US 6,608,098 B1 · Isoindole derivatives

Abstract

This invention relates to compounds represented by the general formula [I] wherein, R represents an azido group, etc., R1 and R2 are the same or different and represent hydrogen atoms, etc., R3 and R4 are the same or different and represent hydrogen atoms, etc., X1 represents an oxygen atom, etc., X2 represents an oxygen atom, etc., Y represents an oxygen atom, etc., and Z represents a condensed aryl group, etc., or a pharmaceutically acceptable salt thereof, preparation processes thereof, and an agent for treating diabetes, a prophylactic agent for chronic complications of diabetes or a drug against obesity, containing, as an effective ingredient, the compound or the pharmaceutically acceptable salt thereof.

A compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof;

wherein,
R represents
(1) an aryl group,
(2) a mono- to tricyclic C7-C15 aromatic carbocyclic group selected from the group consisting of acenaphthylenyl, adamantyl, anthryl, indenyl, norbornyl and phenanthryl,
(3) a 5- or 6-membered heterocyclic group selected from the group consisting of isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrrolyl, pyranyl, furyl, furazanyl, imidazolidinyl, imidazolinyl, tetrahydrofuranyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl and morpholino (hereinafter, “isoxazolyl, . . . and morpholino” is referred to as a series of groups A), or
(4) a mono- to tricyclic aromatic heterocyclic group having per one ring 1 to 5 hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, selected from the group consisting of acridinyl, isoquinolyl, isoindolyl, indazolyl, indolyl, indolizinyl, ethylenedioxyphenyl, carbazolyl, quinazolinyl, quinoxalinyl, quinolidinyl, quinolyl, cumaronyl, chromenyl, phenanthridinyl, phenanthrolinyl, dibenzofuranyl, dibenzothiophenyl, cinnolinyl, thionaphthenyl, naphthyridinyl, phenazinyl, phenoxazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, benzimidazolyl, benzoxazoly0001, benzothiazolyl, benzotriazolyl, benzofuranyl and methylenedioxyphenyl (hereinafter, “acridinyl, . . . and methylenedioxyphenyl” is referred to as a series of groups B),
each of the above-mentioned groups (1) to (4) may optionally have one or more substituents selected from the group consisting of
(5) substituents selected from the group consisting of azido, amino, carbamoyl, carbamoylamino, carbamoyloxy, carboxyl, cyano, sulfamoyl, sulfo, nitro, halogen, hydroxy, formyl, formylamino, cyclic saturated C3-C9 aliphatic groups, cyclic unsaturated C3-C9 aliphatic groups, aralkyl, N-aralkylamino, N,N-diaralkylamino, aralkyloxy, aralkylcarbonyl, N-aralkylcarbamoyl, aryl, N-arylamino, N,N-diarylamino, aryloxy, arylsulfonyl, arylsulfonyloxy, N-arylsulfonylamino, N-arylsulfonylamino C1-C10 alkylamino, N-arylsulfonylamino C1-C10 alkylcarbamoyl, N-arylsulfonylamino C1-C6 alkoxycarbonyl, arylsulfamoyl, arylsulfamoyloxy, N-arylsulfamoyl C1-C10 alkylcarbamoyl, arylsulfamoyl C1-C6 alkoxycarbonyl, N-arylcarbamoyl, aroyl, aroxy, N-(N-aroylamino) C1-C10 alkylcarbamoyl, N-aroylamino C1-C10 alkoxycarbonyl, C2-C6 alkanoyl, N—C2-C6 alkanoylamino, N,N-di-C2-C6 alkanoylamino, N—C1-C6 alkylamino, N,N-di-C1-C6 alkylamino, N—C1-C10 alkylcarbamoyl, N—C1-C10 alkylthiocarbamoyl, N,N-di-C1-C10 alkylcarbamoyl, N,N-di-C1-C10 alkylthiocarbamoyl, N—C2-C6 alkenylcarbamoyl, N,N-di-C2-C6 alkenylcarbamoyl, N-amino C1-C10 alkylcarbamoyl, N—C1-C6 alkoxy C1-C10 alkylcarbamoyl, N—C1-C6 alkoxycarbonyl C1-C10 alkylcarbamoyl, N—C1-C6 alkoxycarbonylamino C1-C10 alkylcarbamoyl, N—C1-C6 alkoxycarbonylamino C1-C6 alkoxycarbonyl, C1-C6 alkylthio, N—C1-C6 alkylsulfamoyl, N,N-di-C1-C6 alkylsulfamoyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, N—C1-C6 alkylsulfonylamino, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, amino C1-C6 alkoxycarbonyl, N—C3-C6 cycloalkylamino, N,N-di-C3-C6 cycloalkylamino, C3-C6 cycloalkyloxy, N—C3-C6 cycloalkylcarbamoyl and N,N-di-C3-C6 cycloalkylcarbamoyl,
(6) 5- or 6-membered heterocyclic groups selected from the group consisting of the above-mentioned series of groups A,
(7) monocyclic to tricyclic aromatic heterocyclic groups having per one ring 1 to 5 hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, selected from the group consisting of the above-mentioned series of groups B,
(8) substituents selected from the group consisting of N—C1-C10 alkylcarbamoyl groups, N—C1-C10 alkylthiocarbamoyl groups, thiocarbonyl groups and carbonyl groups, each substituted with the above-mentioned heterocyclic group or the above-mentioned aromatic heterocyclic group, and
(9) substituents selected from the group consisting of straight-chain or branched and saturated or unsaturated C1-C9 aliphatic groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups and N—C1-C6 alkylamino groups, each of which groups may be substituted with a group selected from the group consisting of the substituents mentioned in the above item (8),
(hereinafter, the above-mentioned groups (5) to (9) are referred to as series of groups C),
R1 and R2 are the same or different, and represent
