HK1093895A - Bicyclo[3.1.1]heptane substituted benzimidazolone and quinazolinone derivatives as agonists on human orl1 receptors - Google Patents

Description

Bicyclo [3.1.1] heptane-substituted benzimidazolone and quinazolinone derivatives as agonists of the human ORL1 receptor

The present invention relates to a group of hydronopol substituted benzimidazolone and quinazolinone derivatives which are agonists of the human ORL1 (nociceptin) receptor. The invention also relates to the preparation of these compounds, pharmaceutical compositions containing a pharmacologically active amount of at least one of these novel benzimidazolone and quinazolinone derivatives as an active ingredient, and the use of these pharmaceutical compositions in the treatment of conditions involving the ORL1 receptor.

The 'opioid receptor 1' (ORL1) receptor was identified from the human cDNA libraryAnd (6) separating. This 'orphan receptor' has been determined to have close homology to the mu-, kappa-and delta-opioid receptors (Mollereau et al,FEBS Lett.， 34133-38, 1994; the number of ions in the sample was one of Bunzow et al,FEBS Lett.， 347,284-288, 1994). Despite their close sequence and structural similarity to opioid receptors, classical opioid receptor ligands do not interact with ORL1 receptors. In 1995, a 17-amino acid neuropeptide was purified from brain extracts and subsequently demonstrated to be a natural ligand of the G-protein coupled ORL1 receptor (Reinscheid et al,Science， 270792-794, 1995; the Meuneer et al, to which,Nature， 377,532-535, 1995). This peptide, designated orphanin FQ or nociceptin, does not bind to three traditional opioid receptors. These findings have led to an intensive study of the functional role of ORL1 receptor and its novel ligands. This has led to the disclosure of hundreds of documents, including some reviews (see, e.g., Grond et al,Anaesthesist， 51996-1005, 2002), and a number of patent applications in which peptide and non-peptide ligands that differ in potency and selectivity (ORL-1 vs. μ -opiates) are described. Since the mu-opiate receptors are widely distributed systemically, the lack of selectivity can lead to a range of undesirable opiate-like side effects, such as sedation, respiratory depression, tolerance and dependence: (Drug News Perspect，14,335, 2001). Six patent applications related to ORL1 relate to benzimidazolone derivatives: WO 98/54168, WO 99/36421, WO 00/006545, WO 00/08013, WO 01/39775 and US 20020128288.

The closest prior art to the present invention is WO 01/39775. However, the benzimidazolone derivatives described therein do not appear to meet the criteria generally considered important for useful ORL 1-based therapeutics. They are characterized in that:

(1) mild potency (affinity to ORL1 receptor in the range of 166-1252 nM);

(2) no selectivity for the μ -opiate receptor (affinity in the range of 19-457 nM);

(3) there is no evidence of effectiveness after oral administration, and

(4) there is no evidence of CNS-effectiveness.

Surprisingly, it has now been found that in a series of hydronopyl substituted benzimidazolone and quinazolinone derivatives, one group of compounds shows a very high affinity for the human ORL1 receptor. Furthermore, these compounds show excellent ORL1 receptor selectivity relative to the μ -opiate receptor, can readily take effect after oral administration and can pass the blood-brain barrier.

The present invention relates to compounds of general formula (1):

wherein:

R₁represents H, alkyl (1-6C), alkyl (1-3C) cycloalkyl (3-6C), alkoxycarbonyl (2-7C) or acyl (2-7C),

[]_mis represented by- (CH)₂)_m-, where m is 0 or 1,

R₂represents halogen, CF₃Alkyl (1-6C), alkyl (1-3C) cycloalkyl (3-6C), phenyl, amino, aminoalkyl (1-3C), alkyl (1-3C) amino, dialkyl (1-3C) amino, cyano, cyanoalkyl (1-3C), hydroxy, hydroxyalkyl (1-3C), (1-3C) alkoxy, OCF₃Acyl (2-7C), trifluoroacetyl, aminocarboxy, (1-3C) alkylsulfonyl or trifluoromethylsulfonyl, and n is an integer of 0 to 4, with the proviso that when n is 2, 3 or 4, R is₂The substituents may be the same or different,

a is a saturated or partially unsaturated ring,

[]_oand 2]_pRespectively represent- (CH)₂)_o-and- (CH)₂)_pProvided that when A is a partially unsaturated ring it may also be-CH-and o and p are independently 0, 1 or 2,

