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WO1996002509A1 - Quinoline derivatives as nk3 antagonists - Google Patents

Quinoline derivatives as nk3 antagonists Download PDF

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Publication number
WO1996002509A1
WO1996002509A1 PCT/EP1995/002638 EP9502638W WO9602509A1 WO 1996002509 A1 WO1996002509 A1 WO 1996002509A1 EP 9502638 W EP9502638 W EP 9502638W WO 9602509 A1 WO9602509 A1 WO 9602509A1
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Prior art keywords
disorders
alkyl
compound
hydrogen
formula
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PCT/EP1995/002638
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French (fr)
Inventor
Carlo Farina
Giuseppe Arnaldo Maria Giardina
Mario Grugni
Luca Francesco Raveglia
Original Assignee
Smithkline Beecham Farmaceutici S.P.A.
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Publication of WO1996002509A1 publication Critical patent/WO1996002509A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2

Definitions

  • the present invention relates to the use of certain quinoline derivatives in medicine.
  • the mammalian peptide Neurokinin B belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA).
  • TK Tachykinin
  • SP Substance P
  • NKB Neurokinin A
  • NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with peptidic NK3 receptor agonists suggest that NKB, by activating the NK3 receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem, 1993, J. Phisiol, 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429;
  • a class of quinoline derivatives are active as selective, non-peptide NK3 antagonists and are far more stable from a metabolic point of view than the known peptidic NK3 receptor antagonists.
  • These derivatives are of potential therapeutic utility in treating pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch (for example, atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety, psychosis).
  • pulmonary disorders asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough
  • skin disorders and itch for example, atopic dermatitis and cutaneous wheal and flare
  • neurogenic inflammation and CNS disorders Parkinsoninson's disease, movement disorders, anxiety, psychosis.
  • the derivatives are also of potential therapeutic utility in treating convulsive disorders (for example epilepsy), renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (for example Alzheimer's disease), psoriasis, Huntington's disease, and depression (hereinafter referred to as the Secondary Disorders).
  • convulsive disorders for example epilepsy
  • renal disorders urinary incontinence
  • ocular inflammation inflammatory pain
  • eating disorders food intake inhibition
  • allergic rhinitis neurodegenerative disorders
  • neurodegenerative disorders for example Alzheimer's disease
  • psoriasis Huntington's disease
  • depression hereinafter referred to as the Secondary Disorders.
  • Ar is an optionally substituted phenyl or naphthvl group or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
  • R is an optionally substituted phenyl, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
  • R is a group CH-R4R5, in which R4 is hydrogen, linear or branched Ci _g alkyl, C3.7 cycloalkyl, C4.7 cycloalkylalkyl, optionally substituted phenyl or phenyl C ⁇ g alkyl, optionally substituted five- membered heteroaromatic rings comprising up to four heteroatom selected from O and N, hydroxy Ci.g alkyl, amino Cj. ⁇ alkyl, Ci.g alkylaminoalkyl, di Ci .g alkylaminoalkyl, C ⁇ _6 acylaminoalkyl, Ci .g alkoxyalkyl, C ⁇ . alkylcarbonyl, carboxy, C ⁇ .
  • alkoxyxcarbonyl Cj-6 alkoxycarbonyl C ⁇ .(. alkyl, aminocarbonyl, C ⁇ _6 alkylaminocarbonyl, di C ⁇ alkylaminocarbonyl, halogeno C ⁇ . alkyl;
  • R5 is a linear or branched Ci . ⁇ alkyl or a group (C b Ar j , where n is 0, 1, 2 or 3 and Ari has the same meaning as Ar:
  • Ri is hydrogen or linear or branched Cj.g alkyl
  • R2 and R3 which may be the same or different, are independently hydrogen, linear or branched Ci .g alkyl, C2-6 alkenyl, aryl, carboxamido, sulphonamido, Cj.g alkoxy, hydroxy, halogen, nitro, cyano.
  • X is O. S, H 2 or N-C ⁇ N: for use as an active therapeutic substance.
  • Ar, R or Arl are phenyl, optionally substituted by one or more Cj.g alkoxy, Cj.g alkoxycarbonyl or one or more trifluoromethyl groups.
  • An example of Cj.g alkoxy is methoxy and an example of Cj.g alkoxycarbonyl is methoxycarbonyl .
  • Examples of Ar, R or Aq as a heterocyclic group are py ⁇ dyl.
  • R is a group CH-R4R5
  • examples of R4 are hydrogen and methoxycarbonyl.
  • R5 examples are i-propyl and when it is a group (CH2)n-Ar ⁇ , typically n is O or 1.
  • R2 and R3 are hydrogen, hydroxy, Cj.g alkyl, preferably methyl and Ci.g alkoxy, preferably methoxy.
  • a preferred group of compounds of formula (I) are those in which: Ar is phenyl, R is a group CH-R4R5, Ri is hydrogen, R2 is hydrogen, Ci.g alkoxy or hydroxy, R3 is hydrogen or Ci _g alkyl and X is oxygen.
  • a further preferred group of compounds of formula (I) are those in which: Ar is phenyl,
  • R is a group CH2Ar ⁇
  • R] is hydrogen
  • R2 is hydrogen, methoxy or hydroxy
  • R3 is methyl, and X is oxygen.
  • the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceuncally acceptable form is meant, inter alia, of a pharmaceutically acceptable level of punty excluding normal pharmaceutical additives such as diluents and earners, and including no material considered toxic at normal dosage levels.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • Examples of pharmaceutically acceptable salts of a compound of formula (I) include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic. phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric. succinic, benzoic, ascorbic, and methanesulphonic.
  • Examples of pharmaceutically acceptable solvates of a compound of formula (I) include hydrates.
  • the compounds of formula (I) may have one or more asymmetric centres and therefore may exist in more than one stereoisomeric form.
  • the invention extends to all such forms and to mixtures thereof, including racemates.
  • the compounds of formula (I) are either known compounds or can be made from known compounds by known methods.
  • Compounds of formula (I), and methods for their manufacture, are disclosed in the following publications:
  • the present invention also provides the use of a Compound, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Disorders (hereinafter referred to as the 'Conditions').
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • a medicament, and a composition of this invention may be prepared by admixture of a Compound with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner. These conventional excipients may be employed for example as in the preparation of compositions of known agents for treating the Conditions.
  • a pharmaceutical composition is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the Conditions.
  • the suitable dosage range for the Compounds depends on the Compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • the Compounds or compositions may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyirolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like.
  • compositions may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose.
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • aqueous or non-aqueous vehicles which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal
  • compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • a pharmaceutically acceptable liquid e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
  • the Compounds may also be administered by inhalation, via the nasal or oral routes. Such administration can be carried out with a spray formulation comprising a Compound and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
  • Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended panicles.
  • the compound panicle size is from about 2 to 10 microns.
