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US 6,645,951 B1Granted
Benzopyran or thiobenzopyran derivatives
AssigneeChugai Seiyaku Kabushiki Kaisha
InventorsJae Chon Jo, Hyun Suk Lim, Jong Min Kim, Ju Su Kim, Kazumi Morikawa, Yoshitake Kanbe, Myung Hwa Kim, Masahiro Nishimoto
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Abstract
The present invention provides novel benzopyran compounds, pharmaceutically acceptable salts thereof and stereoisomers thereof where the benzopyran compounds of the invention are compounds according to Formula I: The present invention further provides pharmaceutical compositions which possess anti-estrogenic activity and comprise at least one benzopyran compound of the invention and a method of treating breast cancer by administration of an effective amount of a benzopyran compound provided by the present invention.
Claims6
A benzopyran or thiobenzopyran derivative represented by the following formula (1):
- pharmaceutically acceptable salt or stereoisomer thereof, in which
- X represents O,
- R1 represents hydrogen, hydroxy, or —OR6(wherein R6 represents acyl or alkyl),
- R2 represents phenyl which is optionally substituted by one or more substituents selected from a group consisting of hydroxy, lower alkyl halogen, nitro, hydroxymethyl, carboxy, alkoxycarbonyl, —OR6(wherein R6 represents acyl or alkyl) and amino which is optionally substituted by one or two lower alkyl, or represents 5- or 6-membered unsaturated heterocycle containing nitrogen, oxygen or sulfur as the hetero atom,
- R3 represents lower alkyl,
- R4 represents hydrogen or lower alkyl,
- A represents hydrogen;
- carboxyvinylphenyl;
- pyrrole substituted by carboxyvinylphenyl;
- or represents a group selected from the following formulae (a) to (l);
- in the above formulae (a) to (l)
- m1, to m3 independently of one another represent an integer of 0 to 15,
- n1, to n2 independently of one another represent an integer of 0, 1 or 2,
- R5 represents cyano;
- alkyl;
- halogenoalkyl;
- alkoxy;
- hydroxy;
- carboxy;
- alkoxycarbonyl;
- carbamoyl;
- monoalkylamino;
- phenyl which is optionally substituted by one or more substituents selected from a group consisting of straight-chain, or branched alkyl, carboxy and cyano;
- piperidinyl which is optionally substituted by one or more substituents selected from a group consisting of carboxy, alkyl and alkoxycarbonyl;
- cyclohexyl which is optionally substituted by carboxy;
- imidazolyl;
- dialkylamino;
- or piperidinyl oxide,
- D1 and D2 independently of one another represent a direct bond, or a group selected from the following:
- wherein
- m, m1 and m2 independently of one another represent an integer of 0 to 15, and
- R5 is defined as above.
29 more elements
A compound which is selected from the group consisting of:
- 7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{9-[4-(4,4,5,5,5-pentafluoropentyl)piperazinyl]nonyl}chroman;
- (3RS,4RS)-7-hydroxy-4-[(11-imino-11-N-butylamino)undecyl]-3-(4-hydroxyphenyl)-3-methylchroman;
- (3RS,4RS)-7-hydroxy-4-[(11-N-butylimino-11-N-butylamino)undecyl]-3-(4-hydroxyphenyl)-3-methylchroman;
- (3RS,4SR)-7-hydroxy-4-{4-{2-{4-{[3,5-bis(t-butyl)phenyl]methyl}piperazinyl}ethoxy}phenyl}-3-(4-hydroxyphenyl)-3-methylchroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]phenyl}-3-methylchroman;
- 4-{4-{2-[2-(4,4,5,5,5-pentafluoropentylsulfinyl)ethoxy]ethoxy}phenyl}-7-hydroxy-3-(4-hydroxyphenyl)-2H-chromene;
- (3RS,4RS)-4-[9-(N-4,4,5,5,5-pentafluoropentylaminosulfonylamino)nonyl]-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman;
- (3RS,4RS)-7-hydroxy-3-methyl-4-[9-(4,4,5,5;5-pentafluoropentylsulfinyl)nonyl]-3-(4-pyridyl)chroman,
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-[N-4,4,5,5,5-pentafluoropentylsulfinyl)pentylamino]propyl}chroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(N-methyl-N-4,4,5,5,5-pentafluoropentyl)aminononyl]chroman;
- N-methyl-N-(4,4,5,5,5-pentafluoropentyl)-9-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl)nonylamine N-oxide;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylaminosulfonyl)nonyl]chroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[8-(4,4,5,5,5-pentafluoropentylsulfonylamino)octyl]chroman;
- (3RS,4RS)-7-hydroxy-3-(4-(hydroxyphenyl)-3-methyl-4-[4-(4-piperidyl-butyloxy)phenyl]chroman;
- (3RS,4RS)-7-hydroxy-3-methyl-3-(4-hydroxyphenyl)-4-(4-(3-(2-(4,4,5,5,5-pentafluoropentylsulfinyl)ethoxy)-(R)-2-hydroxypropyloxy)phenyl)chroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{[4-(4,4,5,5,5-pentafluoropentylsulfinyl)butyloxy]butyl}chroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{5-{N-methyl-N-[3-(4,4,5,5,5-pentafluoropentyl)sulfiny]propyl}aminopentyl}chroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{5-{N-methyl-N-oxo-N-[3-(4,4,5,5,5-pentafluoropentyl)sulfiny]propyl}aminopentyl}chroman;
