Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-19
2002-12-24
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S300000, C544S301000, C544S302000
Reexamination Certificate
active
06498164
ABSTRACT:
The present invention relates to a novel barbituric acid derivative and the method of the prevention and treatment by using the same of malignant hypercalcemia, osteolytic diseases such as Paget's disease of bone and osteoporosis, such diseases with the denaturation and necrosis of a cartilage as osteoarthritis, necrosis of head of femur, and articular rheumatism occurring in a knee, shoulder, and joint.
Japan has been gradually shifting to an aging society and, therefore, bone resorption diseases such as osteoporosis are becoming a big social problem. The bone resorption diseases are diseases of bone caused by abnormal sthenia of bone resorption exemplified by malignant hypercalcemia caused by myeloma and lymphoma, bone Paget's disease by local bone resorption, and osteoporosis caused by many factors such as aging and menopause. Although, at present, a female hormone, calcitonin, activated vitamin D3, parathyroid hormone, bisphosphonate, and ipriflavone, etc. are being used for therapeutic treatment, these agents have some defects respectively so as to remain as a symptomatic therapy.
On the other hand, osteoarthritis, necrosis of head of femur, and joint rheumatism are a disease occurring a defect of cartilage and bone caused by denaturation and necrosis of joint cartilage and subcartilaginous bone by various factors such as mechanical stresses, senescence, inflammation. The defect of bone largely affects the lowering of the quality of life through the deformation and pain of a joint. Any agents have not substantially existed to inhibit or repair effectively the defect of cartilage for the diseases.
Barbituric acid derivatives are a group of compounds which are used for medicinal drugs, agricultural chemicals, and many other purposes, and many derivatives are known.
For example, there are an anticancer drug (refer to WO9116315), photosensitive materials for electronic photography (refer to Japanese Patent Application Laid-open Nos. 179361/91 and 111852/91), a vermifuge (refer to EP 192180), insecticides (EP 455300, DE 3903404, and GB 1339748), herbicides (U.S. Pat. No. 4,797,147 and Japanese Patent Application laid-open No. 154275/75), and a bactericide (EP 517660).
The present inventors first elucidated the structure and the strong inhibiting action of bone resorption, which had not been previously known as far as the inventors' knowledge is concerned, of a series of compounds related to the present invention.
The inventors of the present invention formerly found substances showing a strong inhibiting action of bone resorption among derivatives of polyhydroxyphenol (Japanese Patent Application No. 137991/97). As a result of further research and an analysis of structure-activity relationship of those compounds, the inventors found a strong activity of a novel barbituric acid derivative and finally completed the present invention.
Thus, the purpose of the present invention is to provide a novel and useful barbituric acid derivative, the salt thereof and the solvate thereof, and a method of prevention and treatment of various diseases affecting bones and cartilages by using these compounds.
The subject of the invention is a barbituric acid derivative represented by the following general formula (I), the salt thereof or the solvate thereof:
(wherein each of R or R
1
independently represents a hydrogen atom, a substituted or an unsubstituted alkyl group or an alkenyl group of C
1
-C
15
, a substituted or an unsubstituted arylmethyl group, or a substituted or an unsubstituted aryl group, and R
2
represents a substituted or an unsubstituted alkyl group or an alkenyl group of C
1
-C
15
, a substituted or.
The present invention relates to a barbituric acid derivative shown in said general formula (I), the salt thereof or the solvates thereof containing one or more compounds, and a composition of a medicinal drug containing a carrier that is acceptable for drug manufacturing, preferably, a composition of a medicinal drug being a preventive and therapeutic agent for diseases affecting bones and cartilages.
Further, the present invention relates to a use of a barbituric acid derivative shown in said general formula (I), the salt thereof or the solvate thereof containing one or more compounds for manufacturing a composition of a medicinal drug for prevention and therapy of diseases affecting bones and cartilages.
Furthermore, the present invention relates to a method for prevention and therapy of diseases affecting bones and cartilages by administration of an effective amount of a barbituric acid derivative shown in said general formula (I), the salt thereof or the solvate thereof containing one or more compounds for prevention and therapy of diseases affecting bones and cartilages.
In the compound shown in said general formula (I) of the present invention, alkyl groups are straight-chain or branched alkyl groups of 1-15 carbon atoms, preferably 2-10, more preferably 4-10, and alkenyl groups are straight-chain or branched unsaturated hydrocarbon groups of 2-15 carbon atoms, preferably 3-10, more preferably 4-10; preferably, unsaturated hydrocarbon groups of one or more carbon—carbon double bonds.
In the compound shown in said general formula (I) of the present invention, aryl groups are monocyclic, polycyclic, or condensed ring aryl groups of 6-30 carbon atoms, preferably 6-20, more preferably 6-10; aryl groups of the present invention are monocyclic, polycyclic, or condensed ring heterocyclic aromatic groups of at least one or more nitrogen atoms, oxygen atoms, or sulfur atoms in an aromatic ring, of which size of one ring is 5-20 members, preferably 5-10 members, more preferably 5-7 members, and may be condensed with a ring consisted of saturated or unsaturated hydrocarbon groups.
In the compound shown in said general formula (I) of the present invention, arylmethyl groups are exemplified by methyl groups made by substitution of said aryl group.
In said general formula (I) of the present invention, alkyl groups, alkenyl groups, arylmethyl groups, or aryl groups may be substituted by a substitution group that does not inhibit activities in medical purposes of the present invention.
The compound shown in said general formula (I) of the present invention might be protected by a protecting group allowing production of an active body in a living body to express a physiological activity in the living body.
Substitution groups of said alkyl groups, alkenyl groups, arylmethyl groups, or aryl groups in said general formula (I) of the present invention can be one made by substitution of these groups each other, when mutual substitution of these groups is possible. Examples are aryl groups substituted by an alkyl group, arylmethyl groups substituted by an alkyl group, alkyl groups substituted by an aryl group, and alkenyl groups substituted by an aryl group.
Other substitution groups are exemplified by a hydroxyl group, an amino group, an alkoxy group having said alkyl groups, an alkylthio group, a mono- or a dialkylamino group, halogen atoms such as chlorine, bromine, and fluorine, alkylenedioxy groups such as a methylenedioxy group and a 2,2-dimethylmethylenedioxy group, a cyano group, and a nitro group.
Preferable substitution groups are exemplified by lower alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a t-butyl group, aryl groups such as a phenyl group and a naphthyl group, lower alkoxy groups such as a methoxy group, an ethoxy group, and an n-propoxy group, di- lower alkylamino groups such as a dimethylamino group, a diethylamino group, and a dipropylamino group, halogen atoms such as iodine, bromine, chlorine, and fluorine, alkylenedioxy groups such as a methylenedioxy group, a 2,2-dimethylmethylenedioxy group, a hydroxyl group, an amino group, a cyano group, and a nitro group, etc.
Aryl groups in the compounds shown in said general formula (I) of the present invention are exemplified by a phenyl group, a naphthyl group, an anthracenyl group, a pyridyl group, a quinolyl group, a thienyl group, and a pyr
Sakai Kunikazu
Satoh Yusuke
Aventis Pharma S.A.
Bierman, Muserlian and Lucas
Ford John M.
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