R₃，R₄，R₅and R₆Independently represent hydrogen, alkyl (1-3C) -cycloalkyl (3-6C), CH₂OH, or (R)₃And R₅) Or (R)₃And R₆) Or (R)₄And R₅) Or (R)₄And R₆) Together may form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, R₃Is hydrogen, and when p is 2, R₅Is a hydrogen atom, and is,

[]_qis represented by- (CH)₂)_q-, where q is an integer of 0 to 2,

and pharmacologically acceptable salts and prodrugs thereof.

All compounds of formula (1), racemates, diastereomeric mixtures and individual stereoisomers are included in the invention. Thus compounds in which the substituents on the potentially asymmetric carbon atom are in the R-configuration or S-configuration are encompassed by the present invention. Prodrugs, i.e. compounds which are metabolized to compounds of formula (1) when administered to a human by any known route, are also encompassed by the present invention. In particular, the present invention relates to compounds having primary or secondary amino or hydroxyl groups. Such compounds may be reacted with organic acids to give compounds of formula (I) wherein additional groups are present which can be easily removed after administration, such as, but not limited to, amidines, enamines, mannich bases, hydroxymethylene derivatives, O- (acyloxymethylene carbamate) derivatives, carbamates, esters, amides or enaminones. A prodrug is an inactive compound that is converted to the active form when absorbed (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186. 494-5, eds. F. D. King, page 216).

The invention relates in particular to compounds having formula (1) wherein:

a is a saturated ring, and the ring is,

R₁represents hydrogen, alkyl (1-3C), or acyl (2-4C),

R₃，R₄，R₅and R₆Independently represents hydrogen or alkyl (1-3C), or (R)₃And R₅) Or (R)₃And R₆) Or (R)₄And R₅) Or (R)₄And R₆) Together may form an alkylene bridge having from 1 to 3 carbon atoms, with the proviso that when o is 2, R₃Is hydrogen, and when p is 2, R₅Is hydrogen, and R₂M, n, o, p and q have the meanings given above.

More particularly, the present invention relates to compounds having formula (1) wherein:

a is a saturated ring, m is 0, n is 0 or 1, o is 1, p is 1, q is 0, R is₁H or acetyl, R₂Represents halogen, CF₃Alkyl (1-3C), amino, hydroxy, cyano, OCH₃Or OCF₃，R₃，R₄，R₅And R₆Independently represents hydrogen or alkyl (1-2C), or (R)₄And R₆) Together may form an alkylene bridge having from 1 to 2 carbon atoms.

More preferred are compounds having formula (2) and all stereoisomers thereof.

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

The starting compounds of this general route are obtained as follows:

benzimidazole compoundsKetones (m ═ 0) can be as described inJ.Med.Chem.30, 814-819, 1987 and WO 99/36421 (Pfizer). Quinazolinone (m ═ 1) can be prepared according toChem.Pharm.Bull.33, 1116-1128, 1985.

The hydronopol derivatives having a leaving group X (halogen, mesylate, tosylate) can be synthesized from the corresponding alcohols according to standard methods. The corresponding alcohol can be synthesized as follows:

for the cis-analog of q ═ 0, synthesis starting from (-) - β -pinene, e.g.J.Amer. Chem.Soc.68, 638, 1946 and as described in US patents 2,427,343 and 2,427,345

For the trans analogue of q ═ 0, synthesis starts from trans-myrtanol, e.g.Bull. Soc.Chim.Fr.196, 1958, or by a slightly modified procedure (bromination of alcohol, cyano substitution, conversion to ethyl ester and reduction to the desired alcohol)

For cis and trans analogues of q ═ 1 or 2, synthesized from trans-myrtanol by one or two similar homologation procedures as described for the trans analogue synthesis of q ═ 0.

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

The compounds of the present invention of general formula (1) and salts thereof have ORL1 agonist activity. They are useful in the treatment of disorders in which ORL1 receptors are involved, or which can be treated by the control of ORL1 receptors. For example, for acute and chronic pain conditions, central nervous system disorders, and in particular, but not exclusively, for ameliorating the 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-jakob disease, huntington's disease, parkinson's disease, neurorestoration (post-traumatic encephalopathy); acute brain or spinal cord injury, substance-related disorders including substance use disorders (e.g., dependence and abuse) and substance-induced disorders (e.g., substance withdrawal); eating disorders such as anorexia nervosa and bulimia nervosa, obesity; gastrointestinal disorders, in particular irritable bowel syndrome, inflammatory bowel disease (crohn's disease and ulcerative colitis), urinary tract inflammation, renal disorders characterised by an imbalance in water retention/excretion or salt excretion; cardiovascular disorders such as myocardial infarction, arrhythmia, hypertension, thrombosis, anemia, arteriosclerosis, angina pectoris, skin diseases such as urticaria, lupus erythematosus and pruritus; ophthalmic disorders such as glaucoma; respiratory disorders including cough, chronic obstructive pulmonary disease, bronchitis, and cystic fibrosis; immune system diseases, and viral infections.

In vitro and in vivo ORL1 receptor agonist properties of the compounds of the invention were determined using the methods described below.

Affinity for the human ORL1 receptor

Affinity of the compounds for the human ORL1 receptor as shown by Ardati et al,Mol. Pharmacol.51, 816, 1997 in vitro receptor binding assays. Briefly, the membrane preparation was obtained from CHO (chinese hamster ovary) cells in which the human ORL1 receptor was stably expressed. The [ 2 ] will film³H]-the nociceptin is incubated in the absence of the test compound or in the presence of the test compound diluted to different concentrations in a suitable buffer.

Nonspecific binding is defined at 10^-6Residual binding in the presence of M nociceptin. Bound and free radioactivity were separated by filtration through a Packard GF/B glass fiber filter and washed several times with ice-cold buffer using a Packard cell harvester. Bound radioactivity was determined using a scintillation counter (Topcount, Packard) using a liquid scintillation cocktail (Microscint 0, Packard). Plotting the measured radioactivity against the concentration of displaced test compound and calculating the displacement curve by four parameter logistic regression to obtain IC₅₀Value, i.e. substitution when 50% of the radioligand is displacedThe concentration of the substance. Affinity pK_IValues were corrected for IC by using radioligand concentration₅₀Values were calculated and their affinity for human ORL1 receptor was calculated according to the Cheng-Prusoff equation:

pK_I＝-log(IC₅₀/(1+S/K_d))

wherein the IC₅₀As mentioned above, S is a term used in the test³H]Nociceptin concentration, expressed in mol/L (typically 0.2nM), and K_dIs [ 2 ]³H]Equilibrium dissociation constant of nociceptin with human ORL1 receptor (0.4 nM).

The compounds of the invention have high affinity for the ORL1 receptor in the binding assay described above. This property makes them useful in the treatment of conditions in which ORL1 receptors are involved, or which can be treated by the control of these receptors.

Affinity for mu-opiate receptors

Affinity of compounds to μ -opiate receptors with Childers et al,Eur.J. Pharm55, 11, 1979 in vitro. Briefly, the membrane preparation is obtained from CHO-cells in which the human [ mu ] -opiate receptor is stably expressed, and used³H]Naloxone is incubated in the absence of test compound or in the presence of test compound diluted in a suitable buffer to a concentration range of 10 μ M down to 0.1 nM. Nonspecific binding is defined at 10^-7Residual binding in the presence of M-tartaric acid Livalosin. Separation of bound and free radioactivity is carried out as described above, and the affinity of the compound is in a similar manner, with 1nM of³H]Naloxone concentration (S) and K of 1.3nM_dAnd (4) calculating the value.

In the binding assay described above, most compounds of the invention have a low μ -opiate receptor affinity: typically 100 times less than their affinity for ORL1 receptor. They do not cause the undesirable side effects known to occur with opiates such as morphine.

