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Patent 2250258 Summary

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(12) Patent: (11) CA 2250258
(54) English Title: NOVEL TETRALONE OR BENZOPYRANONE DERIVATIVES AND PROCESS FOR PRODUCING THE SAME
(54) French Title: NOUVEAUX DERIVES DE TETRALONE OU DE BENZOPYRANONE ET PROCEDE DE FABRICATION CORRESPONDANT
Status: Deemed expired
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07C 49/747 (2006.01)
  • A61K 31/122 (2006.01)
  • A61K 31/352 (2006.01)
  • A61K 31/357 (2006.01)
  • A61K 31/445 (2006.01)
  • A61P 5/24 (2006.01)
  • A61P 35/00 (2006.01)
  • C07C 45/74 (2006.01)
  • C07C 49/683 (2006.01)
  • C07C 49/697 (2006.01)
  • C07C 49/755 (2006.01)
  • C07C 65/40 (2006.01)
  • C07C 225/22 (2006.01)
  • C07D 311/22 (2006.01)
  • C07D 317/54 (2006.01)
  • C07D 319/18 (2006.01)
  • C07D 407/06 (2006.01)
(72) Inventors :
  • YOSHIHAMA, MAKOTO (Japan)
  • NAKAKOSHI, MASAMICHI (Japan)
  • NAKAMURA, JUNJI (Japan)
  • NAKAYAMA, SHOJI (Japan)
(73) Owners :
  • DAIICHI PHARMACEUTICAL CO., LTD. (Japan)
(71) Applicants :
  • SNOW BRAND MILK PRODUCTS CO., LTD. (Japan)
(74) Agent: FINLAYSON & SINGLEHURST
(74) Associate agent:
(45) Issued: 2006-02-21
(86) PCT Filing Date: 1998-01-28
(87) Open to Public Inspection: 1998-07-30
Examination requested: 1998-09-28
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/JP1998/000344
(87) International Publication Number: WO1998/032724
(85) National Entry: 1998-09-28

(30) Application Priority Data:
Application No. Country/Territory Date
9-28258 Japan 1997-01-29
9-225564 Japan 1997-08-08

Abstracts

English Abstract





The present invention provides new tetralone or
benzopyranone derivatives and a method for producing the
derivatives useful for a therapeutic agent for preventing
and/or treating hormone dependent diseases.
The present invention is a new tetralone or
benzopyranone derivative represented by a particular
general formula (I)

(see formula I)

wherein R1 represents a hydroxy group, an alkyloxy group or
an aralkyloxy group, R2-R6 represent hydrogen, a hydroxy
group, a straight or branched alkyloxy or aralkyloxy group
having 1-6 carbon atoms, a halogen, an amino group or an
alkylene dioxy group joined at R2 and R3, R3 and R4, R4 and
R5, R5 and R6, and A represents a methylene or oxygen, but
provided that when R1 is methoxy, R2-R6 are all hydrogens
and A is the methylene.
In the production, a particular tetralone or
benzopyranone compound and a particular benzaldehyde
compound are reacted.


French Abstract

Cette invention se rapporte à de nouveaux dérivés de tétralone ou de benzopyranone utiles en tant qu'agents préventifs et/ou remèdes de diverses maladies liées à des hormones mâles ou femelles. Ces dérivés sont représentés par la formule générale (I) dans laquelle R1 et R2 sont chacun hydrogène, hydroxy, alkyloxy ou aralkyloxy; R3 à R7 sont chacun hydrogène, hydroxy, alkyle C1-6 linéaire ou ramifié, alkyloxy, aralkyloxy, halogéno ou amino, ou bien R3 et R4, R4 et R5, R5 et R6, ou R6 et R7 sont liés les uns aux autres de manière à former un alkylènedioxy; et A est méthylène ou oxygène. On fabrique ces dérivés en faisant réagir des dérivés spécifiques de tétralone ou de benzopyranone avec des dérivés spécifiques de benzaldéhyde.

Claims

Note: Claims are shown in the official language in which they were submitted.



21

The embodiments of the invention in which an exclusive property
or privilege is claimed are defined as follows:

1. A tetralone or benzopyranone derivative represented by
the following general formula (I):
Image
wherein R1 and R2 represent a substituent substituted at the 6-
position of said tetralone or the 7-position of said
benzopyranone;
- wherein A is a methylene (in a tetralone skeleton),
R1 is a hydroxy group or a methoxy group at the 6-position of
said tetralone;
R2 is hydrogen;
R3 - R7 represent hydrogen, a hydroxy group, an alkyl
or alkyloxy group having 1 - 6 carbon atoms, a halogen, or an
alkylene dioxy group joined at R3 and R4, R4 and R5, R5 and R6, or
R6 and R7 ;
with the proviso that
(a) when R1 is methoxy and R3 - R6 are hydrogen, then
R7 cannot be hydrogen; and
(b) when R1 is methoxy and R2 , R3 , R6 and R7 are
hydrogen, then both R4 and R5 are not chloride;
- when A is an oxygen (in a benzopyranone skeleton),
R1 is a hydroxy group or methoxy group at the
7-position of said benzopyranone;
R2 is hydrogen;
R3 - R7 represents hydrogen, a hydroxy group, an alkyl
or alkyloxy group having 1 - 6 carbon atoms, a halogen, an amino
group, or an alkylene dioxy group joined at R3 and R4, R4 and R5,
R5 and R6 , or R6 and R7,


22

with the proviso that
(a) when R1 is hydroxy and R2, R3, R4, R6 and R7 are
hydrogen, then R5 cannot be a methoxy group;
(b) when R1 is a hydroxy and R2, R3, R6 and R7 are
hydrogen, then R4 and R5 cannot be a methylene dioxy group;
(c) when R1 is hydroxy and R2, R3, R6 and R7 are
hydrogen, then both R4 and R5 cannot be a methoxy group;
(d) when R1 is hydroxy, R2, R3, R6 and R7, are hydrogen
and R4 is methoxy, then R5 cannot be a hydroxy group;
(e) when R1 is hydroxy and R2, R3, R6 and R7 are
hydrogen, then both R4 and R5 cannot be hydroxy groups.

