Title of Invention	A PROCESS FOR PREPARING A COMPOUND, 4-[PHENYL-(PIPERIDIN-4-YL)-AMINO] BENZAMIDE DERIVATIVE
Abstract	ABSTRACT A PROCESS FOR PREPARING A COMPOUND 4-[PHENYL-fPIPERIDIN-4-YL-AM1NQ)BENZAMIDE DERIVATIVE A process for preparing a compound 4-[Phenyl-(piperidin-4-yl-amino)benzamide derivative of formula I, comprising reacting a compound of the general formula \ N i PG wherein PG is a urethane protecting group, such as Boc and CBZ, or benzyl or substituted benzyl protecting group, such as 2,4 dimethoxybenzyl, with N,N-diethyl-4-bromobenzamide, using a palladium catalyst, such as Pd2(dba)3, in the presence of a base, e.g. sodium tert-butoxide, to give the compounds of general formula III, PG III which is thereafter deprotected, under standard conditions and alkylated under reductive conditions with a compound of the general formula Rl-CHO to give compounds of the general formula I, wherein R1 is selected from anyone of phenyl, pyridinyl, thienyl, furanyl, imidazolyl, triazolyl, pyrrolyl, thiazolyl and pyridyl-N-oxide; wherein each R1 phenyl ring and R1 heteroaromatic ring may independently be further substituted by 1, 2 or 3 substituents independently selected from straight and branched CI-C6 alkyl, N02, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo, as well as salts thereof.

Title of Invention

A PROCESS FOR PREPARING A COMPOUND, 4-[PHENYL-(PIPERIDIN-4-YL)-AMINO] BENZAMIDE DERIVATIVE

Abstract

ABSTRACT A PROCESS FOR PREPARING A COMPOUND 4-[PHENYL-fPIPERIDIN-4-YL-AM1NQ)BENZAMIDE DERIVATIVE A process for preparing a compound 4-[Phenyl-(piperidin-4-yl-amino)benzamide derivative of formula I, comprising reacting a compound of the general formula \ N i PG wherein PG is a urethane protecting group, such as Boc and CBZ, or benzyl or substituted benzyl protecting group, such as 2,4 dimethoxybenzyl, with N,N-diethyl-4-bromobenzamide, using a palladium catalyst, such as Pd2(dba)3, in the presence of a base, e.g. sodium tert-butoxide, to give the compounds of general formula III, PG III which is thereafter deprotected, under standard conditions and alkylated under reductive conditions with a compound of the general formula Rl-CHO to give compounds of the general formula I, wherein R1 is selected from anyone of phenyl, pyridinyl, thienyl, furanyl, imidazolyl, triazolyl, pyrrolyl, thiazolyl and pyridyl-N-oxide; wherein each R1 phenyl ring and R1 heteroaromatic ring may independently be further substituted by 1, 2 or 3 substituents independently selected from straight and branched CI-C6 alkyl, N02, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo, as well as salts thereof.