In vitro ORL1 receptor agonistic activity

Activation of the G protein-coupled ORL1 receptor inhibits adenylate cyclase activity and decreases the intracellular concentration of the second messenger cAMP. With the use of Jenck et al,Proc.Natl.Acad.Sci USA，974938-4943, 2000 to determine the activity of the compound at the ORL1 receptor. They proved to be potent agonists, pEC thereof₅₀The values and their pK_iThe values match.

In vivo ORL1 receptor agonistic activity

In a system such as the Molewijk et al,Psychopharmacologythe conditional ultrasound lesion sonification method described in 117, 32-40, 1995 shows high activity of the compounds of the present invention after intraperitoneal and/or oral administration. This not only demonstrates good bioavailability of the compounds after oral administration, but also that they can cross the blood brain barrier. In this assay, the peptide nociceptin is also active, but it requires administration directly in the brain (by intracerebroventricular injection) to demonstrate its effect.

Specific synthetic examples

Synthesis of example 1 (see table below):

step 1. A solution of (-) -cis-hydronopol (20 g, 0.12 mol) and triethylamine (41.6 ml, 0.30 mol) in dichloromethane (150 ml) was cooled to 0 ℃ and a solution of methanesulfonyl chloride (11.2 ml, 0.15 mol) in dichloromethane (50 ml) was added dropwise under ice cooling. After stirring at room temperature for 16 h, HCl solution (1N, 100 ml) was added. The aqueous layer was washed twice with 70 ml dichloromethane and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The mesylate was obtained as the product as an orange-yellow oil (27.7 g, 11 mol, 92% yield).

Step 2 stirred 4- (1-benzimidazolone) piperidine (ACROS, 6.51 g, 30 mmol), mesylate from the previous reaction stepA solution of (8.9 g, 36 mmol), potassium carbonate (16.8 g, 120 mmol) and sodium iodide (5.4 g, 36 mmol) in methyl ethyl ketone (800 ml) in N₂Heating at 80 deg.C for 16 hr under protection. The reaction mixture was concentrated in vacuo and dichloromethane (500 ml) and NaHCO were added₃Aqueous solution (5%, 300 ml). The aqueous layer was washed with dichloromethane (80 ml 2 times) and the combined organic layers were MgSO₄Dried and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using a mixture of dichloromethane: methanol: ammonia (94.5: 5: 0.5) as eluent. The pure product obtained after concentration in vacuo (7.5 g, 20 mmol, 68% yield) was dissolved in HCl in absolute ethanol (60 ml). The resulting solution was concentrated in vacuo at 30 ℃ to afford the HCl salt of example 1 (8.25 g, 20 mmol, quantitative yield) as a white amorphous solid, M⁺At 368m/z, a melting point of 167-.

Synthesis of example 43

Step 1. in N₂Triphenylphosphine (116 g, 0.44 mol) was dissolved in acetonitrile (1 l) under an atmosphere and cooled in an ice bath. Bromine (22.5 ml, 0.44 mol) was added dropwise. The temperature of the exothermic reaction was maintained below 10 ℃. After the addition was complete, the ice bath was removed and (-) -trans-myrtanol (68.8 g, 0.44 mol, Aldrich) dissolved in 250 ml of acetonitrile was slowly added. After the addition was complete, the pale yellow solution was refluxed with a Dean-Stark apparatus for 3 hours and about 200 ml of solvent was removed from the trap. The resulting reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using a dichloromethane-diethyl ether mixture (1: 1v/v) as eluent. The pure product was obtained as a pale yellow oil (87.8g, 41 mmol, yield 93%).

Step 2. the resulting myrtle alkyl bromide (87.8g, 0.41 mol) was dissolved in 1 liter of dimethylformamide. Sodium cyanide (40 g, 0.81 mol) was added and the mixture was stirred at reflux for 5 hours. After cooling, the mixture was diluted with water (3 l) and extracted with methyl tert-butyl ether (3 times, 1.5 l). The organic layer was washed with brine (300 ml) and Na₂SO₄Drying and vacuum concentratingAnd (4) shrinking. The crude product was purified by column chromatography (silica gel) using a dichloromethane-heptane mixture (1: 1v/v) as eluent. The pure product was obtained as a colorless liquid (52.4 g, 0.32 mol, yield 78%).

