Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-30
2002-03-12
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S188000, C548S196000, C548S213000, C548S227000, C548S229000, C548S243000, C548S311400, C548S311700, C548S526000, C548S527000, C549S009000, C544S060000, C544S061000, C544S062000, C544S197000, C544S202000, C544S175000, C514S336000, C514S372000, C514S376000, C514S378000, C514S380000, C514S397000, C514S228200, C514S228800, C514S232800, C514S233500, C514S096000
Reexamination Certificate
active
06355672
ABSTRACT:
TECHNICAL FIELD
The present invention relates to benzothiepine derivatives having an osteogenesis promoting effect and a chondrogenesis promoting effect, to a process for producing the same, and to a pharmaceutical composition comprising the same as effective component.
BACKGROUND ART
Bone diseases are pathological states or disorders in which a certain symptom or risk occurs due to a decrease in bone quantity that has reached a certain level. For example, a major symptom of osteoporosis, one of the bone diseases, is kyphosis, and a fracture in dorsolumbar bone and vertebral centra, neck of the thigh bone, inferior extremity of radius, ribs, superior extremity of humerus, and the like. In osseous tissue, osteogenesis and destruction by bone resorption are repeated, while remaining balanced, and osteoblasts in osteogenesis and osteoclasts play a central role in bone resorption.
Loss of the balance between osteogenesis and destruction by bone resorption is accompanied by a decrease in quantity of the bone. Conventionally, as prophylactic or therapeutic agents, bone resorption-suppressing substances such as estrogens, calcitonins, bisphosphonates, and the like have primarily been used. However, these bone resorption suppressors fail to achieve a satisfactory effect in some cases, due to limitations of the subject or to uncertain efficacy.
So far it has been reported that benzothiepine derivatives have an osteogenesis promoting effect (Japanese Unexamined Patent Publication No. (hereinafter referred to as JP-A) 3-232880/1991; JP-A 4-364179/1992; JP-A 8-231569/1996).
It is desirable to develop more effective prophylactic or therapeutic agents for bone diseases and chondropathy which have an osteogenesis promoting effect and a chondrogenesis promoting effect and which have excellent stability, absorption and bioavailability as oral preparations.
DISCLOSURE OF INVENTION
The present inventors synthesized a variety of benzothiepine derivatives and worked diligently to investigate the biological activity and pharmacological behavior of these derivatives. As a result, they discovered that compounds having a group of the formula:
[wherein R
1
is an optionally substituted non-aromatic heterocyclic group; R
2
is a hydrogen atom or hydrocarbon group which may have a substituent] at the 2 position of benzothiepine structure exhibit an excellent osteogenesis promoting effect and a chondrogenesis promoting effect and are superior in oral absorption. The present inventors further investigated based on these findings and succeeded in establishing the present invention.