(1) groups selected from the group consisting of hydrogen, azido, amino, carbamoyl, carbamoylamino, carbamoyloxy, carboxyl, cyano, sulfamoyl, sulfo, nitro, halogen, hydroxy, formyl, formylamino, cyclic saturated C3-C9 aliphatic groups, cyclic unsaturated C3-C9 aliphatic groups, aralkyl, N-aralkylamino, aralkyloxy, aralkylcarbonyl, aryl, N-arylamino, aryloxy, arylsulfonyl, N-arylsulfonylamino, N-arylsulfonylamino C1-C10 alkylamino, N-arylsulfonylamino C1-C10 alkylcarbamoyl, N-arylsulfonylamino C1-C6 alkoxycarbonyl, C2-C6 alkanoyl, N—C2-C6 alkanoylamino, aroyl, N-aroylamino, N-aroyl C1-C10 alkylamino, N-aroyl C1-C10 alkylcarbamoyl, N—C1-C6 alkylamino, N,N-di-C1-C6 alkylamino, N—C1-C10 alkylcarbamoyl, N,N-di-C1-C10 alkylcarbamoyl, N—C1-C6 alkylsulfamoyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, N—C1-C6 alkylsulfonylamino, C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, N—C3-C6 cycloalkylamino, C3-C6 cycloalkyloxy and N—C3-C6 cycloalkylcarbamoyl (hereinafter, “hydrogen, . . . and N—C3-C6 cycloalkylcarbamoyl” is referred to as a series of groups D), or
(2) straight-chain or branched and saturated or unsaturated C1-C9 aliphatic groups, N—C1-C6 alkylamino groups, C1-C6 alkylthio groups or C1-C6 alkoxy groups, each of which groups may optionally be substituted with a group selected from the group consisting of the series of groups D but excluding hydrogen,
R3 and R4 are the same or different, and represent
(1) groups selected from the group consisting of hydrogen, azido, amidino, amino, carbamoyl, carbamoylamino, carbamoyloxy, carboxyl, guanidino, cyano, sulfamoyl, sulfo, nitro, halogen, hydroxy, formyl, formylamino, cyclic saturated C3-C9 aliphatic groups, cyclic unsaturated C3-C9 aliphatic groups, C2-C6 alkanoyl, N—C2-C6 alkanoylamino, N—C1-C6 alkylamino, N,N-di-C1-C6 alkylamino, N—C1-C10 alkylcarbamoyl, N,N-di-C1-C10 alkylcarbamoyl, C1-C6 alkylthio, N—C1-C6 alkylsulfamoyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, N—C1-C6 alkylsulfonylamino, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, N—C3-C6 cycloalkylamino, C3-C6 cycloalkyloxy and N—C3-C6 cycloalkylcarbamoyl (hererinafter, “hydrogen, . . . and N—C3-C6 cycloalkylcarbamoyl” is referred to as a series of groups E),
(2) straight-chain or branched and saturated or unsaturated C1-C9 aliphatic groups optionally substituted with a group selected from the group consisting of the series of groups E but excluding hydrogen, or
(3)
(3-1) aryl groups,
(3-2) monocyclic to tricyclic C7-C15 aromatic carbocyclic groups selected from the group consisting of acenaphthylenyl, adamantyl, anthryl, indenyl, norbornyl and phenanthryl,
(3-3) 5- or 6-membered heterocyclic groups selected from the group consisting of the aforementioned series of groups A,
(3-4) monocyclic to tricyclic aromatic heterocyclic groups having per one ring 1 to 5 hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, selected from the group consisting of the aforementioned series of groups B, or
(3-5) straight-chain or branched and saturated or unsaturated C1-C9 aliphatic groups optionally substituted with the above-mentioned aryl group, the above-mentioned aromatic carbocyclic group, the above-mentioned heterocyclic group or the above-mentioned aromatic heterocyclic group,
each of the above-mentioned groups (3-1) to (3-5) being optionally substituted with one or more substituents selected from the group consisting of the aforementioned series of group C, or
(4) R3 and R4 combine together to form a straight-chain or branched and saturated or unsaturated C1-C9 aliphatic group, a 5- or 6-membered saturated carbocyclic group, or a 5- or 6-membered unsaturated carbocyclic group,
X1 represents an oxygen atom, a sulfur atom or a group NR5 (wherein R5 represents a group selected from the group consisting of hydrogen, halogen, hydroxy, N—C1-C6 alkylsulfonylamino, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C2-C6 alkanoyl, carbamoyl and N—C1-C10 alkylcarbamoyl;
or a straight-chain or branched and saturated or unsaturated C1-C9 aliphatic group optionally substituted with a group selected from the group consisting of halogen, hydroxy, N—C1-C6 alkylsulfonylamino, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C2-C6 alkanoyl, carbamoyl and N—C1-C10 alkylcarbamoyl),
X2 represents an oxygen atom or a sulfur atom,
R6 represents a group selected from the group consisting of hydrogen, halogen, hydroxy, N—C1-C6 alkylsulfonylamino, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C2-C6 alkanoyl, carbamoyl and N—C1-C10 alkylcarbamoyl;
or a straight-chain or branched and saturated or unsaturated C1-C9 aliphatic group optionally substituted with a group selected from the group consisting of halogen, hydroxy, N—C1-C6 alkylsulfonylamino, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C2-C6 alkanoyl, carbamoyl and N—C1-C10 alkylcarbamoyl,
R7 represents hydrogen or C1-C6 alkyl, and
Z represents a condensed aryl.

31 more elements

Isoindole derivatives

Life of this patent

Isoindole derivatives

Life of this patent

Abstract

Claims7