- (3′RS,4′RS)-2-(4-(7-hydroxy)-3-(4-hydroxyphenyl)-3-methylchroman-4-yl)butyl-6-(4-(4,4,5,5,5-pentafluoropentyl)sulfinyl)hexanoic acid;
- (3RS,4RS)-7-hydroxy-3-(4-(hydroxyphenyl)-3-methyl-4-[5-oxa-9-(4,4,5,5,5-pentafluoropentylsulfonylamino)nonyl]chroman;
- (3′RS,4′RS)-6,6,7,7,7-pentafluoro-2-(2-(4-(4-(7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl)butyl)phenyloxy)ethyl)heptanoic acid;
- (E)-3-[7-hydroxy-3-(4-hydroxyphenyl)-2H-chromen-4-yl]phenylacrylic acid;
- (3′RS,4′RS)-4-{7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]chroman-3-yl}benzoic acid;
- (3′RS,4′RS)-4-{7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]chroman-3-yl}benzyl alcohol;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-[3-(4,4,5,5,5-fluoropentylsulfinyl)propylphenoxy]-1-propyl}chroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-[3-(4,4,5,5,5-pentafluoropentylsulfonyl)propylphenoxy]-1-propyl}chroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{4-[4-(4,4,5,5,5-pentafluoropentylsulfinylethyloxy)phenyl]-1-butyl}chroman;
- 3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{4-[4-(4,4,5,5,5-pentafluoropentylsulfonyl-ethyloxy)phenyl]-1-butyl)chroman;
- (3′RS,4′RS)-1-[7-hydroxy-4-(4-hydroxyphenyl)-3-methylchroman-4-yl]-14,14,15,15,15-pentafluoropentadecan-10-ol;
- (3RS,4RS)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-3-(3-pyridyl)chroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]chroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-(9-oxo-14,14,15,15,15-pentafluoro)pentadecyl-3-methylchroman;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-(9-hydroxy-10-hydroxy carbonyl-14,14,15,15,15-pentafluoro)pentadecyl-3-methylchroman;
- (3RS,4RS)-7-hydroxy-4-[(10-ethoxycarbonyl-14,14,15,15,15-pentafluoro)pentadec-9-enyl]-3-(4-hydroxyphenyl)-3-methylchroman;
- 1,1,1,2,2-pentafluoro-14-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-5-pentadecanone;
- (E)-6,6,7,7,7-pentafluoro-2-{9-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]nonyl}-2-heptenoic acid;
- (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfonylamino)nonyl]chroman;
- (3′RS,4′RS)-N-[2-(4,4,5,5,5-pentafluoropentylsulfinyl)]ethyl-4-{4-[7-hydroxy-3-(4-hydryoxyphenyl)-3-methylchroman-4-yl]butyl}phenyl-N-methylamine;
- 6-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]phe-noxy}-2-(4,4,5,5,5-pentafluoropentyl)hexanoic acid;
- 7-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]phe-noxy}-2-(4,4,5,5,5-pentafluoropentyl)heptanoic acid;
- 8-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]phe-noxy}-2-(4,4,5,5,5-pentafluoropentyl)octanoic acid;
- 9-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]phe-noxy}-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid;
- (3RS,4RS)-9-(7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid;
- (3RS,4RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
- 5-{4-[(3RS,4)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]phe-noxy}-2-(4,4,5,5,5-pentafluoropentyl)pentanoic acid;
- (3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid;
- (3′RS,4′RS)-12-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoic acid;
- (3′RS,4′RS)-9-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid;
- (3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
- (3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,4-pentafluorobutyl)decanoic acid;
- (3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid;
- (3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(6,6,7,7,7-pentafluorophenyl)decanoic acid;
- (3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,4-pentafluorobutyl)undecanoic acid;
- (3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid;
- (3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid;
- (3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid;
- (3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
- (3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid;
- (3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
- (3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid;
- (3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid;
- (3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid;
- (3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid;
- (3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid;
- (3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid;
- (3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid;
- (3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid.
64 more elements
A compound represented by the following formula (17aa):
- pharmaceutically acceptable salt or stereoisomer thereof, in which
- X represents O,
- A11 is a protecting group selected from a group consisting of t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, t-buthyldiphenylmethyl-silyl, methoxymethyl, tetrahydropyranyl and methyl,
- m11 is an integer of 0 to 10.
1 more element
Dependencies are inferred from the claim text.