- 4-(Benzoylindolizinyl)butyric acids; novel nonsteroidal inhibitors of steroid 5α-reductase. III
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A novel series of indolizinebutyric acids with various benzoyl substituents was synthesized to develop nonsteroidal inhibitors of steroid 5α-reductase, and the structure-activity relationships in this series were studied. We previously reported the structure-activity relationships in a series of indolebutyric acids as well as the discovery of the novel nonsteroidal 5α-reductase inhibitor, FK143. We have now made other modifications to this compound to improve in vivo inhibitory activity. By altering the heterocyclic nucleus and changing the benzoyl substituent we have succeeded in identifying the strongly active compound, FK687, (S)-4-[1-[4-[[1-(4-isobutylphenyl)butyl]oxy]benzoyl]indolizin-3-yllbutyric acid, which displays strong in vitro inhibitory activity against the human enzyme and in vivo inhibitory activity against the castrated young rat model. This compound should be a useful agent for the treatment of benign prostatic hyperplasia.
- Sawada,Okada,Kuroda,Watanabe,Sawada,Tanaka
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p. 799 - 813
(2007/10/03)
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- INDOLE DERIVATIVES AND THEIR USE FOR TESTOSTERONE 5-ALPHA-REDUCTASE-MEDIATED DISEASES
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Indole derivatives of the formula and pharmaceutical compositions thereof. They are useful for treating or preventing testosterone 5-alpha-reductase-mediated diseases, such as alopecia, acnes and prostatism
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- Process for preparing α-hydroxy-acids and compounds obtained by this process
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The invention relates to a process for preparing α-hydroxy-acids of general formula: STR1 in which R represents hydrogen or a lower alkyl radical and Cy represents a phenyl, naphthyl or heterocyclic radical, these latter three radicals optionally comprising one or more substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy radicals and halogen atoms, process which comprises the treatment of an α-monohalogenated ketone of general formula: STR2 in which R and Cy have the same meaning as above and X represents chlorine, bromine or iodine, in the presence of an aqueous solution of an alkali metal hydroxide, a non-polar organic solvent selected from an aromatic or alicyclic hydrocarbon and oxygen in excess optionally in the presence of an inert gas, the treatment being carried out at a temperature ranging from the boiling temperature of the reaction medium at atmospheric pressure and 240° C. under pressure and the alkali metal so formed is then acidified to obtain the desired acid.
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- Process for preparing α-hydroxy-alkanoic acids and compounds obtained by this process
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The invention relates to a process for preparing α-hydroxy-alkanoic acids of general formula: STR1 in which R represents hydrogen or a lower alkyl radical and Cy represents phenyl or a heterocyclic radical, both radicals optionally comprising one or more substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl radicals and halogen atoms, process which comprises the treatment of an α,α-dihalogenated ketone of general formula: STR2 in which R and Cy have the same meaning as above and X represents chlorine, bromine or iodine, in the presence of an aqueous solution of an alkali metal hydroxide and a non polar organic solvent selected from an aromatic or alicyclic hydrocarbon, the treatment being carried out at a temperature between the boiling temperature of the reaction medium at atmospheric pressure and 240° C. under pressure and the alkali metal so formed is then acidified to obtain the desired acid.
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