Title of Invention	BICYCLO'3.1.1HEPTANE SUBSTITUTED BENZIMIDAZOLONE AND QUINAZOLINONE DERIVATIVES AS AGONISTS ON HUMAN ORL1 RECEPTORS
Abstract	The invention relates to a group of hydronopol substituted benzimidazolone and quinazolinone derivatives, which are agonists on human ORL1 (nociceptin) receptors. The invention also relates to the preparation of these compounds, to pharmaceutical compositions containing a pharmacologically active amount of at least one of these novel benzimidazolone and quinazolinone derivatives as an active ingredient, as well as to the use of these pharmaceutical compositions for the treatment of disorders in which ORL1 receptors are involved. The invention relates to compounds of the general formula (1) wherein the symbols have the meanings as given in the description.

Title of Invention

BICYCLO'3.1.1HEPTANE SUBSTITUTED BENZIMIDAZOLONE AND QUINAZOLINONE DERIVATIVES AS AGONISTS ON HUMAN ORL1 RECEPTORS

Abstract

The invention relates to a group of hydronopol substituted benzimidazolone and quinazolinone derivatives, which are agonists on human ORL1 (nociceptin) receptors. The invention also relates to the preparation of these compounds, to pharmaceutical compositions containing a pharmacologically active amount of at least one of these novel benzimidazolone and quinazolinone derivatives as an active ingredient, as well as to the use of these pharmaceutical compositions for the treatment of disorders in which ORL1 receptors are involved. The invention relates to compounds of the general formula (1) wherein the symbols have the meanings as given in the description.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See Section 10) TITLE Bicyclo3.1.1!heptane substituted benzimidazolone and quinazolinone derivatives as agonists on human orll receptors” APPLICANT SOLVAY PHARMACEUTICALS B.V. C.J. van Houtenlaan 36 NL-1381 CP Weesp The Netherlands Nationality: a Dutch company The following specification particularly describes the nature of this invention and the manner in which it is to be performed WO 2005/032547 PCT/EP2004/052392 1 BICYCLOP’3.1.1 HEPTANE SUBSTITUTED BENZIMIDAZOLONE AND QUINAZOLINONE DERIVATIVES AS AGONISTS ON HUMAN ORL1 RECEPTORS The present invention relates to a group of hydronopol substituted benzimidazolone and quinazolinone derivatives which are agonists on human ORL1 (nociceptin) receptors. The invention also relates to the preparation of these compounds, to pharmaceutical compositions containing a pharmacologically active amount of at least one of these novel benzimidazolone and quinazolinone derivatives as an active ingredient, as well as to the use of these pharmaceutical compositions for the treatment of disorders in which ORL1 receptors are involved. The Opioid Receptor-Like 1’ (ORL1) receptor was identified from a human cDNA library. It was established that this ‘orphan receptor’ has a close homology with n-, K- and δ-opioid receptors (Mollereau etal., FEBS Lett., 341. 33-38, 1994; Bunzow et al., FEBS Lett., 347, 284-288, 1994). Despite its close sequential and structural resemblance with opioid receptors, classical opioid receptor ligands do not to interact with ORL1 receptors. In 1995 a 17-amino acid neuropeptide was purified from brain extracts, and subsequently shown to be the natural ligand of the G protein-coupled ORL1 receptor (Reinscheid et al., Science. 270. 792-794, 1995; Meunier et al., Nature. 377. 532-535, 1995). This peptide was named orphanin FQ or nociceptin and it does not bind to the three traditional opioid receptors. These findings triggered substantial research into the functional role of, and novel ligands for, the ORL1 receptor. That resulted in several hundreds of publications, including several reviews (see e.g. Grand et a/., Anaesthesist, 51, 996-1005, 2002), and dozens of patent applications, describing both peptide and non-peptide ligands, varying in potency and selectivity (ORL-1 versus µ-opiate). As µ-opiate receptors are widely distributed throughout the body, a lack of selectivity might lead to a range of undesired opiate-like side-effects e.g. sedation, respiratory depression, tolerance and dependence (Drug News Perspect, 14. 335, 2001). Six of the ORL1 related patent applications concern benzimidazolone derivatives: WO 98/54168, WO 99/36421, WO 00/08013, WO 00/006545, WO 01/39775, and US 20020128288. The prior art closest to the present invention is WO 01/39775. However, the benzimidazolone derivatives described therein do not seem to meet the criteria WO 2005/032547 PCT/EP2004/05239 2 generally acknowledged to be of importance for useful ORL1 based therapeutic agents. They are characterized by: (1) modest potency (affinities for ORL1 receptors in the range of 166 - 1252 nM); (2) lack of selectivity towards µ-opiate receptors (affinities in the range 19 -457 nM; (3) no evidence for availability after oral administration, and (4) no evidence for CNS-availability. Surprisingly, it has now been found that in a series of hydronopyl substituted benzimidazolone and quinazolinone derivatives, a group of compounds was shown to have a very high affinity for human ORL1 receptors. Moreover, these compounds show an excellent selectivity for ORL1 receptors relative to µ-opiate receptors, are readily available after oral administration and do penetrate the Blood-Brain-Barrier. The invention relates to compounds of the general formula (1) wherein: Ri represents H, alkyl(1-6C), alkyl(-3C)cycloalkyI(3-6C), carbalkoxy(2-7C) or acyl(2-7C), []m symbolizes — (CH2)m- wherein m is either 0 or 1, R2 represents halogen, CF3, alkyl(1-6C), alkyl(1-3C)cycloalky](3-6C), phen yl, amino, aminoalkyl(1-3C), alkyl(1-3C)amino, dialkyi(1-3C)amino, cyano, cyanoalkyl(1-3C), hydroxy, hydroxyalkyl(1-3C), (1-3C)alkoxy, OCF3, acyl(2-7C), trifluoroacetyl, aminocarboxyl, (1-3C)alkylsuIphonyl or trifluoromethylsulphonyl, and n is an integer from 0-4, with the proviso that when n is 2, 3 or 4, the R2 substituents may be either the same or different WO.2005/032547 PCT7EP2004/052392 3 A is a saturated pr partially unsaturated ring [] and [ ]p represent -(CH2)o- and –(CH2)p- respectively, with the proviso that also the meaning -CH- is possible when A is a partially unsaturated ring, and o and p independently are either 0, 1 or 2, R3, R4. R5 and Re independently represent hydrogen, alkyl(1-3C), alkyl(1-3C)- cycloalkyl(3-6C), CH2OH or (R3 and R5) or (R3 and R6) or (R4 and Rs) or (R4 and R6) together can form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, R3 is hydrogen, and when p is 2, R5is hydrogen, []q symbolizes —(CH2)q- wherein q is an integer from 0 to 2 and pharmacologically acceptable salts and prodrugs thereof. To the invention belong all compounds having formula (1), racemates, mixtures of diastereomers and the individual stereoisomers. Thus compounds in which the substituents on potentially asymmetrical carbon atoms are in either the R-configuration or the S-configuration belong to the invention. Also prodrugs, i.e. compounds which when administered to humans by any known route, are metabolised to compounds having formula (1), belong to the invention. In particular this relates to compounds with primary or secondary amino or hydroxy groups. Such compounds can be reacted with organic acids to yield compounds having formula (I) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxymethylene derivative, an 0-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone. A prodrug is an inactive compound, which when absorbed is converted into an active form (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F. D. King, p. 216). The invention particularly relates to compounds having formula (1) wherein : A is a saturated ring, R1 represents hydrogen, alkyl(1 -3C), or acyl(2-4C), WO 205/032547 PCT7EP2004/05239 4 R3, R4, R5 and R6 independently represent hydrogen or alkyl(1-3C) or (R3 and R5) or (R3 and R6) or (R4 and R5) or (R4 and R6) together can form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, R3 is hydrogen, and when p is 2, Rs is hydrogen, and R2, m, n, o. p and q have the meanings as given above. More particular the invention relates to compounds of formula (1) wherein: A is a saturated ring, m=0, n=0 or 1, o=1, p=1, q=0, R1 =H or acetyl, R2 represents halogen, CF3, alkyl(1-3C), amino, hydroxy, cyano, OCH3 or OCF3, R3, R4, R5 and R6 independently represent hydrogen or alkyl(1-2C) or (R4 and R6) together can form an alkylene bridge of 1 to 2 carbon atoms Even more preferred is the compound having formula (2) and all its stereoisomers. The compounds of the invention and their salts can be obtained according to the general route outlined below. Starting compounds for this general route are ob tained as follows: WOO2005/032547 PCT/EP2004/052392 5 Benzimidazolones (m=0) can be synthesized according to the methods described in J. Med. Chem.. 30, 814-819, 1987 and WO 99/36421 (Pfizer). Quinazolones (m=1) can be synthesized according to Chem. Pharm. Bull.. 33. 