2. A method for producing the new tetralone or
benzopyranone derivative claimed in claim 1, characterized in
that it comprises
(a) dissolving a tetralone or benzopyranone compound
represented by the following general formula (II) and a
benzaldehyde compound represented by the following general
formula (III) in an organic solvent,
(b) refluxing with heating under acidic conditions
and
(c) purifying the desired compound from the reaction
mixture of a compound of formula II:

Image

wherein R1 is a hydroxy group or methoxy group, R2 is hydrogen
and A represents a methylene or oxygen, and

Image


23

wherein R3 - R7 represents hydrogen, a hydroxy group, alkyl or an
alkyloxy group having 1 - 6 carbon atoms, a halogen, or an
alkylene dioxy group joined at R3 and R4, R4 and R5, R5 and R6, or
R6 and R7.
3. A pharmaceutical composition comprising a compound of
formula (I) as defined in claim 1 or a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable
carrier or diluent.
4. The use of a therapeutically effective amount in an
administratable form of the compound of formula (I) as defined
in claim 1 or a pharmaceutically acceptable salt thereof for
inhibiting the activity of 17.beta.-HSD in a mammal.
5. The use of a therapeutically effective amount in an
administratable form of the compound of formula (I) as defined
in claim 1 or a pharmaceutically acceptable salt thereof for
treating or preventing an androgen or estrogen dependent disease
in a mammal.
6. A compound of formula (I) as defined in claim 1 or a
pharmaceutically acceptable salt thereof when used in inhibiting
the activity of 17.beta.-HSD.
7. A compound of formula (I) as defined in claim 1 or a
pharmaceutically acceptable salt thereof when used in preventing
or treating an androgen or estrogen dependent disease.
8. The use of a compound of formula (I) as defined in
claim 1 or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for inhibiting the activity of
17.beta.-HSD.


24

9. The use of a compound of formula (I) as defined in
claim 1 or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for treating or preventing androgen
or estrogen dependent diseases.
10. The use according to claim 9, wherein said disease is
a member selected from the group consisting of prostate cancer,
benign prostatic hyperplasia, virilism, mammary cancer,
mastopathy, endometrial cancer, endometriosis and ovarian cancer.
11. 2-((4-dimethylaminophenyl)methylene)-6-hydroxy-1-
tetralone.

Description

Note: Descriptions are shown in the official language in which they were submitted.



CA 02250258 1998-09-28
1
NOVEL TETRALONE OR $ENZOPYRANO1VE DERIVATIVES
AND PKOCESS FOR PRODUCING THE SAME
DESCRT_PTION
Technical Field
The present invention relates to new tetralone or benzopyranone
derivatives and a method for producing the derivatives. The new tetralone or
benzopyranone derivatives of the present invention have inhibition activity of
17 Q -hydroxysteroid dehydrogenase (abbreviated as l7,Ci -HSD, hereinafter),
and these derivatives are useful for a therapeutic agent for preventing and/or
treating androgen or estrogen dependent diseases, particularly, prostatic
cancer, benign prostatic hyperplasia, virilism, mammary cancer, mastopathy,
endometrial cancer, endometriosis, ovarian cancer and the like.
Background Art
Lately, in our country, it causes trouble that androgen dependent
diseases such as prostatic cancer and benign prostatic hyperplasia, and
estrogen dependent diseases such as mammary cancer and endometriosis, are
increasing in the morbidity. For example, the percentage of mortality of the
prostatic cancer was 3.9 men per 100,000 of population by statistical data in
1984, and was about 1/10 of the non Caucasian men in the western country.
However, it is increasing gradually by prolonging people's life due to
improvement of medical treatment and western diet. In 1993, that percentage
is 6.7 men per 100,000 of population and it is coming to European and U.S.
levels. It is expected that the numbers of mortality based on the prostatic
cancer in 2015 will be four times more of those in 1990. This is the worst
increasing percentage in all cancers.
It has become clear from many views that subjective conditions and
objective conditions of the androgen dependent diseases will be improved by
depressing the androgen levels in blood. Therefore, treatment of these
diseases have been accomplished by lowering the androgen in blood by
castration, by administering an agonist of LH-RH to lower the androgen in


CA 02250258 1998-09-28
2
blood to the castration level, and by administering anti-androgen agents
antagonizing an androgen receptor to control the action of the androgen. In
fact, the clinical effects are broadly noticed. However, since the castration
causes a lowering of ~,IOL, it is only proceeded in very limited diseases. The
agonist of LH-RH has problems; side effect such as a bone pain or dysuria
caused by a phenomenon peculiar to the agonist (temporary increase of the
androgen), and rekindling for continuous existence of androgen originated from
adrenal glands. Further, it is indicated that the effect of the anti-androgen
agents is decreased by the development of variants of the androgen receptor
during the medicine is administered. Therefore, "a method of complete blockage
of the androgen" is prescribed for more effective endocrine treatment. The
method is aimed to completely inhibit the androgen in blood by combination of
several endocrine therapeutics, and more effective treatment is expected.
Testosterone exhibiting the most effective androgenic activity in Cis
steroids having androgenic activity can be biosynthesized with l7,Ci -HSD from
a substrate of andorostendione. By inhibiting this 17,Q -HSD, the
concentration of testosterone in blood is directly lowered, so that it is
expected
to effectively treat the above androgen dependent diseases. In addition, since
this enzyme is also a biosynthetic enzyme of estoradiol having the highest
estrogenic activity in Cia steroid having estrogenic activity, it is also
expected
to effectively treat the estrogen dependent diseases such as mammary cancer
and endometriosis.
Steroid compounds and non-steroid compounds have been proposed as 17
,(i -HSD inhibitors. As the non-steroid compounds, for example, flavons and
isoflavons, which are described in Biochemical and Biophysical Research
Communications, Vol. 215, 1137-1144 (1995), and fatty acids, which are
described in Journal of Steroid Biochemistry, Vol. 23, 35?-363 (1985), are
known. However, since the activity of these compounds is not satisfied, it is
expected to obtain materials having higher activity.


CA 02250258 2005-05-18
3
Disclosure of Invention
Considering the above problems, the inventors of the
present invention earnestly have studied and found that new
tetralone or benzopyranone derivatives have an excellent
inhibition activity of 17a-HSD. Therefore, the present
invention aims to provide the new tetralone or benzopyranone
derivatives and a method for producing the derivatives.
The present invention relates to new tetralone or
benzopyranone derivatives and a method for producing the
derivatives. The new tetralone or benzopyranone derivatives
of the present invention have inhibition activity of 17(3-
hydroxysteroid dehydrogenase (abbreviated as 17~i-HSD,
hereinafter), and these derivatives are useful for a
therapeutic agent for preventing and/or treating androgen or
estrogen dependent diseases, particularly, prostatic cancer,
benign prostatic hyperplasia, virilism, mammary cancer,
mastopathy, endometrial cancer, endometriosis, ovarian cancer
and the like.
In one aspect,the invention provides a tetralone or
benzopyranone derivative represented by the following general
formula ( I )
R2 R 4
fI)
Rs
R~ R~ Rs
wherein R1 and R2 represent a substituent substituted at the 6-
position of said tetralone or the 7-position of the
benzopyranone, wherein A is a methylene (in a tetralone
skeleton), R1 is a hydroxy group or a methoxy group at the 6-
position of the tetralone, RZ is hydrogen, R3 - R? represent
hydrogen, a hydroxy group, as alkyl or alkyloxy group having 1
- 6 carbon atoms, a halogen, or an alkylene dioxy group joined
at R3 and R,, R4 and R5, RS and R6, or R6 and R~, with the
proviso that (a) when Ri is methoxy and R3 - R6 are hydrogen,


