Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-01
2003-04-22
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S233500, C514S320000, C514S376000, C514S456000, C549S402000, C548S183000, C548S192000, C548S215000, C548S226000, C546S196000, C544S151000
Reexamination Certificate
active
06552054
ABSTRACT:
This application is the National Stage of International Application No. PCT/JP00/05910, filed on Aug. 31, 2000.
TECHNICAL FIELD
The present invention relates to chromone derivatives having an osteogenesis promoting effect, their production and use.
BACKGROUND OF THE INVENTION
Osteoporosis is a pathological state or disorder in which certain symptoms or risks occur due to a decrease in bone quantity that has reached a certain level. For example, a major symptom of it, is kyphosis, and a fracture in thoracic and lumbar vertebrae and vertebral bodies, femoral neck, distal extremity of radius, costa, proximal extremity of humerus, and the like. In osseous tissue, bone formation and destruction by bone resorption occur continuously, with a balance between them being kept, and osteoblasts in osteogenesis and osteoclasts in bone resorption play a central role in that. Loss of the balance between bone formation and bone resorption results in osteoporosis accompanied by a decrease in quantity of the bone.
Conventionally, as preventive or therapeutic agents, bone resorption-suppressing substances such as estrogens, calcitonins, bisphoshonates, and the like have primarily been used. When these bone resorption-suppression agents are given, however, in some cases, the patients to whom the agents can be administered are limited, or the effect is uncertain, and no sufficient effect is attained. Accordingly, it is desirable to develop osteogenesis promoting agents, which increase the decreased bone quantity actively as preventive or therapeutic agents for osteoporosis.
Benzopyran derivatives having an osteogenesis promoting effect are disclosed in Japanese Unexamined Patent Publication No. (hereinafter referred to as JP-A 7-291983).
BRIEF SUMMARY OF THE INVENTION
The present invention provides chromone derivatives having an excellent osteogenesis promoting effect, the production thereof and osteogenesis promoting agents containing them as effective components. The present inventors worked diligently to investigate and develop a compound having an osteogenesis promoting effect and they discovered that chromone derivatives having a non-aromatic heterocyclic group have a prominent osteogenesis promoting effect. The present inventors made further investigations based on these findings and succeeded in establishing the present invention.
That is, the present invention relates to:
(1) a chromone derivative of the formula:
wherein the ring A is an optionally substituted benzene ring; R
1
is an optionally substituted non-aromatic heterocyclic group; R
2
is a hydrogen atom or a hydrocarbon group; R
3
is a hydrogen atom, a hydrocarbon group or halogen; n is an integer of 0 to 3; or a salt thereof,
(2) a compound described in the above item (1), wherein the ring A is a benzene ring which may be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, acyloxy, mercapto, halogen atom, C
1-10
alkyl, C
1-10
alkoxy, C
1-10
alkylthio and alkylenedioxy of the formula: —O—(CH
2
)
m
—O— (wherein m is an integer of 1-4); R
2
is a hydrogen atom or a C
1-6
alkyl; and R
3
is a hydrogen atom; or a salt thereof,
(3) a compound described in the above item (1), wherein a substructure containing the ring A is represented by the formula:
(wherein R
4
is a hydrogen atom or a hydroxy group, each of R
5
to R
7
may be same or different and each is a hydrogen atom, a halogen atom, a C
1-10
alkyl or a C
1-10
alkoxy), R
2
is a hydrogen atom or a C
1-6
alkyl group; R
3
is a hydrogen atom, or a salt thereof,
(4) a compound as described in the above item (1), wherein the non-aromatic heterocyclic group of the optionally substituted non-aromatic heterocyclic group represented by R
1
is a 5- to 7-membered non-aromatic heterocyclic group containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, or a salt thereof,