  • a further mode of administration of the Compounds comprises transdermal delivery utilising a skin-patch formulation.
  • a preferred formulation comprises a Compound dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient.
  • pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
  • the effective dose of Compound depends on the particular Compound employed, the condition of the patient and on the frequency and route of administration.
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in pa ⁇ icular 50, 100, 150, 200, 250. 300, 350, 400, 450, or 500 mg.
  • composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • the present invention also provides a method for the treatment and/or prophylaxis of the Primary and Secondary Disorders in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and or prophylaxis an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • NK3 ligands The activity of the Compounds, as NK3 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK3 ligands, [ 125 I]-[Me-Phe 7 ]-NKB or [ ⁇ HJ-Senktide, to guinea-pig and human NK3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-1 14; Buell et al, 1992, FEBS, 299(1), 90-95: Chung et al, 1994, Biochem. Biophys. Res. Com un., 198(3), 967-972).
  • binding assays allow the determination of the concentration of the individual compound required to reduce by 50% the [ ⁇ 5 .[Me-Phe ⁇ ]-NKB and [3H]-Senktide specific binding to NK3 receptor in equilibrium conditions (IC50). Binding assays provide for each Compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate.
  • the most potent Compounds show IC50 values in the range 100-2000 nM; in particular, in guinea-pig conex membranes by displacement of [125 _[M e _ph e 7].
  • the NK3-antagonist activity of the Compounds is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. Pharmacol., 101, 996- 1000) and rabbit isolated iris sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and human NK3 receptors mediated Ca “1 " 1 " mobilization (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658).
  • Guinea-pig and rabbit in-vitro functional assays provide for each Compound tested a mean Kg value of 3-8 separate experiments, where Kjj is the concentration of the individual Compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide.
  • Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca" 1-1" mobilization induced by the agonist NKB. In this assay, the Compounds behave as antagonists.
  • the therapeutic potential of the Compounds in treating the Conditions can be assessed using rodent disease models.
  • the following Descriptions illustrate the preparation of the intermediates, whereas the Examples illustrate the preparation of the Compounds.
  • the Compounds of the Examples are summarised in the Table.
  • reaction mixture was ice-cooled and quenched with 150 ml of H2O; the solvent was evaporated in-vacuo, 100 ml of CH2CI2 were added and the mixture was filtered over celite. The organic layer was separated, dried over N 2SO4, filtered and evaporated in-vacuo to dryness to yield 6.0 g of the title compound.
  • reaction mixture was evaporated in-vacuo to dryness to yield 1.5 g of the title compound, used without further purification.
  • the precipitated dicyclohexylurea was filtered off and the solution evaporated in- vacuo to dryness.
  • the residue was dissolved in CH2CI2 and washed with H2O, sat. sol. NaHCO3, 5% citric acid, sat. sol. NaHCO3 an ⁇ ⁇ sa so1 - NaCl.
  • reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO3.
  • the organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness.
  • the crude product was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/ethyl acetate 3:2 containing 0.5% NH4OH.
  • the purified solid was dissolved in Et2 ⁇ and acidified with HCl/Et2 ⁇ ; the precipitate was collected by filtration and triturated with a mixture of -PrOH/z ' -PnO 1 : 1 to yield 0.1 g of the title compound.
  • N,N'-carbonyldiimidazole were added and the reaction mixture was kept at room temperature for 3 hours.
  • 0.65 ml (5.9 mmol) of benzylamine, dissolved in 5 ml of dry CT Cb, were added dropwise and the solution was kept at room temperature for 6 days and then evaporated in-vacuo to dryness.
  • the crude product was washed with warm CTbCb and MeOH and the residue was collected by filtration.
  • the reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO3-
  • the organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness.
  • the residual oil was flash chromatographed on 230-400 mesh silica gel. eluting with ethyl acetate.
  • the purified solid obtained was triturated with /-PoO, filtered, washed and dried to yield 1.8 g of the title compound as a white solid.
  • thermospray interface eluent water/ acetonirrile 50 : 50.
  • the residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/ethyl acetate 50:50.
  • the purified solid obtained was triturated with -Pr2 ⁇ , filtered, washed and dried to yield 0.4 g of the title compound as a yellow solid.
  • the residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/ethyl acetate 80:20 containing 0.5% NH4OH.
  • the purified solid obtained was crystallized from toluene, filtered, washed and dried to yield 2.3 g of the title compound as a white solid.
  • the precipitated dicyclohexylurea was filtered off and the solution evaporated in- vacuo to dryness.
  • the residue was dissolved in CT Cb and washed with H2O, sat. sol. NaHCO3, 5% citric acid.
  • sat. sol. NaHCO3 ancl sat - so1 - Na Cl-
  • the organic layer was separated, dried over Na2 ⁇ 4 and evaporated in-vacuo to dryness; the residue was dissolved in 20 ml of CH2CI2 and left overnight.

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Abstract

NK3 receptor antagonists of formula (I) are useful in the treatment of pulmonary and CNS disorders.

Description

qUINOLINE DERIVATIVES AS NK3 ANTAGONISTS
The present invention relates to the use of certain quinoline derivatives in medicine. The mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA). Pharmacological and molecular biological evidence has shown the existence of three subtypes of TK receptor (NKi , NK2 and NK3) and NKB binds preferentially to the NK3 receptor although it also recognises the other two receptors with lower affinity (Maggi et al , 1993, J. Auton. Pharmacol., 13, 23-93).
Selective peptidic NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with peptidic NK3 receptor agonists suggest that NKB, by activating the NK3 receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem, 1993, J. Phisiol, 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429;
Mccarson and Krause, 1994, J. Neurosci., 14(2), 712-720; Arenas et al., 1991, J. Neurosci., 11, 2332-8).
However, the peptide-like nature of the known antagonists makes them likely to be too labile, from a metabolic point of view, to serve as practical therapeutic agents.
We have now found that a class of quinoline derivatives, some of which are already known compounds, are active as selective, non-peptide NK3 antagonists and are far more stable from a metabolic point of view than the known peptidic NK3 receptor antagonists. These derivatives are of potential therapeutic utility in treating pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch (for example, atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety, psychosis). These disorders are referred to hereinafter as the Primary Disorders. The derivatives are also of potential therapeutic utility in treating convulsive disorders (for example epilepsy), renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (for example Alzheimer's disease), psoriasis, Huntington's disease, and depression (hereinafter referred to as the Secondary Disorders).
