Sulfonamide derivative and medicinal use thereof
Sulfonamide compounds of a specific chemical structure in which a sulfonamide group having, as a substituent, a phenyl group or a heterocyclic group having a hetero atom(s) as a constituent element(s) is present at its terminal, and pharmaceutically acceptable salts thereof. These compounds are novel compounds having excellent α4 integrin-inhibitory action. The compounds have formulae represented by:
1. A sulfonamide compound represented by any one of the following formulae or a pharmaceutically acceptable salt thereof:
or represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
wherein
A represents a group represented by the following general formula (2-1), (2-2), or (2-3),
wherein
Arm is a cyclic alkyl group or aromatic ring containing 0, 1, 2, 3, or 4 hetero atoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms,
R 1 , R 11 , and R 21 each independently represent any one of a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxy group, a lower halogenoalkyl group, a lower halogenoalkoxy group, a lower halogenoalkylthio group, a lower halogenoalkenyl group, a nitro group, a cyano group, an amino group, a lower alkylamino group, a (lower alkylamino)lower alkyl group, a carboxyl group, a lower alkyloxycarbonyl group, a carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylsulfonyl group, a sulfamoyl group, and an ammonium group,
R 12 , R 13 , and R 14 each independently represent any one of a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxy group, a lower halogenoalkyl group, a lower halogenoalkoxy group, a lower halogenoalkylthio group, a lower halogenoalkenyl group, a nitro group, a cyano group, an amino group, a lower alkylamino group, a (lower alkylamino)lower alkyl group, a carboxyl group, a lower alkyloxycarbonyl group, a carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylsulfonyl group, a sulfamoyl group, and an ammonium group,
R 2 , R 3 , R 22 , R 23 , R 24 , and R 25 each independently represent any one of a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxy group, a lower halogenoalkyl group, a lower halogenoalkoxy group, a lower halogenoalkylthio group, a lower halogenoalkenyl group, a nitro group, a cyano group, an amino group, a lower alkylamino group, a (lower alkylamino)lower alkyl group, a carboxyl group, a lower alkyloxycarbonyl group, a carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylsulfonyl group, a sulfamoyl group, and an ammonium group,
B represents any one of a lower alkoxy group optionally substituted with an aryl group(s), a hydroxyl group(s), a lower alkyl group(s), a lower alkylamino group(s), and/or a heterocyclic group(s), a hydroxyl group, and a hydroxyamino group,
R 41 represents a hydrogen atom or a lower alkyl group,
a, b, c, and d each independently represent C—R 31 , C—R 32 , C—R 33 , and C—R 34 , respectively, but one or two of a, b, c, and d may each represent a nitrogen atom,
R 31 , R 32 , R 33 , and R 34 each independently represent any one of a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, and a nitro group, provided that any one of R 31 , R 32 , R 33 , and R 34 is a halogen atom or a lower alkyl group,
e, f, g, and h each independently represent C—R 35 , C—R 36 , C—R 37 , and C—R 38 , respectively, but one or two of e, f, g, and h may each represent a nitrogen atom,
R 35 , R 36 , R 37 , and R 38 are each independently any one of a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, and a nitro group,
D represents a phenyl group or heterocyclic group optionally having a substituent(s) selected from the group consisting of halogen atoms, hydroxyl groups, lower alkyl groups, lower alkenyl groups, lower alkynyl groups, lower alkoxy groups, lower alkylthio groups, lower hydroxyalkyl groups, lower hydroxyalkenyl groups, lower hydroxyalkoxy groups, lower halogenoalkyl groups, lower halogenoalkoxy groups, lower halogenoalkylthio groups, lower halogenoalkenyl groups, nitro groups, cyano groups, amino groups, carboxyl groups, lower alkyloxycarbonyl groups, carbamoyl groups, lower alkanoyl groups, aroyl groups, lower alkylsulfonyl groups, sulfamoyl groups, and ammonium groups, and
E represents a 5- or 6-membered heterocyclic group optionally having a substituent(s) selected from the group consisting of halogen atoms, hydroxyl groups, lower alkyl groups, lower alkenyl groups, lower alkynyl groups, lower alkoxy groups, lower alkylthio groups, lower hydroxyalkyl groups, lower hydroxyalkenyl groups, lower hydroxyalkoxy groups, lower halogenoalkyl groups, lower halogenoalkoxy groups, lower halogenoalkylthio groups, lower halogenoalkenyl groups, nitro groups, cyano groups, amino groups, 4- to 6-membered cyclic amino groups, carboxyl groups, lower alkyloxycarbonyl groups, carbamoyl groups, lower alkanoyl groups, aroyl groups, lower alkylsulfonyl groups, sulfamoyl groups, and ammonium groups; an aminocarbonyl group optionally having a substituent(s) selected from the group consisting of hydroxyl groups, lower alkyl groups, lower alkenyl groups, lower alkynyl groups, lower alkoxy groups, lower hydroxyalkyl groups, lower hydroxyalkenyl groups, lower hydroxyalkoxy groups, lower halogenoalkyl groups, lower halogenoalkoxy groups, lower halogenoalkenyl groups, amino groups, lower alkylamino groups, aryl groups, heterocyclic groups, heterocycle-substituted lower alkyl groups, lower alkylsulfonyl groups, and sulfamoyl groups; a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxy group, a lower halogenoalkyl group, a lower halogenoalkoxy group, a lower halogenoalkylthio group, a lower halogenoalkenyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a dihydroxyboryl group, a lower alkylcarbonyl group, a lower alkyloxycarbonyl group, a carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylsulfonyl group, a sulfamoyl group, an ammonium group, or a lower alkylaminoalkylene group, provided that the lower alkylcarbonyl group and the lower alkyloxycarbonyl group may each be bonded to the phenyl group represented by D to form a condensed ring.
