http://rdf.ncbi.nlm.nih.gov/pubchem/patent/AR-068757-A2
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filingDate | 2008-10-08-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
publicationDate | 2009-12-02-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
publicationNumber | AR-068757-A2 |
titleOfInvention | LIGANDOS DERIVED FROM HIGH AFFINITY PIPERIDINE FOR THE NOCICEPTINE RECEIVER ORL-1; PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEM AND THE USE OF THE SAME FOR THE MANUFACTURE OF MEDICINES |
abstract | Ligands derived from high affinity piperidine for the ORL-1 nociceptin receptor, characterized in that they comprise a compound represented by the formula (1) or a pharmaceutically acceptable salt or solvate thereof where: the dotted line represents an optional double bond; X1 is R5-C1-12 alkyl, R5-C3-12 cycloalkyl, R7-aryl, R8-heteroaryl, R10-C3-7 heterocycloalkyl; X2 is -CHO, -CN, -NHC (= NR26) NHR26, -CH (= NOR26), -NHOR26, R7-aryl, R7-arylalkyl C1-6, R7-arylalkyl C1-6, R7-arylalkyl-C1-6 , - (CH2) vOR13, - (CH2) vCOOR27, - (CH2) vCONR14R15, - (CH2) vNR21R22 or - (CH2) vNHC (O) R21, where v is 0, 1, 2 or 3; or X1 is from the group of formulas (2) and X2 is hydrogen; or X1 and X2 together form a spiro group having the formula of the formula group (3); m is 1 or 2; n is 1, 2 or 3, with the proviso that when n is 1, one of R16 and R17 is -C (O) R28; p is 0 or 1, Q is -CH2-, -O-, -S-, -SO-, -SO2- or -NR17-; R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and C1-6 alkyl, or (R1 and R4) or (R2 and R3) or (R1 and R3) or (R2 and R4) together can form a alkylene bridge of 1 to 3 carbon atoms; R5 represents 1 to 3 substituents, independently selected from the group consisting of H, R7-aryl, R6-C3-12 cycloalkyl, R8-heteroaryl, R10-C3-7 heterocycloalkyl, -NR19R20, -OR13 and S (O) 0 -2R13; R6 is 1 to 3 substituents independently selected from the group consisting of H, C1-6 alkyl, R7-aryl, -NR19R20, -OR13, -SR13; R7 represents 1 to 3 substituents selected from the group consisting of hydrogen, halo, C1-6 alkyl, R25-aryl, C3-12 cycloalkyl, -CN, -CF3, -OR19, -C1-6-OR19 alkyl, -OCF3 , -NR19R20, -C1-6-NR19R20, -NHSO2R19, -SO2N (R26) 2, -SO2R19, -SOR19, -SR19, -NO2, -CONR19R20, -NR20COR19, -COR19, -COCF3, -OCOR19, - OCO2R19, -COOR19, -C1-6 alkyl-NHCOOC (CH3) 3, -C1-6 alkyl-NHCOCF3, -C1-6 alkyl-NHSO2-C1-6 alkyl, -C1-6 alkyl-NHCONH-C1-6 alkyl - or a remainder of formula (4), where f is 0 to 6; or the R7 substituents on the adjacent carbon atoms of the ring may together form a methylenedioxy or ethylenedioxy ring; R8 represents 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, C1-6 alkyl, R25-C3-12 cycloalkyl CF3, -OR19, -C1-6-OR19 alkyl, -OCF3, -NR19R20, - C1-6-NR19R20 alkyl, -NHSO2R19, -SO2N (R26) 2, -NO2, -CONR19R20, -NR20COR19, -COR19, -OCOR19, -OCO2R19, -COOR19, R9 is hydrogen, C1-6 alkyl, halo, - OR19, -NR19R20, -NHCN, -SR19 or -C 1-6 alkyl-NR19R20; R10 is H, C1-6 alkyl, -OR19, -C1-6-OR19 alkyl, -NR19R20, or C1-6-NR19R20 alkyl; R11 is independently selected from the group consisting of H, R5-C1-6 alkyl, R6-C3-12 cycloalkyl, -C1-6 alkylC3-12 cycloalkyl, -C1-6-OR19 alkyl, -C1-6-NR19R20 alkyl and a remainder of formulas (5) where qya are as defined above; R12 is H, C1-6 alkyl, halo, -NO2, -CF3, -OCF3, -OR19, -C1-6 alkyl-OR19, -NR19R20, or C1-6-NR19R20 alkyl; R13 is H, C1-6 alkyl, R7-aryl, -C1-6-OR19 alkyl, -C1-6-NR19R20 alkyl, -C1-6-SR19 alkyl or C1-6 arylalkyl; R14 and R15 are independently selected from the group consisting of H, R5-C1-6 alkyl, R7-aryl and the remainder of formula (6) where q is 1 to 3 and a is 1 or 2; R16 and R17 are independently selected from the group