Organic compounds
The present invention provides a compound of formula I: Said compound is inhibitor of aldosterone synthase and aromatase, and thus can be employed for the treatment of a disorder or disease mediated by aldosterone synthase or aromatase. Accordingly, the compound of formula I can be used in treatment of hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, inflammation, increased formation of collagen, fibrosis such as cardiac or myocardiac fibrosis and remodeling following hypertension and endothelial dysfunction, gynecomastia, osteoporosis, prostate cancer, endometriosis, uterine fibroids, dysfunctional uterine bleeding, endometrial hyperplasia, polycystic ovarian disease, infertility, fibrocystic breast disease, breast cancer and fibrocystic mastopathy. Finally, the present invention also provides a pharmaceutical composition.
1. A compound of formula (III)
wherein
R is hydrogen, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, —C(O)O—R 10 , or —C(O)N(R 11 )(R 12 ), said (C 1 -C 4 ) alkyl and (C 2 -C 4 ) alkenyl are optionally substituted by one to three substituents independently selected from hydroxyl, (C 1 -C 4 ) alkoxy, halo, —NH 2 , or (C 1 -C 4 )-[(alkyl)(alkyl)N—];
wherein R 10 , R 11 and R 12 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkyl-, (C 3 -C 8 ) cycloalkyl, or (C 2 -C 4 ) alkenyl, each of which is optionally substituted by one to three substituents independently selected from halo, hydroxyl, or (C 1 -C 4 ) alkoxy;
R 1 is a (C 1 -C 4 ) alkoxy;
R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, halo, cyano, —NH 2 , (C 1 -C 4 )-[(alkyl)(alkyl)N—], (C 1 -C 4 ) alkoxy, (C 2 -C 4 ) alkenyl, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 6 -C 10 ) aryl, or (5-9)-membered heteroaryl, said (C 1 -C 4 ) alkoxy, (C 2 -C 4 ) alkenyl, (C 1 -C 4 ) alkyl and (C 6 -C 10 ) aryl being optionally substituted by one to three substituents independently selected from halo, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkyl, —NH 2 , cyano, nitro, (C 1 -C 4 ) alkoxy-(C 1 -C 4 ) alkyl-, or (C 1 -C 4 ) haloalkyl, with the proviso that no more than three of R 2 , R 3 , R 4 , and R 5 are simultaneously hydrogen;
R 6 and R 7 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 1 -C 4 ) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) alkoxy;
when R 6 and R 7 are attached to the same carbon atom, they optionally form a moiety (A) represented by the following structure:
wherein R a and R b are independently hydrogen, or (C 1 -C 4 ) alkyl, or R a and R b taken together with said carbon atom optionally form a 3-8-membered ring;
or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers.
2. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and one or more pharmaceutically acceptable carriers.
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and one or two or more therapeutically active agents selected from angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof, HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof; angiotensin converting enzyme (ACE) Inhibitor or a pharmaceutically acceptable salt thereof; calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof; endothelin antagonist or a pharmaceutically acceptable salt thereof; renin inhibitor or a pharmaceutically acceptable salt thereof; diuretic or a pharmaceutically acceptable salt thereof; an ApoA-I mimic; an anti-diabetic agent; an obesity-reducing agent; an aldosterone receptor blocker; an endothelin receptor blocker; a CETP inhibitor; an inhibitor of Na-K-ATPase membrane pump; a beta-adrenergic receptor blocker or an alpha-adrenergic receptor blocker; a neutral endopeptidase (NEP) inhibitor; and an inotropic agent.
4. A pharmaceutical combination comprising a therapeutically effective amount of a compound according to claim 1 and one or two or more therapeutically active agents selected from an antiestrogen; an anti-androgen; a gonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; an anti-neoplastic anti-metabolite; a platin compound; a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid phosphatase activity, a anti-angiogenic compound; a compound which induces cell differentiation processes; monoclonal antibodies; a cyclooxygenase inhibitor; a bisphosphonate; a heparanase inhibitor; a biological response modifier; an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase inhibitor; a proteasome inhibitor; agents which target, decrease or inhibit the activity of Flt-3; an HSP90 inhibitor; antiproliferative antibodies; an HDAC inhibitor; a compound which targets, decreases or inhibits the activity/function of serine/theronine mTOR kinase; a somatostatin receptor antagonist; an anti-leukemic compound; tumor cell damaging approaches; an EDG binder; a ribonucleotide reductase inhibitor; an S-adenosylmethionine decarboxylase inhibitor; a monoclonal antibody of VEGF or VEGFR; an Angiostatic steroid; an implant containing corticosteroids; an AT1 receptor antagonist; and an ACE inhibitor.