According to the present invention there is provided a compound, or a solvate or salt thereof, of formula (I):
Figure imgf000004_0001
in which: Ar is an optionally substituted phenyl or naphthvl group or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
R is an optionally substituted phenyl, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
or R is a group CH-R4R5, in which R4 is hydrogen, linear or branched Ci _g alkyl, C3.7 cycloalkyl, C4.7 cycloalkylalkyl, optionally substituted phenyl or phenyl Cμg alkyl, optionally substituted five- membered heteroaromatic rings comprising up to four heteroatom selected from O and N, hydroxy Ci.g alkyl, amino Cj.^ alkyl, Ci.g alkylaminoalkyl, di Ci .g alkylaminoalkyl, Cι_6 acylaminoalkyl, Ci .g alkoxyalkyl, C\. alkylcarbonyl, carboxy, C\. alkoxyxcarbonyl, Cj-6 alkoxycarbonyl C\.(. alkyl, aminocarbonyl, Cι_6 alkylaminocarbonyl, di C ^ alkylaminocarbonyl, halogeno C\. alkyl;
and R5 is a linear or branched Ci .β alkyl or a group (C b Arj, where n is 0, 1, 2 or 3 and Ari has the same meaning as Ar:
Ri is hydrogen or linear or branched Cj.g alkyl;
R2 and R3, which may be the same or different, are independently hydrogen, linear or branched Ci .g alkyl, C2-6 alkenyl, aryl, carboxamido, sulphonamido, Cj.g alkoxy, hydroxy, halogen, nitro, cyano. carboxy, C\.(, alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono- and di-Ci .g alkylamino, hydroxyalkyl, aminoalkyl, mono-or di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; comprising up to four R2 substituents in the quinoline nucleus: X is O. S, H2 or N-C≡N: for use as an active therapeutic substance.
Examples of Ar, R or Arl are phenyl, optionally substituted by one or more Cj.g alkoxy, Cj.g alkoxycarbonyl or one or more trifluoromethyl groups. An example of Cj.g alkoxy is methoxy and an example of Cj.g alkoxycarbonyl is methoxycarbonyl .
Examples of Ar, R or Aq as a heterocyclic group are pyπdyl. When R is a group CH-R4R5, examples of R4 are hydrogen and methoxycarbonyl.
Examples of R5 are i-propyl and when it is a group (CH2)n-Arι , typically n is O or 1.
Examples of R2 and R3 are hydrogen, hydroxy, Cj.g alkyl, preferably methyl and Ci.g alkoxy, preferably methoxy.
A preferred group of compounds of formula (I) are those in which: Ar is phenyl, R is a group CH-R4R5, Ri is hydrogen, R2 is hydrogen, Ci.g alkoxy or hydroxy, R3 is hydrogen or Ci _g alkyl and X is oxygen.
A further preferred group of compounds of formula (I) are those in which: Ar is phenyl,
R is a group CH2Arι,
R] is hydrogen,
R2 is hydrogen, methoxy or hydroxy,
R3 is methyl, and X is oxygen.
The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceuncally acceptable form is meant, inter alia, of a pharmaceutically acceptable level of punty excluding normal pharmaceutical additives such as diluents and earners, and including no material considered toxic at normal dosage levels.
A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate. One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.
Examples of pharmaceutically acceptable salts of a compound of formula (I) include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic. phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric. succinic, benzoic, ascorbic, and methanesulphonic.
Examples of pharmaceutically acceptable solvates of a compound of formula (I) include hydrates. The compounds of formula (I) may have one or more asymmetric centres and therefore may exist in more than one stereoisomeric form. The invention extends to all such forms and to mixtures thereof, including racemates.
The compounds of formula (I) are either known compounds or can be made from known compounds by known methods. Compounds of formula (I), and methods for their manufacture, are disclosed in the following publications:
• Ger. Offen. DE 3,721,222 (Nippon) 14-01-88, Chem. Abst. 109: 93604.
• Eur. Pat. Appl. EP 384,313 (BASF), 29-08-90, Chem. Abst. 114: 209232u.
• Jpn. Kokai Tokkio Koho JP 02,129,169 (Yoshitomi Pharm. Ind.), 17-05-90, Chem. Abst. 113: 132029c. • Acta Pol. Pharm., 34(3), 271, 1977.
• Pharm. Sci., 72(9), 1082, 1983.
• Indian J. Pharm. Sci., 50(5), 269, 1988.
• Eur. J. Med. Chem., 27(9), 877, 1992.
The activity of the compounds of formula (I) (the Compounds) as NK3 receptor antagonists in standard tests indicates that they are of potential therapeutic utility in both the Primary and Secondary Disorders hereinbefore referred to.
Accordingly, the present invention also provides the use of a Compound, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Disorders (hereinafter referred to as the 'Conditions').
The present invention further provides a pharmaceutical composition comprising a Compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. Such a medicament, and a composition of this invention, may be prepared by admixture of a Compound with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner. These conventional excipients may be employed for example as in the preparation of compositions of known agents for treating the Conditions.
Preferably, a pharmaceutical composition is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the Conditions.
The suitable dosage range for the Compounds depends on the Compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration. The Compounds or compositions may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient. Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyirolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate. Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients. Compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose. carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats: emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
The Compounds may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation. The Compounds may also be administered by inhalation, via the nasal or oral routes. Such administration can be carried out with a spray formulation comprising a Compound and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended panicles. Preferably, the compound panicle size is from about 2 to 10 microns.
A further mode of administration of the Compounds comprises transdermal delivery utilising a skin-patch formulation. A preferred formulation comprises a Compound dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient. For a constant rate of percutaneous absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used. As mentioned above, the effective dose of Compound depends on the particular Compound employed, the condition of the patient and on the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in paπicular 50, 100, 150, 200, 250. 300, 350, 400, 450, or 500 mg. The composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
No unacceptable toxicological effects are expected with the Compounds when administered in accordance with the invention.
The present invention also provides a method for the treatment and/or prophylaxis of the Primary and Secondary Disorders in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and or prophylaxis an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
The activity of the Compounds, as NK3 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK3 ligands, [125I]-[Me-Phe7]-NKB or [^HJ-Senktide, to guinea-pig and human NK3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-1 14; Buell et al, 1992, FEBS, 299(1), 90-95: Chung et al, 1994, Biochem. Biophys. Res. Com un., 198(3), 967-972).
The binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the [^5 .[Me-Phe^]-NKB and [3H]-Senktide specific binding to NK3 receptor in equilibrium conditions (IC50). Binding assays provide for each Compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate.
The most potent Compounds show IC50 values in the range 100-2000 nM; in particular, in guinea-pig conex membranes by displacement of [125 _[Me_phe7]. NKB, the compound of Example 8 displays an IC5Q of 620 nM (n=2), and in the CHO cell membranes expressing the human NK3 receptor, the compound of Example 14 displays an IC50 of 15° nM <n=2)-
The NK3-antagonist activity of the Compounds is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. Pharmacol., 101, 996- 1000) and rabbit isolated iris sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and human NK3 receptors mediated Ca"1"1" mobilization (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). Guinea-pig and rabbit in-vitro functional assays provide for each Compound tested a mean Kg value of 3-8 separate experiments, where Kjj is the concentration of the individual Compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide. Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca"1-1" mobilization induced by the agonist NKB. In this assay, the Compounds behave as antagonists.
