Patent EA-004860-B1 (EA)
Title: Monoamine reuptake inhibitors for treatment of cns disorders
Inventor: ELLIOTT MARK LEONARD
IPC: C07C235/34
Filed: 2000-02-02
Abstract: 1. A compound of the formula wherein A and B rings are phenyl rings; n and m are, selected, independently, from one, two and three; R<1> and R<2> are selected, independently, from hydrogen, (C1-C4) alkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl, or R<1> and R<2> together with the nitrogen to which they are attached, form a four to eight membered saturated ring containing one or two heteroatoms, including the nitrogen to which R<1> and R<2> are attached, wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C1-C6) alkyl; R<3> and R<4> are selected, independently, from hydrogen and (C1-C4) alkyl optionally substituted with from one to three fluorine atoms, or R<3> and R<4> together with the carbon to which they are attached, form a four to eight membered saturated carbocyclic ring, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C1-C6) alkyl; or R<2> and R<3>, together with the nitrogen to which R<2> is attached and the carbon to which R<3> is attached, form a four to eight membered saturated ring containing one or two heteroatoms, including the nitrogen to which R<2> is attached, wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C1-C6) alkyl; each X is selected, independently, from hydrogen, halo (i. e., chloro, fluoro, bromo or iodo), (C1-C4) alkyl optionally substituted with from one to three fluorine atoms, (C1-C4) alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, amino, (C1-C4) alkylamino, di-[(C1-C4)alkyl]amino, NR<5>(C=O)(C1-C4) alkyl, SO2NR<5>R<6> and SO2(C1-C6) alkyl, wherein R<5> and R<6> are selected, independently, from hydrogen and (C1-C6) alkyl, and p is zero, one or two; and each Y is selected, independently, from hydrogen, (C1-C6) alkyl and halo; with the proviso that: (a) no more than one of NR<1>R<2>, CR<3>R<4> and R<2>NCR<3> can form a ring; and (b) at least one X must be other than hydrogen when (i) R<3> and R<4> are both hydrogen, (ii) R<1> and R<2> are selected, independently, from hydrogen and (C1-C4) alkyl, and (iii) ring B is mono- or disubstituted with, respectively, one or two halo groups; or a pharmaceutically acceptable salt thereof. 2. A compound or salt according to claim 1, wherein n is one, X is fluoro, R<3> and R<4> are hydrogen, R<1> is hydrogen, R<2> is methyl, m is two and Y is Ym is 3,4-dichloro. 3. A compound or salt according to claim 1, wherein m is zero, n is one, R<3> and R<4> are hydrogen, X is chloro, bromo, iodo or methyl, R<1>is hydrogen and R<2> is methyl. 4. A compound or salt according to claim 1, wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: [2-(3,4-Dichlorophenoxy)-5-fluorobenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-fluorobenzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethylbenzyl]-dimethylamine; N-[4-(3,4-Dichlorophenoxy)-3-dimethylaminomethylphenyl]-acetamide; {1-[2-(3,4-Dichlorophenoxy) phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3, 4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4,5-dimethoxybenzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; [2-(3-Chloro-4-fluorophenoxy)-5-fluorobenzyl]-methylamine; (+/-)-2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-pyrrolidine; (-)-2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-pyrrolidine; (+)-2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-pyrrolidine; and 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-N-methylpyrrolidine. 5. A pharmaceutical composition for treating a disorder or condition selected from hypertension, depression, (depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, in a mammal, preferably a human, comprising an amount of a compound according to claim 1 that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier. 10. A pharmaceutical composition for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, dopamine or norepinephrine in a mammal, preferably a human, comprising an amount of a compound of the formula 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier. 11. A method for treating a disorder or condition selected from hypertension, depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder in a mammal, preferably a human, comprising an amount of a compound according to claim 1 that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier. 12. A method for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, dopamine or norepinephrine in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound according to claim 1, that is effective in treating such disorder or condition. 13. A pharmaceutical composition for treating a condition or disorder that can be treated by inhibiting the reuptake of serotonin, dopamine or norepinephrine in a mammal, comprising: a) a pharmaceutically acceptable carrier; b) a compound according to claim 1; and c) an NK-1 receptor antagonist or a 5HT1D receptor antagonist, or a pharmaceutically acceptable salt thereof; wherein the amount of the active compounds (i. e., the compound of formula I and the NK-1 receptor antagonist or <5>HT1D receptor antagonist) are such that the combination is effective in treating such disorder or condition. 14. A method for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, dopamine or norepinephrine in a mammal, comprising administering to a mammal requiring such treatment: a) a compound of the formula 1, defined above, or a pharmaceutically acceptable salt thereof; and b) an NK-1 receptor antagonist or 5HT1D receptor antagonist, or a pharmaceutically acceptable salt thereof; wherein the amounts of the active compounds (i. e., the compound of formula I and the NK-1 receptor antagonist or 5HT1D receptor antagonist) are such that the combination is effective in treating such disorder or condition.