CA 02250258 2005-05-18
4
then R~ cannot be hydrogen, and (b) when R1 is methoxy and R2,
R3 , R6 and R., are hydrogen, then both R4 and R5 are not
chloride, when A is an oxygen (in a benzopyranone skeleton), R1
is a hydroxy group or methoxy group at the 7-position of the
benzopyranone, RZ is hydrogen, R3 - R~ represents hydrogen, a
hydroxy group, an alkyl or alkyloxy group having 1 - 6 carbon
atoms, a halogen, an amino group, or an alkylene dioxy group
joined at R3 and R4, R4 and R5, R5 and R6, or R6 and R." with the
proviso that (a) when R, is hydroxy and Ra, R3, R" R6 and R., axe
hydrogen, then RS cannot be a methoxy group, (b) when Rl is a
hydroxy and R2, R3, R6 and R., are hydrogen, then R4 and RS cannot
be a methylene dioxy group , ( c ) when Rl is hydroxy and Rz , R3 ,
R6 and R., are hydrogen, then both R4 and RS cannot be a methoxy
group , ( d ) when Rl i s hydroxy, RZ , R3 , R6 and R, are hydrogen
and R4 is methoxy, then RS cannot be a hydroxy group, (e) when
R1 is hydroxy and Rz, R3, R6 and R, are hydrogen, then both R4
and RS cannot be hydroxy groups.
In a second aspect, the invention provides a method for
producing the new tetralone or benzopyranone derivative
claimed in claim 1, characterized in that it comprises (a)
dissolving a tetralone or benzopyranone compound represented
by the following general formula (II) and a benzaldehyde
compound represented by the following general formula (III) in
an organic solvent, (b) refluxing with heating under acidic
conditions and (c) purifying the desired compound from the
reaction mixture of a compound of formula II:
(I?)
A


CA 02250258 2005-05-18
4a
wherein R, is a hydroxy group or methoxy group, RZ is hydrogen
and A represents a methylene or oxygen, and
p
(TII)
R~~ ~s
wherein R3 - R~ represents hydrogen, a hydroxy group, alkyl or
an alkyloxy group having 1 - 6 carbon atoms, a halogen, or an
alkylene dioxy group joined at R3 and R4, R4 and R5, R5 and R6,
or R6 and R~ .
In a third aspect, the present invention provides a
pharmaceutical composition comprising a compound of formula
(I) as defined above or a pharmaceutically acceptable salt
thereof and a pharmaceutically acceptable carrier or diluent.
In a fourth aspect, the present invention provides a
method of inhibiting the activity of 178-HSD or treating or
preventing androgen or estrogen dependent diseases in a mammal
comprising administering to the mammal a therapeutically
effective amount of a compound of formula (I) as defined above
or a pharmaceutically acceptable salt thereof.


CA 02250258 2001-10-24
- 5 -
As embodiments of new tetralone or benzopyranone derivatives
represented by the following general formula (I), the following compounds can
be exemplified. (The numbers of compounds and examples described in Figs. 1-
3 are coincident.)
(1) 2-[(3,4-dihydroxyphenyl)methylene]-6-hydroxy-1-tetralone
(2) 2-(phenylmethylene)-6-hydroxy-1-tetralone
(3) 2-((3-hydroxyphenyl)methylene]-6-hydroxy-1-tetralone
(4) 2-[(4-hydroxyphenyl)methylene]-6-hydroxy-1-tetralone
(5) 2-[(2-methoxyphenyl-4-carboxylic acid)methylene]-6-hydroxy-1-tetralone
l0 (6) 2-[(4-dimethylaminophenyl)methylene]-6-hydroxy-1-tetralone
('n 2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-1-tetralone
(8) 2-[(3,5-dimethoxyphenyl)methylene]-6-hydroxy-1-tetralone
(9) 2-[(4-bromophenyljmethylene]-6-hydroxy-1-tetralone
(10) 2-((4-chlorophenyl)methylene]-6-hydroxy-1-tetralone
(I l) 2-[(4-fluorophenyl)methylene]-6-hydroxy-1-tetralone
(12) 6-hydroxy-2-piperonylidene-1-tetralone
(13) 2-[(3,4-benzodioxane)-6-methylene]-6-hydroxy-1-tetralone
(14) 2-[(3,4-dihydroxyphenyl)methylene]-7-hydroxy-4(4H)-benzopyranone
(15) 7-hydroxy-3-piperonylidene-4-(4H)-benzopyranone
2p (16) 3-[(1,4-benzodioxane)-6-methylene]-7-hydroxy-4(4H)-benzopyranone
(17) 3-[(3,4-dimethoxyphenyl)methylene]-7-hydroxy-4(4H)-benzopyranone
(18) 3-[(3-ethoxy-4-methoxyphenyl)methylene]-?-hydroxy-4(4H)-
benzopyranone
(19) 3-[(3-methoxy-4-ethoxyphenyl)methylene]-7-hydroxy-4(4H)-
benzopyranone
(20) 3-[(3,4-diethoxyphenyl)methylene]-7-hydroxy-4(4H)-benzopyranone
(21) 3-[(3-methyl-4-methoxyphenyl)methylene]-7-hydroxy-4(4H)-
benzopyranone
(22) 2-methoxy[(3-methoxy-4-ethoxyphenyl)methylene]-6-methoxy-1-tetralone
The derivatives of the present invention contain, in addition to the


CA 02250258 1998-09-28
6
above-mentioned compounds, stereospecific isomers of these compounds, and
salts formed with acids or bases. As the salts of bases, for example, salts of
inorganic bases of sodium, potassium, magnesium, calcium or aluminum, salts
of organic bases of lower alkyl amines or lower alcohol amines, salts of basic
amino acids such as lysine, alginine, or ornithine, or ammonium salts are
exemplified. Further, the derivatives may form hydrates, solvates of lower
alcohols, and crystal polymorphs.
The derivatives of the present invention can be prepared by the following
methods. As an example, above-mentioned tetralone or benzopyranone
compounds (II) and above-mentioned benzaldehyde compounds (III) are
dissolved in solvent such as methanol, ethanol or propanol, concentrated
hydrochloric acid is added, the solution is refluxed with heating for 1- 24
hours
and cooled, precipitated crystals are filtered to obtain desired new
derivatives of
the present invention (I). When crystals are not precipitated, water 100- 400
ml
is added to precipitate crystals, and the crystals are filtered and dried to
obtain
the desired derivatives of the present invention. Otherwise, sodium hydroxide
or potassium hydroxide is added to compounds (II) and (III) in solvent such as
methanol, ethanol or propanol, the solution is stirred for 1- 24 hours and
acidified with hydrochloric acid, and precipitated crystals are filtered to
obtain
the desired derivatives of the present invention. In addition, the desired
derivatives of the present invention can be obtained by dissolving the above
compounds in a hydrochloric gas-saturated solution of organic solvent such as
methanol, ethanol, propanol or ether; then cooling, allowing to stand at room
temperature or heating the solution; stirring for 1-24 hours; adding water to
precipitate the desired derivatives as crystals; and filtering the
precipitated
crystals.
The derivatives of the present invention can safely be orally or
parenterally administered as medicines to man or animals. In the case of
parenteral administration, intravenous injection, intramuscular injection,


CA 02250258 1998-09-28
7
subcutaneous injection, intra-abdominal injection, percutaneous
administration, administration through the lungs, intranasal injection,
administration through the intestines, administration from oral cavity, and
administration through mucosae can be exemplified, and these medicines are
administered. Injections, suppository, aerosols and percutaneous absorption
tapes and the like can be exemplified. As the medicines of oral
administration,
tablets (including sugar-coated tablets, coating tablets and buccal tablets),
powder, capsules (including a soft capsule), granules (including a coating
granule), pills, troches, liquid preparations, or sustained release
preparations of
these medicines, which are pharmaceutically allowable, can be exemplified.
As the liquid for oral administration, suspension, emulsion, syrup (including
dry syrup), and elixir can be exemplified. These pharmaceuticals are prepared
by conventional methods of manufacturing pharmacy and administered as drug
compositions along with pharmacologically allowable carriers, vehicles,
disintegrators, lubricants, coloring matters and the like.
As the carriers and vehicles used in these pharmaceuticals, lactose,
glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate,
calcium phosphate, calcium sulfate, crystalline cellulose, powdered
glycyrrhiza,
and powdered gentian can be exemplified. As the binders, starch, tragacanth
gum, gelatin, syrup, polyvinylalcohol, polyvinylether, polyvinylpyrrolidone,
hydroxypropylcellulose, methylcellulose, ethylcellulose, and
carboxymethylcellulose can be exemplified. As the disintegrators, starch,
agar, powdered gelatin, sodium carboxymethylcellulose, calcium
carboxymethylcellulose, crystalline cellulose, calcium carbonate, calcium
bicarbonate, and sodium alginic acid can be exemplified. As the lubricants,
magnesium stearate, talc, hydrogenated vegetable oil, and macrogol can be
exemplified. As the coloring matters, matters which are allowed to add to
medicines can be used.
The tablets and granules can be coated with sucrose, gelatin,


CA 02250258 1998-09-28
8
hydroxypropylcellulose, purified shellac, gelatin, glycerin, sorbitol,
ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,
polyvinylpyrrolidone, phthalic acid cellulose acetate,
hydroxypropylmethylcellulose phthalate, methylmethacrylate, methacryic acid
polymer or the like, and one or more coatings may be used. Capsules of
ethylcellulose or gelatin may be used. Further, when the injections are
prepared, if necessary, a pH adjustor, a buffering agent, a stabilizer, a
solubilizing agent or the like may be added to the basis by a conventional
method.
When the derivatives of the present invention are administered to
patients, the dose is not particularly limited because conditions such as the
condition of illness, and patient's age, health condition and weight are
different,
it is about 1 mg - 1,000 mg per day for an adult, preferably 50 - 200 mg,
orally or
parenterally one time or more a day.
Further, the derivatives of the present invention, in the production of
semiconductor devices and the like, can be used in a photoresist composition
of a
positive type, which gives high sensitive resolution, development properties,
heat-resisting properties, and resist patterns having excellent resist forms.
Brief Description of the Drawings
[Fig. A drawing, which shows the results
1] of examples.


[Fig. 2] A drawing, which shows the results
of examples.


[Fig. 3] A drawing, which shows the results
of examples.


Best mode for Carrying Out the Invention
The following Examples are intended to further illustrate the present
invention and not to limit the invention by these Examples.
Example 1
Synthesis of 2-fl3 4-dihvdroxvnhenvl)methvlenel-6-hvdroxv-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and 3,4-dihydroxybenzaldehyde 0.85 g
were added to a mixture of concentrated hydrochloric acid 50 ml and methanol


CA 02250258 1998-09-28
9
75 ml, the mixture was refluxed for 2.5 hours and cooled to room temperature,
and water 357 ml was added. The precipitated crystals were filtered. The
crystals were dried over phosphorous pentoxide for six hours under reduced
pressure to obtain the desired compound 1.25 g.
FAB MASS (M+1); 283
1H-NMR (ppm, in DMSO-ds); 2.83 (2H, m), 3.02 (2H, m), 6.66 (1H, d, J=2.lHz),
6.75 (1H, dd, J=8.5, 2.4Hz), 6.79 (1H, d, J=7.9Hz), 6.83 (1H, dd, J=8.3,
l.9Hz),
6.94 (1H, d, J=l.BHz), 7.49 (1H, s), 7.81 (1H, d, J=8.5Hz), 9.09 (1H, s), 9.35
(1H,
s), 10.31 (1H, s)
Example 2
Synthesis of 2-(phenylmethylene)-6-hydroxp-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and benzaldehyde 0.42 ml were added
to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the
mixture was refluxed for two hours and cooled to room temperature, and water
400 ml was added. The precipitated crystals were filtered. The crystals were
dried over phosphorous pentoxide for six hours under reduced pressure to
obtain
the desired compound 0.756 g.
FAB MASS (M+1); 251
1H-NMR (ppm, in DMSO-ds); 2.83 (2H, m), 3.02 (2H, m), 6.66 (1H, s), 6.76 (1H,
d, J=8.6Hz), 7.44 (4H, m), 7.62 (1H, s), 7.84 (1H, d, J=8.8Hz), 10.37 (1H, s)
Example 3
Synthesis of 2-[(3-hydroxyphen,yl)methvlene]-6-hydroxv-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and 3-hydroxybenzaldehyde 0.903 g
were added to a mixture of concentrated hydrochloric acid 50 ml and methanol
75 ml, the mixture was refluxed for one hour and cooled to room temperature,
and water 400 ml was added. The precipitated crystals were filtered. The
crystals were dried over phosphorous pentoxide for six hours under reduced
pressure to obtain the desired compound 0.92 g.
FAB MASS (M+1); 267


