Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-25
2003-01-28
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S336000, C514S278000, C546S015000, C546S283700, C546S297000
Reexamination Certificate
active
06511995
ABSTRACT:
TECHNICAL FILED
The present invention relates to a novel pyridine derivative or a salt thereof, which inhibits collagen synthesis, and a pharmaceutical containing said compound, which is useful for prophylaxis or treatment of fibrosis.
BACKGROUND ART
At present, it is said that 130 or more types of diseases exist as diseases referred to as fibrosis, including rare diseases. Typical disease of fibrosis includes, for example, pulmonary fibrosis, hepatic fibrosis, glomerulosclerosis, etc.
Pulmonary fibrosis generally refers to syndrome wherein the function of lung is lost because of reconstructed lesion in the alveror region, that is, an alveolar structure is broken by the inflammatory reaction to cause growth of fibroblasts and excess increase in extracellular matrix composed mainly of collagen, resulting in lung sclerosis.
On the other hand, hepatic fibrosis refers to the condition of diseases wherein necrosis of hepatocytes is caused by various hepatopathy such as chronic virus hepatitis, alcoholic hepatopathy, etc. and, thereafter, extracellular matrix increases to recruit for the site, resulting in hepatic fibrogenesis. The terminal status of this condition of disease leads to liver cirrhosis wherein the whole liver tissue atrophies and scleroses.
Conventional drugs which inhibit hepatic fibrogenesis described above includes, for example, penicillamine known as a remedy for Wilkinson's disease which occurs due to accumulation of copper in liver as a result of abnormal metabolism of copper, Lufironil which has been studied as a proline hydroxylase inhibitor, etc.
However, these drugs are not sufficient as a drug for preventing hepatic fibrogenesis in view of side effects and validity. At present, a remedy (or therapy) which is effective for fibrosis represented by hepatic fibrogenesis has not been established, and it has been studied how the process of causing fibrogenesis is specifically inhibited.
As described above, it has been known that an excess increase in extracellular matrix composed mainly of collagen occurs in the process of causing fibrogenesis in lung tissues and hapatocytes. It has also been known that an increase in extracellular matrix in hepatocytes mainly occurs in a sinusoid wall Disse space and that Ito cells as mesenchymal cells of liver constitute a main production source.
Accordingly, it is important that an excess increase in extracellular matrix (i.e. collagen) is inhibited to inhibit fibrogenesis in liver, lung, etc.
Thus, an object of the present invention is to provide a novel compound which is superior in effect of inhibiting production of collagen, and a pharmaceutical containing the same, which is useful for prophylaxis or treatment of fibrosis.
DISCLOSURE OF THE INVENTION
The present inventors have intensively studied to solve the problems described above. As a result, they have obtained such a knowledge that a pyridine derivative represented by the general formula (1) described below and a pharmaceutically acceptable salt thereof are superior in effect of inhibiting collagen production, thus completing the present invention.