2. The sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
E represents a 5- or 6-membered heterocyclic group optionally having a substituent(s) selected from the group consisting of halogen atoms, hydroxyl groups, lower alkyl groups, lower alkenyl groups, lower alkynyl groups, lower alkoxy groups, lower alkylthio groups, lower hydroxyalkyl groups, lower hydroxyalkenyl groups, lower hydroxyalkoxy groups, lower halogenoalkyl groups, lower halogenoalkoxy groups, lower halogenoalkylthio groups, lower halogenoalkenyl groups, nitro groups, cyano groups, amino groups, carboxyl groups, lower alkyloxycarbonyl groups, carbamoyl groups, lower alkanoyl groups, aroyl groups, lower alkylsulfonyl groups, sulfamoyl groups, and ammonium groups; an aminocarbonyl group optionally having a substituent(s) selected from the group consisting of hydroxyl groups, lower alkyl groups, lower alkenyl groups, lower alkynyl groups, lower alkoxy groups, lower hydroxyalkyl groups, lower hydroxyalkenyl groups, lower hydroxyalkoxy groups, lower halogenoalkyl groups, lower halogenoalkoxy groups, lower halogenoalkenyl groups, amino groups, lower alkylamino groups, aryl groups, heterocyclic groups, lower alkylsulfonyl groups, and sulfamoyl groups; a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxy group, a lower halogenoalkyl group, a lower halogenoalkoxy group, a lower halogenoalkylthio group, a lower halogenoalkenyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a dihydroxyboryl group, a lower alkyloxycarbonyl group, a carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylsulfonyl group, a sulfamoyl group, an ammonium group, or a lower alkylaminoalkylene group.
3. The sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
D is a phenyl group optionally having a substituent(s) selected from the group consisting of lower alkyl groups, halogen atoms, hydroxyl groups, and lower alkoxy groups.
4. The sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
D is a 6-membered aromatic heterocyclic group containing a nitrogen atom(s) as a ring-constituent atom(s) and optionally having a substituent(s) selected from the group consisting of lower alkyl groups, halogen atoms, and lower alkoxy groups.
5. The sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
the heterocyclic group represented by D is a pyridyl group or pyrrole group optionally having a substituent(s) selected from the group consisting of lower alkyl groups, halogen atoms, and lower alkoxy groups.
6. The sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
E is a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3, or 4 hetero atoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms and optionally having a substituent(s) selected from the group consisting of lower alkyl groups, lower alkoxy groups, and halogen atoms.
7. The sulfonamide derivative according to claim 6 or a pharmaceutically acceptable salt thereof, wherein
the aromatic heterocyclic group is selected from the group consisting of a pyridyl group, a pyridazyl group, a pyrimidyl group, a pyrazinyl group, a pyrrolyl group, a furanyl group, a thiophenyl group, a thiazolyl group, an oxazolyl group, a triazolyl group, and a tetrazole group.
8. The sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
E is (i) an aminocarbonyl group optionally substituted with a lower alkyl group(s), a heterocyclic group(s), and/or a heterocycle-substituted lower alkyl group(s); or (ii) a lower alkylaminoalkylene group.
9. The sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 , R 11 , and R 21 are lower alkyl groups.
10. The sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
Arm is selected from the group consisting of a phenyl group, a pyridyl group, and an imidazolyl group.
11. The sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
one of R 31 , R 32 , R 33 , and R 34 is a halogen atom, and the rest are hydrogen atoms, or two of R 31 , R 32 , R 33 , and R 34 are halogen atoms, and the rest are hydrogen atoms.
12. The sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
A is a group represented by general formula (2-1) or (2-2), in which Arm is a pyridyl group or an imidazolyl group, and R 1 and R 11 are lower alkyl groups,
two of R 31 , R 32 , R 33 , and R 34 are halogen atoms, and the rest are hydrogen atoms,
g is a carbon or nitrogen atom,
e is a carbon or nitrogen atom,
D is a phenyl group optionally having a halogen atom(s), a lower alkyl group(s), and/or a lower alkoxy group(s), a furyl group, or a pyridyl group optionally having a halogen atom(s), a lower alkyl group(s), and/or a lower alkoxy group(s), and
E is a pyridyl group, pyrimidyl group, triazolyl group, or pyrrolyl group optionally having a lower alkyl group(s) and/or a 4- to 6-membered cyclic amino group(s), or an aminocarbonyl group optionally substituted with a lower alkyl or heterocycle-substituted lower alkyl group(s).
13. A pharmaceutical composition comprising the sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
14. An agent for treating inflammatory bowel disease or multiple sclerosis, the method comprising administering an agent comprising, as an active ingredient, the sulfonamide compound according to claim 1 or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
15. A compound represented by any one of the following formulae or a pharmaceutically acceptable salt thereof: