Title of Invention	FUSED PYRIDINE DERIVATIVES FOR USE AS VANILLOID RECEPTOR ANTAGONISTS FOR TREATING PAIN
Abstract	The invention provides compounds of formula I wherein R<sup>1</sup> R<sup>2</sup>, R<sup>3</sup>, R<sup>4</sup> and R<sup>5</sup> are as defined in the description, and the preparation thereof. The compounds of formula I are useful as pharmaceuticals.

Full Text

FUSED PYRIDINE DERIVATIVES FOR USE AS VANILLOID RECEPTOR ANTAGONISTS FOR TREATING PAIN Pvriclino dorivativoo The present invention relates to novel pyridine derivatives, to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them. Compounds of the invention exist in free or salt, e.g. add or base addition salt form. The invention is to be understood as including the compounds of formula I in free as well as in salt form, e.g. as trifluoroacetate or hydrochloride salt. Suitable pharmaceutically acceptable acid addition salts for pharmaceutical use in accordance with the invention include in particular the hydrochloride salt. The invention also provides a process for the production of a compound of formula I comprising the step of Compounds of formula I wherein R3 R4 and R5 have the above meanings and R^ and R^ together are a group -N=C(CI)-N=C(CI)- may be reacted with hydrogen under standard conditions to give compounds of formula I wherein R3 R4 and R5 have the above meanings and R1and R2 together are a group -N=CH-NH"CHr. In general, the reactions may be carried out in accordance with standard procedures. However, the yield to obtain compounds of fonnula I is improved by minimi^ng the hydrolysis of the enamine back to ketone, e.g. to 1-(4-chlorophenyi)*3,3-dimethyl-2-butanone. Durmg the reaction for the first 12-20 hours, the temperature of the reaction solution is kept below 75X, preferably below 73°C. Then the reaction is healed to about 100°C for 2-4 hours, preferably 3 hours. The solvent is removed using a toluene - heptane mixture. Other solvent mixtures can be of an aromatic hydrocarbon solvent with a lower aliphatic hydrocarbon (C3-C8) solvent. Aqueous workup followed by precipitation gives the free base. The salt forms are made by standard procedures known to the skilled artisan, e.g. 6-(4- chlorophenyl)-7-(1,1-dimethylethyl)-2.3-dihydro-2-thioxo-pyrido[2,3-d]pyrimidine-4(1H)-one is purified either as the potassium salt, followed by conversion to the free acid form and recrystallization from ethanol and water or by isolating the crude free acid fonn followed by the recrystallization from ethanol and water. Compounds of fonnula I may be further derivatised to arrive at different compounds of formula I- pharmaceuticals. In particular the agents of invention are functional blockers of the human vanillold receptor 1 (hVR1). Vanilloid receptor interaction of the agents of invention may be demonstrated by their ability to block ion flow through vanilloid receptor 1 ion channels, e.g. by measuring intracellular calcium levels by e.g. a fluorometric determination of calcium with a calcium sensitive dye, such as by the FLIPR method, or by detemining 45Ca-uptake or °C-guanidinium efflux, as demonstrated in accordance with the following test method. Activity specifically as analgesic agents may be demonstrated in accordance with standard test methods, e.g. as described in the following test. Test: Anti-hyperalgesic effects in a model of neuropathic pain In the rat The agents of invention are potent and efficacious anti-hyperalgesic agents following oral administration in the following rat model of neuropathic pain. Peripheral neuropathy is induced by partial ligation of the left sciatic nerve. Mechanical hyperalgesia is assessed from paw withdrawal thresholds measured on the ipsilateral (ligated) and contralateral (non-ligated) hindpaws using standard paw pressure methods. Drug effects are studied 11-15 days post ligation. The mean paw withdrawal threshold ± s.e.m. for the left (ligated) paw is compared to that of the right (non-ligated) paw. The agents of invention are administered, e.g. orally in 20 % cremophor/water in a volume of 1 ml. The post-drug percentage hyperalgesia values are obtained by comparison to the pre-drug value for the right (non-ligated) paw; this enables a true measure of the reduction in hyperalgesia to be obtained without the added complication of any drug effects on the right paw. Single oral administration of the agents of invention produces a highly effective reversal of mechanical hyperalgesia in the partially denervated rat hind paw. The agents of invention produce a reversal of mechanical hyperalgesia at 0.1-100 mg/kg and show a rapid Offset of activity with a long duration of action. The agents of invention are thus useful as vanilloid receptor antagonists, e.g. for the treatment of pain of various genesis or aetiology and as anti-inflammatory and/or anti-oedemic agents for the treatment of inflammatory reactions, diseases or conditions, as well as for the treatment of allergic responses. Having regard to their analgesic/anti-inflammatory profile they are useful fcr the treatment of inflammatory pain, for the treatment of hyperalgesia and, in particular, for the treatment of severe chronic pain. They are, for example, useful for the treatment of pain, inflammation and/or oedema consequential to trauma, e.g. associated with bums, sprains, fracture or the like, subsequent to surgical intervention, e.g. as post-operative analgesics, as well as for the treatment of inflammatory pain of diverse genesis, e.g. for the treatment of osteo and rheumatoid arthritis and rheumatic disease, teno-synovitis and gout. They are further suitable as analgesics for the treatment of pain associated with, e.g., angina, menstruation or cancer. As anti-lnflammatory/anti-oedema agents, they are further useful, e.g., for the treatment of inflammatory skin disorders, for example psoriasis and eczema. Inflammatory or obstructive airways diseases to which the present invention is applicable further include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and, in particular, byssinosis. Further