Cyclohexyldiamines as selective alpha 1a/1d adrenoreceptor antagonists for the treatment of benign prostatic hypertrophy and lower urinary tract symptoms

• US 20060173015A1
• Filed: 10/28/2005
• Published: 08/03/2006
• Est. Priority Date: 10/29/2004
• Status: Abandoned Application

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Connolly, Peter J., Middleton, Steven A., Pulito, Virginia L., Chiu, George, Liu, Jessica J., Li, Shengjian
• Application Number:
  US11/262,551
• Publication Number:
  US 20060173015A1
• Time in Patent Office: Days
• US Class Current: 514/252.130
• CPC Class Codes: C07D 213/71 to which a second hetero atom is attached
• CPC Class Codes: C07D 295/116 with the doubly bound oxygen or sulfur atoms directly attached to a carbocyclic ring

Abstract

The present invention relates to compounds of Formula (I)
or a pharmaceutically acceptable form thereof, as dual selective α_1a/α_1d adrenoreceptor antagonists for the treatment of benign prostatic hypertrophy and lower urinary tract symptoms. The present invention also relates to pharmaceutical compositions comprising said new compounds, new processes to prepare these new compounds and new uses as a medicine as well as method of treatments.

Claims

1. A compound of formula (I)

and pharmaceutically acceptable forms thereof, wherein

R₁ is selected from the group consisting of

(1) aryl,

(2) C_1-8alkyl(aryl),

(3) C_3-8cycloalkyl,

(4) C_1-8alkyl(C_3-8cycloalkyl),

(5) heteroaryl,

(6) C_1-8alkyl(heteroaryl),

(7) heterocyclyl, and

(8) C_1-8alkyl(heterocyclyl),

wherein (1), (3), (5) and (7) and the aryl, C_3-8cycloalkyl, heteroaryl and heterocyclyl portions of (2), (4), (6) and (8) respectively are optionally substituted with up to four substituents independently selected from the group consisting of

(i) C_1-8alkyl,

(ii) C_1-8alkoxy,

(iii) C_1-8alkyl(C_1-8alkoxy),

(iv) C_1-8alkyl(halogen)_1-17,

(v) C_1-8alkoxy(halogen)_1-17,

(vi) C_1-8alkyl(hydroxy)_1-3,

(vii) CO₂(C_1-8alkyl),

(viii) SO₂ substituted on sulfur with a substituent selected from the group consisting of C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(ix) amino optionally mono- or di-substituted with C_1-8alkyl,

(x) cyano,

(xi) halogen,

(xii) hydroxy,

(xiii) nitro,

(xiv) C_1-8alkyl(amino) optionally mono- or di-substituted on amino with C_1-8alkyl,

(xv) C_1-8alkyl(aryl), (xvi) C_1-8alkoxy(aryl),

(xvii) C_1-8alkyl(heteroaryl),

(xviii) C_1-8alkyl(heterocyclyl);

(xix) CO substituted on carbon with a substituent selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(xx) SO substituted on sulfur with a substituent selected from the group consisting of C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(xxi) C(O)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(xxii) SO₂N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(xxiii) NHSO₂ substituted on sulfur with a substituent selected from the group consisting of C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(xxiv) NH(CO) substituted on carbon with a substituent selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(xxv) NHSO₂N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(xxvi) NH(CO)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(xxvii) C_3-8cycloalkyl,

(xxviii) aryl,

(xxix) heteroaryl, and

(xxx) heterocyclyl;

R₂ is selected from the group consisting of hydrogen and C_1-8alkyl;

R₃ is up to four optionally present substituents independently selected from the group consisting of

(1) C_1-8alkyl,

(2) C_1-8alkoxy,

(3) C_1-8alkyl(C_1-8alkoxy),

(4) C_1-8alkyl(halogen)_1-17,

(5) C_1-8alkoxy(halogen)_1-17,

(6) C_1-8alkyl(hydroxy)_1-3,

(7) CO₂(C_1-8alkyl),

(8) SO₂ substituted on sulfur with a substituent selected from the group consisting of C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(9) amino optionally mono- or di-substituted with C_1-8alkyl,

