Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-01
2002-03-12
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S240000
Reexamination Certificate
active
06355663
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel substituted isoxazolylthiophene compound and a pharmaceutical composition comprising the same as an active ingredient, which is useful for enhancing the action of cell differentiation induction factors.
BACKGROUND ART
Compounds which have been reported as being therapeutically or prophylactically effective against bone diseases or nerve diseases by enhancing the action of the cell differentiation induction factors present in or administered to a living body include fused thiophene derivatives disclosed in W098/09958, but no such report covers the compounds of the present invention.
DISCLOSURE OF INVENTION
We extensively studied and found that certain substituted isoxazolylthiophene compounds are effective for treatment or prevention of bone diseases or nerve diseases, and finally completed the invention.
More specifically, the present invention is directed to a substituted isoxazolylthiophene compound represented by the formula (I)
wherein R
1
and R
2
individually represent an alkyl group of 1-5 carbon atoms, R
3
represents a cyano group or a group CONR
5
R
6
(in which R
5
and R
6
individually represent a hydrogen atom or an alkyl group of 1-10 carbon atoms), R
4
represents an alkyl group of 1-5 carbon atoms or a phenyl group, and n is an integer of 0-2, or a salt thereof.
The alkyl group of 1-5 carbon atoms used herein means a straight or branched alkyl group and includes, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group and an n-pentyl group.
The alkyl group of 1-10 carbon atoms as used herein means a straight or branched alkyl group and includes, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-pentyl group, an n-hexyl group and an n-octyl group.
The salt as used herein may include salts with pharmaceutically acceptable acids (such as hydrochloric acid, sulfuric acid, nitric acid, tartaric acid, citric acid, maleic acid, fumaric acid, etc.), as well as their hydrates.
The invention may further encompass the compounds which are capable of producing the active compounds of this invention through in vivo metabolism after administration, or the compounds which are capable of producing the active compounds per se as produced by the metabolism of the compounds of the invention through in vivo metabolism.
The compounds (I) of the invention may be prepared, for example, according to the following processes:
1) The compounds (I) wherein R
3
is a cyano group and n is 0 may be prepared, for example, according to the process as illustrated by Reaction Scheme 1.
In the Reaction Scheme 1, R
1
and R
2
have the same meanings as defined above, and R
7
is a group COCH
3
, COCH
2
R
4
or CH
2
COR
4
(wherein R
4
has the same meaning as defined above).
The Reaction Scheme 1 will be explained in detail below.
1)-(1) The present compounds (Ia) and (Ib) may be prepared using as a starting material the diketone compound (II) wherein R
7
represents COCH
3
.
More specifically, the diketone compound (II) wherein R
7
represents COCH
3
may be condensed with carbon disulfide (CS
2
) in the presence of a base and then the resulting condensed product may be converted to the thiophene compound (III) wherein R
7
represents COCH
3
by thioetherification of one of the sulfur atoms derived from carbon disulfide with a haloacetonitrile such as chloroacetonitrile or bromoacetonitrile and the remaining sulfur atom with R
2
—X
1
(wherein R
2
has the same meaning as defined above and X
1
is a leaving group such as a halogen atom, e.g., a chlorine atom or a bromine atom or a methylsulfoxy group), simultaneously with intramolecular cyclization reaction.
The base which may be used in this reaction may include alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (lithium carbonate, sodium carbonate, potassium carbonate, etc.), alkali metal hydrogencarbonates (sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), inorganic bases (metallic sodium, metallic potassium, sodium amide, etc.), alkali metal alkoxides (sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), organic bases (triethylamine, diisopropylethylamine, tri-n-butylamine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,8-diazabicyclo[5.4.0]-7-undecene, pyridine, N,N -dimethylaminopyridine, etc.), organometallic compounds (n-butyl lithium, s-butyl lithium, t-butyl lithium, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, etc.) and the like.
The reaction may be carried out in the presence or absence of a solvent. The solvent which may be used includes methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, water and the like.
The base and solvent to be used, as well as use or no use of the solvent should be properly selected depending on the substrates and reaction parameters used in the reaction.
Then, R
7
of the thiophene compound (III) wherein R
7
is a group COCH
3
is condensed with an activated carboxylic acid derivative represented by R
4
—COOH (wherein R
4
has the same meaning as above) such as an alkyl ester, e.g., methyl ester or ethyl ester or an acid halide or an acid anhydride, to convert R
7
to a group COCH
2
COR
4
. Subsequent condensed cyclization reaction using hydroxylamine or a derivative thereof may produce the compound (Ia) or (Ib) of this invention.
This condensation reaction is preferably carried out in the presence of a base. The base which may be used in this reaction includes alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (lithium carbonate, sodium carbonate, potassium carbonate, etc.), alkali metal hydrogencarbonates (sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), inorganic bases (metallic sodium, metallic potassium, sodium amide, etc.), alkali metal alkoxides (sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), organic bases (triethylamine, diisopropylethylamine, tri-n-butylamine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,8-diazabicyclo[5.4.0]-7-undecene, pyridine, N,N-dimethylaminopyridine, etc.), organometallic compounds (n-butyl lithium, s-butyl lithium, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, etc.) and the like.
The reaction may be carried out in the presence or absence of a solvent. The solvent which may be used includes methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, carbon terachloride, water and the like.
The hydroxylamine which is used for condensed cyclization reaction may be in the form of a salt with hydrochloric acid, sulfuric acid or the like, and the reaction is preferably carried out in the presence of a base. The bases which may be used in this reaction include alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (lithium carbonate, sodium carbonate, potassium carbonate, etc.), alkali metal hydrogencarbonates (sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), inorganic bases (metallic sodium, metallic potassium, sodium amide, etc.), alkali metal alkoxides (sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), organic bases (triethylamine, diisopropylethylamine, tri-n-butylamine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,8-
Harada Masahiro
Nakamura Toshio
Saito Shiuji
Takeda Junko
Gerstl Robert
Lorusso & Loud
Taisho Pharmaceutical Co. Ltd.
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