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; rule 13] A PROCESS FOR PREPARING A CONPOUND OF FORMULA (1) A PROCESS FOR PREPARING A COMPOUND 4-[PHENIL -(PIPERDIN -4 -YL) -AMINO)] BENZAMIDE DERIVATIVE. / AstraZeneca AB, a Swedish company of S-l5l 85 SoSertalje, Sweden, The following specification particularly describes the nature of the invention and the manner in which it is to be performed :- The present invention relates to a process for preparing a compound 4-[Phenyl-(piperidin-4-yl-amino)benzamide derivative. Field of the Invention The present invention is directed to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain, anxiety and functional gastrointestinal disorders. Background of the Invention .The 6 receptor has been identified as having a role in many bodily functions such as circulatory andpain systems. Ligands for the 5 receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the 5 receptor have also been shown to possess immunomodulatory activities. The identification of at least three different populations of opioid receptors (p., 8 and K) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated. With few exceptions, currently available selective opioid 8 ligands are peptidic in nature and are unsuitable for administration by systemic routes. One example of a non-peptidic 5-agonist is SNCSO (Bilaky E.J. et al., Journal of Pharmacology and Experimental Therapeutics, 273(1), pp. 359-366 (1995)). There is however still a need for selective S-agonists having not only improved selectivity, but also an improved side-effect profile. Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current u agonists, as well as having improved systemic efficacy. Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred 8agonist compounds, described within the prior art, show significant convulsive effects when administered systemically. We have now found certain compounds that exhibit surprisingly improved properties, i.a. improved 5-agonist potency, in vivo potency, pharmacokinetic, bioavailability, in vitro stability and/or lower toxicity. Outline of the Invention The novel compounds according to the present invention are defined by the formula I wherein R is selected from any one of (i) phenyl; -WO 02/0947S3 JCT/SE02/0U9.I5 (ix) pyridyl-N-oxide where each R1 phenyl ring and R heteroaromatic nng niay optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C1 -C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fiuoro, bromo, and iodo. The substitutions on the phenyl ring and on the heteroaromatic ring may ta-ke place in any position on said ring systems; When the R phenyl ring and the R heteroaromatic ring(s) are substituted, the preferred substituents are selected from anyone of CF3, methyl, iodo, bromo, fiuoro and chloro. A further embodiment of the present invention is a compound according to figure I wherein R is as defined above and each R phenyl ring and R1 heteroaromatic ring may independently be further substituted by a methyl group A further embodiment of the present invention is a compound according to figure I wherein R is phenyl, pyrrolyl, pyridinyl, thienyl or furanyl, optionally with 1 or 2 of the preferred substituents on the R phenyl or R heteroaromatic ring. Another embodiment of the present invention is a compound according to figure I wherein R is phenyl, pyrrolyl or pyridinyl, optionally with 1 or 2 of the preferred substituents on the R phenyl or R heteroaromatic ring. Another embodiment of the present invention is a compound according to figure I wherein R is thienyl or furanyl, optionally with 1 or 2 of the preferred substituents an the R heteroaromatic ring- Within the scope of the invention are also salts and enantiomers of the compounds of the formula I, including salts of enantiomers. Reaction step b in Scheme 1, vide infra, is performed by reacting an intermediate compound of the general formula II II wherein PG is a urethane protecting group, such as Boc and CBZ, or benzyl or substituted benzyl protecting group, such as 2,4-dimethoxybenzyl; withN,N--diethyl-4- bromobenzamide, using a palladium catalyst, e.g. tris(dibenzylideneacetone) dipalladium(0)-[Pd2(dba)3], in the presence of a base, e.g. tert-BuO'Na. and a phosphine Iigand such as bis-diphenylphosphanyl-dimethyl-9H-xanthene (xantphos), to give the compounds of general formula III, O which is thereafter 1) deprotected, under standard conditions, 2) hydrolyzed under basic conditions and 3) alkylated using either: 6- -WQ 02/0917-33 PCT/GE02/0U!)IJ— i) a compound of the general formula R'-CH2-X, wherein R is as defined above and X is a halogen, preferably bromine or chlorine and a suitable base, or ii) a compound of the general formula R!-CHO, wherein R1 is as defined above, and a suitable reducing agent, to give compounds of the general formula I. Suitable bases to be used in the standard alkyiation step i) above include, but are not .limited to, friethylamine and potassium carbonate, Suitable reducing agents to be used in the standard reduction step ii) include, but are not limited to, sodium cyanoborohydride and sodium triacetoxyborohydride. The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain,'acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical-needs, for collagen diseases, various allergies, for use as anti-tumour agents-and anti viral agents. Compounds of the invention are useful in disease states where degeneration or dysfunction of opioi d receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET). Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obesessive compulsive disorder; urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel WO 02/094783" PCT/SE02/0094S Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following myocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension. Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects Aeeded to maintain the anaesthetic state (eg. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids. Also within the scope of the invention is the use of any of the compounds according to the formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above. A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment. A further aspect of the present invention is intermediates of the general formula II and III,' PG PG wherein PG is a urethane protecting group, such as Boc and cbz or benzyl or substituted benzyl protecting group, such as 2,4-dimethoxybenzyl 8 WO 02/094793 A further embodiment of the present invention is intermediates of the Formula X wherein R is as described above in relation to Formula I. hi another alternative synthetic route, reaction step b in Scheme 2, vide infra, is performed by reacting an intermediate compound of the general formula IV H-N wherein PG is a urethane or benzyl-like protecting group, such as Boc, N,N-diethyl-4-bromobenzamide, using a palladium catalyst, e.g. tris(dibenzylideneacelone) dipalladium(O) [ Pd2(dba)3], in the presence of a base, e.g. tert-BuONa and a phosphine ligand such as bis-diphenylphosphanyl-dimethyl-9H-xanthene (xantphos), to give the compounds of general formula V, which is thereafter 1) deprotected, under standard conditions, 2) hydrolyzed under basic conditions and 3) alkylated using either: i) a compound of the general formula R1 -CH2-X, wherein R1 is as defined above and X is a halogen, preferably bromine or chlorine and a suitable base, or ii) a compound of the general formula R]-CHO, wherein R1 is as defined above, and a .suitable reducing agents to give compounds of the general formula I. This is followed by conversion of the ketal functionality to a primary amide under standard conditions via 1) hydrolysis of the ketal to the aldehyde (formula VI), followed by 2) oxidation of the aldehyde to the corresponding carboxylic acid (formula VII), followed by 3) amidation with ammonium chloride to the primary amide giving compounds of the general formula I. Suitable hydrolysis conditions to be used in the standard hydrolysis step (i) include, but are not limited to aqueous hydrochloric acid in tetrahydrofuran. Suitable conditions for the oxidation step (ii) include, but are not limited to stirring at 0°C in aqueous sodium dihydrogen phosphate and sodium chlorite in the presence of excess 2-methyl-2-butenc. Suitable conditions for the amidation step (iii) include but are not limited to treatment with excess ammonium chloride in the presence of a coupling agent such as benzotriazole-1-yloxy-trisphosphonium hexafluorophosphate (hereinafter Py-BOP). Methods of preparation EXAMPLES The invention will now be described in more detail by (he following Schemes and Examples, which are not to be construed as limiting the invention. Scheme 1: Synthesis of Intermediate Amine (compound 3) Used in Reductive Animations Method 1A (compound 1): 3-(l-Benzyl-piperidin-4-vlaminoV4-fluoro-benzonitrile. To a dry flask containing 3-bromo-4-fluoro benzonitrile (6.56g, leq) was added dry toluene (lOOmL), 4-amino-l-benzyl piperidine (1.2eq), racemic BINAP (612mg, 0.03eq) ' palladium acetate (220mg, 0.02eq) and sodium tert-butoxide (4.4g, 1.4eq). The reaction was heated to 80°C under and inert atmosphere for 20 hours . The reaction was cooled, diluted with ethyl acetate (2Q0mL) and washed with water (lOOmL). The combined organics were dried (MgSO4), filtered and concentrated. Purification by flash chromatography, eluting 3% methanol in dichloromethane yielded amine (1) as a yellow solid (6.655g, 66%). Method IB (compound 2): r(l-Benzy3-piperidin-4-yl)-(5-cyano-2-fluoro-phenyl)-aminol-N. N-diethyl -benzamide. To a solution of amine (1) (3,50g, leq.) in dry toluene (50mL) was added aryl bromide (4.35g, 1.5eq), xantphos (393mg, 0.06eq), Pd2(dba)3 (331mg, 0.03eq) and sodium tert-butoxide (1.52g, 1.4eq). The reaction was heated to reflux for 14 hours then was cooled and diluted with ethyl acetate (lOOmL). The solution was washed with water (lOOmL) then the organics were dried (MgSO4), filtered and concentrated. Purification by flash chromatography, eluting 65% ethyl acetate 35% hexanes, rising to 70% ethyl acetate 30% hexanes yielded amine (2) as an orange oil (3.568g, 65% yield). Method IC (compound 3): [(5-Cvano-2-fluoro-phenvl)-niperidin-4-yl-aminol- N ,N--diethvl-benzamide. To a solution of amine (2) (3.564g, leq) in 1,2-dichloroethane (65mL) at 0°C was added 1 -chloroethyl chloroformate (920µL, 1.15eq). After 1 hour at 0°C the reaction was warmed to room temperature then was heated to 70°C for 90 minutes. The reaction was then cooled and concentrated. The residue was dissolved in methanol (60niL) then heated to 700C for 1 hour. The solution was then cooled and concentrated. Purification by flash chromatography, eluting 10% methanol in dichloromethane, rising to 40% methanol in dichloromethane gave amine as a yellow foam (2.786g, 96%). - Scherae 2: Alternative synthesis Via Intermediate 7 Intermediate 4: (1-Benzyl-piperidin:_4-yl')-(1,3dioxolan-2-vl-2-fluoro-phenyl)-amine. To a dry flask containing 2-(3-bromo-4-fhioropheny])-l ,3-dioxaolane (1 .Deo) and amine, (1.2eq) in dry toluene is added BINAP (0.03eq), palladium acetate (0.02eq) and sodium tert-butoxide (1.4eq). The reaction is heated to 80°C under nitrogen. After about 24 hours the solution is cooled, diluted with ethyl acetate and washed with one portion water. The organics are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography, eluting with a methanol in dichloromethane gradient. Intermediate 5: [(1-Benzyl-piperidin-4-yl-(5-[1,3]dioxolan-2-yl-2-fluoro-phenvlVaminol-N,N-diethyl-benzamide. To a dry flask containing amine 4 in dry toluene (about 6mL per millimole of 4) is added aryl bromide (1.4eq), xantphos (0.06eq), Pd2(dba)3 (0.03eq) and sodium ferr-butoxide (1.4eq). The reaction is heated to 110°C under nitrogen. After about 24 hours the solution is cooled, diluted with ethyl acetate and washed with one portion water. The organics are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography, during with a methanol in dichloromethane gradient. Intermediate 6: [(-Benzvl-piperidin-4-yl)-(2-fluoro-5-formvl-phenvl)-amino1 N,N-diethyl-benzamide. To a solution of acetal 5 in tetrahydrofuran is added 2N HC1 solution (2,0eq). After 16 hours at room temperature, dichlororaetliane is added and the aqueous layer is neutralized with aqueous saturated sodium bicarbonate solution. The organic layer is removed and the aqueous layer extracted with two portions of dichloromethane. The combined organic extracts are dried (MgS04), filtered and concentrated and the residue is purified by flash chromatography, eluting with an ethyl acetate in hexanes gradient. Intermediate 7: [(1--Benzvl-piperidin-4-yl')-(4-diethvlcarbamoyl-phenvl')-amino]-4-fluoro-benzoic acid. To a solution of aldehyde 6 (l.Oeq) in tert-butanol is added 2-methyl-2-butene (lO.Oeq) and tire solution is cooled to 0UC. A solution of sodium dihydrogen phosphate (9eq) and sodium chlorite (9eq) 'in water is added and the reaction is stirred for 30 minutes at 0°C. The rerr-butanol is removed and the reaction mixture is extracted with dichloromethane. The combined organic extracts are dried (MgS04), filtered and concentrated and the residue is purified by flash chromatography, eluting with a methanol/dichloromethane gradient. Example 1: [(l-Benzvl-piperidin-4-yl)-(4-dicthylcarbamoyl-phenvlVaminol-4-fluoro-benzamide (alternative synthesis). 14 To a solution of acid 7 (1 .Oeq) in DMF is added pyBOP (1.5eq); HOBt (1.5eq), diisopropylethylamine (4.Oeq) and ammonium chloride (2eq). After 16-24 hours at room temperature the reaction is concentrated. The residue is dissolved in ethyl acetate and is washed with two portions of water and one portion of saturated sodium bicarbonate solution. The organic layer is dried (MgSO4), filtered and concentrated and the residue is purified by flash chromatography, eluting with a methanol in dichloromethane gradient. Additional examples were synthesized via the general procedures described below. A. Reductive amination of intermediate 3: NaBH(OAc)3, THF or 1,2-dichloroethane R1-CHO (aldehyde) Room temp. O To a solution of the amine, 3, in dry tetrahydrofurari (THF) or 1,2-dichloroethane is added the aldehyde (1-1.5 eq.), followed by sodium triacetoxyborohydride (1-1.6 eq.). The . reaction is stirred at room temperature under a nitrogen atmosphere for an extended period of time (6-48 hours) to ensure complete reaction. The reaction mixture is then subjected to a standard work-up procedure and a standard purification. The amount of THF or 1,2-dichloroethane is not crucial. An amount corresponding to about lmL/30 mg is preferred. Procedure 2A in the synthesis of Example 2 below is typical. B. Hydrolysis of the intermediate cyano compound: 15 CN KOH, tert-BuOH reflux 'N' o To a solution of the cyano intermediate in tert-butanol, is added ground potassium hydroxide (KOH) (2.5 eq.) and the resulting mixture is heated to reflux for about two hours. The mixture was then cooled to room temperature and subjected to a standard work-up procedure and a standard purification. The amount of tert-butanol is not crucial. An amount corresponding to about lmL/30 mg is preferred. Procedure 2B in the synthesis of Example 2 below is typical. Example 2: [(4-DiethylcarbamoyI-phenyl)-(l-pyridin-2-ylmethyl-piperidin-4-yl)-amino]-4-fluoro-benzamide. NaBH(OAc)3, THF 70% 2A: [(5-Cvano-2-fluoro-phenvl)-fl-pyridin-2-ylmethvl-rjiperidin-4-yI)-aminol]N,N- diethyl-benzamide. To a solution of amine (370mg) in dry tetrahydrofuran (lOmL) was added pyridine-2- carboxaldehyde (116µL; I.3eq) and sodium triacetoxyborohydride (279mg; 1.4eq). The reaction was stirred at room temperature under nitrogen. After 24 hours the reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The — aqueous was extracted with two portions dichloromethane and the combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting 4% methanol in dichloromethane. A colorless foam was obtained (317.5mg; 70% yield). 2B;([4-Diemvlcarbamovl-phgnyl)-(1-Pyridin-2-y'lmethyl--piperidin--4--yl')-aminol-4-fluoro-benzamide. To a solution of nitrile (3l7mg) in tert-butanol (lOmL) was added ground potassium hydroxide (92mg; 2.5eq) and the reaction was heated to reflux. After 90 minutes the solution was cooled, diluted with dichloromethane and washed with one portion water. The organics. was removed and the aqueous neutralized with 2M hydrochloric acid and extracted with two portions dichloromethane. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 5% methanol in dichloromethane, rising to 7% methanol in dichloromethane. A colorless foam was obtained (164.0mg; 50% yield). The foam was dissolved in ether (8mL) containing some dichloromethane and IN HCl/ether (l.OmL; = 3.0eq) was added After 1 hour the solution was concentrated and the solid dried under high vacuum. Additional Examples are prepared analogously. Analytical data for synthetic Examples is shown in Table 1, on the following pages, -17- Table 1: Analyical data for ExampI ss. EX R NAME NMRdata(400MHZ CD3OD) i \| vj 4-yl)-(4-diethYl- ; 2.31 (d, J=14Hz, 2H, CH2); 3,25-3.55 (m, carbarnoyl-phenyl)- aminoj-fluoro- benzamide 8H, NCH2); 4.31 (s, 2H, NCH2Ar); 4.42-4.4 2 [ (4-D ie thylc arb amo yl-phenyl)-(l -pyridin-2-ylmethyl-piperidin-4-yl)- amino] -fluoro-benzamide 1.17 (brs, 6H, CH3); 1.81-1.85 (m, 2H, CH2) ; 2.31 (d, J=14Hz, 2H, CH2); 3.36-3.42 (m, 6H, NCH2); 3.63 (d, J=12Hz, 2H, NCH2); 4.48-152 (m, 3H, NCH2 and NCH) ; 6.70 (d, J=8:5Hz, 2H, Ar-H) ; 7.26 (d, >8.5Hz, 2H, Ar-H); 7.41 (t, J=8.5Hz, 1H, Ai-H) ; 7.51-7.54 (m, 1H, Ar-H); 7.60 (d, J=7.5Hz, 1H, Ar-H); 7.84-7.86 (m, 1H, Ar-H); 7.98-8.01 (m, 2H, Ar-H); 8.68 (d, J=6.5Hz, 1H, Ar-H). 3 [(4- D i ethylc arbamoyl-phenyl)-( 1 -thiophen-3-ylmethyl-p ip eridin-4-y])-arnino]-fluoro-benzamide 1.16 (brs, 6H, CH3); 1.63-1.74 (m, 2H, CH2) ; 2.31 (d, J=14Hz, 2H, CH2); 3.19-3.25 (m, 2H, NCH2); 3.40 (br s, 4H, NCH2); 3.52 (d, J=l3Hz, 2H, NCH2); 4.31 (s, 2H, NCH2Ar); 4.36-4.45 (m, 1H, NCH), 6.67 (d, J=9.5Hz, 2H, Ar-H) ; 7.18-7.27 (in, 3H, Ar-H); 7.38 (t, J=9Hz, 1H, Ar-H); 7.54-7.56 (m, 1H, Ar-H); 7.65-7.66 (m, 1H, Ar-H) ; 7.81 (dd, J=2, 7.5Hz, 1H, Ar-H); 7.97-8.01 (m, 1H, Ar-H). 4 [(4-D i ethyl c arbamoy] -phenyl)-(l -niran-3-ylme thyl -pip eridin-4-J jy))-2minc>) -AUDIO- , benzamide 1.16 (brs, 6H, CH3); 1.57-1.67 (m, 2H, CH2) ; 2.32 (d, J=l4Hz, 2H, CH2); 3.17-3.23 (m, 2H, NCH2) ; 3.42 (br s, 4H, NCH2); 3.56 (d, J=12Hz, 2H, NCH2); 4.1S (s, 2H, NCH2Ar) ; 4.39-4.4$(m, IK, NCK) ; 6\56(^ (K, Ai-ffj; 6.67 (d, J=9.5Hz, 2H, Ar-H); 7.23-7.27 (m, 2H, Ar-H); 7.39 (t, J=9.5Hz, 1H, Ar-H) ; 7.61 (t, J-2Hz, 1H, Ar-H); 7.74 (s, 1H, Ar-H); 7.81 (dd, J=2.5, 7.5Hz, 1H, Ar-H); 7.97-8.01 (m, 1H, Ar-H) 5 [(4-Diethykarbamoyl-phenyl)-(l -thiophen-2-ylmethyl-piperidin-4-yl)-arnmo]-fluoro-benzamide 1.16 (brs, 6H, CH3); 1.63-1.74 (m,2H, CH2) ; 2.33 (d, J=14Hz, 2H, CH2); 3.24 (t, J=l 1Hz, 2H, NCH2); 3.40 (br s, 4H, ^cm); 3.57 (d, J=12Hz, 2H, NCH2); 4.39-4.45 (m, 1H, NCH) ; 4.54 (s, 2H, NCH2Ar); 6.67 (d, J-9.5Hz, 2H, Ar-H) ; 7.11-7.13 (m, 1H, Ar-H); 7.22-7.26 (m, 2H, Ar-H), 7.31 (d, J-3.5H2, 1H, Ar-H); 7.39 (t, J=9.5Hz, 1H, Ar-H); 7.61 (d, J=6.5Hz, 1H, Ar-H); 7.80-7.82 (m, 1H, Ar-H) ; 7.97-8.0! (m, 1H, Ar-H). WO 02/00 1703- PCT/SE02/00!M5 A$r Tab \|.Eac.;# lei (c ontinued): Analytical data for synthe 'R. ' [■ Name ■ :"■ tic Examples. . NMR'data(4G0MHz, GD3OD) ■ 1 6 1 1 [[l-(Z,4-Dichi0TQ- benzyl)-piperidin-4-yl] - (4- diethylcarbam -oyl-phenyl) -amino] -fluoro-benzamide J I. 16 (brs, 6Rt CHi); 1.6?-1.77 fa, ZH, CH2) ) ; 2.31 (d, J=14Hz, 2H, CH2); 3.30-3.50 (m, 6H, NCH2); 3.59 (d, J=12Hz, 2H, NCH2); 4.42-4.48 (m, 3H, NCH and NCH2Ar) ; 6.67 (d, J=9.5Hz, 2H, Ar-H); 7.23 (d, J=8.5Hz, 2H, Ar-H); 7.38 (t, J=9.5Hz, 1H, Ar-H); 7.45-7.48 (ra, 1H, Ar-H) ; 7.59 (d, J=8.5Hz, 1H, Ar-H) ; 7.66 (d, J=2Hz, 1H, Ar-H); 7.80 (J=2, 7.5Hz, 1H, Ar-H); 7.96-8.00 (m, 1H, Ar-H). 7 [(4-D iethylcarb amo yl-phenyl)-(l-thiazoI-2-ylmethyl-piperidin-4-yl)-amino]"fluoro- benzamide 1.16 (br s, 6H, CH3); 1.77-1.82 (m, 2H; CH2) ; 2.33 (d, J=I4Hz, 2H, CH2); 3.40-3.53 (m, 6H, NCH2); 3.71 (d, J=l 1Hz, 2H, NCH2); 4.48-4.53 (ra, 1H, NCH); 4.73 (s, 2H, NCH2Ar); 6.73 (d, J=8.5Hz, 2H, Ar-H); 7.30 (d, J=8.5Hz, 2H, Ar-H); 7.39-7.43 (m, 1H, Ar-H); 7.77 (d, J-3Hz, 1H, Ar-H); 7.84 (d, J=5.5Hz, 1H, Ar-H) ; 7.93 (d, J=3Hz, 1H, Ar-H); 8.00-8.04 (m, 1H, Ar-H). 8 [[l-(4-Bromo-benzyl)-piperidin-4-yl]-(4-d iethylcarb amoyl-phenyl)-amino]-fluoro-benz amide 1.16 (brs, 6H, CH3); 1.64-1.75 (m, 2H3 CH2) ; 2.30 (d, J=14Hz, 2H, CH2) ; 3.22-3.28 (m, 2H, NCH2); 3.42-3.53 (m, 6H,NCH2); 4.27 (s, 2H,NCH2Ar) ; 4.38-4.46 (m, 1H, NCH); 6.67 (d, J=8.5Hz, 2H, Ar-H) ; 7.24 (d, J=8.5Hz, 2H, Ar-H) ; 7.36-7.41 (m, 3H, Ar-H); 7.63 (d, J=8.5Hz, 2H, Ar-H); 7.80 (dd, J=2, 7.5 Hz, 1H, Ar-H); 7.97-8.00 (ra, 1H, Ar-H). 9 [(4-Diethylcarbamoyl-phenyl)-(l-furan-2-ylmethyl-piperidin-4-yl)-amino]-fluoro-benzamide 1.16 (brs, 6H, CH3); 1.63-1.73 (ra, 2H, CH2) ; 2.32 (d, J=14Hz, 2H, CH2) ; 3.22-3.48 (m, 6H, NCH2j ;3.S3 (6, /=X Jflz, 2H, HCK2); 4.37 (s, 2H, NCH2Ar); 4.39-4.44 (m, 1H, NCH); 6.50-6.52 fa 1H, Ar-H); 6.65-6.10 (m, 3H, Ar-H); 7.21 (d, J=3Hz, 2H, Ar-H) ; 7.39 (t, J=9.5Bz, M, Ar-H) ; 7.65 (s, 111, Ar-H); 7.81 (dd, J=2, 7.5Hz, 1H, Ar-H) ; 7.90-8.01 (m, lH.Ar-H). 10 [(4-Diethylcarbamoyl- phenyl)-(l-pyridin-4-ylmethyl-piperidin-4-yl)-amino]-fluoro-benz amide 1.16 (brs, 6H, CH3); 1.85-1.94 (m, 2H, CH2) ; 2.31 (d, >13Hz, 2H, CH2); 3.30-3.48 fa 6H, NCH2); 3.60 (d, J=l 1Hz, 2H, NCH2); 4.45-4.51 (ra, 1H, NCH) ; 4.68 (s, 2H, NCH2Ar); 6.69 (d, J=8.5Hz, 2H, Ar-H); 7.24 (d, J=9.5Hz, 2H, Ar-H) ; 7.38 (t, J=9.5Hz, 1H, Ar-H); 7.82 (d, J=6.5Hz, 1H, Ar-H); 7.97-8.01 (m, 1H, Ar-H) ; 8.32 (d, J-7.5Hz, 2H, Ar-H"); 8.98 (d, J-6.5Hz, 2H, Ar-H). -n- Table ] (continued); Analytical data for synthetic Examples. Ex.# Name. ,. NMRdata(400MHz, CD3OD) 11 [[l-(4-Chloro- benzyl)-piperidin-4- yl]-(4-diethyl- carbamoyl-phenyl)- amino] -fluoro- benzamide 1.14 (br s, 6H, CH3); 1.62-1.73 (m, 2H, CH2); 2.28 (d, J-15HZ, 2H, CH2); 3.23 (t, J=13Hz, 2H, NCH2); 3.39 (br s, 4H, NCH2) ; 3.50 (d, J=13Hz, 2H, NCH2); 4.26 (s, 2H, NCH2AJ) ; 4.36-4.44 (m, 1H, NCH); 6.64 (d, J=8.5Hz, 2H; Ar-H); 7.20 (d, J=9.5Hz, 2H, Ar-H); 7.36 (t, J=9.5Hz, 1H, Ar-H) ; 7.42-7.47 (m, 4H, Ar¬H) ; 7.78 (dd, J=2, 7.5Hz, 1H, Ar-H) ; 7.94-7.98'(m, lH,Ar-H). 12 [(4- Diethylcarbarnoyl- phenyl)-(l-pyridin-3- ylmethyl-piperidin-4- yl)-amino]-fluoro- benzamide 1.15 (br s, 6H, CH3) ; 1.80 (q, J=-12Hz, 2H, CH2) ; 2.29 (d, J=14Hz, 2H, CH2) ; 3.35-3.47 (m, 6H, NCH2); 3.60 (d, J=12Hz, 2H, NCH2); 4.42-4.49 (m, 1H, NCH) ; 4.60 (s, 2H, NCH2Ar) ; 6.66 (d, J=8.5Hz, 2H, Ar-H) ; 7.22 (d, J=8.5Hz, 2H, Ar-H); 7.35 (t, J=9.5Hz, 1H, Ar-H) ; 7:79 (d, J=6.5Hz, 1H, Ar-H) ; 7.94-7.9S (in, 1H, Ar-H) ; 8.11-8.15 (m, 1H, Ar-H) ; 8.78 (d, J=8.5Hz, 1H, Ar-H); 8.94 (d, J=5.5Hz, 1H, Ar-H); 9.14(8, 1H, Ar-H). 13 {(4- . Diethylcarb amoyl- phenyl)-[l-(3H- imidazoI-4- ylmethyl)-pip eridin- 4-yl] -amino} -fluoro- benzamide 1.14 (br s, 6H, CH3); 1.79-1.85 (m, 2H, CH2); 2.31 (d, J=14Hz, 2H, CH2); 3.32-3.46 (m, 6H, NCH2); 3.60 (d, J=llHz, 2H,NCH2); 4.41-4.47 (m, 1H, NCH); 4.50 (s, 2H, NCH2Ar); 6.67 (d, J=9.5Hz, 2H, Ar-H); 7.22 (d, J=8.5Hz, 2H, Ar-H); 7.36 (t, J=9.5Hz; 1H, Ar-H) ; 7.80 (d, J=5.5Hz, 1H, Ar-H); 7.86 (s, 1H, Ar-H) ; 7.95-7.99 (m, 1H, Ax-H); 9.05 (d, J-2Hz, 1H, Ar-H). 14 {(4- Di ethyl carbamo yl- phenyl)-[l-(lH- imidazol-2- ylmethyl)-piperidin- 4-yl]-amino}-fluoro- 1.14 (br s, 6H, CH3); 1.79-1.85 (m, 2H, Cll2); 2.31 (d, J=14Hz, 2H, CH2); 3.32-3.46 (m, 6H, NCH2); 3.60 (d, J=l 1Hz, 2H, NCH2) ; 4.41-4.47 (m, 1H, NCH); 4.50 (s, 2H3 NCH2Ar); 6.67 (d, J-9.5Hz, 2H, Ar-H); 7.22 (d, J-8.5Hz, 2H, Ar-H); 7.36 (t, J=9.5Hz, 1H, Ar-H) ; 7.80 (d, J=5.5Hz, 1H, Ar-H); 7.86 (s, 1H, Ar-H); 7.95-7.99 (m, 1H, Ar-H) ; 9.05 (d, J=2Hz, 1H, Ar-H). 15 {(4- D iethyl c arb am oyl- phenylMHlH- . pyrrol-2-ylmethy^-piperidin^-yl]-amino}-fluoro-benz amide 1.13 (brs3 6H, CH3); 1.58-1.69 (m,2H,'CH2); 2.29 (d, J=13Hz, 2H, CH2); 3.10 (d, J=llHz, 1B, NCH); 3.14 (d, J=llHz, 1H, NCH); 3.38 (br s, 4H, NCH2); 3.47 (d, J=13Hz, 2H, NCH2) ; 4.21 (s, 2H, NCH2A,) ; 4.31-4.39 (m31H, NCH); 6.12 (ID, 1H, Ar-H) ; 6.29 (s, IE, Ar-H); 6.63 (d, J=8.5Hz, 2H, Ar-H); 6.83-6.84 (in, 1H, Ar-H); 7.20 (d, J=9Hz, 2H, Ar-H); 7.35 (t, J=9.5Hz, 1H, Ar-H) ; 7.77-7.79 (m, 1H, Ar-H) ; 7.94-7.98 (m, 1H, Ar-H); 10.60 (br s, 1H, NH) --J2C- Pharmaceutical compositions The novel compounds according to the present invention may be administered orally, sublingually^intrarnuscularly, subcutaneously, topically, intranasally, mtraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. A preferred route of administration is orally, intravenously or intramuscularly. The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen' and dosage level as the most appropriate for a particular patient. For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-me]ting wax, cocoa butter, and the like. Salts include, but are not limited to, pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts within the scope of the present invention include; acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate,' camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fhmarate, glucaptate, gluconate, glutamate, giycollylars anil ate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, isethionate, lactate, Iactobionate, malate, maleate, mandelate, mesylate, methylbromide, methyinitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, and benzathine. Examples of pharmaceutically unacceptable salts within the scope of the present invention include: hydroiodide, perchlorate, tetrafluoroborate. Pharmaceutically unacceptable salts could be of use because of their advantageous physical and/or chemical properties, such as crystallimty. Preferred pharmaceutically acceptable salts are hydrochlorides, sulfates and bitartrates. The hydrochloride and sulfate salts are particularly preferred. The term composition is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included. , Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Liquid from compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. Preferably the pharmaceutical compositions is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms. BIOLOGICAL EVALUATION In vitro model Cell culture A. Human 293S cells expressing cloned human \i, 8, and K receptors and neomycin resistance were grown in suspension at 37°C and 5% CO2 in shaker flasks containing -23- calcium-free DMEM10% FBS, 5% BCSS 0.1% Pluronic F-68, and 600 pg/ml geneticin. B. B. Mouse and rat brains were weighed and rinsed in ice-cold PBS (containing 2.5mM EDTA, pH 7.4). The brains were homogenized with a polytron for 15 sec (mouse) or 30 sec (rat) in ice-cold lysis buffer (50mM Tris, pH 7.0, 2.5mM EDTA, with phenylmethylsulfony] fluoride added just prior use to 0.5MmM from a 0.5M stock in DMSO:ethanol). Membrane preparation Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0,2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 M stock in ethanol), incubated on ice for 15 min, then homogenized with a polytron for 30 sec. The suspension was spun at lOOOg (max) for 10 min at 4°C. The supernatant was saved on ice and the pellets resuspended and spun as before. The supematants from both spins were combined and spun at 46,000 g(max) for 30 min. The pellets were resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) and spun again. The final pellets were resuspended in membrane buffer ( 50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dry ice/ethanol and stored at -70°C until use. The protein concentrations were determined by a modified Lowry assay with SDS. Binding assays Membranes were thawed at 37°C, cooled on ice, passed 3 times through a 25-gauge needle, and diluted into binding buffer (50 mM Tris, 3 mM MgCl2,1 mg/ml BSA (Sigma A-7888), pH 7.4, which was stored at 4°C after filtration through a 0.22 m filter, and to which had been freshly added 5 pg/ml aprotinin, 10 uM bestatin, 10 uM diprotin A, no DTT). Aliquots of 100 pi were added to iced 12x75 mm polypropylene tubes containing 100 pi of the appropriate radioligand and 100 pi of test compound at various concentrations. Total (TB) and nonspecific (NS) binding were determined in the absence and presence of 10 uM naloxone respectively. The tubes were vortexed and incubated at 25°C for 60-75 min, after which time the contents are rapidly vacuum-filtered and washed with about 12 ml/tube iced wash buffer (50 mM Tris, pH 7.0, 3 rr M MgCI2) through GF/B filters (Whatman) presoaked for at least 2h in 0.1 % polyethyleneimine. The radioactivity (dpm) retained on the filters was measured with a beta counter after soaking the filters for at least ]2h in minivials containing 6-7 ml scintillation fluid. If the assay is set up in 96-place deep well plates, the filtration is over 96-place PEI-soaked unifilters, which were washed with 3 x 1 ml wash buffer, and dried in an oven at 55°C for 2h. The filter plates were counted in a TopCount (Packard) after adding 50 µ l MS-20 scintillation fluid/well. Functional Assays The agonist activity of the compounds is measured by determining the degree to which the compounds receptor complex activates the binding of GTP to G-proteins to which the receptors are coupled. In the GTP binding assay, GTP[y]35S is combined with test compounds and membranes from HEK-293S cells expressing the cloned human opioid receptors or from homogenised rat and mouse brain. Agonists stimulate GTP[y] S binding in these membranes. The EC50 and Ema)t values of compounds are determined from dose-response curves. Right shifts of the dose response curve by the delta antagonist naltrmdole are performed to verify that agonist activity is mediated through delta receptors. Procedure for rat brain GTP Rat brain membranes are thawed at 37°C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPyS binding (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl2, pH 7.4, Add fresh: 1 mM DTT, 0.1% BSA). 120nM GDP final is added membranes dilutions. The EC50 and Emax of compounds are evaluated from 10-point dose-response curves done in 300ul with the appropriate amount of membrane protein (20ug/well) and 100000-130000 dpm of GTPy^S per well (0.11 -0.14nM). The basal and maximal stimulated binding are determined in absence and presence of 3uM SNC-80 Data analysis The specific binding (SB) was calculated as TB-NS, and the SB in the presence of various test compounds was expressed as percentage of control SB. Values of IC50 and Hill coefficient (nH) for ligands in displacing specifically bound radioligand were calculated from logit plots or curve fitting programs such as Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit. Values of Kj were calculated from the Cheng-Prussoff equation. Mean ± S.E.M. values of IC50, Kj and nH were reported for ligands tested in at least three displacement curves. Biological activity of the compounds of the present invention is indicated in Table 2. Table 2: Biological data. Ex. HDELTA (nM) ■ RAT BRAIN (nM) MOUSE BRArN (UM) IC50 EC50 %EMax EC5o %EMax EC50 %EMax 1-15 0.247-5.405 0.115-338.89 84.69-110.25 0.563-73.672 100.1-176.86 0.807-48.164 93.36-163.19 Receptor saturation experiments Radioligand K8 values were determined by performing the binding assays on cell membranes with the appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated Kg (up to 10 times if amounts of radioligand required are feasible). The specific radioligand binding was expressed as pmole/mg membrane protein. Values of Kg and Bmax from individual experiments were obtained from nonlinear firs of specifically bound (B) vs. nM free (F) radioligand from individual according to a one-site model. Acetic acid ("AcOH): 120 µ L of Acetic.Acid is added to 19.88 ml of distilled water in order to obtain a final volume of 20 ml with a final concentration of 0.6% AcOH. The solution is then mixed (vortex) and ready for injection. Compound ("drug): Each compound is prepared and dissolved in the most suitable vehicle according to standard procedures. (ii) Solutions administration The compound (drug) is administered orally, intraperitoneally (i.p.), subcutaneously (s.c.) or intravenously (i.v.)) at 10 ml/kg (considering the average mice body weight) 20, 30 or 40 minutes (according to the class of compound and its characteristics) prior to testing. When the compound is delivered centrally: Intraventricularly (i.c.v.) or intrathecally (i.t.) a volume of 5 µ L is administered. The AcOH is administered intraperitoneally (i.p.) in two sites at 10 ml/kg (considering the average mice body weight) immediately prior to testing. (iii) Testing The animal (mouse) is observed for a period of 20 minutes and the number of occasions (Writhing reflex) noted and compiled at the end of the experiment. Mice are kept in individual "shoe box" cages with contact bedding. A total of 4 mice are usually observed at the same time: one control and three doses of drug. For the anxiety and anxiety-like indications, efficacy has been established in the geller-seifter conflict test in the rat. For the functional gastrointestina disorder indication, efficacy can be established in the assay described by Coutinho SV et al, in American Journal of Physiology -Gastrointestinal & Liver Physiology. 282(2):G307-16, 2002 Feb, in the rat. WE CLAIM: 1. A process for preparing a compound^ 4-[Phenyl-(piperidin-4-yl)~ comprising reacting a compound of the general formula II aminofbenzamide derivative.of.formula I, wherein PG is a urethane protecting group, such as Boc and CBZ, or benzyl or substituted benzyl protecting group, such as 2,4 dimethoxybenzyl, with N,N-diethyl-4-bromobenzamide, using a palladium catalyst, such as Pd2(dba)3, in the presence of a base, e.g. sodium tert-butoxide, to give the compounds of general formula III, -30- which is thereafter deprotected, under standard conditions and alkylated under reductive conditions with a compound of the general formula R1-CHO to give compounds of the general formula I, wherein R1 is selected from anyone of phenyl, pyridinyl, thienyl, furanyl, imidazolyl, triazolyl, pyrrolyl, thiazolyl and pyridyl-N-oxide; wherein each R1 phenyl ring and R1 heteroaromatic ring may independently be further substituted by 1, 2 or 3 substituents independently selected from straight and branched C1-C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo, as well as salts thereof. Dated this 3rd day of November, 2003. 1 / (RANdJNA MEHTA DUTT) OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

Full Text

FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
COMPLETE SPECIFICATION
[See Section 10; rule 13]

A PROCESS FOR PREPARING A CONPOUND OF

FORMULA (1)

A PROCESS FOR PREPARING A COMPOUND

4-[PHENIL -(PIPERDIN -4 -YL) -AMINO)]

BENZAMIDE DERIVATIVE.

/

AstraZeneca AB, a Swedish company of S-l5l 85 SoSertalje, Sweden,

The following specification particularly describes the nature of the invention and the manner in which it is to be performed :-

The present invention relates to a process for preparing a compound 4-[Phenyl-(piperidin-4-yl-amino)benzamide derivative.
Field of the Invention
The present invention is directed to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain, anxiety and functional gastrointestinal disorders.
Background of the Invention
.The 6 receptor has been identified as having a role in many bodily functions such as circulatory andpain systems. Ligands for the 5 receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the 5 receptor have also been shown to possess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (p., 8 and K) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid 8 ligands are peptidic in nature and are unsuitable for administration by systemic routes. One example of a non-peptidic 5-agonist is SNCSO (Bilaky E.J. et al., Journal of Pharmacology and Experimental Therapeutics, 273(1), pp. 359-366 (1995)). There is however still a need for selective S-agonists having not only improved selectivity, but also an improved side-effect profile.
Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current u agonists, as well as having improved systemic efficacy.

Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred 8agonist compounds, described within the prior art, show significant convulsive effects when administered systemically.
We have now found certain compounds that exhibit surprisingly improved properties, i.a. improved 5-agonist potency, in vivo potency, pharmacokinetic, bioavailability, in vitro stability and/or lower toxicity.
Outline of the Invention
The novel compounds according to the present invention are defined by the formula I

wherein
R is selected from any one of
(i) phenyl;

-WO 02/0947S3 JCT/SE02/0U9.I5
(ix) pyridyl-N-oxide

where each R1 phenyl ring and R heteroaromatic nng niay optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C1 -C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fiuoro, bromo, and iodo. The substitutions on the phenyl ring and on the heteroaromatic ring may ta-ke place in any position on said ring systems;
When the R phenyl ring and the R heteroaromatic ring(s) are substituted, the preferred substituents are selected from anyone of CF3, methyl, iodo, bromo, fiuoro and chloro.
A further embodiment of the present invention is a compound according to figure I wherein R is as defined above and each R phenyl ring and R1 heteroaromatic ring may independently be further substituted by a methyl group
A further embodiment of the present invention is a compound according to figure I wherein R is phenyl, pyrrolyl, pyridinyl, thienyl or furanyl, optionally with 1 or 2 of the preferred substituents on the R phenyl or R heteroaromatic ring.
Another embodiment of the present invention is a compound according to figure I wherein R is phenyl, pyrrolyl or pyridinyl, optionally with 1 or 2 of the preferred substituents on the R phenyl or R heteroaromatic ring.
Another embodiment of the present invention is a compound according to figure I wherein R is thienyl or furanyl, optionally with 1 or 2 of the preferred substituents an the R heteroaromatic ring-

Within the scope of the invention are also salts and enantiomers of the compounds of the formula I, including salts of enantiomers.
Reaction step b in Scheme 1, vide infra, is performed by reacting an intermediate compound of the general formula II

II
wherein PG is a urethane protecting group, such as Boc and CBZ, or benzyl or substituted
benzyl protecting group, such as 2,4-dimethoxybenzyl; withN,N--diethyl-4-
bromobenzamide, using a palladium catalyst, e.g. tris(dibenzylideneacetone)
dipalladium(0)-[Pd2(dba)3], in the presence of a base, e.g. tert-BuO'Na. and a phosphine
Iigand such as bis-diphenylphosphanyl-dimethyl-9H-xanthene (xantphos), to give the
compounds of general formula III,
O

which is thereafter 1) deprotected, under standard conditions, 2) hydrolyzed under basic conditions and 3) alkylated using either:
6-

-WQ 02/0917-33 PCT/GE02/0U!)IJ—

i) a compound of the general formula R'-CH2-X, wherein R is as defined above and X is a halogen, preferably bromine or chlorine and a suitable base, or
ii) a compound of the general formula R!-CHO, wherein R1 is as defined above, and a suitable reducing agent, to give compounds of the general formula I.
Suitable bases to be used in the standard alkyiation step i) above include, but are not .limited to, friethylamine and potassium carbonate,
Suitable reducing agents to be used in the standard reduction step ii) include, but are not limited to, sodium cyanoborohydride and sodium triacetoxyborohydride.
The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain,'acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical-needs, for collagen diseases, various allergies, for use as anti-tumour agents-and anti viral agents.
Compounds of the invention are useful in disease states where degeneration or dysfunction of opioi d receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obesessive compulsive disorder; urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel

WO 02/094783" PCT/SE02/0094S
Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following myocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects Aeeded to maintain the anaesthetic state (eg. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.
Also within the scope of the invention is the use of any of the compounds according to the formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment.
A further aspect of the present invention is intermediates of the general formula II and III,'

PG PG
wherein PG is a urethane protecting group, such as Boc and cbz or benzyl or substituted benzyl protecting group, such as 2,4-dimethoxybenzyl
8

WO 02/094793

A further embodiment of the present invention is intermediates of the Formula X

wherein R is as described above in relation to Formula I.
hi another alternative synthetic route, reaction step b in Scheme 2, vide infra, is performed by reacting an intermediate compound of the general formula IV

H-N

wherein PG is a urethane or benzyl-like protecting group, such as Boc, N,N-diethyl-4-bromobenzamide, using a palladium catalyst, e.g. tris(dibenzylideneacelone) dipalladium(O) [ Pd2(dba)3], in the presence of a base, e.g. tert-BuONa and a phosphine ligand such as bis-diphenylphosphanyl-dimethyl-9H-xanthene (xantphos), to give the compounds of general formula V,

which is thereafter 1) deprotected, under standard conditions, 2) hydrolyzed under basic
conditions and 3) alkylated using either:
i) a compound of the general formula R1 -CH2-X, wherein R1 is as defined above and X is
a halogen, preferably bromine or chlorine and a suitable base, or ii) a compound of the general formula R]-CHO, wherein R1 is as defined above, and a
.suitable reducing agents to give compounds of the general formula I. This is followed by conversion of the ketal functionality to a primary amide under standard conditions via 1) hydrolysis of the ketal to the aldehyde (formula VI), followed by 2) oxidation of the aldehyde to the corresponding carboxylic acid (formula VII), followed by 3) amidation with ammonium chloride to the primary amide giving compounds of the general formula I.

Suitable hydrolysis conditions to be used in the standard hydrolysis step (i) include, but are not limited to aqueous hydrochloric acid in tetrahydrofuran.

Suitable conditions for the oxidation step (ii) include, but are not limited to stirring at 0°C in aqueous sodium dihydrogen phosphate and sodium chlorite in the presence of excess 2-methyl-2-butenc.
Suitable conditions for the amidation step (iii) include but are not limited to treatment with excess ammonium chloride in the presence of a coupling agent such as benzotriazole-1-yloxy-trisphosphonium hexafluorophosphate (hereinafter Py-BOP).
Methods of preparation
EXAMPLES
The invention will now be described in more detail by (he following Schemes and
Examples, which are not to be construed as limiting the invention.
Scheme 1: Synthesis of Intermediate Amine (compound 3) Used in Reductive Animations

Method 1A (compound 1): 3-(l-Benzyl-piperidin-4-vlaminoV4-fluoro-benzonitrile.
To a dry flask containing 3-bromo-4-fluoro benzonitrile (6.56g, leq) was added dry toluene (lOOmL), 4-amino-l-benzyl piperidine (1.2eq), racemic BINAP (612mg, 0.03eq)

'
palladium acetate (220mg, 0.02eq) and sodium tert-butoxide (4.4g, 1.4eq). The reaction was heated to 80°C under and inert atmosphere for 20 hours . The reaction was cooled, diluted with ethyl acetate (2Q0mL) and washed with water (lOOmL). The combined organics were dried (MgSO4), filtered and concentrated. Purification by flash chromatography, eluting 3% methanol in dichloromethane yielded amine (1) as a yellow solid (6.655g, 66%).
Method IB (compound 2): r(l-Benzy3-piperidin-4-yl)-(5-cyano-2-fluoro-phenyl)-aminol-N. N-diethyl -benzamide.
To a solution of amine (1) (3,50g, leq.) in dry toluene (50mL) was added aryl bromide (4.35g, 1.5eq), xantphos (393mg, 0.06eq), Pd2(dba)3 (331mg, 0.03eq) and sodium tert-butoxide (1.52g, 1.4eq). The reaction was heated to reflux for 14 hours then was cooled and diluted with ethyl acetate (lOOmL). The solution was washed with water (lOOmL) then the organics were dried (MgSO4), filtered and concentrated. Purification by flash chromatography, eluting 65% ethyl acetate 35% hexanes, rising to 70% ethyl acetate 30% hexanes yielded amine (2) as an orange oil (3.568g, 65% yield).
Method IC (compound 3): [(5-Cvano-2-fluoro-phenvl)-niperidin-4-yl-aminol- N ,N--diethvl-benzamide.
To a solution of amine (2) (3.564g, leq) in 1,2-dichloroethane (65mL) at 0°C was added 1 -chloroethyl chloroformate (920µL, 1.15eq). After 1 hour at 0°C the reaction was warmed to room temperature then was heated to 70°C for 90 minutes. The reaction was then cooled and concentrated. The residue was dissolved in methanol (60niL) then heated to 700C for 1 hour. The solution was then cooled and concentrated. Purification by flash chromatography, eluting 10% methanol in dichloromethane, rising to 40% methanol in dichloromethane gave amine as a yellow foam (2.786g, 96%).

-

Scherae 2: Alternative synthesis Via Intermediate 7
Intermediate 4: (1-Benzyl-piperidin:_4-yl')-(1,3dioxolan-2-vl-2-fluoro-phenyl)-amine. To a dry flask containing 2-(3-bromo-4-fhioropheny])-l ,3-dioxaolane (1 .Deo) and amine, (1.2eq) in dry toluene is added BINAP (0.03eq), palladium acetate (0.02eq) and sodium tert-butoxide (1.4eq). The reaction is heated to 80°C under nitrogen. After about 24 hours the solution is cooled, diluted with ethyl acetate and washed with one portion water. The organics are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography, eluting with a methanol in dichloromethane gradient.