Step 3 sulfuric acid (190 ml) was added dropwise to 500 ml ethanol under ice-bath cooling. The resulting solution of myrtle alkyl cyanide (52.4 g, 0.32 mol) in ethanol (100 ml) was added thereto, and the mixture was stirred under reflux for 16 hours. After cooling and addition of 1.5 l of water, the mixture is extracted three times with 1.5 l of methyl tert-butyl ether. The organic layer was washed with saturated NaHCO₃Washed with aqueous solution (1 l) and Na₂SO₄Dried and concentrated in vacuo. The crude ester (54.2 g, 0.26 mol, 81% yield) was obtained as a nearly colorless liquid.

Step 4. the ester obtained in the previous reaction step (54.2 g, 0.26 mol) was added to a suspension of lithium aluminium hydride (20 g, 0.52 mol) in tetrahydrofuran (1 l). After the addition was complete, the mixture was refluxed for 1 hour. After cooling in an ice bath, 1 l of aqueous HCl (1N) was carefully added. After the addition was complete, the mixture was further diluted with 1 liter of water and extracted three times with 1.5 liters of methyl tert-butyl ether. The organic layer was washed with brine (250 ml) and Na₂SO₄Dried and concentrated in vacuo. The crude mixture was purified by Kugelrohr distillation (at 3.10)^-2Bp 85 ℃ in mbar) to yield 35 g (0.17 mol, 65%) of (-) -trans-hydronopol as a colorless oil.

Step 5. A solution of prepared (-) -trans-hydronopol (5 g, 28 mmol) and triethylamine (9.4 ml, 68 mmol) in dichloromethane (50 ml) was cooled to 0 ℃. Under ice-cooling, a solution of methanesulfonyl chloride (2.7 ml, 35 mmol) in dichloromethane (13 ml) was added dropwise. After stirring at room temperature for 16 h, HCl solution (1N, 50 ml) was added. The aqueous layer was washed with dichloromethane (30 ml 2 times), and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The mesylate was purified by column chromatography (silica gel) using a mixture of dichloromethane-methanol (90: 10) as eluent. The pure product was obtained as a colorless liquid (5.6 g, 23 mmol, yield 81%).

Step 6. A stirred solution of 4- (1-benzimidazolone) piperidine (ACROS, 1.8 g, 8.3 mmol), the mesylate (2.5 g, 10 mmol) obtained in the previous reaction step, potassium carbonate (4.7 g, 34 mmol) and sodium iodide (1.5 g, 10 mmol) in methyl ethyl ketone (300 mL) in N₂Heating at 80 deg.C for 16 hr under protection. The reaction mixture was concentrated in vacuo and diisopropyl ether (300 ml) was added. The resulting pale yellow precipitate was filtered off, washed with petroleum ether (100 ml) and dried in vacuo. The precipitate was again dissolved in refluxing ether (300 ml) and the original material was removed by filtration. The precipitate obtained after cooling was collected by filtration and dried in vacuo to yield 1.85 g (5 mmol, yield 61%) of pure product as a white amorphous solid, its M⁺At 368m/z, a melting range of 220-.

Synthesis of example 17

Step 1. 3-fluoro-4-nitrotoluene (Aldrich, 4.65 g, 30 mmol), 4-amino-1-benzylpiperidine (Aldrich, 6.1 ml, 30 mmol), K₂CO₃(6.63 g, 48 mmol) in dimethylformamide (50 ml) in N₂Stirring was carried out at 65 ℃ for 18 hours under protection. After cooling to room temperature, the mixture was poured into water (200 ml) -dichloromethane (350 ml). The aqueous layer was extracted with dichloromethane (70 ml 2 times) and the combined organic layers were washed with water (50 ml twice) over MgSO₄Dried and concentrated in vacuo. The crude product obtained is purified by column chromatography (silica gel) using a mixture of dichloromethane-methanol (97: 3) as eluent. After concentration in vacuo, the pure product was obtained as a yellow oil (9.1 g, 28 mmol, 93% yield).