consisting of hydrogen, R5-C1-6 alkyl, R7-aryl, C3-12 cycloalkyl, R8-heteroaryl, R8-heteroarylalkyl C1-6-C (O) R28, -C1 alkyl 6-C3-7 heterocycloalkyl, -C1-6-OR19 alkyl and -C1-6-SR19 alkyl; R19 and R20 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-12 cycloalkyl, aryl, and C1-6 arylalkyl; R21 and R22 hydrogen, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkyl C1-6-heterocycloalkyl C3-7, -C1-6 alkyl-heterocycloalkyl C3-7, R7-aryl, R7-aryl-C1 alkyl -6-, R8-heteroaryl-C1-6 alkyl, C1-6-OR19 alkyl, -C1-6 alkyl, NR19R20, -C1-6-SR19 alkyl, and C1-6-NR18 alkyl-C1-6-NR18 alkyl -C 1-6 alkyl; R18 is hydrogen or C1-6 alkyl; Z1 and Z2 are each R7-aryl; Z3 is hydrogen or C1-6 alkyl; R25 represents 1 to 3 substituents independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy and halo; R26 is independently selected from the group consisting of H, C1-6 alkyl and R25-C6H4-CH2-; R27 is H, C1-6 alkyl, R7-C1-6 arylalkyl, or C3-12 cycloalkyl; R28 is C1-6 alkyl, C1-6 alkyl C3-12 cycloalkyl, R7-aryl, R7-aryl-C1-6-R8-heteroaryl C1-6-NR19R20 alkyl, -C1-6-OR19 alkyl, or C1- alkyl 6-SR19 with the proviso that when X1 and X2 together are a compound of the group of formulas (7) and Z1 and Z2 are each R7-phenyl, R7 is not -OCH2-aryl and at least one is ortho-halo or ortho-C 1-6 alkyl; aryl (including the aryl alkyl aryl portion) represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring where said aryl group may optionally be fused to aryl, C3-7 cycloalkyl, heteroaryl or C3-7 heteroaryl-cycloalkyl; and where R7-aryl means that any of the substitutable carbon and nitrogen atoms available in said aryl group and / or fused rings is optionally and independently substituted, and where the aryl ring is substituted with 1-3 R7 groups; heteroaryl represents cyclic groups having one to three heteroatoms selected from O, S and N, said heteroatom (s) interrupting a carbocyclic ring structure and having a sufficient amount of delocalized pi electrons to provide aromatic character, with aromatic heterocyclic groups containing from 5 to 14 carbon atoms, wherein said heteroaryl group may be optionally fused with one or more aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and where any of the available nitrogen or carbon atoms in said heteroaryl group and / or said fused ring (s) may be optionally and independently substituted and where the heteroaryl ring may be substituted with 1-3 R8 groups ; and heterocycloalkyl represents a saturated ring containing from 3 to 7 carbon atoms, preferably from 4 to 6 carbon atoms, interrupted by 1 to 3 heteroatoms selected from -O-, -S- and NR21, where R21 is as defined. before, and where optionally, said ring may contain one or two unsaturated bonds that do not impart aromatic character to the ring; and wherein any of the substitutable carbon atoms available in the ring may be substituted and where the heterocycloalkyl ring may be substituted with 1-3 R10 groups; Representative heterocycloalkyl groups include 2- or 3-tetrahydrothienyl, 1-, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2-, or 3-piperazinyl, 2- or 4-dioxanyl, morpholinyl, or the structures of the group of formulas (8), wherein R17 is as defined above and t is 0, 1 or 2. Pharmaceutical compositions that include them and the use of said compounds as inhibitors, nociceptin receptors for manufacture of useful medicines for treatment, anxiety, cough, asthma, depression and alcohol abuse. |
priorityDate | 1998-07-27-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
type | http://data.epo.org/linked-data/def/patent/Publication |
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Total number of triples: 123.