WO 97/23466 describes compounds as having an analgesic effect of a general and one preferred formula: .
WO 98/28270 describes compounds as having an analgesic effect of a general and one preferred formula: .
WO 98/28275 describes compounds as having an analgesic effect of a general and one preferred formula: .
Amide derivatives of 3-aminotropane have been prepared and described as having potential pharmacological activity, Gutkowska, B., et al., Acta Pol. Pharm., 1984, 41(6), 613-617, of the formula: .
WO 93/15062 describes compounds as delta-opioid (δ-opioid) and mu-opioid (μ-opioid) receptor agonists of (approximately) the general formula: .
The foregoing reference compounds have been described as either δ-opioid or μ-opioid receptor agonists or antagonists.
U.S. Pat. No. 3,793,322 describes compounds of the general formula: wherein R and R′ are hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen or trifluoromethyl and may be the same or different; R″ is lower alkyl, lower alkenyl, cycloalkyl, or phenyl, and R′″ is hydrogen, lower alkyl, lower alkenyl, carboalkoxy, carboalkoxyalkyl, formyl, phenyl, halophenyl, cinnamyl, benzyl or benzhydryl as having hypoglycemic activity. The lower alkyl, lower alkoxy and lower alkenyl groups may be branched or straight chained and contain up to 6 carbon atoms. The cycloalkyl groups contain from 3 to 7 carbon atoms in the ring which may also carry a lower alkyl substituent. The carboalkoxy groups contain alkyl groups having from 1 to 5 carbon atoms and include carbomethoxy, carbethoxy, carbopropoxy, carbobutoxy and the like. Desirably, R and R′ are lower alkyl, preferably methyl, or halogen, preferably chloro; R may be hydrogen and R′ is then chloro, lower alkyl, preferably methyl, or trifluoromethyl; R″ is lower alkyl, preferably isobutyl, and R′″ is carbethoxy. Exemplified compounds include those wherein R is selected from hydrogen, chlorine, fluorine or methyl; R′ is selected from hydrogen, chlorine, fluorine, methyl, methoxy, hydroxy or trifluoromethyl; R″ is selected from hydrogen, chlorine, fluorine, methyl, ethyl, n-propyl, n-butyl, i-butyl, i-amyl, n-hexyl, allyl, cyclohexyl, phenyl or 3,4-dimethylphenyl; R′″ is selected from hydrogen, methyl, ethyl, n-hexyl, allyl, phenyl, 4-Cl-phenyl, benzhydryl, benzyl, 2,4-Cl2-benzyl, 2,3,4-(MeO)3-benzyl, COOEt or CHO.
U.S. Pat. No. 3,962,248 describes compounds of the formula: wherein A signifies the structure R1 is hydrogen, alkoxyalkyl of 2 to 6 carbon atoms in the aggregate thereof, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or acyloxyalkyl of 3 to 22 carbon atoms in the aggregate thereof, R4 is hydrogen, alkyl, alkoxy or alkylthio, wherein the alkyl groups have 1 to 4 carbon atoms, halogen or trifluoromethyl; when A denotes Z1, X is a —CH2, —O—, —S—, —NH or —N-alkyl group wherein the alkyl group has 1 to 3 carbon atoms, R2 is hydrogen, dialkylamino-sulphonyl, alkyl-sulphonyl, wherein the alkyl groups have 1 to 4 carbon atoms, alkoxy or alkylthio of 1 to 4 carbon atoms, halogen, nitro, trifluoromethylsulphonyl, trifluoromethoxy, trifluoromethylthio, acetyl, cyano or trifluoromethyl, and R3 is hydrogen, halogen or alkyl of 1 to 4 carbon atoms, or when A denotes Z2, X is a —CH2— or —S— group as having neuroleptic activity.
The synthesis and binding affinities for 4-Diarylaminotropane compounds of the general formula: wherein R is hydrogen, methyl, propyl, hexyl, 2-ethylbutyl, allyl, 3,3-dimethallyl, cyclohexylmethyl, phenethyl, phenylpropyl, 2,2-diphenylethyl, 3,4-dimethoxyphenethyl, 4-fluorophenethyl, 2-furylmethyl; 3,4-methylenedioxybenzyl, cyano and X is N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N-methyl, N-ethylamino, N-methyl, N-propylamino, N-methyl, N-phenylamino, N-ethyl, N-(4-methyl)benzylamino, N-butyl, N-ethylamino, N-butyl, N-propylamino, [N-ethyl,N-(2-methyl)allyl]amino, hydroxy, O-t-butyl and 1-pyrrolidinyl; and, Y is hydrogen, methoxy and methylthio as δ-opioid agonists have been described (Boyd, R. E., Carson, J. R., Codd, E. E., Gauthier, A. D., Neilson, L. A and Zhang, S-P., Biorg. Med. Chem. Lett., 2000, 10: 1109-1111).
4-[(8-Alkyl-8-azabicyclo[3.2.1]octyl-3-yl)-3-arylanilino]-N,N-diethylbenzamides have also been described as selective δ-opioid ligands (Thomas, J. B., Atkinson, R. N., Rothman, R. B., Burgess, J. P., Mascarella, S. W., Dersch, C. M., Xu, H. and Carroll, F. I., Biorg. Med. Chem. Lett., 2000, 10: 1281-1284).
The benzamidine derivatives of the present invention have not been previously described as δ-opioid receptor modulators.
Accordingly, it is an object of the present invention to provide benzamidine derivatives which are δ-opioid receptor modulators. It is also an object of the present invention to provide benzamidine derivatives which are δ-opioid receptor selective agonists useful as analgesics having reduced side-effects. It is another object of the present invention to provide δ-opioid receptor antagonists useful for treating immune disorders, inflammation, neurological conditions, psychiatric conditions, drug abuse, alcohol abuse, gastritis, diarrhea, cardiovascular disorders or respiratory disorders. It is a further object of the present invention to provide a method for treating a disorder modulated by the δ-opioid receptor.