US 6,387,893 B1 · Spirotricyclic substituted azacycloalkane derivatives and uses thereof

Abstract

Spirotricyclic azacycloalkyl compounds and pharmaceutically acceptable salts thereof are disclosed. The synthesis of these compounds is also described. One application of these compounds, which are alpha 1a adrenergic receptor antagonists, 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 Q is
A1 is a benzene ring, substituted benzene, heterocyclic or substituted heterocyclic, wherein each of the substituents on substituted benzene or substituted heterocyclic is independently halogen, cyano, nitro, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalky;
A2 independently has the same definition as set forth for A1;
Z is C(RbRc)C(RbRc), C(Rb)═C(Rc), C(RbRc)C(═O), or C(═O)C(RbRc);
each Y is independently hydrogen, halogen, cyano, nitro, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
each X1 is independently hydrogen, halogen, cyano, nitro, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
each R1 is a substituent connected to a ring atom other than N or spiro subsituted carbon and is independently hydrogen or C1-C4 alkyl;
R2, R3, R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl;
R6 is hydrogen, C1-C8 alkyl, or fluorinated C1-C8 alkyl;
R7 and R8 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C1-C6 alkoxy, CO2Rd, C2-C8 alkoxyalkyl, and fluorinated C2-C8 alkoxyalkyl;
R9 and R10 are each independently selected from hydrogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, C4-C20 alkylcycloalkyl, C4-C20 cycloalkylalkyl, or CHReRf;
R12 and R14 are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, and fluorinated C2-C8 alkoxyalkyl;
or one of R12 and R14 is CO2Rd or CON(Re)2 and the other of R12 and R14 is as earlier defined;
or R12 and R14 together with the carbon atom to which they are attached form C3-C7 cycloalkyl or substituted C3-C7 cycloalkyl, wherein the each of the substituents on substituted cycloalkyl is independently halogen, cyano, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, CO2Rd, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
R16 and R18 are each independently selected from hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocyclic, and substituted heterocyclic, provided that R16 and R18 are not both hydrogen;
wherein each of the substituents on substituted phenyl or substituted naphthyl is independently halogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, CO2Rd, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
and wherein each of the substituents on substituted heterocyclic is independently halogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, C2-C8 alkoxyalkyl, fluorinated C2-C8 alkoxyalkyl, or phenyl;
Ra is hydrogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, C4-C20 alkylcycloalkyl, or C4-C20 cycloalkylalkyl;
Rb and Rc are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, fluorinated C1-C6 alkyl, phenyl, and substituted phenyl, wherein each of the substituents on the substituted phenyl is independently halo, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, CO2Rd, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
Rd is hydrogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, C4-C20 alkylcycloalkyl, or C4-C20 cycloalkylalkyl;
Re is hydrogen or C1-C6 alkyl;
Rf is phenyl or substituted phenyl, wherein each of the substituents on substituted phenyl is halogen, cyano, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or CO2Rd, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
m and n are each independently integers from 0 to 3;
p is an integer from 1 to 5;
q is 0 or 1, provided that when Q is
then q is 0;
s is an integer from 0 to 4;
t1 is an integer from 0 to 4;
and
t2 is an integer from 0 to 5;
or a pharmaceutically acceptable salt thereof.

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Spirotricyclic substituted azacycloalkane derivatives and uses thereof

Life of this patent

Spirotricyclic substituted azacycloalkane derivatives and uses thereof

Life of this patent

Abstract

Claims23