The present invention relates to:
(1) a compound (I) 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
and R
3
are independently hydrogen atom or an optionally substituted hydrocarbon group; n is an integer of 0-3; or a salt thereof,
(2) a compound as described in the above item (1), wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituents selected from the group consisting of halogen atom, hydroxy, C
1-10
alkyl, C
1-10
alkoxy, alkylenedioxy of the formula: —O—(CH
2
)m—O— (wherein m is an integer of 1-4) and C
1-10
alkylthio; and R
2
and R
3
are independently hydrogen atom, C
1-6
alkyl or phenyl,
(3) a compound as described in the above item (1), wherein the ring A is a group of the formula:
wherein R
4
and R
5
are independently hydrogen atom or C
1-10
alkyl or R
4
and R
5
may be bound to each other to form a C
1-4
alkylene chain; and R
2
and R
3
are independently hydrogen atom or C
1-6
alkyl,
(4) a compound as described in the above item (1) or (3), wherein the non-aromatic heterocyclic group of the optionally substituted non-aromatic heterocyclic group represented by R
1
is a 5- to 6-membered non-aromatic heterocyclic group containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom,
(5) a compound as described in the above item (4), wherein the 5- to 6-membered non-aromatic heterocyclic group is one containing at least 1 nitrogen atom,
(6) a compound as described in the above item (5), wherein the heterocycle of the 5- to 6-membered non-aromatic heterocyclic group is pyrrolidine, imidazolidine, thiazolidine, isothiazolidine, oxazolidine, oxadiazolidine, piperidine, piperazine, thiomorpholine or morpholine,
(7) a compound as described in the above item (1), wherein the substituent or substituents in the optionally substituted non-aromatic heterocyclic group represented by R
1
are 1-3 of halogen atom, hydroxy or 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 or C
1-6
alkoxy-carbonyl,
(8) a compound as described in the above item (3), wherein R
2
is a hydrogen atom; R
3
is C
1-3
alkyl; and R
4
and R
5
may be bound to each other to form a C
1-2
alkylene chain,
(9) a compound as described in the above item (3), wherein R
2
and R
3
are independently a hydrogen atom, and R
4
and R
5
are independently a C
1-3
alkyl group,
(10) N-[4-(4-morpholinylmethyl)phenyl]-1,2,4,5-tetrahydro-7,8-methylenedioxy-4-methyl-5-oxo-3-benzothiepine-2-carboxamide,
N-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenyl]-1,2,4,5-tetrahydro-7,8-methylenedioxy-4-methyl-5-oxo-3-benzothiepine-2-carboxamide, or
N-[4-(2,4-dioxo-oxazolidin-5-ylmethyl)phenyl]-1,2,4,5-tetrahydro-7,8-methylenedioxy-4-methyl-5-oxo-3-benzothiepine-2-carboxamide, or a salt thereof,
(11) an optically active 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 an optionally substituted hydrocarbon group; R
31
is an optionally substituted hydrocarbon group; and n is an integer of 0-3; or a salt thereof,
(12) a process for producing a compound (I) 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
and R
3
are independently a hydrogen atom or an optionally substituted hydrocarbon group; and n is an integer of 0-3; or a salt thereof, which comprises reacting a compound (II) of the formula:
wherein each symbol has the same meanings as mentioned above; or a reactive derivative at the carboxy group thereof or a salt thereof, with a compound (III) of the formula:
wherein each symbol has the same meanings as mentioned above; or a reactive derivative at the amino group thereof or a salt thereof,
(13) a compound (III′) of the formula:
wherein R
11
is pyrrolidinyl, dioxopyrrolidinyl, piperidinyl, mono- or di-oxopiperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, dioxothiazolidinyl, dioxoimidazolidinyl, 1-methyldioxoimidazolidinyl, dioxooxazolidinyl, dioxotetrahydroisothiazolidinyl, momo- or di-oxooxazolidinyl, or dioxooxadiazolidinyl; or a salt thereof,
(14) a prodrug or a salt thereof of the compound as described in the above item (1),
(15) a pharmaceutical composition which comprises a compound (I) 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
and R
3
are independently hydrogen atom or an optionally substituted hydrocarbon group; and n is an integer of 0-3; or a salt thereof,
(16) a pharmaceutical composition according to the above item (15), which is an osteogenesis promoting agent,
(17) a pharmaceutical composition according to the above item (15), which is a prophylactic or therapeutic agent for bone diseases,
(18) a pharmaceutical composition according to the above item (15), which is a prophylactic or therapeutic agent for fracture, and
(19) a pharmaceutical composition according to the above item (15), which is a prophylactic or therapeutic agent for chondropathy.
In the above-mentioned formulae, as for the substituent on the optionally substituted benzene ring represented by the ring A, f
Makino Haruhiko
Mori Akira
Yasuma Tsuneo
Chao Mark
D'Souza Andrea
Ramesh Elaine M.
Solola T. A.
Takeda Chemical Industries Ltd.
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