(10) cyano,

(11) halogen,

(12) hydroxy,

(13) nitro,

(14) C_1-8alkyl(amino) optionally mono- or di-substituted on amino with C_1-8alkyl,

(15) aryl,

(16) C_1-8alkyl(aryl),

(17) C_1-8alkoxy(aryl),

(18) C_3-8cycloalkyl,

(19) C_1-8alkyl(C_3-8cycloalkyl),

(20) C_1-8alkoxy(C_3-8cycloalkyl),

(21) heteroaryl,

(22) C_1-8alkyl(heteroaryl),

(23) heterocyclyl,

(24) C_1-8alkyl(heterocyclyl),

(25) CO substituted on carbon with a substituent selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(26) SO substituted on sulfur with a substituent selected from the group consisting of C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(27) SO₂ substituted on sulfur with a substituent selected from the group consisting of C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(28) C(O)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(29) SO₂N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(30) NHSO₂ substituted on sulfur with a substituent selected from the group consisting of C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(31) NH(CO) substituted on carbon with a substituent selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl,

(32) NHSO₂N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl, and

(33) NH(CO)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C_1-8alkyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl

(34) C_3-8cycloalkoxy;

wherein (15), (18), (21) and (23) and the aryl, C_3-8cycloalkyl, heteroaryl and heterocyclyl portions of (8), (16), (17), (19), (20), (22), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), and (34) are optionally substituted with from one to two substituents independently selected from the group consisting of

(i) C_1-8alkyl,

(ii) C_1-8alkoxy,

(iii) C_1-8alkyl(C_1-8alkoxy),

(iv) C_1-8alkyl(halogen)_1-17,

(v) C_1-8alkoxy(halogen)_1-17,

(vi) C_1-8alkyl(hydroxy)_1-3,

(vii) CO₂(C_1-8alkyl),

(viii) SO₂(C_1-8alkyl),

(ix) amino optionally mono- or di-substituted with C_1-8alkyl,

(x) cyano,

(xi) halogen,

(xii) hydroxy,

(xiii) nitro, and

(xiv) C_1-8alkyl(amino) optionally mono- or di-substituted on amino with C_1-8alkyl; and

R₄ and R₅ are up to two optionally present substituents independently selected from the group consisting of oxo and C_1-6alkyl.

2. A compound according to claim 1, wherein R₁ is selected from the group consisting of

(1) aryl,

(2) C_1-8alkyl(aryl), and

(3) heteroaryl,

wherein (1) and (3) and the aryl portion of (2) is optionally substituted with up to four substituents independently selected from the group consisting of

(i) C_1-8alkyl,

(ii) C_1-8alkoxy,

(iii) C_1-8alkyl(C_1-8alkoxy),

(iv) C_1-8alkyl(halogen)_1-17,

(v) C_1-8alkoxy(halogen)_1-17,

(vi) C_1-8alkyl(hydroxy)_1-3,

(vii) CO₂(C_1-8alkyl),

(viii) SO₂(C_1-8alkyl),

(ix) amino optionally mono- or di-substituted with C_1-8alkyl,

(x) cyano,

(xi) halogen,

(xii) hydroxy,

(xiii) nitro,

(xiv) C_1-8alkyl(amino) optionally mono- or di-substituted on amino with C_1-8alkyl,

(xv) C_1-8alkyl(aryl),

(xvi) C_1-8alkoxy(aryl)

(xvii) C_1-8alkyl(heteroaryl), and

(xviii) C_1-8alkyl(heterocyclyl);

R₂ is selected from the group consisting of hydrogen and C_1-8alkyl; and

R₃ is selected from the group consisting of

(1) C_1-8alkyl,

(2) C_1-8alkoxy,

(3) C_1-8alkyl(C_1-8alkoxy),

(4) C_1-8alkyl(halogen)_1-17,

(5) C_1-8alkoxy(halogen)_1-17,

(6) C_1-8alkyl(hydroxy)_1-3,

(7) CO₂(C_1-8alkyl),

(8) SO₂(C_1-8alkyl),

(9) amino optionally mono- or di-substituted with C_1-8alkyl,

(10) cyano,

(11) halogen,

(12) hydroxy,

(13) nitro,

(14) C_1-8alkyl(amino) optionally mono- or di-substituted on amino with C_1-8alkyl,

(15) aryl,

(16) C_1-8alkyl(aryl),

(17) C_1-8alkoxy(aryl),

(18) C_3-8cycloalkyl,

(19) C_1-8alkyl(C_3-8cycloalkyl),

(20) C_1-8alkoxy(C_3-8cycloalkyl),

(21) heteroaryl,

(22) C_1-8alkyl(heteroaryl),

(23) heterocyclyl,

(24) C_1-8alkyl(heterocyclyl), and

(25) C_3-8cycloalkoxy.