The therapeutic potential of the Compounds in treating the Conditions can be assessed using rodent disease models. The following Descriptions illustrate the preparation of the intermediates, whereas the Examples illustrate the preparation of the Compounds. The Compounds of the Examples are summarised in the Table.
DESCRIPTION 1 2-phenylquinoline-4-carboxyiic acid chloride
11.7 ml (136.3 mmol) of oxalyl chloride were dissolved in 150 ml of CH2CH The solution was cooled at - 10°C and 20 g (80.2 mmol) of commercially available 2- phenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 22 g of the title compound, used without further purification. C16H10C1NO M.W. = 267.76
DESCRIPTION 2
7-methoxy-2-phenylquinoline-4-carboxylic acid
5 g (28.2 mmol) of 6-methoxyisatine, 4 ml (33.8 mmol) of acetophenone and 5.2 g (92.6 mmol) of potassium hydroxide were dissolved in 22.9 ml of abs. EtOH and the slurry heated at 80°C for 42 hours After cooling of the reaction mixture, 50 ml of water were added and the solution extracted with 50 ml of EtoO. The ice-cooled aqueous phase was acidified to pH 1 with 37% HC1 and the precipitate collected by filtration and washed with water. The solid obtained was dried in-vacuo at 40°C to yield 7 0 g of the title compound. C17H13NO3 M.P. = 226-228°C M.W. = 279.30
Elemental analysis: Calcd. C.73.1 1; H.4.69. N.5.01; Found C.72.07; H.4.59. N.4.90.
I.R. (KBr): 3420; 1630 cm" 1
DESCRIPTION 3
7-methoxy-2-phenyiquinoline-4-carboxylic acid chloride
2.8 ml (32.3 mmol) of oxalyl chlonde were dissolved in 60 ml of CT Cb- The solution was cooled at -10°C and 6 g (19.0 mmol) of 7-methoxy-2-phenylquιnoline- 4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 7 g of the title compound, used without further purification. C17HJ2C1NO2 M.W. = 297.74
DESCRIPTION 4 7-hydroxy-2-phenvlquinoline-4-carboxylic acid hydroiodide
1.5 g (5.4 mmol) of 7-methoxy-2-phenylquιnolιne-4-carboxylιc acid were added pomonwise to 50 ml of 57% aqueous HI. The reaction mixture was refluxed and vigourously stirred for 5 hours; then it was evaporated in-vacuo to dryness to yield 2.1 g of the title compound. Cι6HnNO3. HI M.W = 393.17 I.R. (KBr): 3120, 1650; 1620 cm" 1
DESCRIPTION 5
4-hydroxymethyl-7-methoxy-2-phenytquinoline
15 g (50.4 mmol) of 7-methoxy-2-phenylquιnolιne-4-carboxylιc acid chlonde were suspended, under nitrogen atmosphere, in 300 ml of dry THF The reaction mixture was cooled at -78°C and 80 ml (80.0 mmol) of Li(r-BuO)3AlH (1M sol. in THF) were added dropwise. The solution was kept at -78°C for 2 hours and then at room temperature overnight.
The reaction mixture was ice-cooled and quenched with 150 ml of H2O; the solvent was evaporated in-vacuo, 100 ml of CH2CI2 were added and the mixture was filtered over celite. The organic layer was separated, dried over N 2SO4, filtered and evaporated in-vacuo to dryness to yield 6.0 g of the title compound.
Additional 2.3 g of the title compound were obtained by washing the aluminum salts several times with EtOAc and C^Cb-
Figure imgf000012_0001
M.P. = 165-168°C
M.W. = 265.32
I.R. (KBr): 3400-3000; 1620 cm" 1.
300 MHz 1H-NMR (CDCI3): δ 8.15 (d, 2H); 7.85 (d, 2H); 7.40-7.60 (m, 4H); 7.20 (d, 1H); 5.20 (s, 2H); 3.95 (s, 3H); 1.60 (s broad,
1H).
MS (El; source 200 °C; 70 V; 200mA): 265 (M+.); 236; 220; 193.
DESCRIPTION 6 7-methoxy-2-phenylquinoline-4-carboxaldehyde
6.0 g (46.0 mmol) of Mnθ2 were suspended, under nitrogen atmosphere, in 150 ml of dry CH2C1 .
3.3 g (12.4 mmol) of the product of Description 5, dissolved in 500 ml of dry CH2CI2, were added dropwise and the reaction mixture was stirred for 2 days. 1.0 g
(11.5 mmol) of Mnθ2 were added and the reaction stirred for 1 day; 0.5 g (5.7 mmol) of Mnθ2 were added and the reaction stirred for another day; additional 0.5 g (5.7 mmol) of Mnθ2 were added and the reaction stirred for another day.
The mixture was filtered over celite and the solvent evaporated in-vacuo to dryness; the residue was triturated with /-PnO to yield 2.7 g of the title compound.
C17H13NO2
M.P. = 123-126°C
M.W. = 263.30
I.R. (KBr): 1710 cm" 1. 300 MHz ΪH-NMR (CDCI3): δ 10.55 (s, 1H); 8.90 (d, 1H); 8.20 (d, 2H); 8.10 (s,
1H); 7.40-7.60 (m, 4H); 7.30 (d, 1H); 4.00 (s, 3H).
MS (El; source 200 °C; 70 V; 200mA): 263 (M+.); 235; 220: 204: 192; 191.
DESCRIPTION 7 4-(N-benzyl)iminomethyl-7-methoxy-2-phenylquinoline
1.0 g (3.8 mmol) of the product of Description 6 and 0.44 g (4.1 mmol) of benzylamine were dissolved in 30 ml of toluene; a catalytic amount of p- toluensulphonic acid (PTSA) was added and the solution was boiled for 36 hours, distilling away H2O with a Dean-Stark apparatus.
The reaction mixture was evaporated in-vacuo to dryness to yield 1.5 g of the title compound, used without further purification.
EXAMPLE 1
N-(2-me.hoxycarbonylphenyl)-2-phenylquinoline-4-carboxamide
2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen atmosphere, in 70 ml of dry THF and 30 ml of CH3CN. 1.21 g (8.0 mmol) of methyl anthranilate and 2.5 g (18.5 mmol) of N- hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled at 0°C.
1.81 g (8.8 mmol) of DCC, dissolved in 10 ml of CH2G2, were added dropwise and the solution was kept at 0°-5°C for 1 hour and then at room temperature for 2 hours.
The precipitated dicyclohexylurea was filtered off and the solution evaporated in- vacuo to dryness. The residue was dissolved in CH2CI2 and washed with H2O, sat. sol. NaHCO3, 5% citric acid, sat. sol. NaHCO3 an<^ sa so1- NaCl.