1116-1128, 1985. Hydronopol-derivatives with X as leaving group (halogen, mesylate, tosylate) can be synthesized from the corresponding alcohols following standard procedures. The corresponding alcohols can be synthesized as follows: • for the cis analog with q = 0 from (-}-β-pinene as described in J. Amer. Chem. Soc. 68. 638,1946 and US patents 2,427,345 and 2.427.345 • for the trans analog with q = 0 from trans-myrtano! as described in Bull. 10 Soc. Chim. Fr.. 196, 1958 or via a slightly alternative procedure (bromination of the alcohol, substitution by cyano, conversion to the ethylester and reduction to the desired alcohol) • for both the cis and trans analogs with q = 1 or 2, by one or two cycles of an analogous homologation procedure as described for the synthesis of the trans analog with q = 0 from trans-myrtanol. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid such as hydrochloric acid, or with an organic acid. The compounds of the invention of the general formula (1), as well as the salts thereof, have ORL1 agonistic activity. They are useful in the treatment of disorders in which ORL1 receptors are involved, or that can be treated via manipulation of those receptors. For instance in acute and chronic pain conditions, central nervous system disorders, especially, but not limited to amelioration of symptoms of anxiety and stress disorders, depression, various forms of epilepsy, stroke, disorders characterized by impairment of cognition and memory such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain lesions); acute brain or spinal cord injury, substance related disorders, including substance use disorders (like dependence and abuse) and substance induced disorders (like substance withdrawal); eating disorders like anorexia nervosa and bulimia nervosa, obesity; gastro-intestinal disorders in particular irritable bowel syndrome, inflammatory bowel disease(Crohn’s disease and ulcerative colitis), urinary tract inflammation, renal disorders characterized by imbalances of water retention/excretion or salt excretion WO 2005/032547 PCT/EP2004/052392 6 cardiovascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma; respiratory disorders including cough, chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; diseases of the immune system, and viral infections. The in vitro and in vivo ORL1 receptor agonistic properties of the compounds of the invention were determined using the methods outlined below. Affinity for human ORL1 receptors Affinity of the compounds for human ORL1 receptors was determined using the in vitro receptor binding assay described by Ardati et al., Mol. Pharmacol.. 51. 816,1997. Briefly, membrane preparations were obtained from CHO (Chinese Hamster Ovary)-cel!s in which the human ORL1 receptor was stably expressed. Membranes were incubated with [3H]-nociceptin in the absence or presence of test-compounds in different concentrations, diluted in a suitable buffer. Non-specific binding was defined as binding remaining in the presence of 10-6 M nociceptin. Separation ofbound radioactivity from free was done by filtration through Packard GF/B glass fiber filters with several washings with ice-cold buffer using a Packard cell harvester. Bound radioactivity was measured with a scintillation counter (Topcount, Packard) using a liquid scintillation cocktail (Microscint 0, Packard). Measured radioactivity was plotted against the concentration of the displacing test compound and displacement curves were calculated by four-parameter logistic regression, resulting in IC50 values, i.e. that concentration of displacing compound by which 50% of the radioligand is displaced. Affinity pK1 values were calculated by correcting the IC50 values for radioligand concentration and its affinity for the human ORL1 receptor according to the Cheng-Prusoff equation: pK1= -log(lC50/(1+S/Kd)) in which the IC50 is as described above, S is the concentration [3H]- ociceptin used in the assay expressed in mol/l (typically 0.2 nM), and Kd is the equilibrium dissociation constant of [3H]-nociceptin for human ORL1 receptors (0.4 nM). WO2005/03247 PCT/EP2004/052392 7 The compounds of the invention have a high affinity for ORL1 receptors in the binding assay described above. This property makes them useful in the treatment of disorders in which ORL1 receptors are involved, or that can be treated via manipulation of these receptors. Affinity for µ-opiate receptors Affinity of the compounds for µ-opiate receptors was determined using the in vitro receptor binding assay described by Childers et a/, Eur. J. Pharm 55, 11, 1979.Briefly, membrane preparations were obtained from CHO-cells in which the human µ-opiate receptor was stably expressed, and were incubated with the [3H]-naloxone in the absence or presence of test-compounds in a concentration range from 10 uM down to 0.1 nM, diluted in a suitable buffer. Non specific binding was defined as binding remaining in the presence of 10-7 M levallorphan.tartrate. Separation ofbound radioactivity from free was done as described above, and the affinity of the compounds was calculated in a similar way, using a concentration (S) of 1 nM [3H]-naloxone and with a Kd value of 1.3 nM. Most of the compounds of the invention have a low affinity for µ-opiate receptors in the binding assay described above: typically a factor 100 below their affinity for ORL1 receptors. Thus they are unlikely to evoke the unwanted side effects known to occur with opiates like morphine. In vitro ORL1 receptor agonism Activation of the G protein-coupled ORL1 receptor inhibits adenylate cyclase activity and reduces the intracellular concentration of the second messager cAMP. Using the assay as decribed by Jenck et a/., Proc. Natl. Acad. Sci USA 97. 4938-4943, 2000, the activity of the compounds on ORL1 receptors was measured. They were demonstrated to be potent agonists with pEC50-values matching their pK1 values. WO.2005/032547 PCT/EP2004/052392 8 In vivo ORL1 receptor agonism After intraperitoneal and/or oral administration the compounds of the invention were shown to be highly active in the conditioned ultrasonic distress vocalisation procedure as described by Molewijk et al., Psvchopharmacologv. 117. 32-40, 1995. This demonstrates not only that the compounds have a good bioavailability after oral administration, but also that they cross the Blood-Brain-Barrier. The peptide nociceptine is also active in this assay, but in order to demonstrate its effect, it needs to be administered directly into the brain (by intracerebro -ventricular injection). SPECIFIC EXAMPLES OF SYNTHESES Synthesis of example 1 (see table below): Step 1. A solution of (-)-cis hydronopol (20 g, 0.12 mole) and triethylamine (41.6 ml, 0.30 mole) in dichloromethane (150 ml) was cooled to 0ºC and under ice-cooling a solution of mesylchloride (11.2 ml, 0.15 mole) in dichloromethane (50 ml) was dropwise added. After stirring at room temperature for 16 hours a solution of HCI (1N, 100 ml) was added. The aqueous layer was washed twice with 70 ml dichloromethane, and the combined organic layers were dried over magnesium sulphate and concentrated in vacuo. The mesylate was obtained as a yellow orange coloured oily product (27.7 g, 11 mole, 92% yield). Step 2. A stirred solution of 4-(1 -benzimidazolone) piperidine (ACROS, 6.51 g, 30 mmole), the mesylate obtained in the previous reaction step (8.9 g, 36 mmole), potassium carbonate (16.8 g, 120 mmole) and sodium iodide (5.4 g, 36 mmole) in methyl ethyl ketone (800 ml) was heated under N2 at 80°C for 16 hours. After concentration of the reaction mixture in vacuo, dichloromethane (500 ml) and 30 aqueous NaHC03 (5%, 300 ml) were added. The aqueous layer was washed with dichloromethane (2 times 80 ml) and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane :methanol:ammonia (94.5:5:0.5) as the eluent. A solution of the pure product resulting after concentration in vacuo (7.5 g, 20 mmole, 68% yield) was dissolved in a solution of WO 2005/032547 PCT/EP2004/052392 9 HC1 in absolute ethanol (60 ml). Concentration in vacuo of the resulting solution at 30°C afforded the HCI salt of example 1 (8.25 g, 20 mmole, quantitative yield) as a white amorphous solid with a M+of 368 m/z and a melting point of 167-174°C Synthesis of example 43 Step 1. Triphenylphosphine (116 g, 0.44 mole) was dissolved in acetonitriie (1 liter) and cooled in an ice bath under N2 atmosphere. Bromine (22.5 ml, 0.44 mole) was added dropwise. The temperature of the exothermic reaction was maintained below 10 10°C. After complete addition the ice bath was removed and (-)-trans-myrtanoI (68.8 g, 0.44 mole, Aldrich) dissolved in 250 ml acetonitriie was slowly added. After complete addition the light yellow solution was refluxed for 3 hours using a Dean-Stark equipment, under removal of about 200 ml of solvent from the water trap. The resulting reaction mixture was concen-trated in vacuo. The crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane -diethylether (1:1 v/v) as the eluent. The pure product was obtained as a light yellow oil (87.8 g , 41 mmole, 93 % yield) Step 2. The obtained myrtanylbromide (87.8 g, 0.41 mole) was dissolved in 1 liter dimethylformamide. Sodium cyanide (40 g, 0.81 mole) was added and the mixture was stirred at reflux for 5 hours. After cooling the mixture was diluted with water (3 liter) and extracted with methyl f-butyl ether (3 times 1.5 liter). The organic layer was washed with brine (300 ml), dried over Na2S04 and concentrated in vacuo. The crude product was purified by column chroma -tography (silicagel) with a mixture of dichloromethane-heptane (1:1 v/v) as the eluent The pure product was obtained as a colorless liquid (52.4 g , 0.32 mole, 78 % yield). Step 3. Sulphuric acid (190 ml) was added dropwise to 500 ml ethanol cooled in an ice bath. A solution of the obtained myrtanyl cyanide (52.4 g, 0.32 mole) in ethanol (100 ml) was added and the mixture was stirred at reflux for 16 hours. After cooling and addition of 1.5 liter water, the mixture was extracted three times with 1.5 liter methyl t-butyl ether. The organic layer was washed with saturated aqeous NaHCO 3 (1 liter), dried over Na2So4 and concentrated in vacuo. The crude ester (54.2 g, 0.26 mole, 81 % yield) was obtained as a nearly colorless liquid. WO2005/032547 PCT/EP2004/052392 10 Step 4. The ester obtained in the previous reaction step (54.2 g, 0.26 mole) was added to a suspension of lithium aluminium hydride (20 g, 0.52 mole) in tetrahydrofuran (1 liter). After complete addition the mixture was r efluxed for 1 hour. After cooling in an ice bath 1 liter of aqueous HCl (1N) was carefully added. After complete addition, the mixture was further diluted with 1 liter of water and three times extracted with 1.5 liter methyl t-butyl ether. The organic layer was washed with brine (250 ml), dried over Na2SO4 and concentrated in vacuo. The crude mixture was purified by Kugelrohr distillation (bp 85°C at 3.10-2 mbar) giving 35 g (0.17 mole, 65%) of the (-)-trans hydronopol as a colourless oil. Step 5. A solution of the prepared (-)-trans hydronopol (5 gr, 28 mmole) and triethylamine (9.4 ml, 68 mmole) in dichloromethane (50 ml) was cooled to 0 °C. Under ice-cooling a solution of mesylchloride (2.7 ml, 35 mmole) in dichloromethane (13 ml) was dropwise added. After stirring at room temperature for 16 hours asolution of HCl (1N, 50 ml) was added. The aqueous layer was washed with dichloromethane (2 times 30 ml) and the combined organic layers were dried over magnesium sulphate and concentrated in vacuo. The mesylate was purified by column chromatography (silicagel) with a mixture of dichloromethane-methanol (90:10) as the eluent The pure product was obtained as a colorless liquid (5.6 g , 23 mmole, 81 % yield). Step 6. A stirred solution of 4-(1-benzimidazolone) piperidine (ACROS, 1.8 g, 8.3 mmole), the mesylate obtained in the previous reaction step (2.5 g, 10 mmole), potassium carbonate (4.7 g, 34 mmole) and sodium iodide (1.5 g, 10 mmole) in methyl ethyl ketone (300 ml) was heated under N2 at 80°C for 16 hours. After concentration of the reaction mixture in vacuo, diisopropylether (300 ml) was added. The obtained light yellow precipitate was filtered off, washed with petroleum ether (100 ml) ands dried in vacuo. The precipitate was once more dissolved in refluxing ether (300 ml) and filtered to remove base-line material. The precipitate obtained after cooling was collected by filtration and dried in vacuo to give 1.85 g, (5 mmole, 61% yield) of the pure product as a white amorphous solid with a M+ of 368 m/z and a melting range of 220-239°C WO2005/032547 PCT/EP2004/0S2392 11 5 10 Synthesis of Example 17. Step 1. A solution of 3-fluoro-4-nitrotoluene (Aldrich, 4.65 gr, 30 mmole), 4 -amino-1-benzyl-piperidine (Aldrich, 6.1 ml, 30 mmole), K2CO3 (6.63 gr, 48 mmole) in dimethylformamide (50 ml) was stirred at 65°C under N2 for 18 hours. After cooling to room temperature the mixture was poured into water (200 ml)-dichloromethane (350 ml). The aqueous layer was extracted with dichloromethane (two times 70 ml) and the combined organic layers were washed with water (two times 50 ml), dried over MgSO4 and concentrated in vacuo. The resulting crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane-methanol (97:3) as the eluent After concentration in vacuo the pure product was obtained as a yellow oily substance (9.1 gr, 28 mmole, 93% yield). Step 2. A portion of Raney-Ni (Aldrich R 2800 [7440-02-0], approximately 600 mg) was washed with 96% ethanol (twice 10 ml) and subsequently added under N2 to a solution of the product from the previous reaction step (9.1 g, 28 mmole) in 96% ethanol (200 ml). The solution was hydrogenated at room temperature and a pressure of 1 atmosphere for 18 hours. The mixture was subsequently filtered over Hyfio, washed with 96% ethanol (3 times 100 ml) and the filtrate concentrated in vacuo and two times co-evaporated with ethyl acetate to give the reduced product as a purple oily substance (8.3 g, 28 mmole, 100% yield). Step 3. To a solution of the product from the previous step (8.3 g, 28 mmo le) in acetonitrile (100 ml), stirred at room temperature under nitrogen, a portion of 1,1’ -carbonyldiimidazole (ACROS, 6.5 g, 40 mmole) was added. The precipitate, starting to form at 5 minutes and increasing up to 3 hours, was collected by"filtration, washed with acetonitrile (20 ml) and diisopropylether (100 ml) and dried in vacuo. The crude product (5.5 g) was purified by column chromatography (silicagel) with a mixture of dichloromethane-methanol (95 : 5) as the eluent. After concentration in vacuo the pure product was obtained as a white solid (5.0 g, 15 mmole, 55% yield). Step 4. To a solution of 5.0 g (15 mmole ) of the product from the previous step in300 ml methanol stirred under N2, a 1N alcoholic HCI solution prepared from 1.22 g (15 mmole) acetyl chloride in 50 ml absolute ethanol) was added. After addition of 10% P /C (approximately 500 mg) the mixture was hydrogenated at room WO 2005/032547 PCT/EP2004/052392 12 temperature and a pressure of 1 atmosphere for 2½ hours. The mixture was subsequently filtered over Hyflo, washed with methanol (2 times 100 ml) and the filtrate concentrated in vacuo, giving 4.15 g (15 mmole, 100% yield) of the product as a white solid. Step 5. A stirred solution of the product from the previous step (4.15 g, 15 mmole), the mesylate from Step 1 of Example 1 (8.9 g, 16 mmole), potassium carbonate (10.4 g, 75 mmole) and sodium iodide (2.4 g, 16 mmole) in methyl ethyl ketone (250 ml) was heated under N2 at 80ºC for 16 hours. After concentration of the reaction mixture in vacuo, dichloromethane (500 ml) and aqueous NaHCO3 (5%, 300 ml) were added. The aqueous layer was washed with dichlorometfiane (2 times 80 ml) and the combined organic layers were dried over MgS04 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with a mixture of dichloromethane- methanol-ammonia (92:7.5:0.5) as