Intermediate 5: [(1-Benzyl-piperidin-4-yl-(5-[1,3]dioxolan-2-yl-2-fluoro-phenvlVaminol-N,N-diethyl-benzamide.
To a dry flask containing amine 4 in dry toluene (about 6mL per millimole of 4) is added aryl bromide (1.4eq), xantphos (0.06eq), Pd2(dba)3 (0.03eq) and sodium ferr-butoxide (1.4eq). The reaction is heated to 110°C under nitrogen. After about 24 hours the solution is cooled, diluted with ethyl acetate and washed with one portion water. The organics are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography, during with a methanol in dichloromethane gradient.
Intermediate 6: [(-Benzvl-piperidin-4-yl)-(2-fluoro-5-formvl-phenvl)-amino1 N,N-diethyl-benzamide.
To a solution of acetal 5 in tetrahydrofuran is added 2N HC1 solution (2,0eq). After 16 hours at room temperature, dichlororaetliane is added and the aqueous layer is neutralized with aqueous saturated sodium bicarbonate solution. The organic layer is removed and the aqueous layer extracted with two portions of dichloromethane. The combined organic extracts are dried (MgS04), filtered and concentrated and the residue is purified by flash chromatography, eluting with an ethyl acetate in hexanes gradient.
Intermediate 7: [(1--Benzvl-piperidin-4-yl')-(4-diethvlcarbamoyl-phenvl')-amino]-4-fluoro-benzoic acid.
To a solution of aldehyde 6 (l.Oeq) in tert-butanol is added 2-methyl-2-butene (lO.Oeq) and tire solution is cooled to 0UC. A solution of sodium dihydrogen phosphate (9eq) and sodium chlorite (9eq) 'in water is added and the reaction is stirred for 30 minutes at 0°C. The rerr-butanol is removed and the reaction mixture is extracted with dichloromethane. The combined organic extracts are dried (MgS04), filtered and concentrated and the residue is purified by flash chromatography, eluting with a methanol/dichloromethane gradient.
Example 1: [(l-Benzvl-piperidin-4-yl)-(4-dicthylcarbamoyl-phenvlVaminol-4-fluoro-benzamide (alternative synthesis).
14

To a solution of acid 7 (1 .Oeq) in DMF is added pyBOP (1.5eq); HOBt (1.5eq), diisopropylethylamine (4.Oeq) and ammonium chloride (2eq). After 16-24 hours at room temperature the reaction is concentrated. The residue is dissolved in ethyl acetate and is washed with two portions of water and one portion of saturated sodium bicarbonate solution. The organic layer is dried (MgSO4), filtered and concentrated and the residue is purified by flash chromatography, eluting with a methanol in dichloromethane gradient.
Additional examples were synthesized via the general procedures described below.

A. Reductive amination of intermediate 3:

NaBH(OAc)3,
THF or 1,2-dichloroethane
R1-CHO (aldehyde)
Room temp.
O

To a solution of the amine, 3, in dry tetrahydrofurari (THF) or 1,2-dichloroethane is added the aldehyde (1-1.5 eq.), followed by sodium triacetoxyborohydride (1-1.6 eq.). The . reaction is stirred at room temperature under a nitrogen atmosphere for an extended period of time (6-48 hours) to ensure complete reaction. The reaction mixture is then subjected to a standard work-up procedure and a standard purification. The amount of THF or 1,2-dichloroethane is not crucial. An amount corresponding to about lmL/30 mg is preferred.
Procedure 2A in the synthesis of Example 2 below is typical. B. Hydrolysis of the intermediate cyano compound:
15

CN KOH, tert-BuOH reflux
'N'

o

To a solution of the cyano intermediate in tert-butanol, is added ground potassium hydroxide (KOH) (2.5 eq.) and the resulting mixture is heated to reflux for about two hours. The mixture was then cooled to room temperature and subjected to a standard work-up procedure and a standard purification. The amount of tert-butanol is not crucial. An amount corresponding to about lmL/30 mg is preferred. Procedure 2B in the synthesis of Example 2 below is typical.
Example 2: [(4-DiethylcarbamoyI-phenyl)-(l-pyridin-2-ylmethyl-piperidin-4-yl)-amino]-4-fluoro-benzamide.

NaBH(OAc)3, THF 70%

2A: [(5-Cvano-2-fluoro-phenvl)-fl-pyridin-2-ylmethvl-rjiperidin-4-yI)-aminol]N,N-
diethyl-benzamide.
To a solution of amine (370mg) in dry tetrahydrofuran (lOmL) was added pyridine-2-
carboxaldehyde (116µL; I.3eq) and sodium triacetoxyborohydride (279mg; 1.4eq). The
reaction was stirred at room temperature under nitrogen. After 24 hours the reaction was
diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The

—

aqueous was extracted with two portions dichloromethane and the combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting 4% methanol in dichloromethane. A colorless foam was obtained (317.5mg; 70% yield).

2B;([4-Diemvlcarbamovl-phgnyl)-(1-Pyridin-2-y'lmethyl--piperidin--4--yl')-aminol-4-fluoro-benzamide.
To a solution of nitrile (3l7mg) in tert-butanol (lOmL) was added ground potassium hydroxide (92mg; 2.5eq) and the reaction was heated to reflux. After 90 minutes the solution was cooled, diluted with dichloromethane and washed with one portion water. The organics. was removed and the aqueous neutralized with 2M hydrochloric acid and extracted with two portions dichloromethane. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 5% methanol in dichloromethane, rising to 7% methanol in dichloromethane. A colorless foam was obtained (164.0mg; 50% yield). The foam was dissolved in ether (8mL) containing some dichloromethane and IN HCl/ether (l.OmL; = 3.0eq) was added After 1 hour the solution was concentrated and the solid dried under high vacuum.
Additional Examples are prepared analogously. Analytical data for synthetic Examples is shown in Table 1, on the following pages,
-17-

Table 1: Analyical data for ExampI ss.
EX R NAME NMRdata(400MHZ CD3OD) i
| vj 4-yl)-(4-diethYl- ; 2.31 (d, J=14Hz, 2H, CH2); 3,25-3.55 (m,
carbarnoyl-phenyl)-
aminoj-fluoro-
benzamide 8H, NCH2); 4.31 (s, 2H, NCH2Ar); 4.42-4.4 2 [ (4-D ie thylc arb amo yl-phenyl)-(l -pyridin-2-ylmethyl-piperidin-4-yl)- amino] -fluoro-benzamide 1.17 (brs, 6H, CH3); 1.81-1.85 (m, 2H, CH2) ; 2.31 (d, J=14Hz, 2H, CH2); 3.36-3.42 (m, 6H, NCH2); 3.63 (d, J=12Hz, 2H, NCH2); 4.48-152 (m, 3H, NCH2 and NCH) ; 6.70 (d, J=8:5Hz, 2H, Ar-H) ; 7.26 (d, >8.5Hz, 2H, Ar-H); 7.41 (t, J=8.5Hz, 1H, Ai-H) ; 7.51-7.54 (m, 1H, Ar-H); 7.60 (d, J=7.5Hz, 1H, Ar-H); 7.84-7.86 (m, 1H, Ar-H); 7.98-8.01 (m, 2H, Ar-H); 8.68 (d, J=6.5Hz, 1H, Ar-H).
3 [(4-
D i ethylc arbamoyl-phenyl)-( 1 -thiophen-3-ylmethyl-p ip eridin-4-y])-arnino]-fluoro-benzamide 1.16 (brs, 6H, CH3); 1.63-1.74 (m, 2H, CH2) ; 2.31 (d, J=14Hz, 2H, CH2); 3.19-3.25 (m, 2H, NCH2); 3.40 (br s, 4H, NCH2); 3.52 (d, J=l3Hz, 2H, NCH2); 4.31 (s, 2H, NCH2Ar); 4.36-4.45 (m, 1H, NCH), 6.67 (d, J=9.5Hz, 2H, Ar-H) ; 7.18-7.27 (in, 3H, Ar-H); 7.38 (t, J=9Hz, 1H, Ar-H); 7.54-7.56 (m, 1H, Ar-H); 7.65-7.66 (m, 1H, Ar-H) ; 7.81 (dd, J=2, 7.5Hz, 1H, Ar-H); 7.97-8.01 (m, 1H, Ar-H).
4 [(4-D i ethyl c arbamoy] -phenyl)-(l -niran-3-ylme thyl -pip eridin-4-J jy))-2minc>) -AUDIO- , benzamide 1.16 (brs, 6H, CH3); 1.57-1.67 (m, 2H, CH2) ; 2.32 (d, J=l4Hz, 2H, CH2); 3.17-3.23 (m, 2H, NCH2) ; 3.42 (br s, 4H, NCH2); 3.56 (d, J=12Hz, 2H, NCH2); 4.1S (s, 2H, NCH2Ar) ; 4.39-4.4$(m, IK, NCK) ; 6\56(^ (K, Ai-ffj; 6.67 (d, J=9.5Hz, 2H, Ar-H); 7.23-7.27 (m, 2H, Ar-H); 7.39 (t, J=9.5Hz, 1H, Ar-H) ; 7.61 (t, J-2Hz, 1H, Ar-H); 7.74 (s, 1H, Ar-H); 7.81 (dd, J=2.5, 7.5Hz, 1H, Ar-H); 7.97-8.01 (m, 1H, Ar-H)
5 [(4-Diethykarbamoyl-phenyl)-(l -thiophen-2-ylmethyl-piperidin-4-yl)-arnmo]-fluoro-benzamide 1.16 (brs, 6H, CH3); 1.63-1.74 (m,2H, CH2) ; 2.33 (d, J=14Hz, 2H, CH2); 3.24 (t, J=l 1Hz, 2H, NCH2); 3.40 (br s, 4H, ^cm); 3.57 (d, J=12Hz, 2H, NCH2); 4.39-4.45 (m, 1H, NCH) ; 4.54 (s, 2H, NCH2Ar); 6.67 (d, J-9.5Hz, 2H, Ar-H) ; 7.11-7.13 (m, 1H, Ar-H); 7.22-7.26 (m, 2H, Ar-H), 7.31 (d, J-3.5H2, 1H, Ar-H); 7.39 (t, J=9.5Hz, 1H, Ar-H); 7.61 (d, J=6.5Hz, 1H, Ar-H); 7.80-7.82 (m, 1H, Ar-H) ; 7.97-8.0! (m, 1H, Ar-H).

WO 02/00 1703-

PCT/SE02/00!M5

A$r

Tab |.Eac.;# lei (c ontinued): Analytical data for synthe 'R. ' [■ Name ■ :"■ tic Examples.
. NMR'data(4G0MHz, GD3OD) ■ 1
6 1 1 [[l-(Z,4-Dichi0TQ-
benzyl)-piperidin-4-yl] - (4- diethylcarbam -oyl-phenyl) -amino] -fluoro-benzamide J I. 16 (brs, 6Rt CHi); 1.6?-1.77 fa, ZH, CH2) ) ; 2.31 (d, J=14Hz, 2H, CH2); 3.30-3.50 (m, 6H, NCH2); 3.59 (d, J=12Hz, 2H, NCH2); 4.42-4.48 (m, 3H, NCH and NCH2Ar) ; 6.67 (d, J=9.5Hz, 2H, Ar-H); 7.23 (d, J=8.5Hz, 2H, Ar-H); 7.38 (t, J=9.5Hz, 1H, Ar-H); 7.45-7.48 (ra, 1H, Ar-H) ; 7.59 (d, J=8.5Hz, 1H, Ar-H) ; 7.66 (d, J=2Hz, 1H, Ar-H); 7.80 (J=2, 7.5Hz, 1H, Ar-H); 7.96-8.00 (m, 1H, Ar-H).
7 [(4-D iethylcarb amo yl-phenyl)-(l-thiazoI-2-ylmethyl-piperidin-4-yl)-amino]"fluoro-
benzamide 1.16 (br s, 6H, CH3); 1.77-1.82 (m, 2H; CH2) ; 2.33 (d, J=I4Hz, 2H, CH2); 3.40-3.53 (m, 6H, NCH2); 3.71 (d, J=l 1Hz, 2H, NCH2); 4.48-4.53 (ra, 1H, NCH); 4.73 (s, 2H, NCH2Ar); 6.73 (d, J=8.5Hz, 2H, Ar-H); 7.30 (d, J=8.5Hz, 2H, Ar-H); 7.39-7.43 (m, 1H, Ar-H); 7.77 (d, J-3Hz, 1H, Ar-H); 7.84 (d, J=5.5Hz, 1H, Ar-H) ; 7.93 (d, J=3Hz, 1H, Ar-H); 8.00-8.04 (m, 1H, Ar-H).
8 [[l-(4-Bromo-benzyl)-piperidin-4-yl]-(4-d iethylcarb amoyl-phenyl)-amino]-fluoro-benz amide 1.16 (brs, 6H, CH3); 1.64-1.75 (m, 2H3 CH2) ; 2.30 (d, J=14Hz, 2H, CH2) ; 3.22-3.28 (m, 2H, NCH2); 3.42-3.53 (m, 6H,NCH2); 4.27 (s, 2H,NCH2Ar) ; 4.38-4.46 (m, 1H, NCH); 6.67 (d, J=8.5Hz, 2H, Ar-H) ; 7.24 (d, J=8.5Hz, 2H, Ar-H) ; 7.36-7.41 (m, 3H, Ar-H); 7.63 (d, J=8.5Hz, 2H, Ar-H); 7.80 (dd, J=2, 7.5 Hz, 1H, Ar-H); 7.97-8.00 (ra, 1H, Ar-H).
9 [(4-Diethylcarbamoyl-phenyl)-(l-furan-2-ylmethyl-piperidin-4-yl)-amino]-fluoro-benzamide 1.16 (brs, 6H, CH3); 1.63-1.73 (ra, 2H, CH2) ; 2.32 (d, J=14Hz, 2H, CH2) ; 3.22-3.48 (m, 6H, NCH2j ;3.S3 (6, /=X Jflz, 2H, HCK2); 4.37 (s, 2H, NCH2Ar); 4.39-4.44 (m, 1H, NCH); 6.50-6.52 fa 1H, Ar-H); 6.65-6.10 (m, 3H, Ar-H); 7.21 (d, J=3Hz, 2H, Ar-H) ; 7.39 (t, J=9.5Bz, M, Ar-H) ; 7.65 (s, 111, Ar-H); 7.81 (dd, J=2, 7.5Hz, 1H, Ar-H) ; 7.90-8.01 (m, lH.Ar-H).
10 [(4-Diethylcarbamoyl-
phenyl)-(l-pyridin-4-ylmethyl-piperidin-4-yl)-amino]-fluoro-benz amide 1.16 (brs, 6H, CH3); 1.85-1.94 (m, 2H, CH2) ; 2.31 (d, >13Hz, 2H, CH2); 3.30-3.48 fa 6H, NCH2); 3.60 (d, J=l 1Hz, 2H, NCH2); 4.45-4.51 (ra, 1H, NCH) ; 4.68 (s, 2H, NCH2Ar); 6.69 (d, J=8.5Hz, 2H, Ar-H); 7.24 (d, J=9.5Hz, 2H, Ar-H) ; 7.38 (t, J=9.5Hz, 1H, Ar-H); 7.82 (d, J=6.5Hz, 1H, Ar-H); 7.97-8.01 (m, 1H, Ar-H) ; 8.32 (d, J-7.5Hz, 2H, Ar-H"); 8.98 (d, J-6.5Hz, 2H, Ar-H).

-n-

Table ] (continued); Analytical data for synthetic Examples.
Ex.# Name. ,. NMRdata(400MHz, CD3OD)
11 [[l-(4-Chloro-
benzyl)-piperidin-4-
yl]-(4-diethyl-
carbamoyl-phenyl)-
amino] -fluoro-
benzamide 1.14 (br s, 6H, CH3); 1.62-1.73 (m, 2H, CH2); 2.28 (d, J-15HZ, 2H, CH2); 3.23 (t, J=13Hz, 2H, NCH2); 3.39 (br s, 4H, NCH2) ; 3.50 (d, J=13Hz, 2H, NCH2); 4.26 (s, 2H, NCH2AJ) ; 4.36-4.44 (m, 1H, NCH); 6.64 (d, J=8.5Hz, 2H; Ar-H); 7.20 (d, J=9.5Hz, 2H, Ar-H); 7.36 (t, J=9.5Hz, 1H, Ar-H) ; 7.42-7.47 (m, 4H, Ar¬H) ; 7.78 (dd, J=2, 7.5Hz, 1H, Ar-H) ; 7.94-7.98'(m, lH,Ar-H).
12 [(4-
Diethylcarbarnoyl-
phenyl)-(l-pyridin-3-
ylmethyl-piperidin-4-
yl)-amino]-fluoro-
benzamide 1.15 (br s, 6H, CH3) ; 1.80 (q, J=-12Hz, 2H, CH2) ; 2.29 (d, J=14Hz, 2H, CH2) ; 3.35-3.47 (m, 6H, NCH2); 3.60 (d, J=12Hz, 2H, NCH2); 4.42-4.49 (m, 1H, NCH) ; 4.60 (s, 2H, NCH2Ar) ; 6.66 (d, J=8.5Hz, 2H, Ar-H) ; 7.22 (d, J=8.5Hz, 2H, Ar-H); 7.35 (t, J=9.5Hz, 1H, Ar-H) ; 7:79 (d, J=6.5Hz, 1H, Ar-H) ; 7.94-7.9S (in, 1H, Ar-H) ; 8.11-8.15 (m, 1H, Ar-H) ; 8.78 (d, J=8.5Hz, 1H, Ar-H); 8.94 (d, J=5.5Hz, 1H, Ar-H); 9.14(8, 1H, Ar-H).
13 {(4- .
Diethylcarb amoyl-
phenyl)-[l-(3H-
imidazoI-4-
ylmethyl)-pip eridin-
4-yl] -amino} -fluoro-
benzamide 1.14 (br s, 6H, CH3); 1.79-1.85 (m, 2H, CH2); 2.31 (d, J=14Hz, 2H, CH2); 3.32-3.46 (m, 6H, NCH2); 3.60 (d, J=llHz, 2H,NCH2); 4.41-4.47 (m, 1H, NCH); 4.50 (s, 2H, NCH2Ar); 6.67 (d, J=9.5Hz, 2H, Ar-H); 7.22 (d, J=8.5Hz, 2H, Ar-H); 7.36 (t, J=9.5Hz; 1H, Ar-H) ; 7.80 (d, J=5.5Hz, 1H, Ar-H); 7.86 (s, 1H, Ar-H) ; 7.95-7.99 (m, 1H, Ax-H); 9.05 (d, J-2Hz, 1H, Ar-H).
14 {(4-
Di ethyl carbamo yl-
phenyl)-[l-(lH-
imidazol-2-
ylmethyl)-piperidin-
4-yl]-amino}-fluoro- 1.14 (br s, 6H, CH3); 1.79-1.85 (m, 2H, Cll2); 2.31 (d, J=14Hz, 2H, CH2); 3.32-3.46 (m, 6H, NCH2); 3.60 (d, J=l 1Hz, 2H, NCH2) ; 4.41-4.47 (m, 1H, NCH); 4.50 (s, 2H3 NCH2Ar); 6.67 (d, J-9.5Hz, 2H, Ar-H); 7.22 (d, J-8.5Hz, 2H, Ar-H); 7.36 (t, J=9.5Hz, 1H, Ar-H) ; 7.80 (d, J=5.5Hz, 1H, Ar-H); 7.86 (s, 1H, Ar-H); 7.95-7.99 (m, 1H, Ar-H) ; 9.05 (d, J=2Hz, 1H, Ar-H).
15 {(4-
D iethyl c arb am oyl-
phenylMHlH- . pyrrol-2-ylmethy^-piperidin^-yl]-amino}-fluoro-benz amide 1.13 (brs3 6H, CH3); 1.58-1.69 (m,2H,'CH2); 2.29 (d, J=13Hz, 2H, CH2); 3.10 (d, J=llHz, 1B, NCH); 3.14 (d, J=llHz, 1H, NCH); 3.38 (br s, 4H, NCH2); 3.47 (d, J=13Hz, 2H, NCH2) ; 4.21 (s, 2H, NCH2A,) ; 4.31-4.39 (m31H, NCH); 6.12 (ID, 1H, Ar-H) ; 6.29 (s, IE, Ar-H); 6.63 (d, J=8.5Hz, 2H, Ar-H); 6.83-6.84 (in, 1H, Ar-H); 7.20 (d, J=9Hz, 2H, Ar-H); 7.35 (t, J=9.5Hz, 1H, Ar-H) ; 7.77-7.79 (m, 1H, Ar-H) ; 7.94-7.98 (m, 1H, Ar-H); 10.60 (br s, 1H, NH)
--J2C-

Pharmaceutical compositions
The novel compounds according to the present invention may be administered orally, sublingually^intrarnuscularly, subcutaneously, topically, intranasally, mtraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
A preferred route of administration is orally, intravenously or intramuscularly. The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen' and dosage level as the most appropriate for a particular patient.
For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed

therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-me]ting wax, cocoa butter, and the like.
Salts include, but are not limited to, pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts within the scope of the present invention include; acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate,' camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fhmarate, glucaptate, gluconate, glutamate, giycollylars anil ate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, isethionate, lactate, Iactobionate, malate, maleate, mandelate, mesylate, methylbromide, methyinitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, and benzathine.
Examples of pharmaceutically unacceptable salts within the scope of the present invention include: hydroiodide, perchlorate, tetrafluoroborate. Pharmaceutically unacceptable salts could be of use because of their advantageous physical and/or chemical properties, such as crystallimty.
Preferred pharmaceutically acceptable salts are hydrochlorides, sulfates and bitartrates. The hydrochloride and sulfate salts are particularly preferred.
The term composition is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.