CA 02250258 1998-09-28
1H-NMR (ppm, in DMSO-ds); 2.83 (2H, m), 2.99 (2H, m), 6.66 (1H, d, J=2.4Hz),
6.76 (2H, m), 6.98 (2H, m), 7.23 (1H, t, J=7.OHz), 7.53 (1H, s), 7.84 (1H, d,
J=8.4Hz), 9.54 (1H, s), 10.39 (1H, s)
Example 4
5 Synthesis of 2-[l4-hydroxyphenvl)methvlene]-6-hvdroxy-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and 4-hydroxybenzaldehyde 0.903 g
were added to a mixture of concentrated hydrochloric acid 50 ml and methanol
75 ml, the mixture was refluxed for one hour and cooled to room temperature,
and water 200 ml was added and allowed to stand for one hour. The precipi-
10 tated crystals were filtered. The crystals were dried over phosphorous pent-

oxide for four hours under reduced pressure to obtain the desired compound
0.941 g.
FAB MASS (M+1); 267
1H-NMR (ppm, in DMSO-ds); 2.81 (2H, m), 3.00 (2H, m), 6.65 (1H, d, J=2.4Hz),
6.75 (1H, dd, J=8.5, 2.lHz), 6.84 (2H, d, J=8.5Hz), 7.35 (1H, d, J=8.8Hz),
7.55
(1H, s), 7.82 (1H, d, J=8.5Hz), 9.84 (1H, s), 10.33 (1H, s)
Example 5
Synthesis of 2-j(2-methoxvphenyl-4-carboxylic acid~methylene~-6-hydroxv-1-t
etralone
After 6-hydroxy-1-tetralone 1.0 g and 4-formyl-2-methoxyphenyl acetate
1.44 g were added to a mixture of concentrated hydrochloric acid 50 ml and
methanol 75 ml, the mixture was refluxed for one hour and cooled to room
temperature, and water 400 ml was added and allowed to stand for two hours.
The precipitated crystals were filtered. The crystals were dried over
phosphorous pentoxide for four hours under reduced pressure to obtain the
desired compound 0.671 g.
FAB MASS (M+1); 325
1H-NMR (ppm, in DMSO-ds); 2.82 (2H, m), 3.05 (2H, m), 3.81 (3H, s), 6.66 (1H,
d, J=2.lHz), 6.75 (1H, dd, J=8.2, 2.lHz), 6.85 (1H, d, J=7.9Hz), 6.98 (1H, dd,


CA 02250258 1998-09-28
11
J=8.2, l.BHz), 7.07 (1H, d, J=l.BHz), 7.58 (1H, s), 7.83 (1H, d, J=8.5Hz)
Example 6
Synthesis of 2-f(4-dimethvlaminophenyl)methylene]-6-hydroxy-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and 4-dimethylaminobenzaldehyde
0.97 g were added to a mixture of concentrated hydrochloric acid 50 ml and
methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room
temperature, and water 400 ml was added. The precipitated crystals were
filtered. The crystals were dried over phosphorous pentoxide for six hours
under reduced pressure to obtain the desired compound 0.885 g.
FAB MASS (M+1); 294
1H-NMR (ppm, in DMSO-ds); 2.81 (2H, m), 2.98 (6H, s), 3.03 (2H, m), 6.66 (1H,
d, J=2.5Hz), 6.75 (1H, dd, J=8.5, 2.4Hz), 6.83 (1H, d, J=8.8Hz), 7.40 (1H, d,
J=8.8Hz), 7.58 (1H, s), 7.82 (1H, d, J=8.5Hz)
Example 7
Synthesis of 2-j(3.4-dimethoxyphenyl)methvlene]-6-hydroxy-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and 3,4-dimethoxybenzaldehyde 1.23 g
were added to a mixture of concentrated hydrochloric acid 50 ml and methanol
75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature,
and the precipitated crystals were filtered. The crystals were dried over
phosphorous pentoxide for 5.5 hours under reduced pressure to obtain the
desired compound 1.60 g.
FAB MASS (M+1); 311
iH-NMR (ppm, in DMSO-ds); 2.82 (2H, m), 3.06 (2H, m), 3.80 (6H, s), 6.66 (1H,
d, J=2.lHz), 6.76 (1H, dd, J=8.5, 2.4Hz), 7.01 (1H, d, J=8.8Hz), 7.07 (2H, m),
7.60 (1H, s), 7.84 (1H, d, J=8.5Hz), 10.19 (1H, s)
Example 8
Synthesis of 2-[13.5-dimethoxyphenyl)methylenel-6-hydroxy-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and 3,5-dimethoxybenzaldehyde 1.23 g
were added to a mixture of concentrated hydrochloric acid 50 ml and methanol


CA 02250258 1998-09-28
12
75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature,
and the precipitated crystals were filtered. The crystals were dried over
phosphorous pentoxide for four hours under reduced pressure to obtain the
desired compound 1.276 g.
FAB MASS (M+1); 311
1H-NMR (ppm, in DMSO-ds); 2.82 (2H, m), 2.93 (2H, s), 3.83 (3H, s), 3.87 (3H,
s), 6.57 (1H, dd, J=8.2, 2.lHz), 6.63 (1H, dd, J=8.6, 2.lHz), 6.77 (1H, dd,
J=8.5,
2.4Hz), 7.29 (1H, d, J=8.5Hz), 7.83 (1H, s), 7.84 (1H, d, J=8.5Hz)
Example 9
Synthesis of 2-[~4-bromophenybmethylene)-6-hydroxv-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and 4-bromobenzaldehyde 1.37 g were
added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml,
the mixture was refluxed for one hour and cooled to room temperature, and
water 250 ml was added. The precipitated crystals were filtered. The crystals
were dried over phosphorous pentoxide for four hours under reduced pressure to
obtain the desired compound 0.72 g.
FAB MASS (M+1); 330
1H-NMR (ppm, in DMSO-ds); 2.82 (2H, m), 2.97 (2H, m), 6.66 (1H, d, J=l.SHz),
6.77 (1H, dd, J=8.5, 2.4Hz), 7.43 (2H, d, J=8.5Hz), 7.56 (1H, s), 7.61 (2H, d,
J=8.5Hz), 7.85 (1H, d, J=8.5Hz), 10.42 (1H, s)
Example 10
Synthesis of 2-[(4-chlorophenyl)methylenel-6-hydroxv-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and 4-chlorobenzaldehyde 1.03 g were
added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml,
the mixture was refluxed for 1.5 hours and cooled to room temperature, and
water 250 ml was added. The precipitated crystals were filtered. The crystals
were dried over phosphorous pentoxide for four hours under reduced pressure to
obtain the desired compound 0.77 g.
FAB MASS (M+1); 285