The organic layer was separated, dried over Na2SO4 and evaporated in-vacuo to dryness; the residue was dissolved in 20 ml of CH2CI2 and left overnight. Some more dicyclohexylurea precipitated and was filtered off. The solution was evaporated in-vacuo to dryness and the residue flash chromatographed on 230-400 mesh silica gel, eluting with a mixture hexane/ethyl acetate 1: 1 containing 0.5% NH4OH, to afford 0.45 g of a purified product which was triturated with /-PnO and then recrystallized from -PrOH to yield 0.34 g of the title compound. C24H18N2O3
M.P. = 137-138°C
M.W. = 382.42
Elemental analysis: Calcd. C75.38: H,4.74: N.7.33: Found C74.45; H.4.77; N.7.22. I.R. (KBr): 3280-3260: 1700; 1685 cm" 1.
300 MHz JH-NMR (DMSO-dg): δ 1 1.30 (s, 1H); 8.44 (s, 1H); 8.39-8.31 (m, 3H);
8.27 (d, 1H); 8.19 (d, 1H); 7.97 (dd, 1H); 7.88 (ddd, 1H); 7.78-7.66 (m, 2H); 7.64-7.52 (m. 3H); 7.56 (ddd, 1H); 3.80 (s, 3H). MS (El; source 200 °C: 70 V: 200mA): 382 (M+.); 323; 232: 204.
EXAMPLE 2 (R^)-N-[(l-methoxycarbonyl-2-phenyl)ethyl]-2-phenylquinoline-4-carboxamide
2 g (7.8 mmol) of (D,L) methyl phenylalaninate hydrochloride and 2.7 ml (19.5 mmol) of triethylamine (TEA) were dissolved, under nitrogen atmosphere, in 50 ml of a 1 : 1 mixture of dry O^Cb and CH3CN.
2.0 g (7.8 mmol) of 2-phenylquinoline-4-carbonylchloride, dissolved in 50 ml of a 1:4 mixture of dry CH2CI2 and DMF, were added dropwise to the ice-cooled solution of the amines and the reaction was kept at 0°- 5° C for 1 hour and left at room temperature overnight.
The reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO3. The organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness.
The residual oil was crystallized twice from EtOAc to yield 1.6 g of the title compound as a grey solid.
C26H22N2O3
M.P. = 152-154°C. M.W. = 410.48
Elemental analysis: Calcd. C 6.08; H.5.40; N.6.82;
Found C.75.97; H,5.44; N.6.82.
I.R. (KBr): 3300; 1735; 1640 cm"1.
300 MHz 1H-NMR (CDCI3): δ 8.19 (d, 1H); 8.13 (dd, 2H) 8.03 (d, 1H); 7.80 (s, 1H); 7.75 (ddd, 1H); 7.59-7.47 ( , 4H); 7.39-7.23
(m, 5H); 6.50 (d broad. 1H); 5.25 (dt, 1H); 3.85 (s, 3H); 3.45 (dd, 1H); 3.23 (dd, 1H).
MS (El; source 200 °C; 70 V; 200mA): 410 (M+.); 351; 248: 232: 204; 91.
EXAMPLE 3
4-[(N-benzyl)aminomethyl]-7-methoxy-2-phenylquinoline dihydrochloride
1.3 g (3.7 mmol) of the crude product of Description 7 were dissolved, under nitrogen atmosphere, in 60 ml of AcOH. The reaction mixture was cooled at 20°C, 2.0 g (9.4 mmol) of Na(AcO)3BH were added in about 15 minutes and the reaction was left at room temperature overnight.
Additional 1.5 g (7.0 mmol) of Na(AcO)3BH were added and the reaction mixture was then evaporated in-vacuo to dryness. The residue was dissolved in Q Cb and washed with NaHCO^ and H2O; the organic layer was separated, dried over Na2S04, filtered and evaporated in-vacuo to dryness.
The crude product was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/ethyl acetate 3:2 containing 0.5% NH4OH. The purified solid was dissolved in Et2θ and acidified with HCl/Et2θ; the precipitate was collected by filtration and triturated with a mixture of -PrOH/z'-PnO 1 : 1 to yield 0.1 g of the title compound.
C24H22N2O.2HCI
M.P. = 216-218°C M.W. = 427.37
I.R. (KBr): 3420; 1635; 1605 cm" 1.
300 MHz iH-NMR (DMSO-d6): δ 10.00 (s broad, 2H); 8.35 (s, 1H); 8.30 (dd, 2H);
8.13 (d, 1H); 7.69-7.53 (m, 6H); 7.47-7.42 (m, 4H); 7.36 (dd. 1H); 4.79 (t, 2H); 4.39 (t, 2H); 4.00 (s, 3H).
MS (El; source 200 °C; 70 V; 200mA): 354 (M-κ); 249; 91.
EXAMPLE 4
N-benzvl-7-hydroxv-2-phenvlquinoIine-4-carboxamide
0.85 g (3.0 mmol) of crude 7-hydroxy-2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen atmosphere, in 15 ml of dry CH2CI2; 0.52 g (3.3 mmol) of
N,N'-carbonyldiimidazole were added and the reaction mixture was kept at room temperature for 3 hours. 0.65 ml (5.9 mmol) of benzylamine, dissolved in 5 ml of dry CT Cb, were added dropwise and the solution was kept at room temperature for 6 days and then evaporated in-vacuo to dryness. The crude product was washed with warm CTbCb and MeOH and the residue was collected by filtration.
The solid was dissolved in a mixture of CHCI3 (200 ml) / MeOH (8 ml) and washed with H2O (10 ml). The extracted organic layer was dried over Na2SO4, filtered, evaporated in vacuo to dryness and triturated with 5 ml of warm MeOH to yield
0.045 g of the title compound.
C23H18N2O2
M.P. = 292-293°C M.W. = 354.41
I.R. (KBr): 3270; 1640: 1620 cm" 1.
300 MHz iH-NMR (DMSO-d6): δ 9.30 (t, 1H): 8.25 (dd. 2H); 8.06 (d, 1H); 7.91 (s,
1H); 7.59-7.50 (m, 3H); 7.45-7.37 (m, 5H); 7.35 (d, 1H); 7.19 (dd, 1H); 4.60 (d, 2H). MS (FAB; positive ion mode: Xe beam at 8 KeV: matrix thioglycerol: source 50 °C):
355 (MH)+.
EXAMPLE 5 N-(3,4-dimethoxybenzyI)-7-methoxy-2-phenylquinoline-4-carboxamide
1.5 g (9.0 mmol) of 3,4-dimethoxybenzylamine and 1.2 g (9.0 mmol) of anhydrous potassium carbonate were dissolved, under nitrogen atmosphere, in 40 ml of dry DMF. 1.3 g (4.5 mmol) of 7-methoxy-2-phenylquinoline-4-carbonylchloride, dissolved in 30 ml of dry DMF, were added dropwise to the ice-cooled solution of the amine and the reaction was kept at 0°- 5° C for 1 hour and left at room temperature overnight. The reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO3- The organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/ethyl acetate 6:4 containing 0.2% NH4OH. The purified solid obtained (250 mg) was crystallized from a mixture of EtOAc/toluene EtOH to yield 114 mg of the title compound as a yellow solid.
