride according to the procedure described in Example 1, part C. MW (calcd.): 429.5, MW (found) [M+l]: 430.3; IH NMR (400 MHz, methanol-d4) δ ppm 1.13 (t, J=7.3 Hz, 3H), 3.18 (q, J=7.2 Hz, 2H), 3.74 (s, 3H), 4.32 (s, 2H), 6.81 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 7.33 (dd, J=2.3, 8.8 Hz, IH), 7.40 (t, J=7.8 Hz, IH), 7.60 (d, J=8.6 Hz, IH), 7.68 (d, J=7.6 Hz, IH), 7.8 (d, J=8.6 Hz, lH), 7.81 (br.d, IH).

Example 5 Dimethylsulfamic acid 8-[3-(3,5-dimethoxy-phenyl)-ureido]-naphthalen-2-yl ester

To a solution of l-(3,5-dimethoxyphenyl)-3-(7-hydroxynaphthalen-l-yl)-urea (Example 1, part A, 100 mg (0.3 mmol)) in dichloromethane (1 ml) triethylamine (0.2 ml) was added followed by dimethylsulfamoyl chloride (0.06 ml), and the mixture was stirred at rrom temperature for 20 h. The volatiles were removed in vacuum, and the residue was chromatographed on a column packed with silica gel using ethyl acetate in heptane (1 : 1) as an eluent to yield the title compound (52%). MW (calcd.): 445.5, MW (found) [M+l]: 446.2; 1H NMR (400 MHz, methanol-d4) δ ppm 2.97 (s, 6H), 3.76 (s, 6H), 6.19 (t, J=2.0 Hz, IH), 6.72 (d, J=2.1 Hz, 2H), 7.47 (dd, J=2.2, 8.8 Hz, IH), 7.51 (t, J=7.8 Hz, IH), 7.75 (d, J=8.1 ,Hz, IH), 7.83 (d, J=7.5 Hz, IH), 7.94 (d, J=2.1 Hz, IH), 7.98 (d, J=9.0 Hz, IH). ' >

Example 6

Methanesulfonic acid 8-[3-(3,5-dimeihoxyphenyl)-ureido]-naphthalen-2-yl ester

To a solution of l-(3,5-dimethoxyphenyl)-3-(7-hydroxynaphthalen-l-yl)-urea (Example 1, part A, 338 mg₅ 1 mmol) in dry tetrahydrofuran (2 ml) triethylamine (1.5 mmol) was added followed by a solution of methansulfonyl chloride (1.5 mmol) in dry tetrahydrofuran (1 ml) at 0-5°C. The mixture was stirred at room temperature for 5 h. Methanol (2 ml) was added and the volatiles were removed in vacuum. The residue was chromatographed on a short column packed with silica gel, using a mixture of hexane and ethyl acetate as an eluent to yield the title compound (335 mg, 81%). IH NMR (400 MHz, DMSO-d6) δ ppm 3.51 (s, 3H), 3.73 (s, 6H), 6.15 (t, J=2.4 Hz, IH), 6.76 (d, J=2.4 Hz, 2H), 7.51 - 7.56 (m, 2H), 7.72 (d, J=8.1 Hz, IH), 8.04 - 8.10 (m, 2H), 8.21 (br.d, IH), 9.07 (br.s, IH), 9.49 (br.s, IH).

Example 7

Methanesulfonic acid 8-[3-(4-methoxybenzyl)-ureido]-naphthalen-2-yl ester The title compound was synthesized from l-(7-hydroxynaphthalen-l-yl)-3-(4- methoxybenzyl)-urea (Example 2, part A) and methansulfonyl chloride according to the procedure described in Example 6. IH NMR (400 MHz, CDC1₃) δ ppm 3.15 (s, 3H), 3.76 (s, 3H), 4.34 (d, J=6.1 Hz, 2H), 5.19 (t, J=5.9 Hz, IH), 6.77 - 6.82 (m, 3H), 7.17 (d, J=8.6 Hz, 2H), 7.41 - 7.49 (m, 2H), 7.66 (d, J= 7.6 Hz, IH), 7.71 (d, J=8.1 Hz, IH), 7.85 - 7.91 (m, 2H).

Pharmacology

1. hVRl FLIPR (Fluorometric Image Plate Reader) screening assay

Transfected CHO cells, stably expessing hVRl (15,000 cells/well) are seeded in 50 ul media in a black clear bottom 384 plate (Greiner) and grown in a humidified incubator (37°C, 2% C0₂), 24-30 hours prior to experiment.

Subsequently, the media is removed from the cell plate by inversion and 2 μM Fluo-4 is added using a multidrop (Labsystems). Following the 40 minutes dye incubation in the dark at 37°C and 2% Cθ₂,^' the extracellular dye present is washed away using an EMBLA ' ^■ (Scatron), leaving the cells in 40ul of assay buffer (1 X HBSS, 10 mM D-Glucose, 1 mM CaCl₂ , 10 mM HEPES, 10 X 7.5% NaHC0₃ and 2.5 mM Probenecid).