Step 2. A portion of Raney-Nickel (Aldrich R2800 [7440-02-0 ]]Approximately 600 mg) was washed with 96% ethanol (10 ml twice), then N₂Added with protection to a solution of the product from the previous reaction step (9.1 g, 28 mmol) in 96% ethanol (200 ml). The solution was hydrogenated at room temperature and a pressure of 1 atm for 18 hours. Then will beThe mixture was filtered through Hyflo, washed with 96% ethanol (100 ml, 3 times), and the filtrate was concentrated in vacuo and co-evaporated twice with ethyl acetate to give the reduced product as a violet oil (8.3 g, 28 mmol, 100% yield).

Step 3 to a stirred solution of the product from the previous step (8.3 g, 28 mmol) in acetonitrile (100 ml) was added one portion of 1, 1' -carbonyldiimidazole (ACROS, 6.5 g, 40 mmol) at room temperature under nitrogen. A precipitate began to form at 5 minutes and increased continuously until 3 hours, collected by filtration, washed with acetonitrile (20 ml) and diisopropyl ether (100 ml) and dried in vacuo. The crude product (5.5 g) was purified by column chromatography (silica gel) using a mixture of dichloromethane-methanol (95: 5) as eluent. After concentration in vacuo, the pure product was obtained as a white solid (5.0 g, 15 mmol, yield 55%).

Step 4. in N₂To a stirred solution of 5.0 g (15 mmol) of the product from the preceding step in 300 ml of methanol under an atmosphere was added a 1N ethanolic HCl solution (prepared by dissolving 1.22 g (15 mmol) of acetyl chloride in 50 ml of absolute ethanol). After addition of 10% Pd/C (about 500 mg), the mixture was hydrogenated at room temperature under a pressure of 1 atm for 2.5 hours. The mixture was then filtered over Hyflo, washed with methanol (100 ml 2 times) and the filtrate was concentrated in vacuo to give 4.15 g (15 mmol, 100% yield) of product as a white solid.

Step 5. a stirred solution of the product from the previous step (4.15 g, 15 mmol), the mesylate from example 1 step 1 (8.9 g, 16 mmol), potassium carbonate (10.4 g, 75 mmol) and sodium iodide (2.4 g, 16 mmol) in methyl ethyl ketone (250 ml) in N₂Heating at 80 deg.C for 16 hr under protection. The reaction mixture was concentrated in vacuo and dichloromethane (500 ml) and NaHCO were added₃Aqueous solution (5%, 300 ml). The aqueous layer was washed with dichloromethane (80 ml 2 times) and the combined organic layers were MgSO₄Dried and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using dichloromethane-methanolA mixture of ammonia (92: 7.5: 0.5) as eluent. After concentration in vacuo, the pure product (5.0 g, 13 mmol) was obtained as an oil. After addition of 100 ml of diisopropyl ether 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 of product (8.6 mmol, 57% yield), M⁺At 382m/z, a melting point of 214-.

By these and equivalent methods, 45 specific examples were synthesized. They are intended to illustrate the invention in further detail and should not be construed as limiting the scope of the invention in any way. The structural information of these compounds, all represented by the general formula (1), is provided in the following table.

	Substitution pattern												Three-dimensional configuration
nr	R1	m	R2	n	A	o	p	R3	R4	R6	R5	q	1	2	4

1	H	0	-	0	Saturation of	1	1	H	H	H	H	0	S	S	S
																2	H	1	-	0	Saturation of	1	1	H	H	H	H	0	S	S	S
3	CH3	0	-	0	Saturation of	1	1	H	H	H	H	0	S	S	S
																4	CH3	1	-	0	Saturation of	1	1	H	H	H	H	0	S	S	S
5	H	0	4-F	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																6	H	0	5-F	1	Saturation of	1	1	H	H	H	H	0	S	S	S
7	H	0	6-F	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																8	H	0	7-F	1	Saturation of	1	1	H	H	H	H	0	S	S	S
9	H	0	5-CF3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																10	H	0	6-CF3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
11	H	0	4-Cl	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																12	H	0	5-Cl	1	Saturation of	1	1	H	H	H	H	0	S	S	S
13	H	0	6-Cl	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																14	H	0	7-Cl	1	Saturation of	1	1	H	H	H	H	0	S	S	S
15	H	0	4-CH3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																16	H	0	5-CH3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
17	H	0	6-CH3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																18	H	0	7-CH3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
19	H	0	4-OCH3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																20	H	0	5-OCH3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
21	H	0	6-OCH3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																22	H	0	6-OH	1	Saturation of	1	1	H	H	H	H	0	S	S	S
23	H	0	6-NHCOCH3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																24	H	0	6-CN	1	Saturation of	1	1	H	H	H	H	0	S	S	S
25	H	0	6-CH2CN	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																26	H	0	6-SO2CH3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
27	H	0	6-SO2CF3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																28	H	0	6-COCH3	1	Saturation of	1	1	H	H	H	H	0	S	S	S