C26H24N2O4 M.P. = 170-172°C. M.W. = 428.49 I.R. (KBr): 3280; 1650 cm" 1.
300 MHz iH-NMR (DMSO-d6): δ 9.28 (t broad, 1H); 8.29 (dd, 2H); 8.12 (d, 1H);
8.00 (s, 1H); 7.61-7.49 (m, 4H); 7.29 (dd, 1H); 7.03 (s, 1H); 6.95 (s, 2H); 4.52 (d, 2H); 3.97 (s,
3H); 3.77 (s, 3H); 3.75 (s, 3H). MS (El; source 200 °C: 70 V; 200mA): 428 (M- ); 413; 263: 235: 191; 151; 77.
EXAMPLE 6 N-[3 -bis(trinuoromethyl)benzyl]-7-methoxy-2-phenylquinoline-4-carboxamide
2.0 g (6.6 mmol) of 3,5-bistrifluoromethylbenzylamine and 1.0 g (6.6 mmol) of anhydrous potassium carbonate were suspended in 40 ml of DMF. The reaction mixture was cooled at 0°C and 1.0 g (3.3 mmol) of 7-methoxy-2-phenylquinoline-4- carbonylchloride, dissolved in 30 ml of DMF, were added dropwise. The reaction mixture was left overnight at room temperature, evaporated in-vacuo to dryness, dissolved in water and extracted with EtOAc.
The organic layer was dried over Na2SO4, filtered and evaporated in-vacuo to dryness; the residue was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/ethyl acetate 65:35 containing 0.27c of NH4OH to yield 0.4 g of the title compound.
C26H18F6N2°2 M.P. = 179-181°C M.W. = 504.44
I.R. (KBr): 3290; 1645; 1620 cm" 1.
300 MHz H-NMR (Acetone.dg): δ 8.70 (t broad, 1H); 8.28 (dd, 3H); 8.22 (d, 1H);
8,17 (s broad, 1H); 8.19 (s, 1H); 7.98 (s broad, 1H); 7.59 -7.49 (m, 4H); 7.25 (dd, 1H); 4.96 (d, 2H); 4.02 (s, 3H).
MS (El; source 200 °C; 70 V; 200mA): 504 (M+.); 235 ;191; 77.
EXAMPLE 7
N-(2-pyridylmethyl)-7-methoxy-2-phenylquinoline-4-carboxamide
1.3 ml (12.6 mmol) of 2-aminomethylpyridine and 1.7 g (12.6 mmol) of anhydrous potassium carbonate were suspended, under nitrogen atmosphere, in 25 ml of dry
CH C^- 1.9 g (6.3 mmol) of 7-methoxy-2-phenylquinoline-4-carbonylchloride, dissolved in 30 ml of dry CH2CI2, were added dropwise to the ice-cooled solution of the amine and the reaction was kept at 0°- 5° C for 1 hour and left at room temperature overnight.
The reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO3- The organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residual oil was flash chromatographed on 230-400 mesh silica gel. eluting with ethyl acetate. The purified solid obtained was triturated with /-PoO, filtered, washed and dried to yield 1.8 g of the title compound as a white solid.
Figure imgf000017_0001
M.P. = 135-136°C. M.W. = 369.42
Elemental analysis: Calcd. C/74.78; H.5.18: N.1 1.38;
Found C.75.90: H,5.24: N, 11.39.
I.R. (KBr): 3230; 1660 cm"1.
300 MHz lH-NMR (CDCl3): δ 8.55 (d broad, 1H); 8.21 (d, 1H); 8.16 (d, 2H); 7.89 (s, 1H); 7.74 (ddd. 1H); 7.58-7.47 (m, 6H); 7.39 (d,
1H); 7.26 (d, 1H); 7.24 (dd, 1H); 4.89 (d, 1H); 3.99 (s, 3H).
LC/MS (flow injection: thermospray interface: eluent water/ acetonirrile 50 : 50.
0.05% TFA, source 250 °C): 370 (MH)+. EXAMPLE 8
N-benzyl-2-phenylquinoline-4-carboxamide
2.6 ml (24.0 mmol) of benzylamine and 3.3 g (24.0 mmol) of anhydrous potassium carbonate were dissolved, under nitrogen atmosphere, in 20 ml of dry DMF. 3.1 g (12.0 mmol) of 2-phenylquinoline-4-carbonylchloride, dissolved in 40 ml of dry DMF, were added dropwise to the ice-cooled solution of the amine and the reaction was kept at 0°- 5° C for 1 hour and left at room temperature overnight. The reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO3- The organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/ethyl acetate 80:20 containing 0.5% NH4OH. The purified solid obtained was crystallized from EtOAc, filtered, washed and dried to yield 2.7 g of the title compound as a white solid. C23H18 2O M.P. = 189-190°C. M.W. = 338.41 Elemental analysis: Calcd. C.81.63; H,5.36; N,8.28;
Found C.81.72; H,5.32; N.8.22. I.R. (KBr): 3270; 1635 cm"1.
300 MHz H-NMR (DMSO-dg): δ 9.39 (t, 1H); 8.32 (dd, 2H); 8.21 (d, 1H); 8.19 (s,
1H); 8.14 (d, 1H); 7.84 (ddd. 1H); 7.65 (ddd, 1H); 7.62-7.51 (m, 3H); 7.46-7.36 (m. 4H); 7.29 (dd,
1H); 4.60 (d, 2H). MS (El; source 200 °C; 70 V; 200mA): 338 (M+.); 261; 204; 91.
EXAMPLE 9 N-phenyl-7-methoxy-2-phenylquinoline-4-carboxamide
1.7 ml (18.8 mmol) of aniline and 2.5 g ( 18.8 mmol) of anhydrous potassium carbonate were dissolved, under nitrogen atmosphere, in 15 ml of dry DMF. 2.9 g (9.4 mmol) of 7-methoxy-2-phenylquinoline-4-carbonylchloride, dissolved in 40 ml of dry DMF, were added dropwise to the ice-cooled solution of the amine and the reaction was kept at 0°- 5° C for 1 hour and left at room temperature overnight. The reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO3. The organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/ethyl acetate 80:20 containing 0.5% NH4OH. The purified solid obtained was crystallized from toluene, filtered, washed and dried to yield 1.9 g of the title compound as a white solid. C23H18N2O2 M.P. = 222-224°C. M.W. = 354.41
Elemental analysis: Calcd. 77.95; H.5.12; N,7.90:
Found C.78.05; H.5.10: N.7.86. I.R. (KBr): 3200; 1640 cm" 1.