3. A compound according to claim 1, wherein the compound is a compound of Formula (II)

and pharmaceutically acceptable forms thereof, wherein

R₁ is selected from the group consisting of

(1) aryl,

(2) C_1-8alkyl(aryl),

(3) C_3-8cycloalkyl,

(4) C_1-8alkyl(C_3-8cycloalkyl),

(5) heteroaryl,

(6) C_1-8alkyl(heteroaryl),

(7) heterocyclyl, and

(8) C_1-8alkyl(heterocyclyl),

wherein (1), (3), (5) and (7) and the aryl, C_3-8cycloalkyl, heteroaryl and heterocyclyl portions of (2), (4), (6) and (8) respectively are optionally substituted with from one to two substituents independently selected from the group consisting of

(i) C_1-8alkyl,

(ii) C_1-8alkoxy,

(iii) C_1-8alkyl(C_1-8alkoxy),

(iv) C_1-8alkyl(halogen)_1-17,

(v) C_1-8alkoxy(halogen)_1-17,

(vi) C_1-8alkyl(hydroxy)_1-3,

(vii) CO₂(C_1-8alkyl),

(viii) SO₂(C_1-8alkyl),

(ix) amino optionally mono- or di-substituted with C_1-8alkyl,

(x) cyano,

(xi) halogen,

(xii) hydroxy,

(xiii) nitro,

(xiv) C_1-8alkyl(amino) optionally mono or disubstituted on amino with C_1-8alkyl,

(xv) C_1-8alkyl(aryl), and

(xvi) C_1-8alkoxy(aryl).

4. A compound according to claim 1, wherein the compound is a compound of Formula (V)

and pharmaceutically acceptable forms thereof, wherein

R₃ is up to four optionally present substituents independently selected from the group consisting of

(1) C_1-8alkyl,

(2) C_1-8alkoxy,

(3) C_1-8alkyl(C_1-8alkoxy),

(4) C_1-8alkyl(halogen)_1-17,

(5) C_1-8alkoxy(halogen)_1-17,

(6) C_1-8alkyl(hydroxy)_1-3,

(7) CO₂(C_1-8alkyl),

(8) SO₂(C_1-8alkyl),

(9) amino optionally mono- or di-substituted with C_1-8alkyl,

(10) cyano,

(11) halogen,

(12) hydroxy,

(13) nitro,

(14) C_1-8alkyl(amino) optionally mono- or di-substituted on amino with C_1-8alkyl,

(15) aryl,

(16) C_1-8alkyl(aryl),

(17) C_1-8alkoxy(aryl),

(18) C_3-8cycloalkyl,

(19) C_1-8alkyl(C_3-8cycloalkyl),

(20) C_1-8alkoxy(C_3-8cycloalkyl),

(21) heteroaryl,

(22) C_1-8alkyl(heteroaryl),

(23) heterocyclyl,

(24) C_1-8alkyl(heterocyclyl), and

(25) C_3-8cycloalkoxy,

wherein (15), (18), (21) and (23) and the aryl, C_3-8cycloalkyl, heteroaryl and heterocyclyl portions of (16), (17), (19), (20), (22), (24), and (25) are optionally substituted with from one to two substituents independently selected from the group consisting of