the eluent.Concentration in vacuo gave the pure product (5.0 g, 13 mmole) as an oily substance. After addition of 100 ml diisopropylether to this oil and stirring at room temperature for 30 minutes, the product precipitated as a white solid. The solid was collected by filtration and dried in vacuo to give 3.3 g (8.6 mmole, 57 % yield) with a M+ of 382 m/z and a melting point of 214-217°C By these and comparable methods, 45 specific examples were synthesized. They are intended to further illustrate the invention in more detail, and therefore are not deemed to restrict the scope of the invention in any way. Structural information of these compounds, all represented by the general formula (1), is presented in the table below. WO 2005/032547 PCT/EP2004/052392 13 Substitution pattern stereo nr R1 m R2 n A O P R3 R4 R6 R5 q 1 2 4 1 H 0 - 0 sat 1 1 H H H H 0 S S S 2 H 1 - 0 sat 1 1 H H H H 0 S S S 3 CH3 0 - 0 sat 1 1 H H H H 0 S S S 4 CH3 1 - 0 sat 1 1 H H H H 0 S S S 5 H 0 4-F 1 sat 1 1 H H H H 0 S S S 6 H 0 5-F 1 sat 1 1 H H H H 0 S S S 7 H 0 6-F 1 sat 1 1 H H H H 0 S S S 8 H 0 7-F 1 sat 1 1 H H H H 0 S S S 9 H 0 5-CF3 1 sat 1 1 H H H H 0 S S S 10 H 0 6-CF3 1 sat 1 1 H H H H 0 S S S 11 H 0 4-CI 1 sat 1 1 H H H H 0 S S S 12 H 0 5-CI 1 sat 1 1 H H H H 0 S S S 13 H 0 6-CI 1 sat 1 1 H H H H 0 S S S 14 H 0 7-CI 1 sat 1 1 H H H H 0 S S S 15 H 0 4-CH3 1 sat 1 1 H H H H 0 S S S 16 H 0 5-CH3 1 sat 1 1 H H H H 0 S S S 17 H 0 6-CH3 1 sat 1 1 H H H H 0 S S S 18 H 0 7-CH3 1 sat 1 1 H H H H 0 S S S 19 H 0 4-OCH3 1 sat 1 1 H H H H 0 S S S 20 H 0 5-OCH3 1 sat 1 1 H H H H 0 S S S 21 H 0 6-OCH3 1 sat 1 1 H H H H 0 S S S 22 H 0 6-OH 1 sat 1 1 H H H H 0 S S S 23 H 0 6-NHCOCH3 1 sat 1 1 H H H H 0 S S S 24 H 0 6-CN 1 sat 1 1 H H H H 0 S S S 25 H 0 6-CH2CN 1 sat 1 1 H H H H 0 S S S 26 H 0 6-SO2CH3 1 sat 1 1 H H H H 0 S S S 27 H 0 6-S02CF3 1 sat 1 1 H H H H 0 S S S 28 H 0 6-COCH3 1 sat 1 1 H H H H 0 S S S 29 H 0 6-COCF3 1 sat 1 1 H H H H 0 S S S 30 H 0 6-CONH2 1 sat 1 1 H H H H 0 S S S 31 H 0 6-OCF3 1 sat 1 1 H H H H 0 S S S WO2005/032547 PCT/EP2004/052392 14 32 H 0 6,7-F 2 sat 1 1 H H H H 0 S S S 33 H 0 4-F,6-OCH3 2 sat 1 1 H H H H 0 S S S 34 H 0 4-CH3,6-OCH3 2 sat 1 1 H H H H 0 S S S 35 H 0 - 0 uns 1 1 H H H H 0 S S S 36 H 0 - 0 sat 1 0 H H H H 0 S S S 37 H 0 - 0 sat 0 0 H H H H 0 S S S 38 H 0 - 0 sat 1 1 CH3 H H H 0 S S S 39 H 0 - 0 sat 1 1 H CH3 H H 0 S S S 40 H 0 - 0 sat 1 1 H H H CH3 0 S S S 41 H 0 - 0 sat 1 1 H H CH3 H 0 S S S 42 H 0 - 0 sat 1 1 H CH2 CH2 H 0 S S S 43 H 0 - 0 sat 1 1 H H H H 0 R S S 44 H 0 - 0 sat 1 1 H H H H 1 S S S 45 H 0 - 0 sat 1 1 H H H H 1 R S S 46 H 0 - 0 sat 1 1 H H H H 0 R R R 47 H 0 - 0 sat 1 1 H H H H 0 S R R nr R1 m R2 n A O P R3 R4 R6 R5 q 1 2 4 Substitution pattern stereo EXAMPLE OF FORMULATION OF COMPOUND AS USED IN ANIMAL STUDIES Formulation of example 1: For oral (p.o.) administration : to the desired quantity (0.5-5 mg) of the solid Example 1 in a glass tube, some glass beads were added and the solid was milled by vortexing for 2 minutes. After addition of 1 ml of a solution of 1% Methylcellulose in water and 2% (v/v) of Poloxamer 188 (Lutrol F68). the compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1 N). Remaining particles in the suspension were further suspended by using an ultrasonic bath. For intraperitoneal (i-P-) administration: to the desired quantity (0.5-15 mg) of the solid Example 1 in a glass tube, some glass beads were added and the solid was milled by vortexing for 2 minutes. After addition of 1 ml of a solution of 1% methylcellulose and 5% mannitol in water, the compound was suspended by vortexing for 10 minutes. Finally the pH was adjusted to 7 WO2005/032547 PCT/EP2004/052392 15 Pharmacological data afiinity In vitro agoagonism In vivo agonism ORL1 µ-opiate cAMP assay C.U. D.V.* i p p.o Ex PK1 PK1 PEC50 ED 50 ED 50 mg/kg mg/kg 1 8.4 7.2 8.6 1.4 6.0 2 7.8 7.3 8.5 7.4 *CUDV = conditioned Distress Vocztion; 5.i.p.=intrapertioneal administration;p.o=(per os) oral administration. WO 2005/032547 PCT/EP2004/052392 16 claims 1 Compounds of the general formula (1) wherein: R1 represents H, alkyl(1 -6C), alkyl(1 -3C)cycloalkyl(3-6C), carbalkoxy(2-7C) or acyl(2-7C), []m symbolizes -(CH2)m- wherein m is either 0 or 1, R2 represents halogen, CF3, alkyl(1-6C), alkyl(1-3C)cycloalkyl(3-6C), phenyl, amino, aminoalkyl(i -3C), alkyl(1-3C)amino, dialkyl(1-3C)-amino, cyano, cyanoa!kyl(1 -3C), hydroxy, hydroxyalkyl(1 -3C), (1-3C)alkoxy, OCF3, acyl(2-7C), trifluoro acetyl, aminocarboxyl, (1-3C)alkylsulphonyl or trifluoromethylsulphonyl, and n is an integer from 0-4, with the proviso that when n is 2, 3 or 4, the R2 substituents may be either the same or different, A is a saturated or partially unsaturated ring []0and [] p represent -(CH2)0- and -(CH2)P- respectively, with the proviso that 25also the meaning -CH- is possible when A is a partially nsaturated ring, and o and p independently are either 0, 1 or 2, R3, R4, R5 and Re independently represent hydrogen, alkyl(1 -3C), alkyl(1- 3C)- cydoalkyl(3-6C), CH2OH or (R3 and R5) or (R3 and R6) or (R4 and R5)or (R4 R5or(R4 R6) together can form an alkylene bridge of 1 to 3 carbon WO2005/032547 PCT/EP2004/052392 17 atoms, with the proviso that when o is 2, R3 is hydrogen, and when p is 2, R5 is hydrogen, []q symbolizes -(CH2)q- wherein q is an integer from 0 to 2 all stereoisomers, as well as pharmacologically acceptable salts and prodrugs thereof, prodrugs being derivatives of the compounds having formula (1) wherein a group is present which is easily removed after administration, such as amidine, enamine, a Mannich base, a hydroxyl- methylene derivative, an 0-(acyloxymethylene carbamate) derivative, carbamate, ester, amide orenaminone. 2 Compounds as claimed in claim 1 of the general formula (1) wherein A is a saturated ring, R1represents hydrogen, alkyl(1 -3C), or acyl(2-4C), R3, RA, R5 and R6 independently represent hydrogen or alkyl(1 -3C) or (R3 and R5) or (R3 and R6) or (R4 and R5) or (R4 and R6) together can form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, R3 is hydrogen, and when p is 2, Rs is hydrogen, and R2, m, n, o, p and q have the meanings as given in claim 1. 3 Compounds as claimed in claim 1 of the general formula (1) wherein: A is a saturated ring, m=0, n=0 or 1, o=1, p=1, q=0, R1=H or acetyl, R2 represents halogen, CF3, alkyl(1-3C), amino, hydroxy, cyano, OCH3 or OCF3, R3, R4, R5 and R6 independently represent hydrogen or alkyl(1 -2C) or (R4 and Re) together can form an alkylene bridge of 1 to 2 carbon atoms 4 Compound as claimed in claim 1 having formula (2) and stereoisomers thereof; WO 2005/032547 PCT7EP2004/052392 18 5. Pharmaceutical compositions containing a pharmacologically active amount of at least one of the compounds as claimed in any of the claims 1-4. 6. A compound as claimed in any of the claims 1 - 4, or a salt thereof, for use as a medicament 7. Use of a compound as claimed in any of the claims 1 - 4 for the preparation of a pharmaceutical composition for the treatment of disorders in which ORL1 receptors are involved, or that can be treated via manipulation of those receptors, 8. Use as claimed in claim 6 characterized in that said disorders are acute and chronic pain conditions, central nen/ous system disorders, especially, but not limited to amelioration of symptoms of anxiety and stress disorders, depression, various forms of epilepsy, stroke, disorders characterized by impairment of cognition and memory such as Alzheimer’s disease, Creutzfeldt-Jacob disease, Huntington’s disease, Parkinson’s disease, neurorehabilltation (post-traumatic brain lesions); acute brain or spinal cord injury, substance related disorders, including substance use disorders (like independence and abuse) and substance induced disorders (like substance withdrawal); eating disorders like anorexia nervosa and bulimia nervosa, obesity; gastro-intestinal disorders in particular irritable bowel syndrome, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), urinary tract inflammation,. renal disorders characterized by imbalances of water retention/excretion or salt excretion; cardiovascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma; respiratory disorders including cough, chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; diseases of the immune system, and viral infections.

