Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Silicon containing doai
Reexamination Certificate
2002-04-18
2003-02-11
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Silicon containing doai
C514S341000, C514S397000, C514S400000, C546S275100, C548S110000, C548S312100, C548S341100, C548S336100, C548S341500, C548S315400, C548S338100, C548S342100, C548S315100
Reexamination Certificate
active
06518257
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical agent, particularly, a novel 1-substituted phenyl-1-(1H-imidazol-4-yl)alcohol having a steroid C
17,20
-lyase inhibitory action and a pharmaceutical composition containing the same.
BACKGROUND ART
Sex hormones have various physiological activities such as differentiation and proliferation of cells and the like. On the other hand, it has been found that androgen and estrogen act as an exacerbation factor in some diseases. It is known that steroid C
17,20
-lyase is involved in the final stage in the biosynthesis of androgen in vivo. That is, steroid C
17,20
-lyase converts, as a substrate, 17-hydroxypregnenolone and 17-hydroxyprogesterone derived from cholesterol to dehydroepiandrosterone and androstenedione, respectively. Therefore, a medicine having a steroid C
17,20
-lyase inhibitory activity suppresses formation of androgen, as well as estrogen produced from androgen as a substrate, and is useful as an agent for the prophylaxis or treatment of diseases whose exacerbation factor is androgen or estrogen. As the disease for which androgen or estrogen is an exacerbation factor, there are mentioned, for example, prostate cancer, prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, breast cancer, uterine cancer, ovarian cancer, mastopathy, uterus myoma, endometriosis, adenomyosis of uterus, polycystic ovary syndrome, and the like.
Steroid type compounds and non-steroid type compounds are already known as steroid C
17-20
-lyase inhibitors. The steroid type compounds are disclosed in, for example, WO 92/15404, WO 93/20097, EP-A 288053, EP-A 413270 and the like. As non-steroid type compounds, for example, (1H-imidazol-1-yl)methyl-substituted benzimidazole derivatives are shown in Japanese Published Unexamined Patent Application No. 85975/1989, carbazole derivatives are shown in WO94/27989 and WO96/14090, azole derivatives are shown in WO95/09157, 1H-benzimidazole derivatives are shown in U.S. Pat. No. 5,491,161, dihydronaphthalene derivatives are shown in WO99/18075, and (1H-imidazol-1-yl)methylbiphenyl derivatives are shown in Bioorganic Medicinal Chemistry, vol. 7, pp 1913-1924 (1999).
Heretofore, steroid C
17,20
-lyase inhibitors usable for medical purposes have not been obtained, and early development of steroid C
17,20
-lyase inhibitors highly useful as medicine is awaited.
DISCLOSURE OF INVENTION
The present inventors have conducted intensive studies in an attempt to find a superior steroid C
17,20
-lyase inhibitor and first synthesized a novel compound characterized by a chemical structure, wherein a methylene group that connects a benzene ring represented by the formula (I) and an imidazole ring is substituted by lower alkyl or cyclic hydrocarbon group and hydroxyl group, and a salt thereof, and found that the obtained compound (I) and a salt thereof have, based on the specific chemical structure, unexpectedly superior pharmaceutical use, particularly a superior steroid C
17,20
-lyase inhibitory activity, low toxicity and superior properties as a pharmaceutical product, and based on these findings, completed the present invention.
Accordingly, the present invention relates to
(1) a compound represented by the formula:
wherein
R is a hydrogen atom or a protecting group,
R
1
is a lower alkyl group or a cyclic hydrocarbon group,
R
2
is an aromatic hydrocarbon group optionally having substituents or an aromatic heterocyclic group optionally having substituents,
R
3
is a hydrocarbon group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, and
n is an integer of 0 to 4,
or a salt thereof;
(2) the compound of the above-mentioned (1), wherein R is 1) a hydrogen atom, 2) a formyl, 3) a C
1-6
alkylcarbonyl optionally substituted by 1 to 3 groups selected from Group 1, 4) a phenylcarbonyl optionally substituted by 1 to 3 groups selected from Group 1, 5) a C
