US 6,319,932 B1 · Oxazolidinones useful as alpha 1A adrenoceptor antagonists

Abstract

Novel oxazolidinone compounds and pharmaceutically acceptable salts thereof are disclosed. The synthesis of these compounds and their use as alpha 1a adrenergic receptor antagonists is also described. One application of these compounds is in the treatment of benign prostatic hyperplasia. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha 1a receptor subtype without at the same time inducing hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia can be achieved.

A compound of formula:

wherein R1 is phenyl, mono- or poly-substituted phenyl, naphthyl, mono- or poly-substituted naphthyl, heterocyclic, or mono- or poly-substituted heterocyclic;
wherein the heterocyclic is selected from the group consisting of pyridyl, pyridyl N-oxide, pyrazinyl, thienyl, thiazolyl, furanyl, and quinazolinyl;
each of the substituents on the substituted phenyl or the substituted naphthyl is independently selected from halo, nitro, cyano, hydroxy, N(Ra)2, N(Ra)C(═O)Ra, N(Ra)C(═O)N(Ra)2, NRaSO2Ra, NRaSO2N(Ra)2, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C3-C8 cycloalkyl, fluorinated C1-C6 alkoxy, (CH2)1-4ORa, (CH2)0-4CO2Ra , (CH2)0-4C(═O)N(Ra)2,(CH2)0-4SO2N(Ra)2, and (CH2)0-4SO2Ra;
and each of substituents on the substituted heterocyclic is independently selected from halo, nitro, cyano, hydroxy, N(Ra)2, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C3-C8 cycloalkyl, fluorinated C1-C6 alkoxy, (CH2)1-4ORa, (CH2)0-4CO2Ra, (CH2)0-4C(═O)N(Ra)2, (CH2)0-4SO2N(Ra)2, (CH2)0-4SO2Ra, and phenyl;
R2 is hydrogen, cyano, CO2Ra, C(═O)N(Ra)2, hydroxy, C1-C6 alkoxy, (CH2)1-4ORa, tetrazole phenyl, mono- or poly-substituted phenyl, naphthyl, mono- or poly-substituted naphthyl, pyridyl, mono- or poly-substituted pyridyl, thienyl, mono- or poly-substituted thienyl, furanyl, or mono- or poly-substituted furanyl;
wherein each of the substituents on the substituted phenyl or substituted naphthyl is independently selected from halo, nitro, cyano, hydroxy, N(Ra)2, N(Ra)C(═O)Ra, N(Ra)C(═O)N(Ra)2, NRaSO2Ra, NRaSO2N(Ra)2, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C3-C8 cycloalkyl, fluorinated C1-C6 alkoxy, (CH2)1-4ORa, (CH2)0-4CO2Ra, (CH2)0-4C(═O)N(Ra)2, (CH2)0-4SO2N(Ra)2, and (CH2)0-4SO2Ra;
and each of the substituents on the substituted pyridyl, substituted furanyl, or substituted thienyl is independently selected from halo, nitro, cyano, hydroxy, N(Ra)2, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C3-C8 cycloalkyl, fluorinated C1-C6 alkoxy, (CH2)1-4ORa, (CH2)0-4CO2Ra, (CH2)0-4C(═O)N(Ra)2, (CH2)0-4SO2N(Ra)2, (CH2)0-4SO2Ra, and phenyl;
each R3 is a substituent connected to a ring atom other than N and CR1R2 and is independently C1-C4 alkyl;
R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl;
R6 is hydrogen or C1-C6 alkyl;
R7 is phenyl, mono- or poly-substituted phenyl, pyridyl, mono- or poly-subsituted pyridyl, thienyl, mono- or poly-substituted thienyl, furanyl, or mono- or poly-substituted furanyl;
wherein each substituent on the substituted phenyl is independently selected from halo, nitro, cyano, hydroxy, N(Ra)2, N(Ra)C(═O)Ra, N(Ra)C(═O)N(Ra)2, NRaSO2Ra, NRaSO2N(Ra)2, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C3-C8 cycloalkyl, fluorinated C1-C6 alkoxy, (CH2)1-4ORa, (CH2)0-4CO2Ra, (CH2)0-4C(═O)N(Ra)2, (CH2)0-4SO2N(Ra)2, and (CH2)0-4SO2Ra;
and each of the substituents on the substituted pyridyl, substituted thienyl or substituted furanyl is independently selected from halo, nitro, cyano, hydroxy, N(Ra)2, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C3-C8 cycloalkyl, fluorinated C1-C6 alkoxy, (CH2)1-4ORa, (CH2)0-4CO2Ra, (CH2)0-4C(═O)N(Ra)2, (CH2)0-4SO2N(Ra)2, (CH2)0-4SO2Ra, and phenyl;
R8 is C(═O)NH2, (CH2)2-4ORb, CORc, or (CH2)1-4Rd;
Ra is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or fluorinated C1-C6 alkyl;
Rb is fluorinated C1-C6 alkyl;
Rc is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, or mono- or poly-substituted phenyl;
wherein each of the substituents on the substituted phenyl is independently selected from halo, nitro, cyano, hydroxy, N(Ra)2, N(Ra)C(═O)Ra, N(Ra)C(═O)N(Ra)2, NRaSO2Ra, NRaSO2N(Ra)2, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C3-C8 cycloalkyl, fluorinated C1-C6 alkoxy, (CH2)1-4ORa, (CH2)0-4CO2Ra, (CH2)0-4C(═O)N(Ra)2, (CH2)0-4SO2N(Ra)2, and (CH2)0-4SO2Ra;
Rd is cyano, N(Ra)C(═O)N(Ra)2, NRaSO2Ra, NRaSO2N(Ra)2, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, morpholinyl,
Re is C1-C6 alkyl, C3-C8 cycloalkyl, or fluorinated C1-C6 alkyl;
l and m are each integers of from 0 to 2, with the proviso that the sum of l+m is less than or equal to 3;
n is an integer of from 1 to 3;
and
p is an integer of from 0 to 2;
or a pharmaceutically acceptable salt thereof.

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Oxazolidinones useful as alpha 1A adrenoceptor antagonists

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Oxazolidinones useful as alpha 1A adrenoceptor antagonists

Life of this patent

Abstract

Claims27