| US 7,524,841 B2 | ||
| 4,4-disubstituted piperidine derivatives having CCR3 antagonism | ||
| Yoshiyuki Matsumoto, Tokyo (Japan); Minoru Imai, Tokyo (Japan); Yoshiyuki Sawai, Tokyo (Japan); Susumu Takeuchi, Tokyo (Japan); Akinobu Nakanishi, Tokyo (Japan); Kunio Minamizono, Tokyo (Japan); and Tomonori Yokoyama, Tokyo (Japan) | ||
| Assigned to Teijin Limited, Osaka (Japan) | ||
| Appl. No. 10/512,339 PCT Filed Apr. 16, 2003, PCT No. PCT/JP03/04842 § 371(c)(1), (2), (4) Date Oct. 22, 2004, PCT Pub. No. WO03/091245, PCT Pub. Date Nov. 06, 2003. |
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| Claims priority of application No. 2002-123883 (JP), filed on Apr. 25, 2002; and application No. 2002-240508 (JP), filed on Aug. 21, 2002. | ||
| Prior Publication US 2007/0037851 A1, Feb. 15, 2007 | ||
| This patent is subject to a terminal disclaimer. | ||
| Int. Cl. C07D 487/04 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01); A61K 31/4523 (2006.01); A61K 31/454 (2006.01); A61P 11/06 (2006.01) | ||
| U.S. Cl. 514—223.2 [544/12; 544/287; 546/199; 546/201; 546/202; 514/266.21; 514/322; 514/323; 514/324] | 25 Claims |
1. A 4,4-(disubstituted)piperidine derivative represented by the following formula (I):
 wherein R1 represents phenyl, C3-C8 cycloalkyl or an aromatic heterocyclic group having 1-3 atoms selected from the group consisting of oxygen, sulfur and nitrogen
as hetero atoms,
the phenyl or aromatic heterocyclic group of R1 may optionally fuse with a benzene ring or aromatic heterocyclic group having 1-3 atoms selected from the group consisting
of oxygen, sulfur and nitrogen as hetero atoms to form a fused ring,
the phenyl, C3-C8 cycloalkyl or aromatic heterocyclic group, or fused ring, in R1 may be unsubstituted, or substituted with one or more substituents selected from the group consisting of halogens, hydroxy,
cyano, nitro, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C5 alkylene, C2-C4 alkyleneoxy, C1-C3 alkylenedioxy, phenyl, phenoxy, phenylthio, benzyl, benzyloxy, benzoylamino, formyl, C2-C7 alkanoyl, C2-C7 alkoxycarbonyl, C2-C7 alkanoyloxy, C2-C7 alkanoylamino, C1-C6 alkylsulfonyl, C3-C8 (alkoxycarbonyl)methyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, carbamoyl, C2-C7 N-alkylcarbamoyl, C4-C9 N-cycloalkylcarbamoyl, N-phenylcarbamoyl, piperidylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, piperazinylcarbonyl,
N-methoxycarbamoyl, (formyl)amino and ureido, and
the substituent of the phenyl, C3-C8 cycloalkyl or aromatic heterocyclic group, or fused ring, of R1 may be unsubstituted, or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, C3-C5 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C6 alkoxy, C1-C6 alkylthio, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, pyrrolidinyl, piperidyl, C3-C7 lactam, carbamoyl, C2-C7 N-alkylcarbamoyl, C2-C7 alkoxycarbonyl, carboxyl, hydroxy, benzoyl, cyano, trifluoromethyl, halogen and tert-butoxycarbonylamino,
provided that when R1 is C3-C8 cycloalkyl, the substituent does not include amino, mono(C1-C6 alkyl)amino or di(C1-C6 alkyl)amino;
p represents an integer of 1-6;
R2 and R3 may be the same or different and each independently represents hydrogen, C1-C6 alkyl or phenyl,
where the C1-C6 alkyl or phenyl group of R2 and R3 may be unsubstituted, or substituted with one or more substituents selected from the group consisting of halogens, hydroxy,
C1-C6 alkyl, C2-C7 alkoxycarbonyl, amino, carbamoyl, carboxyl, cyano and C1-C6 alkoxy;
X represents —CO—, —SO2—, —CH2—, —CS— or a single bond;
q represents 0 or 1;
r represents 0 or 1;
Y represents —(R4)C═C(R5)—, —S— or —NR8—;
R4, R5, R6 and R7 may be the same or different, and each independently represents hydrogen, a halogen, hydroxy, cyano, nitro, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C5 alkylene, C2-C4 alkyleneoxy, C1-C3 alkylenedioxy, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzoylamino, formyl, C2-C7 alkanoyl, C2-C7 alkoxycarbonyl, C2-C7 alkanoyloxy, C2-C7 alkanoylamino, C4-C10 cycloalkanoylamino, C3-C7 alkenoylamino, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, C3-C8 (alkoxycarbonyl)methyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, carbamoyl, C2-C7 N-alkylcarbamoyl, C4-C9 N-cycloalkylcarbamoyl, N-phenylcarbamoyl, N-(C7-C12 phenylalkyl)carbamoyl, piperidylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, piperazinylcarbonyl, N-methoxycarbamoyl,
sulfamoyl, C1-C6 N-alkylsulfamoyl, (formyl)amino, (thioformyl)amino, ureido or thioureido,
where the aforementioned groups of R4, R5, R6 and R7 each may be independently unsubstituted, or substituted with one or more substituents selected from the group consisting of
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, C3-C5 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C6 alkoxy, (C1-C6 alkoxy) (C1-C6 alkoxy), phenyl (C1-C6 alkoxy), C1-C6 alkylthio, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, pyrrolidinyl, piperidyl, (C2-C7 alkanoyl)piperidyl, C3-C7 lactam, carbamoyl, C2-C7 N-alkylcarbamoyl, C4-C9 N-cycloalkylcarbamoyl, N-phenylcarbamoyl, N—(C7-C12 phenylalkyl)carbamoyl, C2-C7 alkanoylamino, C2-C7 alkoxycarbonyl, carboxyl, hydroxy, benzoyl, cyano, trifluoromethyl, halogens, tert-butoxycarbonylamino, C1-C6 alkylsulfonyl and heterocycles or aromatic heterocycles where a heterocycle or aromatic heterocycle has 1-3 atoms selected
from the group consisting of oxygen, sulfur and nitrogen as hetero atoms, and may be substituted with C1-C6 alkyl; and
R8 represents hydrogen or C1-C6 alkyl,
where the C1-C6 alkyl group of R8 may be unsubstituted, or substituted with one or more substituents selected from the group consisting of halogens, hydroxy,
cyano, nitro, carboxyl, carbamoyl, mercapto, guanidino, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, phenyl where phenyl may be substituted, or substituted with one or more substituents selected from the group consisting
of halogens, hydroxy, C1-C6 alkyl, C1-C6 alkoxy and benzyloxy), phenoxy, benzyloxy, benzyloxycarbonyl, C2-C7 alkanoyl, C2-C7 alkoxycarbonyl, C2-C7 alkanoyloxy, C2-C7 alkanoylamino, C2-C7 N-alkylcarbamoyl, C2-C6 alkylsulfonyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino and ureido,
a pharmaceutically acceptable acid adduct thereof, or a pharmaceutically acceptable C1-C6 alkyl adduct thereof.
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