Full Text

FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)
TITLE
Bicyclo3.1.1!heptane substituted benzimidazolone and quinazolinone derivatives as agonists on human orll receptors”
APPLICANT
SOLVAY PHARMACEUTICALS B.V.
C.J. van Houtenlaan 36
NL-1381 CP Weesp
The Netherlands
Nationality: a Dutch company
The following specification particularly describes the nature of this invention and the manner in which it is to be performed
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BICYCLOP’3.1.1 HEPTANE SUBSTITUTED BENZIMIDAZOLONE AND QUINAZOLINONE DERIVATIVES AS AGONISTS ON HUMAN ORL1 RECEPTORS

The present invention relates to a group of hydronopol substituted benzimidazolone and quinazolinone derivatives which are agonists on human ORL1 (nociceptin) receptors. The invention also relates to the preparation of these compounds, to pharmaceutical compositions containing a pharmacologically active amount of at least one of these novel benzimidazolone and quinazolinone derivatives as an active ingredient, as well as to the use of these pharmaceutical compositions for the treatment of disorders in which ORL1 receptors are involved.
The Opioid Receptor-Like 1’ (ORL1) receptor was identified from a human cDNA library. It was established that this ‘orphan receptor’ has a close homology with n-, K- and δ-opioid receptors (Mollereau etal., FEBS Lett., 341. 33-38, 1994; Bunzow et al., FEBS Lett., 347, 284-288, 1994). Despite its close sequential and structural resemblance with opioid receptors, classical opioid receptor ligands do not to interact with ORL1 receptors. In 1995 a 17-amino acid neuropeptide was purified from brain extracts, and subsequently shown to be the natural ligand of the G protein-coupled ORL1 receptor (Reinscheid et al., Science. 270. 792-794, 1995; Meunier et al., Nature. 377. 532-535, 1995). This peptide was named orphanin FQ or nociceptin and it does not bind to the three traditional opioid receptors. These findings triggered substantial research into the functional role of, and novel ligands for, the ORL1 receptor. That resulted in several hundreds of publications, including several reviews (see e.g. Grand et a/., Anaesthesist, 51, 996-1005, 2002), and dozens of patent applications, describing both peptide and non-peptide ligands, varying in potency and selectivity (ORL-1 versus µ-opiate). As µ-opiate receptors are widely distributed throughout the body, a lack of selectivity might lead to a range of undesired opiate-like side-effects e.g. sedation, respiratory depression, tolerance and dependence (Drug News Perspect, 14. 335, 2001). Six of the ORL1 related patent applications concern benzimidazolone derivatives: WO 98/54168, WO 99/36421, WO 00/08013, WO 00/006545, WO 01/39775, and US 20020128288.
The prior art closest to the present invention is WO 01/39775. However, the benzimidazolone derivatives described therein do not seem to meet the criteria
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generally acknowledged to be of importance for useful ORL1 based therapeutic agents. They are characterized by:
(1) modest potency (affinities for ORL1 receptors in the range of 166 - 1252 nM);
(2) lack of selectivity towards µ-opiate receptors (affinities in the range 19 -457 nM;
(3) no evidence for availability after oral administration, and
(4) no evidence for CNS-availability.
Surprisingly, it has now been found that in a series of hydronopyl substituted
benzimidazolone and quinazolinone derivatives, a group of compounds was shown to have a very high affinity for human ORL1 receptors. Moreover, these compounds show an excellent selectivity for ORL1 receptors relative to µ-opiate receptors, are readily available after oral administration and do penetrate the Blood-Brain-Barrier.
The invention relates to compounds of the general formula (1)
wherein:
Ri represents H, alkyl(1-6C), alkyl(-3C)cycloalkyI(3-6C), carbalkoxy(2-7C) or acyl(2-7C),
[]m symbolizes — (CH2)m- wherein m is either 0 or 1,
R2 represents halogen, CF3, alkyl(1-6C), alkyl(1-3C)cycloalky](3-6C), phen yl, amino, aminoalkyl(1-3C), alkyl(1-3C)amino, dialkyi(1-3C)amino, cyano, cyanoalkyl(1-3C), hydroxy, hydroxyalkyl(1-3C), (1-3C)alkoxy, OCF3, acyl(2-7C), trifluoroacetyl, aminocarboxyl, (1-3C)alkylsuIphonyl or trifluoromethylsulphonyl, and n is an integer from 0-4, with the proviso that when n is 2, 3 or 4, the R2 substituents may be either the same or different
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A is a saturated pr partially unsaturated ring
[] and [ ]p represent -(CH2)o- and –(CH2)p- respectively, with the proviso that also the meaning -CH- is possible when A is a partially unsaturated ring, and o and p independently are either 0, 1 or 2,
R3, R4. R5 and Re independently represent hydrogen, alkyl(1-3C), alkyl(1-3C)- cycloalkyl(3-6C), CH2OH or (R3 and R5) or (R3 and R6) or (R4 and Rs) or (R4 and R6) together can form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, R3 is hydrogen, and when p is 2, R5is hydrogen,
[]q symbolizes —(CH2)q- wherein q is an integer from 0 to 2
and pharmacologically acceptable salts and prodrugs thereof.
To the invention belong all compounds having formula (1), racemates, mixtures of diastereomers and the individual stereoisomers. Thus compounds in which the substituents on potentially asymmetrical carbon atoms are in either the R-configuration or the S-configuration belong to the invention. Also prodrugs, i.e. compounds which when administered to humans by any known route, are metabolised to compounds having formula (1), belong to the invention. In particular this relates to compounds with primary or secondary amino or hydroxy groups. Such compounds can be reacted with organic acids to yield compounds having formula (I) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxymethylene derivative, an 0-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone. A prodrug is an inactive compound, which when absorbed is converted into an active form (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F. D. King, p. 216).
The invention particularly relates to compounds having formula (1) wherein :
A is a saturated ring,
R1 represents hydrogen, alkyl(1 -3C), or acyl(2-4C),

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R3, R4, R5 and R6 independently represent hydrogen or alkyl(1-3C) or (R3 and R5) or (R3 and R6) or (R4 and R5) or (R4 and R6) together can form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, R3 is hydrogen, and when p is 2, Rs is hydrogen, and R2, m, n, o. p and q have the meanings as given above.
More particular the invention relates to compounds of formula (1) wherein:
A is a saturated ring, m=0, n=0 or 1, o=1, p=1, q=0, R1 =H or acetyl, R2 represents halogen, CF3, alkyl(1-3C), amino, hydroxy, cyano, OCH3 or OCF3, R3, R4, R5 and R6 independently represent hydrogen or alkyl(1-2C) or (R4 and R6) together can form an alkylene bridge of 1 to 2 carbon atoms
Even more preferred is the compound having formula (2) and all its stereoisomers.

The compounds of the invention and their salts can be obtained according to the general route outlined below.

Starting compounds for this general route are ob tained as follows:

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Benzimidazolones (m=0) can be synthesized according to the methods described in J. Med. Chem.. 30, 814-819, 1987 and WO 99/36421 (Pfizer). Quinazolones (m=1) can be synthesized according to Chem. Pharm. Bull.. 33. 1116-1128, 1985.
Hydronopol-derivatives with X as leaving group (halogen, mesylate, tosylate) can be
synthesized from the corresponding alcohols following standard procedures. The corresponding alcohols can be synthesized as follows:
• for the cis analog with q = 0 from (-}-β-pinene as described in J. Amer. Chem. Soc. 68. 638,1946 and US patents 2,427,345 and 2.427.345
• for the trans analog with q = 0 from trans-myrtano! as described in Bull. 10 Soc. Chim. Fr.. 196, 1958 or via a slightly alternative procedure (bromination of the alcohol, substitution by cyano, conversion to the ethylester and reduction to the desired alcohol)
• for both the cis and trans analogs with q = 1 or 2, by one or two cycles of an analogous homologation procedure as described for the synthesis of the trans analog with q = 0 from trans-myrtanol.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid such as hydrochloric acid, or with an organic acid.

The compounds of the invention of the general formula (1), as well as the salts thereof, have ORL1 agonistic activity. They are useful in the treatment of disorders in which ORL1 receptors are involved, or that can be treated via manipulation of those receptors. For instance in acute and chronic pain conditions, central nervous system disorders, especially, but not limited to amelioration of symptoms of anxiety and stress disorders, depression, various forms of epilepsy, stroke, disorders characterized by impairment of cognition and memory such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain lesions); acute brain or spinal cord injury, substance related disorders, including substance use disorders (like dependence and abuse) and substance induced disorders (like substance withdrawal); eating disorders like anorexia nervosa and bulimia nervosa, obesity; gastro-intestinal disorders in particular irritable bowel syndrome, inflammatory bowel disease(Crohn’s disease and ulcerative colitis), urinary tract inflammation, renal disorders characterized by imbalances of water retention/excretion or salt excretion

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cardiovascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma; respiratory disorders including cough, chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; diseases of the immune system, and viral infections.
The in vitro and in vivo ORL1 receptor agonistic properties of the compounds of the invention were determined using the methods outlined below.

Affinity for human ORL1 receptors
Affinity of the compounds for human ORL1 receptors was determined using the in vitro receptor binding assay described by Ardati et al., Mol. Pharmacol.. 51. 816,1997. Briefly, membrane preparations were obtained from CHO (Chinese Hamster Ovary)-cel!s in which the human ORL1 receptor was stably expressed. Membranes were incubated with [3H]-nociceptin in the absence or presence of test-compounds in different concentrations, diluted in a suitable buffer. Non-specific binding was defined as binding remaining in the presence of 10-6 M nociceptin. Separation ofbound radioactivity from free was done by filtration through Packard GF/B glass fiber filters with several washings with ice-cold buffer using a Packard cell harvester. Bound radioactivity was measured with a scintillation counter (Topcount, Packard) using a liquid scintillation cocktail (Microscint 0, Packard). Measured radioactivity was plotted against the concentration of the displacing test compound and displacement curves were calculated by four-parameter logistic regression, resulting in IC50 values, i.e. that concentration of displacing compound by which 50% of the radioligand is displaced. Affinity pK1 values were calculated by correcting the IC50 values for radioligand concentration and its affinity for the human ORL1 receptor according to the Cheng-Prusoff equation:
pK1= -log(lC50/(1+S/Kd))
in which the IC50 is as described above, S is the concentration [3H]- ociceptin used in the assay expressed in mol/l (typically 0.2 nM), and Kd is the equilibrium dissociation constant of [3H]-nociceptin for human ORL1 receptors (0.4 nM).

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The compounds of the invention have a high affinity for ORL1 receptors in the binding assay described above. This property makes them useful in the treatment of disorders in which ORL1 receptors are involved, or that can be treated via manipulation of these receptors.

Affinity for µ-opiate receptors
Affinity of the compounds for µ-opiate receptors was determined using the in vitro receptor binding assay described by Childers et a/, Eur. J. Pharm 55, 11, 1979.Briefly, membrane preparations were obtained from CHO-cells in which the human µ-opiate receptor was stably expressed, and were incubated with the [3H]-naloxone in the absence or presence of test-compounds in a concentration range from 10 uM down to 0.1 nM, diluted in a suitable buffer. Non specific binding was defined as binding remaining in the presence of 10-7 M levallorphan.tartrate. Separation ofbound radioactivity from free was done as described above, and the affinity of the compounds was calculated in a similar way, using a concentration (S) of 1 nM [3H]-naloxone and with a Kd value of 1.3 nM.
Most of the compounds of the invention have a low affinity for µ-opiate receptors in the binding assay described above: typically a factor 100 below their affinity for ORL1 receptors. Thus they are unlikely to evoke the unwanted side effects known to occur with opiates like morphine.
In vitro ORL1 receptor agonism

Activation of the G protein-coupled ORL1 receptor inhibits adenylate cyclase activity and reduces the intracellular concentration of the second messager cAMP. Using the assay as decribed by Jenck et a/., Proc. Natl. Acad. Sci USA 97. 4938-4943, 2000, the activity of the compounds on ORL1 receptors was measured. They were
demonstrated to be potent agonists with pEC50-values matching their pK1 values.
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In vivo ORL1 receptor agonism
After intraperitoneal and/or oral administration the compounds of the invention were shown to be highly active in the conditioned ultrasonic distress vocalisation procedure as described by Molewijk et al., Psvchopharmacologv. 117. 32-40, 1995. This demonstrates not only that the compounds have a good bioavailability after oral administration, but also that they cross the Blood-Brain-Barrier. The peptide nociceptine is also active in this assay, but in order to demonstrate its effect, it needs to be administered directly into the brain (by intracerebro -ventricular injection).
SPECIFIC EXAMPLES OF SYNTHESES
Synthesis of example 1 (see table below):

Step 1. A solution of (-)-cis hydronopol (20 g, 0.12 mole) and triethylamine (41.6 ml, 0.30 mole) in dichloromethane (150 ml) was cooled to 0ºC and under ice-cooling a solution of mesylchloride (11.2 ml, 0.15 mole) in dichloromethane (50 ml) was dropwise added. After stirring at room temperature for 16 hours a solution of HCI (1N, 100 ml) was added. The aqueous layer was washed twice with 70 ml dichloromethane, and the combined organic layers were dried over magnesium sulphate and concentrated in vacuo. The mesylate was obtained as a yellow orange coloured oily product (27.7 g, 11 mole, 92% yield).

Step 2. A stirred solution of 4-(1 -benzimidazolone) piperidine (ACROS, 6.51 g, 30 mmole), the mesylate obtained in the previous reaction step (8.9 g, 36 mmole), potassium carbonate (16.8 g, 120 mmole) and sodium iodide (5.4 g, 36 mmole) in methyl ethyl ketone (800 ml) was heated under N2 at 80°C for 16 hours. After concentration of the reaction mixture in vacuo, dichloromethane (500 ml) and 30 aqueous NaHC03 (5%, 300 ml) were added. The aqueous layer was washed with dichloromethane (2 times 80 ml) and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane :methanol:ammonia (94.5:5:0.5) as the eluent. A solution of the pure product resulting after concentration in vacuo (7.5 g, 20 mmole, 68% yield) was dissolved in a solution of

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HC1 in absolute ethanol (60 ml). Concentration in vacuo of the resulting solution at 30°C afforded the HCI salt of example 1 (8.25 g, 20 mmole, quantitative yield) as a white amorphous solid with a M+of 368 m/z and a melting point of 167-174°C
Synthesis of example 43
Step 1. Triphenylphosphine (116 g, 0.44 mole) was dissolved in acetonitriie (1 liter) and cooled in an ice bath under N2 atmosphere. Bromine (22.5 ml, 0.44 mole) was added dropwise. The temperature of the exothermic reaction was maintained below 10 10°C. After complete addition the ice bath was removed and (-)-trans-myrtanoI (68.8 g, 0.44 mole, Aldrich) dissolved in 250 ml acetonitriie was slowly added. After complete addition the light yellow solution was refluxed for 3 hours using a Dean-Stark equipment, under removal of about 200 ml of solvent from the water trap. The resulting reaction mixture was concen-trated in vacuo. The crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane -diethylether (1:1 v/v) as the eluent. The pure product was obtained as a light yellow oil (87.8 g , 41 mmole, 93 % yield)
Step 2. The obtained myrtanylbromide (87.8 g, 0.41 mole) was dissolved in 1 liter dimethylformamide. Sodium cyanide (40 g, 0.81 mole) was added and the mixture was stirred at reflux for 5 hours. After cooling the mixture was diluted with water (3 liter) and extracted with methyl f-butyl ether (3 times 1.5 liter). The organic layer was washed with brine (300 ml), dried over Na2S04 and concentrated in vacuo. The crude product was purified by column chroma -tography (silicagel) with a mixture of dichloromethane-heptane (1:1 v/v) as the eluent The pure product was obtained as a colorless liquid (52.4 g , 0.32 mole, 78 % yield).
Step 3. Sulphuric acid (190 ml) was added dropwise to 500 ml ethanol cooled in an ice bath. A solution of the obtained myrtanyl cyanide (52.4 g, 0.32 mole) in ethanol (100 ml) was added and the mixture was stirred at reflux for 16 hours. After cooling and addition of 1.5 liter water, the mixture was extracted three times with 1.5 liter methyl t-butyl ether. The organic layer was washed with saturated aqeous NaHCO 3 (1 liter), dried over Na2So4 and concentrated in vacuo. The crude ester (54.2 g, 0.26 mole, 81 % yield) was obtained as a nearly colorless liquid.

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Step 4. The ester obtained in the previous reaction step (54.2 g, 0.26 mole) was added to a suspension of lithium aluminium hydride (20 g, 0.52 mole) in tetrahydrofuran (1 liter). After complete addition the mixture was r efluxed for 1 hour. After cooling in an ice bath 1 liter of aqueous HCl (1N) was carefully added. After complete addition, the mixture was further diluted with 1 liter of water and three times extracted with 1.5 liter methyl t-butyl ether. The organic layer was washed with brine (250 ml), dried over Na2SO4 and concentrated in vacuo. The crude mixture was purified by Kugelrohr distillation (bp 85°C at 3.10-2 mbar) giving 35 g (0.17 mole, 65%) of the (-)-trans hydronopol as a colourless oil.

Step 5. A solution of the prepared (-)-trans hydronopol (5 gr, 28 mmole) and triethylamine (9.4 ml, 68 mmole) in dichloromethane (50 ml) was cooled to 0 °C. Under ice-cooling a solution of mesylchloride (2.7 ml, 35 mmole) in dichloromethane (13 ml) was dropwise added. After stirring at room temperature for 16 hours asolution of HCl (1N, 50 ml) was added. The aqueous layer was washed with dichloromethane (2 times 30 ml) and the combined organic layers were dried over magnesium sulphate and concentrated in vacuo. The mesylate was purified by column chromatography (silicagel) with a mixture of dichloromethane-methanol (90:10) as the eluent The pure product was obtained as a colorless liquid (5.6 g , 23 mmole, 81 % yield).
Step 6. A stirred solution of 4-(1-benzimidazolone) piperidine (ACROS, 1.8 g, 8.3 mmole), the mesylate obtained in the previous reaction step (2.5 g, 10 mmole), potassium carbonate (4.7 g, 34 mmole) and sodium iodide (1.5 g, 10 mmole) in methyl ethyl ketone (300 ml) was heated under N2 at 80°C for 16 hours. After concentration of the reaction mixture in vacuo, diisopropylether (300 ml) was added. The obtained light yellow precipitate was filtered off, washed with petroleum ether (100 ml) ands dried in vacuo. The precipitate was once more dissolved in refluxing ether (300 ml) and filtered to remove base-line material. The precipitate obtained after cooling was collected by filtration and dried in vacuo to give 1.85 g, (5 mmole, 61% yield) of the pure product as a white amorphous solid with a M+ of 368 m/z and a melting range of 220-239°C

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5

10
Synthesis of Example 17.
Step 1. A solution of 3-fluoro-4-nitrotoluene (Aldrich, 4.65 gr, 30 mmole), 4 -amino-1-benzyl-piperidine (Aldrich, 6.1 ml, 30 mmole), K2CO3 (6.63 gr, 48 mmole) in dimethylformamide (50 ml) was stirred at 65°C under N2 for 18 hours. After cooling to room temperature the mixture was poured into water (200 ml)-dichloromethane (350 ml). The aqueous layer was extracted with dichloromethane (two times 70 ml) and the combined organic layers were washed with water (two times 50 ml), dried over MgSO4 and concentrated in vacuo. The resulting crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane-methanol (97:3) as the eluent After concentration in vacuo the pure product was obtained as a yellow oily substance (9.1 gr, 28 mmole, 93% yield).
Step 2. A portion of Raney-Ni (Aldrich R 2800 [7440-02-0], approximately 600 mg) was washed with 96% ethanol (twice 10 ml) and subsequently added under N2 to a solution of the product from the previous reaction step (9.1 g, 28 mmole) in 96% ethanol (200 ml). The solution was hydrogenated at room temperature and a pressure of 1 atmosphere for 18 hours. The mixture was subsequently filtered over Hyfio, washed with 96% ethanol (3 times 100 ml) and the filtrate concentrated in vacuo and two times co-evaporated with ethyl acetate to give the reduced product as a purple oily substance (8.3 g, 28 mmole, 100% yield).
Step 3. To a solution of the product from the previous step (8.3 g, 28 mmo le) in acetonitrile (100 ml), stirred at room temperature under nitrogen, a portion of 1,1’ -carbonyldiimidazole (ACROS, 6.5 g, 40 mmole) was added. The precipitate, starting to form at 5 minutes and increasing up to 3 hours, was collected by"filtration, washed with acetonitrile (20 ml) and diisopropylether (100 ml) and dried in vacuo. The crude product (5.5 g) was purified by column chromatography (silicagel) with a mixture of dichloromethane-methanol (95 : 5) as the eluent. After concentration in vacuo the pure product was obtained as a white solid (5.0 g, 15 mmole, 55% yield).
Step 4. To a solution of 5.0 g (15 mmole ) of the product from the previous step in300 ml methanol stirred under N2, a 1N alcoholic HCI solution prepared from 1.22 g (15 mmole) acetyl chloride in 50 ml absolute ethanol) was added. After addition of 10% P /C (approximately 500 mg) the mixture was hydrogenated at room
WO 2005/032547 PCT/EP2004/052392
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temperature and a pressure of 1 atmosphere for 2½ hours. The mixture was subsequently filtered over Hyflo, washed with methanol (2 times 100 ml) and the filtrate concentrated in vacuo, giving 4.15 g (15 mmole, 100% yield) of the product as a white solid.

Step 5. A stirred solution of the product from the previous step (4.15 g, 15 mmole), the mesylate from Step 1 of Example 1 (8.9 g, 16 mmole), potassium carbonate (10.4 g, 75 mmole) and sodium iodide (2.4 g, 16 mmole) in methyl ethyl ketone (250 ml) was heated under N2 at 80ºC for 16 hours. After concentration of the reaction mixture in vacuo, dichloromethane (500 ml) and aqueous NaHCO3 (5%, 300 ml) were added. The aqueous layer was washed with dichlorometfiane (2 times 80 ml) and the combined organic layers were dried over MgS04 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with a mixture of dichloromethane- methanol-ammonia (92:7.5:0.5) as the eluent.Concentration in vacuo gave the pure product (5.0 g, 13 mmole) as an oily substance. After addition of 100 ml diisopropylether to this oil and stirring at room temperature for 30 minutes, the product precipitated as a white solid. The solid was collected by filtration and dried in vacuo to give 3.3 g (8.6 mmole, 57 % yield) with a M+ of 382 m/z and a melting point of 214-217°C

By these and comparable methods, 45 specific examples were synthesized. They are intended to further illustrate the invention in more detail, and therefore are not deemed to restrict the scope of the invention in any way. Structural information of these compounds, all represented by the general formula (1), is presented in the table below.

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Substitution pattern stereo
nr R1 m R2 n A O P R3 R4 R6 R5 q 1 2 4

1 H 0 - 0 sat 1 1 H H H H 0 S S S
2 H 1 - 0 sat 1 1 H H H H 0 S S S
3 CH3 0 - 0 sat 1 1 H H H H 0 S S S
4 CH3 1 - 0 sat 1 1 H H H H 0 S S S
5 H 0 4-F 1 sat 1 1 H H H H 0 S S S
6 H 0 5-F 1 sat 1 1 H H H H 0 S S S
7 H 0 6-F 1 sat 1 1 H H H H 0 S S S
8 H 0 7-F 1 sat 1 1 H H H H 0 S S S
9 H 0 5-CF3 1 sat 1 1 H H H H 0 S S S
10 H 0 6-CF3 1 sat 1 1 H H H H 0 S S S
11 H 0 4-CI 1 sat 1 1 H H H H 0 S S S
12 H 0 5-CI 1 sat 1 1 H H H H 0 S S S
13 H 0 6-CI 1 sat 1 1 H H H H 0 S S S
14 H 0 7-CI 1 sat 1 1 H H H H 0 S S S
15 H 0 4-CH3 1 sat 1 1 H H H H 0 S S S
16 H 0 5-CH3 1 sat 1 1 H H H H 0 S S S
17 H 0 6-CH3 1 sat 1 1 H H H H 0 S S S
18 H 0 7-CH3 1 sat 1 1 H H H H 0 S S S
19 H 0 4-OCH3 1 sat 1 1 H H H H 0 S S S
20 H 0 5-OCH3 1 sat 1 1 H H H H 0 S S S
21 H 0 6-OCH3 1 sat 1 1 H H H H 0 S S S
22 H 0 6-OH 1 sat 1 1 H H H H 0 S S S
23 H 0 6-NHCOCH3 1 sat 1 1 H H H H 0 S S S
24 H 0 6-CN 1 sat 1 1 H H H H 0 S S S
25 H 0 6-CH2CN 1 sat 1 1 H H H H 0 S S S
26 H 0 6-SO2CH3 1 sat 1 1 H H H H 0 S S S
27 H 0 6-S02CF3 1 sat 1 1 H H H H 0 S S S
28 H 0 6-COCH3 1 sat 1 1 H H H H 0 S S S
29 H 0 6-COCF3 1 sat 1 1 H H H H 0 S S S
30 H 0 6-CONH2 1 sat 1 1 H H H H 0 S S S
31 H 0 6-OCF3 1 sat 1 1 H H H H 0 S S S