Thus, the present invention mainly relates to:
(1) A pyridine derivative represented by the general formula (1):
wherein R
1
represents a halogen atom or a halogen-substituted lower alkyl group; R
2
and R
3
are the same or different and represent a hydrogen atom or a halogen atom; V represents a group: —C(═O)—H, a group: —NH—C(═O)—, a group: —NH—C(═O)—NH—or a group: —CH═CH—; A represents a group A
1
:
(wherein R
4
represents a hydrogen atom, a lower alkanoyl group, a benzoyl group, a 2-lower alkyl-1,3-dioxolane group or a hydroxy-substituted lower alkyl group; R
5
represents a hydrogen atom, a 2-lower alkyl-1,3-dioxolane group, a lower alkyl group or a lower alkanoyl group; and R
6
represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group), a group A
2
:
(wherein R
7
represents a hydrogen atom or a lower alkyl group; and R
8
is the same or different and represents a hydrogen atom, a hydroxyl group, an oxo group, a lower alkanoyloxy group, an aroyloxy group, a lower alkoxy group, a group:
(wherein k represents an integer of 1 to 3) or a group: ═N—OR
10
(R
10
represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group); p represents an integer of 1 to 2;
{overscore (----)}
represents a single bond or a double bond; Y represents a group: —(CH
2
)
m
—, a group: ═CH(CH
2
)
m-1
— or a group: —(CH
2
)
m-1
CH═; and m represents an integer of 1 to 3) or a group A
3
:
(wherein R
9
is the same or different and represents a hydrogen atom, a hydroxyl group, an oxo group, a lower alkanoyloxy group, an aroyloxy group, a lower alkoxy group, a group:
(wherein k represents an integer of 1 to 3) or a group: ═N—OR
10
(R
10
represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group); q represents an integer of 1 to 2; represents a single bond or a double bond; Z represents a group: —(CH
2
)
n
—, a group: ═CH(CH
2
)
n-1
— or a group: —(CH
2
)
n-1
CH═; and n represents an integer of 1 to 3)] or a salt thereof;
(2) A pharmaceutical comprising a compound of the general formula (1) in claim
1
or a pharmaceutically acceptable salt thereof;
(3) A pharmaceutical composition for prophylaxis or treatment of fibrosis, which comprises an effective amount of a compound of the general formula (1) in claim
1
or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent and/or excipient; and
(4) A method for inhibiting fibrogenesis caused by excess production of collagen in a mammal which comprises administering to said mammal a pharmaceutically effective amount of a compound of the general formula (1) in claim
1
or a pharmaceutically acceptable salt thereof.
The pyridine derivative (1) or a pharmaceutically acceptable salt thereof are superior in effect of inhibiting collagen production, as described above, and has characteristics such as long duration time of drug efficacy, good transition in blood and low toxicity.
Accordingly, the pyridine derivative (1) or a salt thereof is effective for prophylax or treatment of diseases attended with fibrogenesis caused by excess production of collagen, for example, (i) organ diseases such as sudden and interstitial pulmonary fibrosis, pneumoconiosis, ARDS, hepatic fibrosis, neonatal hepatic fibrosis, hepatic cirrhosis, mucoviscidosis and myelofibrosis; (ii) dermal diseases such as scleroderma, elephantiasis, morphea, injury and hypertrophic cicatrix and keloid after burn injury; (iii) vascular diseases such as atherosclerosis and arteriosclerosis; (iv) ophthalmic diseases such as diabetic retinopathy, fibroplasia retrolentalis, vascularization arising along with corneal transplantation, glaucoma, proliferative vitreoretinopathy and corneal cicatrix after operation; (v) renal diseases such as contracted kidney, nephrosclerosis, interstitial nephritis, IgA nephritis, glomerulosclerosis, membranoproliferative nephritis, diabetic nephropathy, chronic interstitial nephritis and chronic glomerulonephritis; and (vi) diseases in cartilage or bone, such as rheumatic arthritis, chronic arthritis and osteoarthritis.
Among them, the pyridine derivative (1) and a salt thereof of the present invention is superior in effect of inhibiting fibrogenesis attended with the organ diseases listed in the above item (i), and can be used as a preventive or a remedy for pulmonary fibrosis and hepatic fibrosis.
The pyridine derivative represented by the general formula (1) of the present invention includes, for example, the following compounds:
(1-1) a pyridine derivative wherein R
1
to R
3
, R
7
to R
10
, m, n, p, q, k, V, Y and Z are as defined in the general formula (1) and A is a group A
2
or a group A
3
, or a pharmaceutically acceptable salt thereof;
(1-2) a pyridine derivative, wherein R
1
to R
6
and V are as defined in the general formula (1) and A is a group A
1
, or a pharmaceutically acceptable salt thereof;
(1-3) a pyridine derivative wherein R
1
to R
3
, R
7
to
Edamatsu Kouji
Hayakawa Satoshi
Kojima Yutaka
Nagahama Takao
Sakamoto Makoto
Fan Jane
Finnegan Henderson Farabow Garrett & Dunner LLP
Otsuka Pharmaceutical Co. Ltd.
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