Patent EA-004704-B1 (EA)
Title: Phenoxypropylamine derivatives
Inventor: NISHIYAMA AKIRA
IPC: C07D401/14
Filed: 2000-05-22
Abstract: 1. A phenoxypropylamine compound of the formula (I) wherein each symbol in the formula means as follows: a bond represented by a solid line and a dotted line shows a double bond or a single bond; X is a hydrogen atom, a hydroxy group, a C1-C8 alkoxy group, acetoxy group, propionyloxy group, butyryloxy group, benzoyloxy group or an oxo group; provided that when R<1> is a group of the following formula (2), X should not be a hydrogen atom; R<1> is a group of the following formula wherein Y is O or S; Ar is benzene or naphthalene, which may be substituted with the group selected from the group consisting of halogen atom, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl, benzyl, oxo and methoxyethyl; R<2> is phenyl group, naphthyl group, tetrahydronaphthyl group, indanyl group or indenyl group, which may be substituted with the group selected from the group consisting of halogen atom, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl, benzyl, oxo and methoxyethyl, or pyridyl, furyl, thienyl, pyrimidinyl, indolyl, benzo(b)thienyl, benzo(b)furyl, 3,4-methylenedioxyphenyl, benzimidazolyl, 1,4-benzodioxanyl, chromanyl, indolinyl, chromenyl, benzo(b)thiinyl, benzoisoxazolyl, benzo(c)furyl, isochromanyl, quinolinyl, 3,4-dihydro-2H-benzo(b)oxin-6-yl, 3,4-dihydro-2H-benzo(c)oxin-6-yl, isoindolinyl or isoquinolinyl, which may be substituted with the group selected from the group consisting of halogen atom, fluoromethyl, difluoromethyl, trifluoromethyl, C1-C4 alkyl, C1-C8 alkoxy, hydroxy, nitro, cyano, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, acetyl, propionyl, bytyryl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, phenoxy, benzyloxy, R'-S(O)t- wherein R' is C1-C4 alkyl and t is 0,1 or 2, Ph-S(O)t- wherein Ph is phenyl and t is 0,1 or 2, carbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl and oxo; R<5> is phenyl group, naphthyl group, tetrahydronaphthyl group, indanyl group or indenyl group, which may be substituted with the group selected from the group consisting of halogen atom, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl, benzyl, oxo and methoxyethyl, or pyridyl, furyl, thienyl, pyrimidinyl, indolyl, benzo(b)thienyl, benzo(b)furyl, 3,4-methylenedioxyphenyl, benzimidazolyl, 1,4-benzodioxanyl, chromanyl, indolinyl, chromenyl, benzo(b)thiinyl, benzoisoxazolyl, benzo(c)furyl, isochromanyl, quinolinyl, 3,4-dihydro-2H-benzo(b)oxin-6-yl, 3,4-dihydro-2H-benzo(c)oxin-6-yl, isoindolinyl or isoquinolinyl, which may be substituted with the group selected from the group consisting of halogen atom, fluoromethyl, difluoromethyl, trifluoromethyl, C1-C4 alkyl, C1-C8 alkoxy, hydroxy, nitro, cyano, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, acetyl, propionyl, bytyryl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, phenoxy, benzyloxy, R'-S(O)t- wherein R' is C1-C4 alkyl and t is 0,1 or 2, Ph-S(O)t- wherein Ph is phenyl and t is 0,1 or 2, carbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl and oxo; Z is void or -CH2-; and R<6> is hydrogen atom, hydroxy group, acetamido group, carboxyl group, C1-C4-alkcoxycarbonyl group, cyano group or C1-C8 alkoxy group; R<3> is a hydrogen atom, a C1-C18 alkyl group or a halogen atom; V is -CH2-, -O-, -S- or the formula -N(R<4>)-, wherein R<4> is hydrogen atom, C1-C18 is alkyl group or phenyl-C1-C4 alkyl group, which can be substituted with a group consisting of halogen atom, fluoromethyl, difluoromethyl, trifluoromethyl, C1-C4 alkyl, C1-C8 alkoxy, hydroxy, nitro, cyano and amino; W is void or -CH2- or -C((O)-; R<7> is a C1-C4 hydroxyalkyl group, acetyl group, propionyl group, butyryl group, pentanoyl group, hexanoyl group or benzoyl group saturated or unsaturated 5- or 6-membered heterocyclic group, optionally comprising 1-3 hetero atoms, selected from the group consisting of a nitrogen atom, an oxygen atom or a sulfur atom, which can be substituted with phenyl, a phenyl substituted with halogen, amino, nitro, hydroxy, C1-C4 alkyl and C1-C4 alkyloxy; C1-C18 alkyl, C1-C2 haloalkyl, C1-C8 alkoxy, a halo atom, C2-C4 alkenyl, C1-C4 hydroxyalkyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, bythoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, acetal, propionyl, butyryl, isobutyryl, acetamido, carboxy, methoxy, ethoxy, propoxy, isopropoxy, buthyloxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, and cyano; benzofuranyl, benzothiophenyl, indole, benzoxazole, benzothiazole, 1,2-benzodioxazole, 1,2-benzoisothiazole or benzimidazolinyl, which can be substituted with a group, selected from the group consisting of halogen, fluoromethyl, difluoromethyl, trifluoromethyl, C1-C4 alkyl, C1-C8 alkoxy, hydroxy, nitro, cyano and amino, C1-C4 alkylsulfonyl group or a group of the formula -Q-R<9>; wherein Q is -C(=O)-, -C(=S)-, -CH2- or -S(=O)2-, and R<9> is a group of the following formula