(5) a compound as described in the above item (4), wherein the 5- to 7-membered non-aromatic heterocyclic group of the optionally substituted 5- to 7-membered non-aromatic heterocyclic group is one containing at least 1 nitrogen atom, or a salt thereof,
(6) a compound as described in the above item (5), wherein the 5- to 7-membered non-aromatic heterocyclic group of the optionally substituted 5- to 7-membered non-aromatic heterocyclic group is pyrrolidine, imidazolidine, thiazolidine, isothiazolidine, oxazolidine, oxadiazolidine, piperidine, piperazine, thiomorpholine or morpholine, or a salt thereof,
(7) a compound as described in the above item (1), wherein the substituents in the optionally substituted non-aromatic heterocyclic group represented by R
1
are 1 to 4 substituents selected from the group consisting of halogen atom, hydroxy, oxo, C
1-10
alkyl, C
1-6
alkoxy, C
1-6
acyl, amino, mono- or di-C
1-6
alkylamino, C
1-6
alkylsulfonyl, carboxy, C
1-6
alkoxy-carbonyl or phosphono, or a salt thereof,
(8) a compound as described in the above item (3), wherein R
2
is a hydrogen atom and R
4
is a hydroxy group, or a salt thereof,
(9) a compound as described in the above item (3), wherein R
2
and R
4
are each a hydrogen atom, or a salt thereof,
(10) a prodrug of the compound as described in the above item (1),
(11) N-4-(2,4-dioxothiazolidin-5-yl)methyl]phenyl]-4-oxo-4H-1-benzopyran-2-carboxamide, N-[4-[(2,4-dioxo-oxazolidin-5-yl)methyl]phenyl]-4-oxo-4H-1-benzopyran-2-carboxamide, N-[4-[(4-morpholinyl)methyl]phenyl]-4-oxo-4H-1-benzopyran-2-carboxamide, 5,7-dihydroxy-N-[4-(2,4-dioxothiazolidin-5-yl)methyl]phenyl]-4-oxo-4H-1-benzopyran-2-carboxamide, N-[4-[2,4-dioxothiazolidin-5-yl]methyl]phenyl]-5-hydroxy-7-methoxy-4-oxo-4H-1-benzopyran-2-carboxamide, 5,7-dihydroxy-N-[4-[(4-morpholinyl)methyl]phenyl]-4-oxo-4H-1-benzopyran-2-carboxamide, 5-hydroxy-N-[4-[(4-morpholinyl)methyl]phenyl]-4-oxo-4H-1-benzopyran-2-carboxamide, N-[4-[(2-oxazolidon-3-yl)methyl]phenyl]-4-oxo-4H-1-benzopyran-2-carboxamide, N-[4-(2,6-dioxo-1-piperidinyl)methyl]phenyl]-4-oxo-4H-1-benzopyran-2-carboxamide, N-[4-(2,4-dioxo-oxazolidin-5-yl)methyl]phenyl]-5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxamide, 5-hydroxy-N-methyl-N-[4-(4-morpholinyl)methyl]phenyl]-4-oxo-4H-1-benzopyran-2-carboxamide, or 4-oxo-N-[4-[(4-oxo-1-piperidinyl)methyl]phenyl]-4H-1-benzopyran-2-carboxamide, or a salt thereof,
(12) A process for producing chromone derivatives of the formula:
wherein the ring A is an optionally substituted benzene ring; R
1
is an optionally substituted non-aromatic heterocyclic group; R
2
is a hydrogen atom or a hydrocarbon group; R
3
is a hydrogen atom, a hydrocarbon group, or a halogen; and n is an integer of 0-3; or a salt thereof, which comprises reacting a compound of the formula:
wherein each symbol has the same meaning as mentioned above; or a reactive derivative at the carboxy group thereof or a salt thereof, with a compound of the formula:
wherein each symbol has the same meaning as mentioned above; or a reactive derivative at the amino group thereof or a salt thereof,
(13) 5,6-methylenedioxy-4-oxo-4H-1-benzopyran-2-carboxylic acid, 5,6-dihydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid, or 5-hydroxy-7-methyl-4-oxo-4H-1-benzopyran-2-carboxylic acid; or a salt thereof,
(14) a pharmaceutical composition which comprises a compound of the formula:
wherein the ring A is an optionally substituted benzene ring; R
1
is an optionally substituted non-aromatic heterocyclic group; R
2
is a hydrogen atom or a hydrocarbon group, R
3
is a hydrogen atom, a hydrocarbon group, or halogen; and n is an integer of 0-3; or a salt thereof,
(15) a pharmaceutical composition according to the above item (14), which is an osteogenesis promoting agent,
(16) a pharmaceutical composition according to the above item (14), which is a prophylactic or therapeutic agent for bone diseases,
(17) a pharmaceutical composition according to the above item (14), which
Kawase Masahiro
Mori Akira
Yasuma Tsuneo
Chao Mark
Owens Amelia
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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