| US 7,452,904 B2 | ||
| 1-alkyl-1-azoniabicyclo' 2.2.2 octane carbamate derivatives and their use as muscarinic receptor antagonists | ||
| Juan Lorenzo Catena Ruiz, L'Hospitalet de Llobregat (Spain); Carles Farrerons Gallemi, Mataro (Spain); Anna Fernandez Serrat, Sant Cugat del Vallès (Spain); Ignacio José Miquel Bono, L'Hospitalet de Llobregat (Spain); Dolors Balsa Lopez, Badalona (Spain); Carmen Lagunas Arnal, L'Hospitalet de Llobregat (Spain); Carolina Salcedo Roca, Corbera (Spain); Natividad Toledo Mesa, Vilanova del Vallès (Spain); and Andrés Fernandez Garcia, Barcelona (Spain) | ||
| Assigned to Chiesi Farmaceutici S.p.A., Parma (Italy) | ||
| Appl. No. 10/499,130 PCT Filed Dec. 18, 2002, PCT No. PCT/EP02/14470 § 371(c)(1), (2), (4) Date Oct. 12, 2004, PCT Pub. No. WO03/053966, PCT Pub. Date Jul. 03, 2003. |
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| Claims priority of application No. 200200043 (ES), filed on Dec. 20, 2001. | ||
| Prior Publication US 2005/0043349 A1, Feb. 24, 2005 | ||
| Int. Cl. A61K 31/439 (2006.01); C07D 453/02 (2006.01) | ||
| U.S. Cl. 514—305 [546/137] | 12 Claims |
1. A compound of general formula (I)
 wherein R1, R2 and R3 are radicals independently selected from the group consisting of H, OH, NO2, SH, CN, F, Cl, Br, I, COOH, CONH2, (C1-C4)-alkoxycarbonyl, (C1-C4-alkylsulfanyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxyl optionally substituted with one or several F, and (C1-C4)-alkyl optionally substituted with one or several F or OH; alternatively, either R1 and R2, or R2 and R3 may be forming a
biradical selected from the group consisting of —CH2—CH2—CH2—, and —CH2—CH2—CH2—CH2—;
R4 is a radical selected from the group consisting of:
a) a C-linked radical of a five or six membered heterocyclic ring containing at least one heteroatom selected from the group
consisting of O, S, and N, being this heterocyclic ring substituted with one or several substituents independently selected
from the group consisting of OH, oxo (═O), SH, NO2, CN, F, Cl, Br, I, CONH2, COOH, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylsulfanyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkyl optionally substituted with one or several F or OH, and (C1-C4)-alkoxyl optionally substituted with one or several F;
b) a C-linked radical of a bicyclic ring system consisting of a phenyl ring fused to a five or six membered heterocyclic ring
containing at least one heteroatom selected from the group consisting of O, S and N, being this bicyclic ring system optionally
substituted with one or several substituents independently selected from the group consisting of OH, oxo (═O), SH, NO2, CN, F, Cl, Br, I, CONH2, COOH, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylsulfanyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkyl optionally substituted with one or several F or OH, and (C1-C4)-alkoxyl optionally substituted with one or several F; and
c) phenyl substituted with one or several substituents independently selected from the group consisting of OH, SH, NO2, CN, F, Cl, Br, I, CONH2, COOH, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylsulfanyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkyl optionally substituted with one or several F or OH, and (C1-C4)-alkoxyl optionally substituted with one or several F;
R5 is a radical selected from the group consisting of:
a) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, all of them optionally substituted with one or several substituents independently
selected from the group consisting of OH, oxo (═O), SH, NO2, CN, F, Cl, Br, I, CONH2, NR7CO—(C1-C4)-alkyl, COOH, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylsulfanyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkyl optionally substituted with one or several F or OH, and (C1-C4)-alkoxyl optionally substituted with one or several F;
b) (C1-C10)-alkyl substituted with one or several radicals independently selected from the group consisting of R6, COR6, NH2, NR6R7, CONR6R7, NR7COR6, OH, OR6, COOR6, OCOR6, SO2R6, SH, SR6, SOR6, COSR6, SCOR6, CN, F, Cl, Br, NO2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, norbornenyl, and bicyclo[2.2. 1] heptanyl;
R6 is a radical selected from the group consisting of:
a) (C1-C5)-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, norbomenyl, bicyclo[2.2.1]heptanyl, all of them optionally
substituted with one or several substituents independently selected from the group consisting of OH, oxo (═O), SH, NO2, CN, F, Cl, Br, I, CONH2, NR7CO—(C1-C4)-alkyl, COOH, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylsulfanyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkyl optionally substituted with one or several F or OH, and (C1-C4)-alkoxyl optionally substituted with one or several F;
b) phenyl optionally substituted with one or several substituents independently selected from the group consisting of OH,
SH, NO2, CN, F, Cl, Br, I, CONH2, NR7CO—(C1-C4)-alkyl, COOH, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylsulfanyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkyl optionally substituted with one or several F or OH, and (C1-C4)-alkoxyl optionally substituted with one or several F;
c) a C-linked radical of a five or six membered heterocyclic ring containing at least one heteroatom selected from the group
consisting of O, S, and N, being this heterocyclic ring optionally substituted with one or several substituents independently
selected from the group consisting of OH, oxo (═O), SH, NO2, CN, F, Cl, Br, I, CONH2, NR7CO—(C1-C4)-alkyl, COOH, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylsulfanyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkyl optionally substituted with one or several F or OH, and (C1-C4)-alkoxyl optionally substituted with one or several F; and
d) a C-linked radical of a bicyclic ring system consisting of a phenyl ring fused to a five or six membered heterocyclic ring
containing at least one heteroatom selected from the group consisting of O, S and N, being this bicyclic ring system optionally
substituted with one or several substituents independently selected from the group consisting of OH, oxo (═O), SH, NO2, CN, F, Cl, Br, I, CONH2, COOH, NR7CO—(C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylsulfanyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkyl optionally substituted with one or several F or OH, and (C1-C4)-alkoxyl optionally substituted with one or several F;
R7 is a radical selected from the group consisting of H, phenoxycarbonyl, benzyloxycarbonyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, (C1-C4)-alkylsulfonyl, and (C1-C5)-alkyl; and
X−is a physiologically acceptable anion.
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