,
Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid from compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
Preferably the pharmaceutical compositions is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
BIOLOGICAL EVALUATION
In vitro model
Cell culture
A. Human 293S cells expressing cloned human \i, 8, and K receptors and neomycin resistance were grown in suspension at 37°C and 5% CO2 in shaker flasks containing
-23-

calcium-free DMEM10% FBS, 5% BCSS 0.1% Pluronic F-68, and 600 pg/ml geneticin.
B. B. Mouse and rat brains were weighed and rinsed in ice-cold PBS (containing 2.5mM EDTA, pH 7.4). The brains were homogenized with a polytron for 15 sec (mouse) or 30 sec (rat) in ice-cold lysis buffer (50mM Tris, pH 7.0, 2.5mM EDTA, with phenylmethylsulfony] fluoride added just prior use to 0.5MmM from a 0.5M stock in DMSO:ethanol).
Membrane preparation
Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0,2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 M stock in ethanol), incubated on ice for 15 min, then homogenized with a polytron for 30 sec. The suspension was spun at lOOOg (max) for 10 min at 4°C. The supernatant was saved on ice and the pellets resuspended and spun as before. The supematants from both spins were combined and spun at 46,000 g(max) for 30 min. The pellets were resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) and spun again. The final pellets were resuspended in membrane buffer ( 50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dry ice/ethanol and stored at -70°C until use. The protein concentrations were determined by a modified Lowry assay with SDS.
Binding assays
Membranes were thawed at 37°C, cooled on ice, passed 3 times through a 25-gauge needle, and diluted into binding buffer (50 mM Tris, 3 mM MgCl2,1 mg/ml BSA (Sigma A-7888), pH 7.4, which was stored at 4°C after filtration through a 0.22 m filter, and to which had been freshly added 5 pg/ml aprotinin, 10 uM bestatin, 10 uM diprotin A, no DTT). Aliquots of 100 pi were added to iced 12x75 mm polypropylene tubes containing 100 pi of the appropriate radioligand and 100 pi of test compound at various concentrations. Total (TB) and nonspecific (NS) binding were determined in the absence

and presence of 10 uM naloxone respectively. The tubes were vortexed and incubated at 25°C for 60-75 min, after which time the contents are rapidly vacuum-filtered and washed with about 12 ml/tube iced wash buffer (50 mM Tris, pH 7.0, 3 rr M MgCI2) through GF/B filters (Whatman) presoaked for at least 2h in 0.1 % polyethyleneimine. The radioactivity (dpm) retained on the filters was measured with a beta counter after soaking the filters for at least ]2h in minivials containing 6-7 ml scintillation fluid. If the assay is set up in 96-place deep well plates, the filtration is over 96-place PEI-soaked unifilters, which were washed with 3 x 1 ml wash buffer, and dried in an oven at 55°C for 2h. The filter plates were counted in a TopCount (Packard) after adding 50 µ l MS-20 scintillation fluid/well.
Functional Assays
The agonist activity of the compounds is measured by determining the degree to which the compounds receptor complex activates the binding of GTP to G-proteins to which the receptors are coupled. In the GTP binding assay, GTP[y]35S is combined with test compounds and membranes from HEK-293S cells expressing the cloned human opioid receptors or from homogenised rat and mouse brain. Agonists stimulate GTP[y] S binding in these membranes. The EC50 and Ema)t values of compounds are determined from dose-response curves. Right shifts of the dose response curve by the delta antagonist naltrmdole are performed to verify that agonist activity is mediated through delta receptors.
Procedure for rat brain GTP
Rat brain membranes are thawed at 37°C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPyS binding (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl2, pH 7.4, Add fresh: 1 mM DTT, 0.1% BSA). 120nM GDP final is added membranes dilutions. The EC50 and Emax of compounds are evaluated from 10-point dose-response curves done in 300ul with the appropriate amount of membrane protein (20ug/well) and 100000-130000 dpm of GTPy^S per well (0.11 -0.14nM). The basal and maximal stimulated binding are determined in absence and presence of 3uM SNC-80

Data analysis
The specific binding (SB) was calculated as TB-NS, and the SB in the presence of various test compounds was expressed as percentage of control SB. Values of IC50 and Hill coefficient (nH) for ligands in displacing specifically bound radioligand were calculated from logit plots or curve fitting programs such as Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit. Values of Kj were calculated from the Cheng-Prussoff equation. Mean ± S.E.M. values of IC50, Kj and nH were reported for ligands tested in at least three displacement curves. Biological activity of the compounds of the present invention is indicated in Table 2.
Table 2: Biological data.

Ex. HDELTA (nM) ■ RAT BRAIN (nM) MOUSE BRArN (UM)
IC50 EC50 %EMax EC5o %EMax EC50 %EMax
1-15 0.247-5.405 0.115-338.89 84.69-110.25 0.563-73.672 100.1-176.86 0.807-48.164 93.36-163.19
Receptor saturation experiments
Radioligand K8 values were determined by performing the binding assays on cell membranes with the appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated Kg (up to 10 times if amounts of radioligand required are feasible). The specific radioligand binding was expressed as pmole/mg membrane protein. Values of Kg and Bmax from individual experiments were obtained from nonlinear firs of specifically bound (B) vs. nM free (F) radioligand from individual according to a one-site model.

Acetic acid ("AcOH): 120 µ L of Acetic.Acid is added to 19.88 ml of distilled water in order to obtain a final volume of 20 ml with a final concentration of 0.6% AcOH. The solution is then mixed (vortex) and ready for injection.
Compound ("drug): Each compound is prepared and dissolved in the most suitable vehicle according to standard procedures.
(ii) Solutions administration
The compound (drug) is administered orally, intraperitoneally (i.p.), subcutaneously (s.c.) or intravenously (i.v.)) at 10 ml/kg (considering the average mice body weight) 20, 30 or 40 minutes (according to the class of compound and its characteristics) prior to testing. When the compound is delivered centrally: Intraventricularly (i.c.v.) or intrathecally (i.t.) a volume of 5 µ L is administered.
The AcOH is administered intraperitoneally (i.p.) in two sites at 10 ml/kg (considering the average mice body weight) immediately prior to testing.
(iii) Testing
The animal (mouse) is observed for a period of 20 minutes and the number of occasions (Writhing reflex) noted and compiled at the end of the experiment. Mice are kept in individual "shoe box" cages with contact bedding. A total of 4 mice are usually observed at the same time: one control and three doses of drug.
For the anxiety and anxiety-like indications, efficacy has been established in the geller-seifter conflict test in the rat.
For the functional gastrointestina disorder indication, efficacy can be established in the assay described by Coutinho SV et al, in American Journal of Physiology -Gastrointestinal & Liver Physiology. 282(2):G307-16, 2002 Feb, in the rat.

WE CLAIM:
1. A process for preparing a compound^ 4-[Phenyl-(piperidin-4-yl)~
comprising reacting a compound of the general formula II
aminofbenzamide derivative.of.formula I,

wherein PG is a urethane protecting group, such as Boc and CBZ, or benzyl or substituted benzyl protecting group, such as 2,4 dimethoxybenzyl, with N,N-diethyl-4-bromobenzamide, using a palladium catalyst, such as Pd2(dba)3, in the presence of a base, e.g. sodium tert-butoxide, to give the compounds of general formula III,
-30-

which is thereafter deprotected, under standard conditions and alkylated under reductive conditions with a compound of the general formula R1-CHO to give compounds of the general formula I, wherein
R1 is selected from anyone of phenyl, pyridinyl, thienyl, furanyl, imidazolyl, triazolyl, pyrrolyl, thiazolyl and pyridyl-N-oxide; wherein each R1 phenyl ring and R1 heteroaromatic ring may independently be further substituted by 1, 2 or 3 substituents independently selected from straight and branched C1-C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo, as well as salts thereof.
Dated this 3rd day of November, 2003. 1 /
(RANdJNA MEHTA DUTT)
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS

Documents:

1016-mumnp-2003-abstract.doc

1016-mumnp-2003-abstract.pdf

1016-mumnp-2003-cancelled pages(14-10-2004).pdf

1016-mumnp-2003-canclled-claims.pdf

1016-mumnp-2003-canclled-description.pdf

1016-mumnp-2003-claims(granted)-(14-10-2004).doc

1016-mumnp-2003-claims(granted)-(14-10-2004).pdf

1016-mumnp-2003-claims.doc

1016-mumnp-2003-claims.pdf

1016-mumnp-2003-correspondence(11-01-2005).pdf

1016-mumnp-2003-correspondence(ipo)-(07-01-2005).pdf

1016-mumnp-2003-correspondence(ipo).pdf

1016-mumnp-2003-correspondence.pdf

1016-mumnp-2003-description(granted).doc

1016-mumnp-2003-description(granted).pdf

1016-mumnp-2003-form 19(03-11-2003).pdf

1016-mumnp-2003-form 19.pdf

1016-mumnp-2003-form 1a(03-11-2003).pdf

1016-mumnp-2003-form 1a.pdf

1016-mumnp-2003-form 2(granted)-(14-10-2004).doc

1016-mumnp-2003-form 2(granted)-(14-10-2004).pdf

1016-mumnp-2003-form 2(granted).doc

1016-mumnp-2003-form 2(granted).pdf

1016-mumnp-2003-form 2(title page).pdf

1016-mumnp-2003-form 3(03-11-2003).pdf

1016-mumnp-2003-form 3(27-12-2004).pdf

1016-mumnp-2003-form 3-03-11-2003.pdf

1016-mumnp-2003-form 3-27-12-2004.pdf

1016-mumnp-2003-form 5(03-11-2003).pdf

1016-mumnp-2003-form pct-ib-304.pdf

1016-mumnp-2003-form pct-ipea-409.pdf

1016-mumnp-2003-form pct-ipea-416.pdf

1016-mumnp-2003-form pct-isa-210.pdf

1016-mumnp-2003-form-pct-ipea-409(03-11-2003).pdf

1016-mumnp-2003-form-pct-isa-210(03-11-2003).pdf

1016-mumnp-2003-international publication report a1.pdf

1016-mumnp-2003-petition under rule 137(11-01-2005).pdf

1016-mumnp-2003-power of authority(12-10-2004).pdf

1016-mumnp-2003-power of authority(20-10-2003).pdf

1016-mumnp-2003-power of authority.pdf

1016-mumnp-2003-statement application.pdf

1016-mumnp-2003-us-patent document.pdf

« Previous Patent

Next Patent »

Patent Number

209891

Indian Patent Application Number

1016/MUMNP/2003

PG Journal Number

31/2008

Publication Date

01-Aug-2008

Grant Date

10-Sep-2007

Date of Filing

03-Nov-2003

Name of Patentee

ASTRAZENECA AB

Applicant Address

S-151 85 SODERTALJE, SWEDEN

Inventors:

#	Inventor's Name	Inventor's Address
1	WILLIAM BROWN	ASTRAZENECA R & D MONTREAL, 7171 FREDERICK-BANTING, ST. LAURENT, MONTREAL, QUEBEC H4S 1Z9, CANADA

PCT International Classification Number

C07D211/58

PCT International Application Number

PCT/SE02/00945

PCT International Filing date

2002-05-16

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0101770-6	2001-05-18	Sweden