300 MHz H-NMR CDC^): δ 8.12 (dd, 2H); 8.10 (d, 1H); 7.92 (s broad, 1H); 7.82
(s, 1H); 7.75 (d, 2H); 7.56-7.41 (m, 6H); 7.22 (d, 1H); 7.21 (dd, 1H); 3.97 (s, 3H). MS (El; source 200 °C; 70 V; 200mA): 354 (M+.); 262; 234; 191; 77.
EXAMPLE 10
N-(2-methoxybenzyl)-7-methoxv-2-phenylquinoline-4-carboxamide
1.6 ml (12.6 mmol) of 2-methoxybenzylamine and 1.7 g (12.6 mmol) of anhydrous potassium carbonate were dissolved, under nitrogen atmosphere, in 10 ml of dry
DMF.
1.9 g (6.3 mmol) of 7-methoxy-2-phenylquinoline-4-carbonylchloride, dissolved in
30 ml of dry DMF, were added dropwise to the ice-cooled solution of the amine and the reaction was kept at 0°- 5° C for 1 hour and left at room temperature overnight. The reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCθ3. The organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness.
The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/ethyl acetate 50:50. The purified solid obtained was triturated with -Pr2θ, filtered, washed and dried to yield 0.4 g of the title compound as a yellow solid.
C25H22N2O3 H2O
M.P. = 196-199°C.
M.W. = 416.49
Elemental analysis: Calcd. C.72.09: H.5.32: N.6.73: Found CY72.62: H.5.62: N.6.80.
I.R. (KBr): 3240; 1660 cm" 1.
300 MHz H-NMR (DMSO-d6): δ 9.16 (t, 1H); 8.30 (dd, 2H); 8.1 1 (d, 1H); 8.01 (s,
1H); 7.60-7.50 (m, 4H): 7.36 (dd, 1H); 7.29 (dd, 1H); 7.28 (ddd, 1H); 7.04 (dd, 1H); 6.96 (ddd. 1H); 4.56 (d. 2H); 3.98 (s, 3H); 3.88 (s, 3H). LC MS (flow injection; thermospray interface; eluent water/acetonitrile 40 : 60,
0.05% TFA, source 250 °C): 399 (MH)+.
EXAMPLE 11
N-phenethyl-7-methoxv-2-phenylquinoline-4-carboxamide
2.4 ml (18.8 mmol) of phenethylamine and 2.5 g (18.8 mmol) of anhydrous potassium carbonate were dissolved, under nitrogen atmosphere, in 15 ml of dry DMF.
2.9 g (2.4 mmol) of 7-methoxy-2-phenylquinoline-4-carbonylchloride, dissolved in 40 ml of dry DMF, were added dropwise to the ice-cooled solution of the amine and the reaction was kept at 0°- 5° C for 1 hour and left at room temperature overnight. The reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO3. The organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/ethyl acetate 80:20 containing 0.5% NH4OH. The purified solid obtained was crystallized from toluene, filtered, washed and dried to yield 2.3 g of the title compound as a white solid.
C25H22 2O2 M.P. = 174-176°C. M.W. = 382.47 Elemental analysis: Calcd. C.78.51; H.5.80: N,7.32;
Found C78.60; H.5.79; N,7.29. I.R. (KBr): 3300; 1635 cm" 1.
300 MHz H-NMR (CDCI3): δ 8.09 (dd, 2H); 7.93 (d, 1H); 7.63 (s, 1H); 7.57-7.47
(m, 4H); 7.40-7.26 (m, 5H); 7.17 (dd, 1H); 6.08 (t broad, 1H); 3.98 (s, 3H); 3.86 (dt, 2H); 3.04 (t, 2H).
LC/MS (flow injection; thermospray interface; eluent water/acetonitrile 40 : 60,
0.05% TFA, source 250 °C): 383 (MH)+.
EXAMPLE 12 N-benzyl-7-methoxy-2-phenylquinoline-4-carboxarnide
0.5 g (1.6 mmol) of 7-methoxy-2-phenylquinoline-4-carboxylic acid and 0.3 g (2.1 mmol) of N,N'-carbonyldiimidazole were dissolved, under nitrogen atmosphere, in 10 ml of dry THF and the solution was stirred for 3 hours. 0.4 ml (2.4 mmol) of benzylamine were added and the solution left at room temperature overnight. The reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in Et2θ and washed twice with a sat. sol. of NaHCO3- The organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness.
The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/ethyl acetate 80:20 containing 0.5% NH4OH. The purified solid obtained was triturated with i-PnO, filtered, washed and dried to yield 0.33 g of the title compound as a white solid. C24H20N2O2
M.P. = 159-161°C. M.W. = 368.43
Elemental analysis: Calcd. C.78.24: H,5.47; N,7.60;
Found C 7.67; H,5.47; N,7.44. I.R. (KBr): 3240; 1665 cm" 1
300 MHz 1H-NMR (DMSO-d6): δ 9.37 (t broad, 1H); 8.30 (dd, 2H); 8.12 (d, 1H);
8.02 (s, 1H); 7.61-7.49 (m, 4H); 7.45-7.35 (m, 4H); 7.31- 7.27 (m, 2H); 4.60 (d, 1H); 3.98 (s, 2H). LC/MS (flow injection; thermospray interface; eluent water/acetonitrile 5 : 95, 0.05% TFA, source 250 °C): 369 (MH)+.
EXAMPLE 13 (±)-(R)-N-[(l-methoxycarbonyl-2-methyl)propyl]-2-phenylquinoline-4- carboxamide
2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen atmosphere, in 70 ml of dry THF and 30 ml of CH3CN. 3.71 g (8.4 mmol) of D-valine methyl ester and 2.1 g (15.5 mmol) of N- hydroxybenzorriazole (HOBT) were added and the reaction mixture was cooled at 0°C. 1.85 g (9.0 mmol) of DCC. dissolved in 10 ml of G-bCb, were added dropwise and the solution was kept at 0°-5°C for 1 hour and then at room temperature for 2 hours. The precipitated dicyclohexylurea was filtered off and the solution evaporated in- vacuo to dryness. The residue was dissolved in CT Cb and washed with H2O, sat. sol. NaHCO3, 5% citric acid. sat. sol. NaHCO3 ancl sat- so1- NaCl- The organic layer was separated, dried over Na2≤θ4 and evaporated in-vacuo to dryness; the residue was dissolved in 20 ml of CH2CI2 and left overnight. Some more dicyclohexylurea precipitated and was filtered off. The solution was evaporated in-vacuo to dryness and the residue flash chromatographed on 230-400 mesh silica gel, eluting with a mixture hexane/ethyl acetate 7: 3 containing 0.5% NH4OH, to afford a purified product which was recrystallized from -PrOH to yield 1.58 g of the title compound. C22H22N2°3 M.P. = 115-1 17°C M.W. = 362.43
[α]D 20 = + 28.6 (c = 0.5, MeOH) Elemental analysis: Calcd. C. 72.91 ; H, 6.12; N, 7.33; Found C, 73.00; H, 6.12; N, 7.74.