(i) C_1-8alkyl,

(ii) C_1-8alkoxy,

(iii) C_1-18alkyl(C_1-18alkoxy),

(iv) C_1-8alkyl(halogen)_1-17,

(v) C_1-8alkoxy(halogen)_1-17,

(vi) C_1-8alkyl(hydroxy)_1-17,

(vii) CO₂(C_1-8alkyl),

(viii) SO₂(C_1-8alkyl),

(ix) amino optionally mono- or di-substituted with C_1-8alkyl,

(x) cyano,

(xi) halogen,

(xii) hydroxy,

(xiii) nitro, and

(xiv) C_1-8alkyl(amino) optionally mono- or di-substituted on amino with C_1-8alkyl;

and

R₆ is selected from the group consisting of

(1) C_1-8alkyl,

(2) C_1-8alkoxy,

(3) C_1-8alkyl(C_1-8alkoxy),

(4) C_1-8alkyl(halogen)_1-17,

(5) C_1-8alkoxy(halogen)_1-17,

(6) C_1-8alkyl(hydroxy)_1-3,

(7) CO₂(C_1-8alkyl),

(8) SO₂(C_1-8alkyl),

(9) amino optionally mono- or di-substituted with C_1-8alkyl,

(10) cyano,

(11) halogen,

(12) hydroxy,

(13) nitro,

(14) C_1-8alkyl(amino) optionally mono- or di-substituted on amino with C_1-8alkyl,

(15) C_1-8alkyl(aryl), and

(14) C_1-8alkoxy(aryl).

5. A compound according to claim 4, wherein the compound is selected from

or pharmaceutically acceptable forms thereof, preferably difumarate salts thereof.

6. The compound of any of claim 1 to 5, wherein the compound is an isolated form thereof.

7. The compound of any of claim 1 to 6, wherein the form of said compound is a pharmaceutical composition or medicament comprising an effective amount of one or more of said compound.

8. The pharmaceutical composition of claim 7, wherein the composition further comprises an effective amount of the compound and a pharmaceutically acceptable carrier.

9. A process for preparing a pharmaceutical composition comprising the step of admixing a compound of any of claim 1 to 6 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of any of claim 7 to 8, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg to about 300 mg/kg of body weight per day.

11. A compound of any of claim 1 to 6 for use as a medicine.

12. A method for treating, ameliorating or preventing an α

_1a and/or α

_1d adrenoreceptor mediated disorder or disease in a subject in need of such treatment, amelioration or prevention comprising administering to the subject a therapeutically or prophylactically effective amount of a compound of any of claim 1 to 6.

13. The method of claim 12, wherein the method further comprises treating Benign Prostatic Hyperplasia in a subject in need of such treatment comprising administering to the subject in need of such treatment a therapeutically effective amount of a compound of any of claim 1 to 6.

14. The method of claim 12, wherein the method further comprises treating Lower Urinary Tract Symptoms in a subject in need of such treatment comprising administering to the subject in need of such treatment a therapeutically effective amount of a compound of any of claim 1 to 6.

15. The method of any of claim 12 to 14, wherein the effective amount of the compound is from about 0.001 mg/kg/day to about 300 mg/kg/day.

16. The method of any of claim 12 to 14, wherein the method further comprises administering to the subject an effective amount of a combination product comprising one or more of the compound and at least one other therapeutic agent.

17. The method of claim 16, wherein the therapeutic agent is selected from a human testosterone 5-α

reductase inhibitor, a 5-α

reductase isoenzyme 2 inhibitor, an anti-antiandrogenic agent, an androgen receptor antagonist, a selective androgen receptor modulator, a urinary incontinence drug, an anti-muscarinic agent or a 5HT-receptor modulator.

18. The method of claim 16, wherein the therapeutic agent is selected from finasteride.

19. A process for preparing a compound of any of claim 1 to 6 comprising the steps of

(a) reacting a Compound A1 in the presence of a base and a suitable solvent to provide a Compound A2;

(b) reacting Compound A2 with a Compound A3 and a reducing agent in the presence of an optional acid catalyst in a suitable solvent to provide a Compound A4;

(c) reacting Compound A4 under acidic conditions in a suitable solvent to provide a deprotected Compound A5;

(d) reacting Compound A5 with a Compound A6 in the presence of a mild base in a suitable solvent to provide a Compound A7 as a racemic mixture; and

(e) separating the Compound A7 mixture in a suitable solvent to provide a cis isomer Compound A8 and a trans isomer Compound A9.