29	H	0	6-COCF3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																30	H	0	6-CONH2	1	Saturation of	1	1	H	H	H	H	0	S	S	S
31	H	0	6-OCF3	1	Saturation of	1	1	H	H	H	H	0	S	S	S
																32	H	0	6，7-F	2	Saturation of	1	1	H	H	H	H	0	S	S	S
33	H	0	4-F，6-OCH3	2	Saturation of	1	1	H	H	H	H	0	S	S	S
																34	H	0	4-CH3，6-OCH3	2	Saturation of	1	1	H	H	H	H	0	S	S	S
35	H	0	-	0	Unsaturated polyester	1	1	H	H	H	H	0	S	S	S
																36	H	0	-	0	Saturation of	1	0	H	H	H	H	0	S	S	S
37	H	0	-	0	Saturation of	0	0	H	H	H	H	0	S	S	S
																38	H	0	-	0	Saturation of	1	1	CH3	H	H	H	0	S	S	S
39	H	0	-	0	Saturation of	1	1	H	CH3	H	H	0	S	S	S
																40	H	0	-	0	Saturation of	1	1	H	H	H	CH3	0	S	S	S
41	H	0	-	0	Saturation of	1	1	H	H	CH3	H	0	S	S	S
																42	H	0	-	0	Saturation of	1	1	H	-CH2-CH2-		H	0	S	S	S
43	H	0	-	0	Saturation of	1	1	H	H	H	H	0	R	S	S
																44	H	0	-	0	Saturation of	1	1	H	H	H	H	1	S	S	S
45	H	0	-	0	Saturation of	1	1	H	H	H	H	1	R	S	S
																46	H	0	-	0	Saturation of	1	1	H	H	H	H	0	R	R	R
47	H	0	-	0	Saturation of	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												Three-dimensional configuration

Formulation examples of Compounds for animal research

Formulation example 1:

for oral (p.o) administration: to the desired amount (0.5-5 mg) of the example 1 solid in a glass tube was added some glass beads and the solid was vortex milled for 2 minutes. After addition of 1 ml of 1% methylcellulose and 2% (v/v) aqueous 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 (0.1N). The particles remaining in the suspension were further suspended with an ultrasonic bath.

For intraperitoneal (i.p) administration: to the desired amount (0.5-15 mg) of the example 1 solid in a glass tube was added some glass beads and the solid was vortex milled for 2 minutes. After addition of 1 ml of an aqueous solution of 1% methylcellulose and 5% mannitol, the compound was suspended by vortexing for 10 minutes. Finally, the pH value is adjusted to 7.

Pharmacological data

	Affinity of		In vitro agonistic activity	In vivo agonistic activity
						ORL1	Mu-opiates	cAMP assay	C.U.D.V.*
					i.p.						p.o.
Examples						pKi	pKi	pEC50	ED50	ED50
					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 ═ conditional ultrasound lesion sounding methods;

i.p. ═ intraperitoneal administration; p.o. (oral) administration.

Claims (8)

1. A compound of the general formula (1):

wherein:

R₁represents H, alkyl (1-6C), alkyl (1-3C) cycloalkyl (3-6C), alkoxycarbonyl (2-7C) or acyl (2-7C),

[]_mis represented by- (CH)₂)_m-, where m is 0 or 1,

R₂represents halogen, CF₃Alkyl (1-6C), alkyl (1-3C) cycloalkyl (3-6C), phenyl, amino, aminoalkyl (1-3C), alkyl (1-3C) amino, dialkyl (1-3C) amino, cyano, cyanoalkyl (1-3C), hydroxy, hydroxyalkyl (1-3C), (1-3C) alkoxy, OCF₃Acyl (2-7C), trifluoroacetyl, aminocarboxy, (1-3C) alkylsulfonyl or trifluoromethylsulfonyl, and n is an integer of 0 to 4, with the proviso that when n is 2, 3 or 4, R is₂The substituents may be the same or different,

a is a saturated or partially unsaturated ring,

[]_oand 2]_pRespectively represent- (CH)₂)_o-and- (CH)₂)_pProvided that when A is a partially unsaturated ring it may also be-CH-and o and p are independently 0, 1 or 2,

R₃，R₄，R₅and R₆Independently represent hydrogen, alkyl (1-3C) -cycloalkyl (3-6C), CH₂OH, or (R)₃And R₅) Or (R)₃And R₆) Or (R)₄And R₅) Or (R)₄And R₆) Together may form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, R₃Is hydrogen, and when p is 2, R₅Is a hydrogen atom, and is,

[]_qis represented by- (CH)₂)_q-, where q is an integer of 0 to 2,

all stereoisomers thereof, as well as pharmacologically acceptable salts and prodrugs, prodrugs are derivatives of the compounds of formula (1) in which groups are present which can be easily removed after administration, such as amidines, enamines, mannich bases, hydroxymethylene derivatives, O- (acyloxymethylene carbamate) derivatives, carbamates, esters, amides or enaminones.

2. A compound of formula (1) according to claim 1, wherein

A is a saturated ring, and the ring is,

R₁represents hydrogen, alkyl (1-3C), or acyl (2-4C),

R₃，R₄，R₅and R₆Independently represents hydrogen or alkyl (1-3C), or (R)₃And R₅) Or (R)₃And R₆) Or (R)₄And R₅) Or (R)₄And R₆) May form an alkylene bridge having from 1 to 3 carbon atoms, with the proviso that when o is 2, R₃Is hydrogen, and when p is 2, R₅Is hydrogen, and R₂M, n, o, p and q have the meanings given in claim 1.

3. A compound of general formula (1) according to claim 1, wherein:

a is a saturated ring, m is 0, n is 0 or 1, o is 1, p is 1, q is 0, R is₁H or acetyl, R₂Represents halogen, CF₃Alkyl (1-3C), amino, hydroxy, cyano, OCH₃Or OCF₃，R₃，R₄，R₅And R₆Independently represents hydrogen or alkyl (1-2C), or (R)₄And R₆) Together may form an alkylene bridge having from 1 to 2 carbon atoms.

4. The compound of claim 1 having the general formula (2):

5. a pharmaceutical composition comprising a pharmacologically active amount of at least one compound according to any one of claims 1 to 4.

6. A compound according to any one of claims 1 to 4, or a salt thereof, for use as a medicament.

7. Use of a compound of any one of claims 1-4 for the preparation of a pharmaceutical composition for the treatment of disorders in which ORL1 receptors are involved, or which may be treated by the control of those receptors.

8. Use according to claim 6, characterized in that the conditions are acute and chronic pain conditions, central nervous system disorders, in particular but not exclusively ameliorating the 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-jakob disease, huntington's disease, parkinson's disease, neurorestoration (post-traumatic encephalopathy); acute brain or spinal cord injury, substance-related disorders including substance use disorders (e.g., dependence and abuse) and substance-induced disorders (e.g., substance withdrawal); eating disorders such as anorexia nervosa and bulimia nervosa, obesity; gastrointestinal disorders, in particular irritable bowel syndrome, inflammatory bowel disease (crohn's disease and ulcerative colitis), urinary tract inflammation, renal disorders characterised by an imbalance in water retention/excretion or salt excretion; cardiovascular disorders such as myocardial infarction, arrhythmia, hypertension, thrombosis, anemia, arteriosclerosis, angina pectoris, skin diseases such as urticaria, lupus erythematosus and pruritus; ophthalmic disorders such as glaucoma; respiratory disorders including cough, chronic obstructive pulmonary disease, bronchitis, and cystic fibrosis; immune system diseases, and viral infections.