CA 02250258 1998-09-28
13
1H-NMR (ppm, in DMSO-ds); 2.82 (2H, m), 2.98 (2H, m), 6.66 (1H, d, J=2.lHz),
6.77 (1H, dd, J=8.5, 2.2Hz), ?.48 (5H, m), 7.59 (1H, s), 7.85 (1H, d,
J=8.5Hz),
10.41 (1H, s)
Example 11
Synthesis of 2-[(4-fluorophenvl)meth~lene~]-6-hvdroxv-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and 4-fluorobenzaldehyde 0.79 ml were
added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml,
the mixture was refluxed for 1.5 hours and cooled to room temperature, and
water 300 mg was added. The precipitated crystals were filtered. The crystals
were dried over phosphorous pentoxide for four hours under reduced pressure to
obtain the desired compound 0.65 g.
FAB MASS (M+1); 269
1H-NMR (ppm, in DMSO-ds); 2.81 (2H, m), 2.98 (2H, m), 6.66 (1H, d, J=2.2Hz),
6.77 (1H, dd, J=8.5, 2.5Hz), 7.25 (2H, m), 7.53 (2H, m), 7.61 (1H, s), 7.84
(1H, d,
J=8.5Hz), 10.41 (1H, s)
Example 12
Synthesis of 6-hydroxy-2-pineronvlidene-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and piperonal 1.11 g were added to a
mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the
mixture was refluxed for 0.5 hours and cooled to room temperature, and the
precipitated crystals were filtered. The crystals were dried over phosphorous
pentoxide for four hours under reduced pressure to obtain the desired compound
1.63 g.
FAB MASS (M+1); 295
1H-NMR (ppm, in DMSO-ds); 2.82 (2H, m), 3.01 (2H, m), 6.06 (2H, s), 6.65 (1H,
d, J=2.lHz), 6.75 (1H, dd, J=8.5, 2.4Hz), 6.98 (1H, d, J=7.9Hz), 7.02 (1H, dd,
J=9.4, l.lHz), 7.08 (1H, d, J=l.SHz), 7.55 (1H, s), 7.82 (1H, d, J=8.5Hz),
10.37
(1H, s)
Example 13


CA 02250258 1998-09-28
14
Synthesis of 2-[13.4-benzodioxane~-6-methylene~-6-hydroxy-1-tetralone
After 6-hydroxy-1-tetralone 1.0 g and 1,4-benzodioxane-6-carbaldehyde
1.21 g were added to a mixture of concentrated hydrochloric acid 50 ml and
methanol 75 ml, the mixture was refluxed for one hour and cooled to room
temperature, and the precipitated crystals were filtered. The crystals were
dried over phosphorous pentoxide for four hours under reduced pressure to
obtain the desired compound 1.57 g.
FAB MASS (M+1); 309
1H-NMR (ppm, in DMSO-ds); 2.81 (2H, m), 3.00 (2H, m), 4.26 (4H, m), 6.65 (1H,
d, J=2.4Hz), 6.75 (1H, dd, J=8.5, 2.lHz), 6.90 (1H, d, J=8.2Hz), 6.98 (1H, dd,
J=8.5, l.BHz), 7.01 (1H, d, J=2.lHz), 7.52 (1H, s), 7.82 (1H, d, J=8.6Hz),
10.36
(1H, s)
Example 14
Synthesis of 2-[13.4-dih~droxyphenyl)methvlene]-7-h derv-4(~4HL
benzopyranone
After 7-hydroxy-4(4H)-benzopyranone 0.5 g and 3,4-
dihydroxybenzaldehyde 0.42 g were added to a mixture of concentrated
hydrochloric acid 25 ml and methanol 35 ml, the mixture was refluxed for 2.5
hours and cooled to room temperature, and water 250 ml was added. The
mixture was allowed to stand for 18 hours and the precipitated crystals were
filtered. The crystals were dried over phosphorous pentoxide for four hours
under reduced pressure to obtain the desired compound 0.61 g.
FAB MASS (M+1); 285
1H-NMR (ppm, in DMSO-ds); 5.34 (2H, d, J=l.6Hz), 6.29 (1H, d, J=2.lHz), 6.53
(1H, dd, J=8.6, 2.2Hz), 6.74 (1H, dd, J=8.2, l.BHz), 6.82 (2H, m), 7.51 (1H,
s),
7.71 (1H, d, J=8.8Hz), 9.19 (1H, s), 9.55 (1H, s), 10.57 (1H, s)
Example 15
Synthesis of 7-hydroxv-3-~neronylidene-4,~4H -benzop~iranone
After ?-hydroxy-4(4H)-benzopyranone 1.0 g and piperonal 1.0 g were


CA 02250258 1998-09-28
added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml,
the mixture was refluxed for two hours and cooled to room temperature, and
water 200 ml was added. The mixture was allowed to stand for one hour and
the precipitated crystals were filtered. The crystals were dried over
5 phosphorous pentoxide for four hours under reduced pressure to obtain the
desired compound 0.266 g.
FAB MASS (M+1); 297
1H-NMR (ppm, in DMSO-ds); 5.33 (2H, d, J=l.6Hz), 6.09 (1H, s), 6.31 (1H, d,
J=2.lHz), 6.53 (1H, dd, J=8.8, 2.5Hz), 6.93 (1H, dd, J=7.9, l.2Hz), 7.02 (2H,
m),
10 7.59 (1H, s), 7.72 (1H, d, J=8.8Hz), 10.64 (1H, s)
Example 16
Synthesis of 3-[(1.4-benzodioxane)-6-methvlene]-7-hydroxy-4(4H)-
benzopyranone
After 7-hydroxy-4(4H)-benzopyranone 1.0 g and 1,4-benzodioxane-6-
15 carboxyaldehyde 1.2 g were added to a mixture of concentrated hydrochloric
acid 50 ml and methanol 40 ml, the mixture was refluxed for 1.5 hours and
cooled to room temperature, and the precipitated crystals were filtered. The
crystals were dried over phosphorous pentoxide for four hours under reduced
pressure to obtain the desired compound 1.066 g.
FAB MASS (M+1); 311
1H-NMR (ppm, in DMSO-ds); 4.29 (4H, m), 5.33 (2H, d, J=l.6Hz), 6.31 (1H, d,
J=2.lHz), 6.53 (1H, dd, J=8.8, 2.4Hz), 6.89- 6.96 (3H, m), 7.56 (1H, s), 7.72
(1H,
d, J=8.5Hz), 10.62 (1H, s)
Example 17
Synthesis of 3-[(3.4-dimethoxyphenyl)methvlene]-7-hvdroxv-4(4H)-
benzopyranone
After 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3,4-
dimethoxybenzaldehyde 1.22 g were added to a mixture of concentrated
hydrochloric acid 50 ml and methanol 40 ml, the mixture was refluxed for 1.5


