Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfonate esters
Patent
1999-07-14
2000-06-06
McKane, Joseph
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfonate esters
546286, 546285, 558411, 558429, 565326, C07D21168, C07D21178, C07C25550, C07C 49115, C07C30300
Patent
active
060720689
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to certain 16-hydroxy-11-(substituted phenyl)-estra4,9-diene derivatives, to processes for their preparation, to pharmaceutical formulations containing them and to their use in medical therapy, in particular in the treatment or prophylaxis of glucocorticoid-dependent diseases.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,089,635 discloses certain 13-alkyl-11.beta.-phenyl-gonanes having antigestagenic and antiglucocorticoid effects. European patent specification No. 0,057,115 discloses 19-nor steroids and 19-nor-D-homo steroids having anti-glucocorticoid activity.
A number of 16-hydroxy-11-(substituted phenyl)-estra-4,9-diene derivatives have now been found which have a highly selective affinity to glucocorticoid receptors and have potent in vivo anti-glucocorticoid activity.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides compounds of formula I ##STR1## wherein R.sub.1 is C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy, triflate, pyridyl or phenyl where the phenyl moiety is optionally substituted by one or more substituents selected from cyano, halogen and C.sub.1-4 alkyl; carboxy-1-oxo-C.sub.1-6 alkyl; one or more substituents selected from C.sub.1-6 alkoxy and halogen; carboxy-1-oxo-C.sub.1-6 alkyl; and
The present invention includes the 16-hydroxy-11-(substituted phenyl)-estra-4,9-diene derivatives of formula I wherein: isopropyl or methyl. example, methyl, ethyl, propyl or t-butyl optionally substituted by C.sub.1-6 alkoxy, such as methoxy. supra or a pharmaceutically acceptable salt or solvate thereof. R.sub.2 is hydrogen, C.sub.1-6 alkyl, 1-oxo-C.sub.1-6 alkyl or carboxy-1-oxo-C.sub.1-6 alkyl; R.sub.3 is hydrogen, halogen or C.sub.1-6 alkyl optionally substituted by one or more substituents selected from C.sub.1-6 alkoxy and halogen; R.sub.4 is hydrogen, C.sub.1-6 alkyl, 1-oxo-C.sub.1-6 alkyl or carboxy-1-oxo-C.sub.1-6 alkyl; and X is (H,OH), O or NOH; or a pharmaceutically acceptable salt or solvate thereof.
Further examples of compounds of formula I above include examples 1 to 4.
As used herein the term alkyl means a straight or branched chain alkyl group. Such alkyl groups include methyl, ethyl, i-propyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and neohexyl. Reference to cycloalkyl includes cyclopropyl, cyclopentyl and cyclohexyl.
The term alkoxy has the meaning as understood by the person skilled in the art and includes straight and branched chains. Examples of alkoxy groups include methoxy and ethoxy. Preferred alkoxy groups include C.sub.1-4 alkoxy.
The term halogen includes chloro, bromo, fluoro and iodo.
Triflate means trifluoromethanesulphonate.
1-oxo-C.sub.1-6 alkyl or carboxy-1-oxo-C.sub.1-6 alkyl groups include 1-oxo-methyl, 1-oxo-ethyl, 1-oxo-propyl, 3-carboxy-1-oxopropyl, 3-carboxy-1-oxobutyl and 3-carboxy-1-oxopentyl.
DETAILED DESCRIPTION OF THE INVENTION
Preferred examples of R.sub.1 are phenyl and C.sub.1-6 alkyl, for example, t-butyl (1,1-dimethylethyl), isopropyl (1-methylethyl) or methyl, most preferably t-butyl and phenyl.
Preferred examples of R.sub.3 include C.sub.1-6 alkyl, most preferably methyl.
Preferred compounds of formula I include those wherein R.sub.1 is phenyl or C.sub.1-6 alkyl, for example, t-butyl, isopropyl or methyl; R.sub.2 is hydrogen; R.sub.3 is C.sub.1-6 alkyl, most preferably methyl; R.sub.4 is hydrogen or C.sub.1-6 alkyl, in particular methyl; and X is O; or a pharmaceutically acceptable salt or solvate thereof.
Particularly preferred 16-hydroxy-11-(substituted phenyl)-estra-4,9-diene derivatives of formula I include: opynyl)estra-4,9-dien-3-one propynyl)estra-4,9-dien-3-one; pynyl)estra-4,9-dien-3-one; -propynyl)estra-4,9-dien-3-one; yl)oxy]phenyl]-17-(1-propynyl)estra4,9-dien-3-one;
For therapeutic use, salts of the compounds of formula I are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the prep
Gebhard Ronald
Groen Marinus Bernard
Akzo Nobel N.V.
Gormley Mark E.
McKane Joseph
Murray Joseph
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