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US 7,442,833 B2Granted
Triphenylethylene compounds as selective estrogen receptor modulators
AssigneeSmithKline Beecham Corporation
InventorsJohn Fred Eaddy, III, Dennis Heyer, Amarjit Sab Randhawa, Vicente Samano, John Albert Ray, Subba Reddy Katamreddy, Michael Tolar Martin, Michael Scott McClure
Life of this patent
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Abstract
Compounds of formula (I): with a variety of therapeutic uses, more particularly novel prodrugs that are particularly useful for delivering a parent compound for selective estrogen receptor modulation.
Claims21
A compound of formula (I):
- including pharmacologically functional salts and solvates thereof, wherein
- R1 is —C(O)-alkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-cycloalkyl, —C(O)—(CH2)n—NR4R5, —C(O)—O-alkyl, —C(O)—(CH2)n—O-alkyl, —C(O)—(CH2)n-haloalkyl, —C(O)—(CH2)n-heterocylcyl, or —PO3H2;
- R4 and R5 each independently are selected from H and alkyl;
- and
- n is 1 to 6.
2 more elements
A compound selected from
- (2E)-3-(4-{(1Z)-2-phenyl-1-[4-(propionyloxy)phenyl]but-1-enyl}phenyl)prop-2-enoic acid;
- (2E)-3-(4-{(1Z)-1-[4-(benzoyloxy)phenyl]-2-phenylbut-1-enyl}phenyl)prop-2-enoic acid;
- (2E)-3-(4-{(1Z)-1-[4-(acetyloxy)phenyl]-2-phenyl but-1-enyl}phenyl)prop-2-enoic acid;
- (2E)-3-(4-{(1Z)-1-[4-(butyryloxy)phenyl]-2-phenylbut-1-enyl}phenyl)prop-2-enoic acid;
- (2E)-3-(4-{(1Z)-1-[4-(2-Furoyloxy)phenyl]-2-phenyl-1-butenyl}phenyl)-2-propenoic acid;
- (2E)-3-[4-((1Z)-1-{4-[(N,N-dimethylglycyl)oxy]phenyl}-2-phenylbut-1-enyl)phenyl]prop-2-enoic acid;
- (2E)-3-[4-((1Z)-1-{4-[(5-Isoxazolylcarbonyl)oxy]phenyl}-2-phenyl-1-butenyl)phenyl]-2-propenoic acid;
- (2E)-3-[4-((1Z)-2-phenyl-1-{4-[(thien-2-ylcarbonyl)oxy]phenyl}but-1-enyl)phenyl]prop-2-enoic acid;
- (2E)-3-[4-((1Z)-1-{4-[(methoxyacetyl)oxy]phenyl}-2-phenylbut-1-enyl)phenyl]prop-2-enoic acid;
- (2E)-3-[4-((1Z)-2-phenyl-1-{4-[(4,4,4-trifluorobutanoyl)oxy]phenyl}but-1-enyl)phenyl]prop-2-enoic acid;
- (2E)-3-[4-((1Z)-1-{4-[(2,2-dimethylpropanoyl)oxy]phenyl}-2-phenyl but-1-enyl)phenyl]prop-2-enoic acid;
- (2E)-3-[4-((1Z)-1-{4-[(cyclohexylcarbonyl)oxy]phenyl}-2-phenylbut-1-enyl)phenyl]prop-2-enoic acid;
- (2E)-3-[4-((1Z)-1-{4-[(morpholin-4-ylacetyl)oxy]phenyl}-2-phenylbut-1-enyl)phenyl]prop-2-enoic acid;
- (2E)-3-[4-((1Z)-2-phenyl-1-{4-[(piperidin-1-ylacetyl)oxy]phenyl}but-1-enyl)phenyl]prop-2-enoic acid;
- (2E)-3-{4-[(1Z)-1-(4-{[(4-methylpiperazin-1-yl)acetyl]oxy}phenyl)-2-phenylbut-1-enyl]phenyl}prop-2-enoic acid;
- (2E)-3-(4-{(1Z)-2-Phenyl-1-[4-(phosphonooxy)phenyl]-1-butenyl}phenyl)-2-propenoic acid;
- (2E)-3-[4-((1Z)-1-{4-[(Ethoxycarbonyl)oxy]phenyl}-2-phenyl-1-butenyl)phenyl]-2-propenoic acid;
- and
- (2E)-3-[4-((1Z)-1-{4-[(Methoxycarbonyl)oxy]phenyl}-2-phenyl-1-butenyl)phenyl]-2-propenoic acid, including pharmaceutically acceptable salts and solvates thereof.
16 more elements
A process for making ester prodrugs of compound 1:
- comprising:
- acylating anisole with 2-phenylbutanoic acid followed by demethylation to yield phenol 8:
- protecting the phenol group;
- treating the protected compound with an organometallic reagent followed by dehydration to yield phenol aldehyde 10:
- acylating phenol aldehyde 10 with an anhydride or an acid chloride in the presence of a base to yield ester intermediate IV:
- wherein R1 is —C(O)-alkyl, —C(O)-aryl, —C(O)-heteroaryl, or —C(O)-cycloalkyl;
- and
- treating the ester intermediate IV with malonic acid to yield ester prodrug V:
- wherein R1 is as described.
6 more elements
An intermediate of formula IV:
- wherein R1 is —C(O)-alkyl, —C(O)-aryl, —C(O)-heteroaryl, or —C(O)-cycloalkyl.
Dependencies are inferred from the claim text.