Patent DE-19963266-A1 (DE)
Title: New cholestane derivatives, useful for reducing plasma levels of lipoprotein A, e.g. for treating or preventing cardiovascular disease
Inventor: BRUMBY THOMAS
IPC: C07J9/00
Filed: 1999-12-16
Abstract: Cholestane derivatives (I) in all optically active forms, as racemates, diastereomers or diastereomer mixtures are new. Cholestane derivatives of formula (I) in all optically active forms, as racemates, diastereomers or diastereomer mixtures are new.   X  = bond, carbonyl, NR<14> or CR<15>R<16>;  R<14>  = hydrogen or with R<3> forms a tetrazole ring;  R<15> and R<16> = hydrogen, hydroxy or -CH2SR<25>, but at least one must be hydrogen;  R<1>  = hydrogen, alpha -CH2SR<25> or a wide range of other groups;  R<2>  = hydrogen, or forms a double bond with R<4>;  R<25>  = 1-4C alkyl, trifluoromethyl, phenyl (optionally substituted by one or more R<17>), or various heterocyclic groups; ;  R<17> and R<17>'  = hydrogen, 1-4C alkyl or alkenyl, hydroxy, methoxy, amino, acetylamino, NMe2 or Me;  R<3>  = hydrogen, hydroxy, carbonyl (with R<4>), OCONH2, -NR<21>R<22>, CH2CONH2, CH2CONMe2, CH2NHCOPh,  beta -CH=CHCONH2, exocyclic =CR<26>R<27> (with R<4>) or several heterocyclic rings (with R<4>), or a double bond (with R<5>) or a bond, with R<7>, when R<8>R<9> represents -NHCOR<23>;  R<21>  = hydrogen, 1-12C alkyl, 2-12C alkenyl, 3-7C cycloalkyl or optionally substituted aryl;  R<22>  = 1-12C alkyl, 2-12C alkenyl, COR<24>, COR<23>, SO2-R<25>, optionally substituted benzoyl or benzenesulfonyl (optionally substituted by 1-4C alkyl or alkoxy, carboxy, trifluoromethyl, halo, acetylamino, cyano or nitro);  R<23> and R<24> = various substituents;  R<26> and R<27>  = various substituents; R<4>  = hydrogen, carboxy, CONH2, trifluoromethyl, hydrocarbyl groups with a wide variety of substituents, or completes a carbonyl oxygen with R<3> or a 3-CH-NH-4 group with R<5> and R<6>;  R<5>  = hydrogen, hydroxy, hydroxymethylene or, with R<6>, a 3-6C carbocycle (optionally interrupted by an oxygen atom) or a carbonyl oxygen, or with R<7> a double bond;  R<6>  = hydrogen, 2-8C alkenyl (optionally substituted by hydroxy or -(1-8C alkyl)-S-R<25>;  R<7>  = hydrogen, methyl (optionally substituted by nitro) or with R<8> or R<9> forms a double bond;  R<8>  = hydrogen, hydroxy or -NHCOR<23>;  R<9>  = hydrogen, -CH2-SR<25> or -NHCO-CHMe-RaRb;  Ra and Rb  = hydroxymethyl, or together form a 2,2,5-trimethyl-1,3-dioxan-5-yl residue;  R<10>  = hydrogen or with R<11> forms a carbonyl oxygen; R<11>  = hydrogen or with R<12> forms a double bond;  R<13>  = hydrogen or  beta -Et;  provisos (1) when R<1>, R<2>, R<5>-R<13>  = hydrogen and R<3> = hydroxy, R<4> is not Me, allyl, or hydroxypropyl; (2) if R<13> =  beta -Et and other Rs are all hydrogen, then, simultaneously, R<11> and R<12> are not double bond and R<3> not hydroxy or R<3> and R<4> not together carbonyl; (3) if R<1> = =CH-OH, R<3> and R<4> can not be carbonyl oxygen and R<5> and R<7> a double bond if other Rs are hydrogen; (4) if X = bond, CO or NH, and R<5> and R<7> form a double bond, not all other Rs can be hydrogen; (5) if R<5> and R<6> are carbonyl oxygen, not all other Rs can be hydrogen; and (6) if R<1> and R<3> form a pyrazole ring, with R<3> and R<5> a double bond, or R<3> with R<7> a tricyclic system, then R<2> and R<4> can not form a double bond. The full definitions are given in the DEFINITIONS (Full Definitions) Field. Independent claims are also included for the following: (1) pharmaceutical compositions containing (I), and some additional compounds excluded by disclaimers; and (2) use of steroids with a non-aromatic A ring for treating diseases associated with high lipoprotein A levels.