CA 02250258 1998-09-28
16
hours and cooled to room temperature, water 100 ml was added and the mixture
was allowed to stand for 30 minutes. The precipitated crystals were filtered.
The crystals were dried over phosphorous pentoxide for seven hours under
reduced pressure to obtain the desired compound 0.255 g.
FAB MASS (M+1); 313
1H-NMR (ppm, in DMSO-ds); 3.80 (3H, s), 3.81 (3H, s), 5.39 (2H, d), 6.32 (1H,
d,
J=2.lHz), 6.54 (1H, dd, J=8.8, 2.2Hz), 6.97-7.05 (3H, m), 7.63 (1H, s), 7.73
(1H,
d, J=8.8Hz)
Example 18
Synthesis of 3-j(3-ethoxy-4-methoxXphenyl)meth l~]-7-hydroxy-414HZ
benzogvranone
After a saturated hydrogen chloride-methanol solution 15 ml was added
to 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3-ethoxy-4-methoxybenzaldehyde
1.30 g, the mixture was srtirred for 22.5 hours, water 100 ml was added, and
the precipitated crystals were filtered. The crystals were added to methanol
30 ml of 55 °C, and the mixture was filtered. The resulting crystals
were dried
over phosphorous pentoxide for four hours under reduced pressure to obtain the
desired compound 0.415 g.
FAB MASS (M+1); 327
1H-NMR (ppm, in DMSO-ds); 1.33 (3H, t), 3.81 (3H, s), 4.05 (2H, d), 5.38 (2H,
d),
6.31 (1H, d, J=2.5Hz), 6.53 (1H, dd, J=8.5, 2.lHz), 6.96- 7.05 (3H, m), 7.62
(1H,
s), 7.73 (1H, d, J=8.5Hz)
Example 19
Synthesis of 3-[(3-methoxy-4-ethoxvphenyl)methylene]-7-hydroxy-4(4H)-
benzopyranone
After a saturated hydrogen chloride-methanol solution 20 ml was added
to ?-hydroxy-4(4H)-benzopyranone 1.0 g and 3-methoxy-4-ethoxybenzaldehyde
1.30 g, the mixture was srtirred for 18 hours, water 100 ml was added, and the
precipitated crystals were filtered. The crystals were added to methanol 100


CA 02250258 1998-09-28
17
ml of 55 °C, and the mixture was stirred for 15 minutes and filtered.
The
resulting crystals were dried over phosphorous pentoxide for four hours under
reduced pressure to obtain the desired compound 0.216 g.
FAB MASS (M+1); 327
1H-NMR (ppm, in DMSO-ds); 1.33 (3H, t), 3.80 (3H, s), 4.05 (2H, c~, 5.38 (2H,
d),
6.31 (1H, d, J=2.lHz), 6.53 (1H, dd, J=8.5, 2.lHz), 6.93-7.03 (3H, m), 7.63
(1H,
s), 7.73 (1H, d, J=8.8Hz)
Example 20
Synthesis of 3-[(3.4-diethoxyphenvl)methylene]-7-hydroxy-4~4H)-
benzopyranone
After a saturated hydrogen chloride-methanol solution 20 ml was added
to 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3,4-diethoxybenzaldehyde 1.58
ml, the mixture was srtirred for 72 hours, water 100 ml was added, and the
precipitated crystals were filtered. The crystals were added to methanol 60 ml
of 55 °C, and the mixture was stirred for 15 minutes and filtered. The
resulting
crystals were dried over phosphorous pentoxide for four hours under reduced
pressure to obtain the desired compound 0.762 g.
FAB MASS (M+1); 341
1H-NMR (ppm, in DMSO-ds); 1.33 (6H, t), 4.07 (4H, c~, 5.37 (2H, d), 6.31 (1H,
d,
J=2.4Hz), 6.53 (1H, dd, J=8.8, 2.4Hz), 6.93- 7.02 (3H, m), 7.62 (1H, s), 7.73
(1H,
d, J=8.6Hz)
Example 21
Synthesis of 3-f(3-methyl-4-methoxvnhenvl)methvlenel-7-hvdroxv-4(4H)-
benzogyranone
After a saturated hydrogen chloride-methanol solution 20 ml was added
to 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3-methyl-4-methoxybenzaldehyde
0.87 g, the mixture was srtirred for 72 hours, water 100 ml was added, and the
precipitated crystals were filtered. The crystals were added to methanol 50 ml
of 55 °C, and the mixture was stirred for 15 minutes and filtered. The
resulting


CA 02250258 1998-09-28
18
crystals were dried over phosphorous pentoxide for four hours under reduced
pressure to obtain the desired compound 0.447 g.
FAB MASS (M+1); 297
1H-NMR (ppm, in DMSO-ds); 2.17 (3H, s), 3.83 (3H, s), 5.35 (2H, d), 6.31 (1H,
d,
J=2.2Hz), 6.53 (1H, dd, J=8.6, 2.2Hz), 7.02 (1H, d, J=8.5Hz), 7.24 (2H, m),
7.59
(1H, s), 7.73 (1H, d, J=8.6Hz)
Example 22
Synthesis of 2-methoxyf(3-methoxy-4-ethoxyphenvl)methvlenel-6-methox
tetralone
After 6-methoxy-1-tetralone 1.0 g and 3-methoxy-4-ethoxybenzaldehyde
1.27 g were added to a mixture of concentrated hydrochloric acid 60 ml and
methanol 50 ml, the mixture was refluxed for 2.5 hours. The reaction mixture
was cooled to room temperature, and ethyl acetate 100 ml was added. The ethyl
acetate solution was washed with water 100 ml twice and saturated salt
solution 100 ml twice. The ethyl acetate solution was dehydrated with
magnesium sulfate, and concentrated to 20 ml at 40 °C under reduced
pressure. The precipitated crystals were filtered. The crystals were dried
over
phosphorous pentoxide for four hours under reduced pressure to obtain the
desired compound 0.89 g.
FAB MASS (M+1); 339
1H-NMR (ppm, in CDCIs); 1.46 (3H, t), 2.89 (2H, m), 3.10 (2H, m), 3.83 (3H,
s),
3.86 (3H, s), 4.22 (2H, q, 4Hz), 6.67 (1H, d, J=8.2Hz), 6.83 (1H, dd, J=8.3,
l.9Hz), 6.85 (1H, d, J=8.2Hz), 6.65 (1H, d, J=l.BHz), 7.00 (1H, dd, J=8.5,
2.lHz), 7.65 (1H, s), 8.07 (1H, d, J=8.8Hz)
in vitro 17,Q -HSD inhibition activity test
17,Q -HSD inhibition activity of the compounds obtained in Examples 1-
22 (abbreviated as a test material hereinafter) was tested. Namely, each test
material was dissolved in ethanol to obtain a solution of 260 nM of final
concentration, placed in a test tube, and evaporated to dryness in nitrogen
gas.