FLIPR assay - IC50 determination protocol

For IC₅o determinations the fluorescence is read using FLIPR filter 1 (em 520-545 nM). A cellular baseline recording is taken for 30 seconds, followed by a 20 μl addition of 10, titrated half-log concentrations of the test compound, yielding cellular concentration ranging from 3 μM to 0.1 nM. Data is collected every 2 seconds for a further 5 minutes prior to the addition of a VRl agonist solution: either 50 nM solution of capsaicin or MES (2-[N-morpholino] ethanesulfonic acid) buffer (pH 5.2), by the FLIPR pipettor. The FLIPR continues to collect data for a further 4 minutes. Compounds having antagonistic properties against the hVRl will inhibit the increase in intracellular calcium in response to the capsaicin addition. This consequently leading to a reduction in fluorescence signal and providing a reduced fluorescence reading, compared with no compound, buffer controls. Data is exported by the FLIPR program as a sum of fluorescence calculated under the curve upon the addition of capsaicin. Maximum inhibition, Hill slope and IC₅₀ data for each compound are generated. 2. DRGs were dissected out from adult Sprague Dawley rats (100-300 g), and placed on ice in LI 5 Leibovitz medium. The ganglia were enzyme treated with Collagenase 80 U/ml + Dispase 34 U/ml dissolved in DMEM + 5% serum, over night at 37 °C. The next day, cells were triturated with fire polished pasteur pipettes, and seeded in the center of 58 mm diameter Nunc cell dishes coated with Poly-D Lysine (1 mg/ml). The DRGs were cultured in a defined medium without foetal bovine serum, containing Dulbecco's MEM / NUT MIX F-12 (1:1) without L-glutamine but with pyridoxine, 6 mg/ml D(+)-Glucose, 100 μg/ml apo-transferrin, 1 mg/ml BSA, 20 μg/ml insulin, 2 mM L-glutamine, 50 IU/ ml Penicillin, 50 μg/ml Streptomycin and 0.01 μg/ml NGF-7S.

When the cells had grown for 2 days up to 4 weeks, the experiments were done. Cells were chosen based on size and presence of neurites. Small cells with long processes were used for recording (most likely to be C neurons, with native VRl receptors).

The cells were recorded with conventional whole celhvoltage clamp patch clamp, using the following solutions (calcium ion free); extracellular solution (in mM): NaCl 137, KC1 5, MgCl₂ * H₂0 1.2, HEPES 10, glucose

10, EGTA 5, sucrose 50, pH to 7.4 with NaOH; intracellular solution (in mM): K-gluconate 140, NaCl 3, MgCl₂ * H₂0 1.2, HEPES 10, EGTA 1 , pH to 7.2 with KOH.

When the cells were penetrated with suction, a puff of capsaicin (500 nM) was used to determine if the cell expressed VRl receptor. If not, a new cell was chosen. If yes, then the compounds were added in increasing doses before the capsaicin pulse (500 nM), to determine the IC₅₀ value.

Results

Typical IC₅₀ values as measured in the assays described above are 10 μM or less. In one embodiment of the invention the IC₅₀ is below 500 nM. In another embodiment of the invention the ICso is below 100 nM. In a further embodiment of the invention the IC₅₀ is below 10 nM.

Abbreviations

FLIPR Fluorometric Image Plate Reader

HEPES 4-(2-Hydroxyethyl)piperazine-l-ethanesulfonic acid

MES 2-[N-morpholino] ethanesulfonic acid

VRl vanilloid receptor 1

IBS irritable bowel syndrome IBD inflammatory bowel disease

GERD gastro-esophageal reflux disease

DRG Dorsal Root Ganglion

BS A Bovine Serum Albumin

EGTA Ethylene glycol-bis(2-aminoethylether)-NN,N',N '-tetraacetic acid DMEM Dulbeccos Modified Eagle's Medium

Claims

1. A compound having the formula I

R¹ is R¹²S0₂;

R² is NHR¹³ orCHR⁷NR⁸R⁹;

R³ is H;

R⁴ and R⁵ are independently selected from the group consisting of H, halo, nitro and

COR⁷;

R⁸ and R⁹ are independently selected from the group consisting of H, Cι_-4alkyl, ^• arylCo-_δalkyl, heteroarylCo-_δalkyl and a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one or more heteroatoms independently selected from N, O or

S, whereby the aryl or heterocyclic ring may be fused with a 5 or 6 membered ring and said aryl and 5 or 6 membered ring may be optionally substituted by one or more A, or

R⁸ and R⁹ form together a 5, 6 or 7 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, which may be fused with a 5 or 6 membered ring and said heterocyclic ring and 5 or 6 membered ring may be optionally substituted by one or more A;

R¹² is d_-4alkyl, C_1-6haloalkyl or NR¹⁶R¹⁷;

R¹³ is C_2-8alkyl, heteroarylC_0-6alkyl or arylCo_-6alkyl, whereby any aryl or heteroaryl may be substituted by one or more A;

R¹⁶ and R¹⁷ are independently selected from the group consisting of H, Cι_-4alkyl and

C_1- haloalkyl;

A is halo, nitro, CHO, CN, OR⁷, COR¹⁴, R¹⁴, Cι_-6alkyl, C_2-6alkenyl, C_2-6alkynyl,

C_3-6cycloalkylCo_-6alkyl, Cι_-4haloalkyl, OC_1-4haloalkyl, C_0-6alkylNR » 1¹4⁴Rτ> 15 , OCι_-6alkylNR¹⁴R¹⁵, C0₂R¹⁴, CONR¹⁴R¹⁵, NR¹⁴(CO)R¹⁵, 0(CO)R¹⁴, COR¹⁴, SR¹⁴, (S0₂)NR¹⁴R¹⁵, (SO)NR¹⁴R¹⁵, S0₃R¹⁴, SO₂R¹⁴, SOR¹⁴or a 5 or 6 membered heterocyclic saturated or partially saturated heterocyclic ring containing one or more heteroatoms independently selected from N, O or S; and

R⁷, R¹⁴ and R¹⁵ are independently selected from the group consisting of H, C_1-4alkyl, heteroarylCo-_δalkyl and arylCo-_δalkyl; or salts, solvates or solvated salts thereof.

2. The compound according to claim 1 wherein R¹ is R¹²S0₂;

R² is NHR¹³; R³, R⁴ and R⁵ are H;

R¹² is Cι_-4alkyl or NR¹⁶R¹⁷;

R⁷ is C_1-4alkyl;

R¹³ is C_2-8alkyl, heteroarylCo-₆alkyl or arylCo_-6alkyl, whereby any aryl or heteroaryl may be substituted by one or more A; R¹⁶ and R¹⁷ are independently selected from the group consisting of H and Cι_-4alkyl; and

Aϊs OR⁷.

3. The compound accroding to claim 1 wherein

R¹ is R¹²S0₂; R¹² is C_1-4alkyl or NR¹⁶R¹⁷; and R¹ and R¹⁷ are independently selected from the group consisting of H, methyl, ethyl and propyl.

4. The compound accroding to claim 1 wherein the group O-R¹ is a residue of sulfamic acid, ethylsulfamic acid dimethylsulfamic acid or methanesulfonic acid.

5. The compound accroding to claim 1 wherein

R¹³ is aryl or arylCι_-4alkyl substituted by one or more A.

6. The compound accroding to claim 1 wherein R¹³ is benzyl or benzylmethyl, substituted

7 7 by one or more OR ; wherein R is methyl, ethyl or propyl.

7. The compounds selected from the group consisting of sulfamic acid 8-[3-(3,5-dimethoxyphenyl)-ureido]-naphthalen-2-yl ester, sulfamic acid 8-[3-(4-methoxy-benzyl)-ureido]-naphthalen-2-yl ester, ethylsulfamic acid 8-[3-(3,5-dimethoxyphenyl)-ureido]-naρhthalen-2-yl ester, ethylsulfamic acid 8-[3-(4-methoxybenzyl)-ureido]-naphthalen-2-yl ester, dimethylsulfamic acid 8-[3-(3,5-dimethoxy-phenyl)-ureido]-naphthalen-2-yl ester, methanesulfonic acid 8-[3-(3,5-dimethoxyphenyl)-ureido]-naphthalen-2-yl ester, and methanesulfonic acid 8-[3-(4-methoxybenzyl)-ureido]-naphthalen-2-yl ester, or salts, solvates or solvated salts thereof.

8. A process for the preparation of the compounds of formula I, wherein R¹ to R¹⁷, are defined as in claim 1, comprising;

(") (UI) (la) wherein R³, R¹² and R¹³ are defined as in claim 1, and whereby an urea of formula II is treated with an sulfonyl chloride of formula III to obtain a compound of formula la.

9. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound according to any one of claims 1 to 7, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

10. The pharmaceutical composition according to claim 9, for use in the treatment of VRl mediated disorders and for treatment of acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic inflammatory pain.

11. The compound according to any one of claims 1 to 7, for use in therapy.

12. Use of the compounds of formula I according to any one of claims 1 to 7, in the manufacture of a medicament for treatment of VRl mediated disorders.

13. The use according to claim 12 for treatment of acute and chronic pain disorders.

14. The use according to claim 12 for treatment of acute and chronic neuropathic pain.

5 15. The use according to claim 12 for treatment of acute and chronic inflammatory pain.

16. The use according to claim 12 for treatment of arthritis, fibromyalgia, low back pain, post-operative pain, visceral pains like chronic pelvic pain, cystitis, irritable bowel syndrome (IBS), pancreatitis, ischeamic, sciatia, diabetic neuropathy, multiple sclerosis, lo interstitial cystitis and pain related to interstitial cystitis, HIV neuropathy, asthma, cough and inflammatory bowel disease (IBD), gastro-esophageal reflux disease (GERD), psoriasis, cancer, emesis, urinary incontinence and hyperactive bladder.

17. The use according to claim 12 for treatment of respiratory diseases.

■15

18. A method of treatment of VRl mediated disorders and for treatment of acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic inflammatory pain, and respiratory diseases, comprising administrering to a mammal, including man in need of such treatment, a therapeutically effective amount of the 20 compounds of formula I, according to any one of claims 1 to 7.