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32 H 0 6,7-F 2 sat 1 1 H H H H 0 S S S
33 H 0 4-F,6-OCH3 2 sat 1 1 H H H H 0 S S S
34 H 0 4-CH3,6-OCH3 2 sat 1 1 H H H H 0 S S S
35 H 0 - 0 uns 1 1 H H H H 0 S S S
36 H 0 - 0 sat 1 0 H H H H 0 S S S
37 H 0 - 0 sat 0 0 H H H H 0 S S S
38 H 0 - 0 sat 1 1 CH3 H H H 0 S S S
39 H 0 - 0 sat 1 1 H CH3 H H 0 S S S
40 H 0 - 0 sat 1 1 H H H CH3 0 S S S
41 H 0 - 0 sat 1 1 H H CH3 H 0 S S S
42 H 0 - 0 sat 1 1 H CH2 CH2 H 0 S S S
43 H 0 - 0 sat 1 1 H H H H 0 R S S
44 H 0 - 0 sat 1 1 H H H H 1 S S S
45 H 0 - 0 sat 1 1 H H H H 1 R S S
46 H 0 - 0 sat 1 1 H H H H 0 R R R
47 H 0 - 0 sat 1 1 H H H H 0 S R R

nr R1 m R2 n A O P R3 R4 R6 R5 q 1 2 4

Substitution pattern stereo

EXAMPLE OF FORMULATION OF COMPOUND AS USED IN ANIMAL STUDIES
Formulation of example 1:
For oral (p.o.) administration : to the desired quantity (0.5-5 mg) of the solid Example 1 in a glass tube, some glass beads were added and the solid was milled by vortexing for 2 minutes. After addition of 1 ml of a solution of 1% Methylcellulose in water and 2% (v/v) of Poloxamer 188 (Lutrol F68). the compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1 N). Remaining particles in the suspension were further suspended by using an ultrasonic bath.
For intraperitoneal (i-P-) administration: to the desired quantity (0.5-15 mg) of the solid Example 1 in a glass tube, some glass beads were added and the solid was milled by vortexing for 2 minutes. After addition of 1 ml of a solution of 1% methylcellulose and 5% mannitol in water, the compound was suspended by
vortexing for 10 minutes. Finally the pH was adjusted to 7

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Pharmacological data

afiinity In vitro agoagonism In vivo agonism
ORL1 µ-opiate cAMP assay C.U. D.V.*
i p p.o
Ex PK1 PK1 PEC50 ED 50 ED 50
mg/kg mg/kg

1 8.4 7.2 8.6 1.4 6.0
2 7.8 7.3 8.5 7.4

*CUDV = conditioned Distress Vocztion;
5.i.p.=intrapertioneal administration;p.o=(per os) oral administration.

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claims
1 Compounds of the general formula (1)

wherein:
R1 represents H, alkyl(1 -6C), alkyl(1 -3C)cycloalkyl(3-6C), carbalkoxy(2-7C) or acyl(2-7C),
[]m symbolizes -(CH2)m- wherein m is either 0 or 1,
R2 represents halogen, CF3, alkyl(1-6C), alkyl(1-3C)cycloalkyl(3-6C), phenyl, amino, aminoalkyl(i -3C), alkyl(1-3C)amino, dialkyl(1-3C)-amino, cyano, cyanoa!kyl(1 -3C), hydroxy, hydroxyalkyl(1 -3C), (1-3C)alkoxy, OCF3, acyl(2-7C), trifluoro acetyl, aminocarboxyl, (1-3C)alkylsulphonyl or trifluoromethylsulphonyl, and n is an integer from 0-4, with the proviso that when n is 2, 3 or 4, the R2 substituents may be either the same or different,
A is a saturated or partially unsaturated ring
[]0and [] p represent -(CH2)0- and -(CH2)P- respectively, with the proviso that 25also the meaning -CH- is possible when A is a partially nsaturated
ring, and o and p independently are either 0, 1 or 2,
R3, R4, R5 and Re independently represent hydrogen, alkyl(1 -3C), alkyl(1- 3C)-
cydoalkyl(3-6C), CH2OH or (R3 and R5) or (R3 and R6) or (R4 and R5)or (R4 R5or(R4 R6) together can form an alkylene bridge of 1 to 3 carbon
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atoms, with the proviso that when o is 2, R3 is hydrogen, and when p is 2, R5 is hydrogen,
[]q symbolizes -(CH2)q- wherein q is an integer from 0 to 2 all stereoisomers, as well as pharmacologically acceptable salts and prodrugs thereof, prodrugs being derivatives of the compounds having formula (1) wherein a group is present which is easily removed after administration, such as amidine, enamine, a Mannich base, a hydroxyl- methylene derivative, an 0-(acyloxymethylene carbamate) derivative, carbamate, ester, amide orenaminone.
2 Compounds as claimed in claim 1 of the general formula (1) wherein A is a saturated ring,
R1represents hydrogen, alkyl(1 -3C), or acyl(2-4C),
R3, RA, R5 and R6 independently represent hydrogen or alkyl(1 -3C) or (R3 and R5) or (R3 and R6) or (R4 and R5) or (R4 and R6) together can form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, R3 is hydrogen, and when p is 2, Rs is hydrogen, and R2, m, n, o, p and q have the meanings as given in claim 1.
3 Compounds as claimed in claim 1 of the general formula (1) wherein:
A is a saturated ring, m=0, n=0 or 1, o=1, p=1, q=0, R1=H or acetyl, R2 represents halogen, CF3, alkyl(1-3C), amino, hydroxy, cyano, OCH3 or OCF3, R3, R4, R5 and R6 independently represent hydrogen or alkyl(1 -2C) or (R4 and Re) together can form an alkylene bridge of 1 to 2 carbon atoms
4 Compound as claimed in claim 1 having formula (2) and stereoisomers thereof;

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5. Pharmaceutical compositions containing a pharmacologically active amount of at least one of the compounds as claimed in any of the claims 1-4.
6. A compound as claimed in any of the claims 1 - 4, or a salt thereof, for use as a medicament
7. Use of a compound as claimed in any of the claims 1 - 4 for the preparation of a pharmaceutical composition for the treatment of disorders in which
ORL1 receptors are involved, or that can be treated via manipulation of
those receptors,
8. Use as claimed in claim 6 characterized in that said disorders are acute and chronic pain conditions, central nen/ous system disorders, especially, but not limited to amelioration of symptoms of anxiety and stress disorders, depression, various forms of epilepsy, stroke, disorders characterized by impairment of cognition and memory such as Alzheimer’s disease, Creutzfeldt-Jacob disease, Huntington’s disease, Parkinson’s disease, neurorehabilltation (post-traumatic brain lesions); acute brain or spinal cord injury, substance related disorders, including substance use disorders (like independence and abuse) and substance induced disorders (like substance withdrawal); eating disorders like anorexia nervosa and bulimia nervosa, obesity; gastro-intestinal disorders in particular irritable bowel syndrome, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), urinary tract inflammation,. renal disorders characterized by imbalances of water retention/excretion or salt excretion; cardiovascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma; respiratory disorders including cough, chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; diseases of the immune system, and viral infections.

Documents:

1146-chenp-2006 complete specification as granted.pdf

1146-chenp-2006-abstract.pdf

1146-chenp-2006-claims.pdf

1146-chenp-2006-correspondnece-others.pdf

1146-chenp-2006-description(complete).pdf

1146-chenp-2006-form 1.pdf

1146-chenp-2006-form 26.pdf

1146-chenp-2006-form 3.pdf

1146-chenp-2006-form 5.pdf

1146-chenp-2006-pct.pdf

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Patent Number

234347

Indian Patent Application Number

1146/CHENP/2006

PG Journal Number

29/2009

Publication Date

17-Jul-2009

Grant Date

25-May-2009

Date of Filing

03-Apr-2006

Name of Patentee

SOLVAY PHARMACEUTICALS B.V.

Applicant Address

C.J. van Houtenlaan 36, NL-1381 CP Weesp

Inventors:

#	Inventor's Name	Inventor's Address
1	DEN HARTOG, Jacobus, A., J.	C.J. van Houtenlaan 36, NL-1381 CP Weesp
2	DAVID, Samuel	DAVID, Samuel , c/o C.J. van Houtenlaan 36, NL-1381 CP Weesp
3	JASSERAND, Daniel,	JASSERAND, Daniel, c/o C.J. van Houtenlaan 36, NL-1381 CP Weesp
4	VAN SCHARRENBURG, Gustaaf, J., M	VAN SCHARRENBURG, Gustaaf, J., M. , c/oC.J. van Houtenlaan 36, NL-1381 CP Weesp
5	VAN STUIVENBERG, Herman, H.	VAN STUIVENBERG, Herman, H., c/o C.J. van Houtenlaan 36, NL-1381 CP Weesp
6	TUINSTRA, Tinka	TUINSTRA, Tinka , c/o C.J. van Houtenlaan 36, NL-1381 CP Weesp

PCT International Classification Number

A61K31/4025

PCT International Application Number

PCT/EP2004/052392

PCT International Filing date

2004-10-01

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	03103671.8	2003-10-03	EUROPEAN UNION
2	60/507,947	2003-10-03	EUROPEAN UNION