CA 02250258 1998-09-28
19
To the material, a buffer solution of 10 mM phosphate 590 ,ul (pH 7.5)
containing 100 mM potassium chloride, 1 mM ethylenediamine tetraacetic acid,
0.5 mM nicotinamide adenine dinucleotidephosphate of a reducing type (all
compounds were available from Wako Junyaku Company) and l,uM [4-
14C]estrone (NEN Research Products Company), and a microsome fraction 10
,ul obtained from human placenta according to a method of E. A. Thompson et
al (J. Biol. Chem., vol. 249, 5364-5372 (1974)) were added, and the mixture
was
reacted with shaking for 30 minutes at a temperature of 37 °C. After
the
reaction, dichloromethane 2 ml was added at once. The mixture was
thoroughly stirred, and centrifuged for five minutes at 3,000 rpm. The
resulting lower layer (a dichloromethane layer) was removed to another test
tube, and evaporated to dryness. To the tube, ethanol 100,u 1 containing
estrone 20,u g and estradiol 20,u g was added, and 20,u 1 of the mixture was
spotted on a TLC plate (silica gel 60 Fas4, Merck Company). After the TLC
plate was developed with benzene:acetone (4:1), spots corresponding to estrone
and estradiol were cut off under ultraviolet light, liquid scintillation
cocktail
(Filter count (trademark); Hewlett Packard Company) was added to determine
the amount of residual [4-14C] estrone, and the amount of [4-14C] estradiol
produced by 17,Q -HSD enzyme activity by using a liquid scintillation counter.
Further, as a control group, similar operation is conducted without adding the
test materials. The 17,(3 -HSD enzyme activity of the control group was
determined as 0% of inhibition ratio, and the 17,Q -HSD enzyme inhibition
ratio
of the test materials were determined by percentage. The results are shown in
Figs. 1-3.
Industrial Applicability
From the above results, it is confirmed that the derivatives of the present
invention (test materials) have excellent 17,Q -HSD inhibition activity.
Accordingly, from the present invention, new tetralone or benzopyranone
derivatives and a method for producing the derivatives can be provided. The


CA 02250258 2001-10-24
derivatives of tire present invention Iravc inhibition activity of 17Q-HSD,
and
for the activity, these derivatives are useful for a therapeutic went for
hreventin~ and/or treating androgen or estrogen dependent diseases,
particularly, prostatic cancer, k~eni~n prostatic hyperplasia, virilisrn,
mammary
cancer, mastopathy, endometrial cancer, endometriosis, ovarian cancer and the
like. Further, these compounds of the present invention can be used in a
photoresist composition of positive type.
In the claims which follow and in the preceding
description of the invention, except where the context
requires otherwise due to express language or necessary
implication, the words "comprises" and "comprising" are
used in the sense of "includes" and "including", i.e. the
features specified may be associated with further
features in various embodiments of the invention.

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date 2006-02-21
(86) PCT Filing Date 1998-01-28
(87) PCT Publication Date 1998-07-30
(85) National Entry 1998-09-28
Examination Requested 1998-09-28
(45) Issued 2006-02-21
Deemed Expired 2009-01-28

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Request for Examination $400.00 1998-09-28
Application Fee $300.00 1998-09-28
Registration of a document - section 124 $100.00 1999-09-22
Maintenance Fee - Application - New Act 2 2000-01-28 $100.00 2000-01-20
Maintenance Fee - Application - New Act 3 2001-01-29 $100.00 2000-11-14
Maintenance Fee - Application - New Act 4 2002-01-28 $100.00 2002-01-11
Registration of a document - section 124 $50.00 2002-03-21
Maintenance Fee - Application - New Act 5 2003-01-28 $150.00 2002-11-14
Maintenance Fee - Application - New Act 6 2004-01-28 $150.00 2003-11-21
Maintenance Fee - Application - New Act 7 2005-01-28 $200.00 2005-01-13
Maintenance Fee - Application - New Act 8 2006-01-30 $200.00 2005-11-08
Final Fee $300.00 2005-12-13
Maintenance Fee - Patent - New Act 9 2007-01-29 $200.00 2007-01-25
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
DAIICHI PHARMACEUTICAL CO., LTD.
Past Owners on Record
NAKAKOSHI, MASAMICHI
NAKAMURA, JUNJI
NAKAYAMA, SHOJI
SNOW BRAND MILK PRODUCTS CO., LTD.
YOSHIHAMA, MAKOTO
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Description 
Date
(yyyy-mm-dd) 
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Abstract 1998-09-28 1 25
Description 1998-09-28 20 818
Claims 1998-09-28 2 50
Drawings 1998-09-28 3 66
Representative Drawing 1998-12-22 1 2
Claims 2003-06-10 4 135
Cover Page 1998-12-22 1 50
Claims 2002-06-04 4 135
Abstract 2001-10-24 1 30
Description 2001-10-24 21 850
Claims 2001-10-24 6 166
Claims 2004-05-10 4 120
Claims 2004-11-24 4 120
Description 2005-05-18 21 878
Claims 2005-05-18 4 120
Representative Drawing 2006-01-19 1 4
Cover Page 2006-01-19 2 52
Correspondence 1998-11-30 1 31
PCT 1998-09-28 6 268
Assignment 1998-09-28 4 114
Assignment 1999-09-22 4 98
Prosecution-Amendment 2001-04-27 2 63
Prosecution-Amendment 2001-10-24 18 519
Prosecution-Amendment 2001-12-10 2 69
Assignment 2002-03-21 2 81
Prosecution-Amendment 2002-06-04 9 287
Prosecution-Amendment 2002-12-10 2 71
Prosecution-Amendment 2003-06-10 8 270
Prosecution-Amendment 2004-10-19 1 31
Prosecution-Amendment 2004-01-05 2 65
Prosecution-Amendment 2004-05-10 5 158
Prosecution-Amendment 2004-11-24 2 46
Prosecution-Amendment 2005-04-27 1 35
Prosecution-Amendment 2005-05-18 5 179
Correspondence 2005-12-13 1 31