or -MH-MH-R<15> wherein R<10> and R<11> are each-independently hydrogen atom, C1-C18 alkyl group, phenyl group, naphthyl group, tetrahydronaphthyl group, indanyl group or indenyl group, which may be substituted with the group selected from the group consisting of halogen atom, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl group, benzyl group, oxo group and methoxyethyl group; phenyl-C1-C4 alkyl group which may be substituted with the group selected from the group consisting of halogen atom, fluoromethyl group, difluoromethyl group, trifluoromethyl group, C1-C4 alkyl, C1-C4 alkoxy; R<12> is a hydrogen atom, phenyl group, naphthyl group, tetrahydronaphthyl group, indanyl group or indenyl group, which may be substituted with the group selected from the group consisting of a halogen atom, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl group, benzyl group, oxo group and methoxyethyl group; C1-C18 alkyl group C1-C8 alkoxy group, acetyl group, propionyl group, butyryl group, pentanoyl group, hexanoyl group or benzoyl group; R<15> is hydrogen atom, phenyl group, C1-C4 alkyl group, C1-C2 halogenated alkyl group, halogen atom, C2-C4alkenyl group, C1-C4 C2-C4 alkenyl group, C1-C4 hydroxyalkyl group, C1-C4 alkoxy- C1-C4 alkyl group, C1-C4 alkyloxycarbonyl group, amino group, mono(C1-C4 alkyl) amino group, di(C1-C2 alkyl) amino group, acetamido group, carboxyl group, acetyl group, propionyl group, butyryl group, pentanoyl group, hexanoyl group benzoyl group, C1-C4 alkoxy group, which may be substituted with the group selected from the group consisting of fluorine and chlorine atoms, C1-C4 alkylthio group or cyano group; provided that when R<1> is a group of the above formula (2), R<7> should not be C1-C4 hydroxyalkyl group or acetyl group, propionyl group, butyryl group, pentanoyl group, hexanoyl group or benzoyl group; and R<10> and R<11> are not each other hydrogen atom at the same time; or R<7> and W in combination may form a ring of the following formula wherein E is oxygen atom or sulfur atom, and Q' is an optionally substituted 4 to 7-membered heterocycle having 1 or 2 hetero atom(s) selected from the group consisting of nitrogen atom and oxygen atom in the ring, which heterocycle may be substituted by C1-C18 alkyl group, C2-C4 alkoxyalkyl group, phenyl group, naphthyl group, tetrahydronaphthyl group, indanyl group or indenyl group, which may be substituted with the group selected from the group consisting of halogen atom, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl, benzyl, oxo and methoxyethyl; phenyl- C1-C4 alkyl group which may be substituted with the group selected from the group consisting of halogen atom, fluoromethyl, difluoromethyl, trifluoromethyl, C1-C4 alkyl, C1-C8 alkoxy, hydroxy, nitro, cyano and amino; oxo group; or thioxo group; and in which case V is hydrogen atom; and Ra, Rb and Rc are each independently a hydrogen atom, a C1-C18 alkyl group, a hydroxy group, a C1-C8 alkoxy group, a halogen atom, an acyl group, a nitro group or an amino group; provided that when R<7> and W are bonded to form a ring of the above formula (14), Ra, Rb and Re are not each hydroxy group or C1-C8 alkoxy group; an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof. 2. The compound of claim 1, which is represented by the formula (I) wherein each symbol in the formula means as follows: a bond represented by a solid line and a dotted line shows a double bond; X is a hydrogen atom, a hydroxy group, a C1-C8 alkoxy group, an acetoxy group, propionyloxy group, butyryloxy group, benzoyloxy group or oxo group; R<1> is a group of the following formula wherein Y is O or S, Ar is benzene or naphthalene, which may be substituted with the group selected from the group consisting of halogen atom, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl, benzyl, oxo and methoxyethyl; R<2> is phenyl group, naphthyl group, tetrahydronaphthyl group, indanyl group or indenyl group, which may be substituted with the group selected from the group consisting of halogen atom, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl, benzyl, oxo and methoxyethyl, or pyridyl, furyl, thienyl, pyrimidinyl, indolyl, benzo(b)thienyl, benzo(b)furyl, 3,4-methylenedioxyphenyl, benzimidazolyl, 1,4-benzodioxanyl, chromanyl, indolinyl, chromenyl, benzo(b)thiinyl, benzoisoxazolyl, benzo(c)furyl, isochromanyl, quinolinyl, 3,4-dihydro-2H-benzo(b)oxin-6-yl, 3,4-dihydro-2H-benzo(c)oxin-6-yl, isoindolinyl or isoquinolinyl, which may be substituted with the group selected from the group consisting of halogen atom, fluoromethyl, difluoromethyl, trifluoromethyl, C1-C4 alkyl, C1-C8 alkoxy, hydroxy, nitro, cyano, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, acetyl, propionyl, bytyryl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, phenoxy, benzyloxy, R'-S(O)t- wherein R' is C1-C4 alkyl and t is 0,1 or 2, Ph-S(O)t- wherein Ph is phenyl and t is 0,1 or 2, carbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl and o