1-6
alkyl-oxycarbonyl optionally substituted by 1 to 3 groups selected from Group 1, 6) a phenyloxycarbonyl optionally substituted by 1 to 3 groups selected from Group 1, 7) a C
7-10
aralkyloxy-carbonyl optionally substituted by 1 to 3 groups selected from Group 1, 8) a trityl optionally substituted by 1 to 3 groups selected from Group 1, 9) a phthaloyl optionally substituted by 1 to 3 groups selected from Group 1 or 10) a N,N-dimethylaminomethylene optionally substituted by 1 to 3 groups selected from Group 1,
R
1
is a C
1-6
alkyl or a C
3-6
cycloalkyl,
R
2
is a C
6-10
aryl group optionally substituted by 1 to 4 groups selected from Group 2 or an aromatic heterocyclic group selected from Group 3, which is optionally substituted by 1 to 4 groups selected from Group 2, and
R
3
is 1) a C
1-4
alkyl, 2) a C
1-4
alkyl having C
2-4
alkanoyl, carboxyl or C
1-4
alkoxy-carbonyl as a substituent, 3) a hydroxyl group, 4) a C
1-4
lower alkoxy, 5) a C
1-4
alkanoyloxy, 6) a carbamoyloxy, 7) a carbamoyloxy substituted by 1 or 2 C
1-4
alkyl groups, 8) a thiol group, 9) a C
1-4
alkylthio group, 10) a C
1-4
alkanoylthio, 11) an amino group, 12) a C
1-4
alkylamino group, 13) a di-C
1-4
alkylamino, 14) a C
1-4
alkanoylamino, 15) a formyl, 16) a C
2-6
alkanoyl, 17) a C
1-4
alkylsulfonyl, 18) a carbamoyl group, 19) a mono- or di-C
1-10
alkylcarbamoyl group, 20) a mono- or di-C
6-14
arylcarbamoyl, 21) a mono- or di-C
7-16
aralkylcarbamoyl group, 22) a sulfamoyl, 23) a mono- or di-C
1-10
alkylsulfamoyl group, 24) a mono- or di-C
6-14
arylsulfamoyl group, 25) a mono- or di-C
7-16
aralkylsulfamoyl group or 26) a halogen atom,
and wherein, in the above,
Group 1 includes
a halogen atom, a formyl group, a C
1-6
alkyl-carbonyl group and a nitro group,
Group 2 includes
1) a C
1-6
alkyl group, 2) a C
1-4
alkyl group substituted by 1 to 5 halogen atoms, 3) a C
1-4
alkyl group substituted by 1 or 2 C
1-4
alkoxy, 4) a hydroxyl group, 5) a C
1-4
alkoxy group, 6) a C
1-4
alkanoyloxy group, 7) a carbamoyloxy group, 8) a carbamoyloxy group substituted by C
1-4
alkyl group, 9) an amino group, 10) a mono- or di-C
1-4
alkylamino group, 11) a C
1-4
alkanoylamino group, 12) a formyl group, 13) a C
2-6
alkanoyl group, 14) a C
1-4
alkylsulfonyl group, 15) a carbamoyl group, 16) a mono- or di-C
1-10
alkylcarbamoyl group, 17) a C
3-6
cycloalkylcarbamoyl group, 18) a mono- or di-C
6-14
arylcarbamoyl group, 19) a mono- or di-C
7-16
aralkylcarbamoyl group, 20) a sulfamoyl group, 21) a mono- or di-C
1-10
alkylsulfamoyl group, 22) a mono- or di-C
6-14
arylsulfamoyl group, 23) a mono- or di-C
7-16
aralkylsulfamoyl group, 24) a halogen atom, 25) a cyano group and 26) an oxo group,
Group 3 includes
a 2-thienyl group, a 3-thienyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-furyl group, a 3-furyl group, a 2-quinolyl group, a 4-quinolyl group, a 8-quinolyl group, a 3-isoquinolyl group, a 4-isoquinolyl group, a pyrazinyl group, a 2-pyrimidinyl group, a 3-pyrrolyl group, a 1-imidazolyl group, a 2-imidazolyl group, a 1-pyrazolyl group, a 2-thiazolyl group, a 4-thiazolyl group, a 5-thiazolyl group, a 3-isothiazolyl group, a 4-isothiazolyl group, a 2-oxazolyl group, a 4-oxazolyl group, a 5-oxazolyl group, a 3-isoxazolyl group, a 3-pyridazinyl group, a 1-indolyl group, a 1-isoindolyl group, a 2-isoindolyl group, a 1-tetrazolyl group, a 2-tetrazolyl group and a 5-tetrazolyl group;
(3) the compound of the above-mentioned (1), wherein
R is a hydrogen atom,
R
1
is a C
1-6
alkyl group or a C
3-6
cycloalkyl group,
R
2
is a phenyl group, a pyridyl group, a thienyl group, a furyl group or an isoindolinyl group, each optionally substituted by 1 to 4 groups selected from Group 4,
n is 0 or 1, and
R
3
is a C
1-4
lower alkoxy group, a C
1-4
alkanoyloxy group or a C
1-4
alkanoylamino group,
and wherein, in the above,
Group 4 includes
1) a C
1-6
alkyl group, 2) a C
1-4
alkyl group substituted by 1 to 5 halogen atoms, 3) a C
1-4
alkyl group substituted by 1 or 2
Kaku Tomohiro
Kusaka Masami
Tasaka Akihiro
Chao Mark
Ramesh Elaine M.
Stockton Laura L.
Takeda Chemical Industries Ltd.
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