I.R. (KBr): 3270; 1752; 1740; 1645; 1590; 1540 cm"1.
300 MHz iH-NMR (DMSO-d6): δ 9.17 (d, 1H); 8.30 (d, 1H); 8.30 (d, 1H); 8.15 (d,
2H); 8.08 (s, 1H); 7.82 (dd, 1H); 7.66 (dd, 1H); 7.62-7.50 (m, 3H); 4.50 (dd, 1H): 3.76 is, 3H); 2.21 (dqq, 1H); 1.00 (d, 6H).
MS (El; source 200 °C; 70 V; 200 mA): 362 (M+.); 303; 232; 204.
EXAMPLE 14
N-benzyl-3-methyl-2-phenylquinoline-4-carboxamide
2.0 g (7.6 mmol) of 3-methyl-2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen atmosphere, in 70 ml of dry THF and 30 ml of CH3CN.
0.88 ml (8.0 mmol) of benzylamine and 1.95 g (14.4 mmol) of N-hydroxybenzotriazole
0HOBT) were added and the reaction mixture was cooled at 0°C. 1.73 g (8.4 mmol) of DCC, dissolved in 10 ml of CH2CI2, were added dropwise and the solution was kept at 0°-5°C for 1 hour and then at room temperature for 2 hours.
Additional 0.27 ml (2.5 mmol) of benzylamine were added and the reaction stirred overnight.
The precipitated dicyclohexylurea was filtered off and the solution evaporated in- vacuo to dryness. The residue was dissolved in CT Cb and washed with H2O. sat. sol. NaHCO3, 5% citric acid. sat. sol. NaHCO3 and sat- so1- NaC1-
The organic layer was separated, dried over Na2SO4 and evaporated in-vacuo to dryness; the residue was dissolved in 20 ml of CH2CI2 and left overnight. Some more dicyclohexylurea precipitated and was filtered off. The solution was evaporated in-vacuo to dryness and the residue was triturated with
EtOAc/ i'-PoO and then recrystallized from -PrOH to yield 0.77 g of the title compound.
C24H20N2O
M.P. = 159-160°C M.W. = 352.44
Elemental analysis: Calcd. C. 81.79: H. 5.72: N, 7.95: Found C. 81.81 : H, 5.70; N, 7.96. I.R. (KBr): 3285; 3030; 1635: 1580; 1555: 1495 cm" 1. 300 MHz ]H-NMR (DMSO-d6): δ 9.29 (t br. IH): 8.03 (d, IH): 7.75 (dd, IH); 7.74
(d, IH); 7.63-7.48 (m. 6H); 7.48-7.27 (m. 5H): 4.61
(d, 2H): 2.30 (s, 3H).
MS (El; source 200 °C: 70 V; 200 mA): 352 (M+.): 337; 261; 217: 91.
Figure imgf000024_0001

Claims

Claims
1. A compound, or a solvate or salt thereof, of formula (I):
Figure imgf000025_0001
in which:
Ar is an optionally substituted phenyl or naphthyl group or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
R is an optionally substituted phenyl, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
or R is a group CH-R4R5, in which R4 is hydrogen, linear or branched C 1 _g alkyl, C3.7 cycloalkyl, C4.7 cycloalkylalkyl, optionally substituted phenyl or phenyl C^.^ alkyl, optionally substituted five-membered heteroaromatic rings comprising up to four heteroatom selected from O and N, hydroxy C\.(. alkyl, amino C\. alkyl, C 1-6 alkylaminoalkyl, di C ι _6 alkylaminoalkyl, Ci.g acylaminoalkyl, Cι _6 alkoxyalkyl, Cj.g alkylcarbonyl, carboxy, Ci.g alkoxyxcarbonyl, C[. alkoxycarbonyl C 1.5 alkyl, aminocarbonyl, Ci .g alkylaminocarbonyl, di Cι_6 alkylaminocarbonyl, halogeno C \.^ alkyl;
and R5 is a linear or branched C 1.5 alkyl or a group (CH2)n-Arι , where n is 0, 1, 2 or 3 and Ai\ has the same meaning as Ar;
Rl is hydrogen or linear or branched C i .g alkyl; R2 and R3, which may be the same or different, are independently hydrogen, linear or branched Cι_6 alkyl, C2-6 alkenyl, aryl, carboxamido, sulphonamido, Cι_6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, Ci .g alkoxycarbonyl, trifluoromethyl, acyloxy, pht alimido, amino, mono- and i-Cι.6 alkylamino,hydroxyalkyl, aminoalkyl, mono-or di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino, mono- or di- alkylaminoacylamino; comprising up to four R2 substituents in the quinoline nucleus;
and X is O, S, H2 or N-C≡N; for use as an active therapeutic substance.
2. A use according to claim 1 , in which, in the compound of formula (I),
Ar, R or A is phenyl, optionally substituted by one or more Ci.g alkoxy, Ci _6 alkoxycarbonyl or trifluoromethyl groups.
3. A use according to claim 1, in which, in the compound of formula (I), R is CH-R4R5, in which R4 is hydrogen or methoxycarbonyl.
4. A use according to claim 1 , in which, in the compound of formula (I),
Ar is phenyl,
R is a group CH-R4R5, in which R4 and R5 are as defined in claim 1, Ri is hydrogen, R2 is hydrogen, C 1.5 alkoxy or hydroxy,
R3 is hydrogen or C i.g alkyl and X is oxygen.
5. A use according to claim 1, in which, in the compound of formula (I),
Ar is phenyl,
R is a group CHoAri , in which Ari is as defined in claim 1, Ri is hydrogen,
R2 is hydrogen, methoxy or hydroxy, R3 is methyl and X is oxygen.
6. A use according to anyone of claims 1 to 5 in which the use is for the treatment of pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch
(atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety, psychosis).
7. A use according to any one of claims 1 to 5 in which the use is for the treatment of convulsive disorders, renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, and depression.
8. The use of a compound of formula (I) as defined in claim 1 , or a salt or solvate thereof, in the manufacture of medicament for the treatment of pulmonary disorders (asthma, chronic obstructive pulmonary diseases - COPD-, airway hyperreactivity, cough), skin disorders and itch (atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety, psychosis), convulsive disorders, renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, and depression.
9. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, or a salt or solvate thereof, and a pharmaceutically acceptable carrier.
10. A method for the treatment and/or prophylaxis of pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch (atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety, psychosis), convulsive disorders, renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, and depression in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of a compound of formula (I), as defined in claim 1, or a salt or solvate thereof.
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