inflammatory or obstructive ain^^ays diseases and conditions for which the agents of invention may be used include adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary or ainways disease (COPD or COAD), and bronchitis. The agents of invention may also be used for the treatment of allergic and vasomotor rhinitis. combination with one or more pharmaceutically acceptable cam'es, especially suitable for enteral or parenteral application. For the above indications the appropriate dosage of the agents of invention will, of course, vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated as well as the relative potency of the particular agent of invention employed. For example, the amount of active agent required may be detemiined on the basis of known in vitro and in vivo techniques, detemiining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect. In general, satisfactory results in animals are indicated to be obtained at daily dosages of from about 0.01 to about 20.0 oig/kg p.o. In humans, an indicated daily dosage is in the range of from about 0.7 to about 1400 mg/day p.o., e.g. from about 50 to 200 mg, conveniently administered once or in divided doses up to 4 x per day or in sustakied release form. Oral dosage forms accordingly suitably comprise from about 0.2 or 2,0 to about 700 or 1400 mg agent of invention admixed with an appropriate pharmaceutically acceptable diluent or earner therefore. (2) A pharmaceutical composition comprising a compound of formula I in free base or pharmaceutically acceptable acid addition salt form as under (1) as active ingredient together with a pharmaceutically acceptable diluent or carrier therefore; (2') A compound of formula I in free base or pharmaceutically acceptable acid addition salt form for the treatment or prevention of a disease or condition in which vanilloid receptor plays a role or is implicated comprising a compound of formula I and a carrier. (3) A method for the treatment of any of particular indication hereinbefore set forth in a subject in need thereof which comprises administering an effective amount of a compound of formula I in free base or pharmaceutically acceptable acid addition salt fonn as under (1); The preferred compound of formula I is the 7-.tert.-butyl-6-(4-chlorophenyl)-2-thioxo-2,3-dihydro-1 .H.-pyrido[2.3-.d.]-pyrimidin-4-one (example 2). This compound is a potent vanilloid In the examples the following abbreviations are used: DMF: dimethyl fomiamide; RT: room temperature; THF: tetrahydrofuran; LCMS: Liquid Chromotagrophy mass spectrometry methylacetonitrile (5 mL) is added and the resulting suspension is heated at reflux overnight under an atmosphere of dry nitrogen. The reaction mixture is cooled to 0C and a solution of concentrated hydrochloric acid (22 mL) in water (40 mL) is added slowly. The resulting solid is filtered off and dried under vacuum to give 1-(4-chlorobenzyl)-2,2-dimethyl-propyl-ideneamine hydrochloride. 4-bromochloroben2ene in 850 mL of dry toluene. The mixture is heated to a temperature at 95-100°C using a heating mantle temperature set at about 95-125°C over a period of filtered over a pad of 70 g of Celite and the pad was washed with 300 mL of toluene. Filtrates are combined and concentrated under vacuum (30-80 torr) at an internal temperature at 25-40°C (maximum jacket temperature 50°C) to collect about 800 g or 925 mL of solvent to afford 275 g of crude 2-(4°Chlorophenyl)-1-(dimethylamino)-4,4-dimethyl-1-pentene-3-one (Theoretical yield: 173.6 g). This crude product is dissolved in 440 mL (380 g) of toluene and the removal of excess N,N,-dimethylformamide dimethyl acetal is confirmed by 1H NMR. The solution can be held at 21-23°C under nitrogen and then used in the next step. pyrido[2,3-.d.]-pyrimidin-4-one. A 12 L, 4-necked, round-bottomed flask, equipped with a mechanical stin-er, digital themiometer, reflux condenser, nitrogen inlet-outlet, and addition funnel is charged with the 148 g of crude 7-.tert.-butyl-6-(4-chlorophenyl)-2-thioxo-2.3-dihydro-1.H.-pyrido[2,3-.d.]"pyrimidin-4-one from the preceding step and 5.18 L of ethyl alcohol, 200 proof. The suspension is heated to an intemal temperature at 76-80**C (reflux condition, external temperature 85-100°C) over 1 hour and stirred at this temperature for 2 hours to get a clear solution. The mixture is cooled to 70-75°C over 20 minutes and line-filtered by pressure and saved. The solution is added into a 12 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital themiometer, reflux condenser, nitrogen inlet-outlet, and addition funnel, and heated to 76-80°C (reflux condition) over 30 minutes 3.11 L of water is added (ratio of ethanol: water 1.0:0.6 v/v) over a period of 1.5 In the following examples compounds of formula I wherein R^ and R^ together are -NH-C(S)-NH-C(0)- and R^ is hydrogen are prepared analogously to the above Examples and exhibit the following characterizing data: Claims: 2. A compound of formula I substituted by C(0)0Ci-C4alkyl; or phenyl substituted by C1-C4alkyl; R12 is hydrogen, 7. A compound of claim 1 in free base or pharmaceutically acceptable acid addition salt form, for use as a pharnaceutical. 8. A compound of claim 1 in free base or phamiaceutically acceptable acid addition salt form, for use in the treatment or prevention of a disease or condition in which vanllloid receptor activation plays a role or is implicated. 9. A pharmaceutical composition comprising a compound of claim 1 in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. iii) reacting the intermediate 2-(4-chlorophenyl)-1-(dimethylamino)-4,4-dimethyM -penten-3-one with 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate in toluene and acetic acid at 70°C for 15 hours, then at 100°C tor 2 hours; and purifying and recovering the obtained compound, in free base or in acid addition salt form. 15. A compound substantially as herein described and exemplified. 16. A pharmaceutical composition substantially as herein described and exemplified.

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