Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-28
2004-07-06
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S539000
Reexamination Certificate
active
06759429
ABSTRACT:
TECHNICAL FIELD
The present invention relates to pyrrole derivatives exhibiting TGF-&bgr; inhibitory activity and being useful as fibrosis inhibitors for organs or tissues, a prodrug thereof, and pharmaceutically acceptable salts thereof.
BACKGROUND ART
Fibrosis of organs or tissues is induced by excessive accumulation of extracellular matrix within the organ, as repair or defenses, when said organ is invaded or damaged by some causes. The extracellular matrix is a substance surrounding the cells of tissues, and representative ones thereof are, for example, fibrinoproteins such as collagen, elastin, etc., complex carbohydrates such as proteoglycan, etc., glycoproteins such as fibronectin, laminin, etc. When the degree of the degeneration of organs, etc. by invasion or injury is not serious, then the organs, etc. can return to normality without any scarring of repair. However, when the degree of the degeneration of organs, etc. by invasion or injury is serious or the degeneration of organs persists, then the fibrosis of scarring of repair will further damage the original function of said organ, etc. And, further fibrosis is induced by said damage. Then, it falls into a vicious cycle thereof. Eventually, there will be caused a deficiency of organs, and at worst, the patient will die.
TGF-&bgr; (Transforming Growth Factor-&bgr;) plays an important role in the accumulation of extracellular matrix. When TGF-&bgr; is administered to normal animals, there occurred many fibrotic events at various organs of said animals (International Review of Experimental Pathology, 34B: 43-67, 1993). In addition, it was reported that the fibrosis of tissues was observed in transgenic mice which highly express TGF-&bgr; (Proc. Natl. Acad. Sci. USA, 92:2572-2576, 1995; Laboratory Investigation, 74:991-1003, 1995).
TGF-&bgr; participates in the fibrosis of tissues in the following manner:
(1) Acting on cells, the extracellular matrix such as fibronectin (Journal of Biological Chemistry, 262:6443-6446, 1987), collagen (Proc. Natl. Acad. Sci. USA, 85:1105-1108, 1988), proteoglycan (Journal of Biological Chemistry, 263:3039-3045, 1988), etc. is potently produced:
(2) Decreasing the expression of an enzyme for degrading extracellular matrix (Journal of Biological Chemistry, 263:16999-17005, 1988) and potently promoting the expression of inhibitors of the extracelluar matrix degrading enzyme (Cancer Research, 49:2533-2553, 1989), by which the degradation of extracellular matrix is inhibited:
(3) Proliferating cells producing extracellular matrix (American Journal of Physiology, 264:F199-F205, 1993).
Thus, the inhibition of TGF-&bgr; is a useful means for inhibiting the accumulation of extracellular matrix. In fact, it is reported that the fibrosis is alleviated by administering antiserum of TGF-&bgr; to animal models for fibrosis (Nature, 346:371-374, 1990).
DISCLOSURE OF INVENTION
An object of the present invention is to provide a compound being useful as fibrosis inhibitors for organs or tissues. In order to solve the above problems, the present inventors have intensively studied, and found that pyrrole derivatives inhibit the fibrosis of organs or tissues, and have accomplished the present invention.
The present invention is as follows:
[1] A pyrrole derivative of the formula:
wherein Ring Z is an optionally substituted pyrrole ring, an optionally substituted indole ring, an optionally substituted thiophene ring, an optionally substituted pyrazole ring, an optionally substituted benzene ring, an optionally substituted imidazole ring, or an optionally substituted isothiazole ring;
W
2
is —CO—, —SO
2
—, —CONR—, an optionally substituted C
1
-C
4
alkylene or an optionally substituted C
2
-C
4
alkenylene, and R is hydrogen or an alkyl;
Ar
2
is an optionally substituted aryl or an optionally substituted heteroaryl;
W
1
and Ar
1
mean the following (1) or (2):
(1) W
1
is an optionally substituted C
1
-C
4
alkylene or an optionally substituted C
2
-C
4
alkenylene; Ar
1
is an optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms:
(2) W
1
is an optionally substituted C
2
-C
5
alkylene, an optionally substituted C
2
-C
5
alkenylene, an optionally substituted C
2
-C
5
alkynylene, or —Y—W
3
—, Y is an oxygen atom or a cycloalkanediyl, and W
3
is an optionally substituted C
1
-C
5
alkylene, an optionally substituted C
2
-C
5
alkenylene, or an optionally substituted C
2
-C
5
alkynylene; and Ar
1
is an aryl or monocyclic heteroaryl, which is substituted at the ortho- or meta-position thereof with respect to the binding position of W
1
by a group selected from carboxyl, an alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, an alkyl-sulfonylcarbamoyl, an arylsulfonylcarbamoyl, an alkylsulfonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, tetrazolyl, cyano, an alkoxy and an alkylsulfonylamino, and said aryl or monocyclic heteroaryl being optionally further substituted, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[2] The pyrrole derivative according to the above [1], wherein the divalent group including Ring Z may be any one of the following divalent groups (any direction of bonds is included), or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
wherein the number of R
1
is one or more, and each is independently hydrogen, a halogen or an optionally substituted alkyl.
[3] The pyrrole derivative according to the above [1] or [2], wherein Ring Z is an optionally substituted pyrrole ring, an optionally substituted indole ring or an optionally substituted thiophene ring, or a prodrug, or a pharmaceutically acceptable salt thereof.
[4] The pyrrole derivative according to the above [1], which is a compound of the formula:
wherein W
1
, W
2
, Ar
1
, Ar
2
and R
1
are as defined above, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[5] The pyrrole derivative according to any one of the above [1] to [4], wherein W
2
is —CO—, —SO
2
—, —CONR—, methylene, or hydroxymethylene, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[6] The pyrrole derivative according to any one of the above [1] to [5], wherein Ar
2
is a substituted phenyl, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[7] The pyrrole derivative according to any one of the above [1] to [6], wherein W
1
is an optionally substituted C
2
-C
5
alkylene, an optionally substituted C
2
-C
5
alkenylene, or an optionally substituted C
2
-C
5
alkynylene; and Ar
1
is an aryl, which is substituted at the ortho-position thereof with respect to the binding position of W
1
by a group selected from carboxyl, an alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, an alkylsulfonylcarbamoyl, an arylsulfonylcarbamoyl, an alkylsulfonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, tetrazolyl, cyano, an alkoxy and an alkylsulfonylamino, and said aryl being optionally further substituted,
or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[8] The pyrrole derivative according to any one of the above [1] to [6], wherein W
1
is an optionally substituted trans-C
3
-C
4
alkenylene; and Ar
1
is an aryl, which is substituted at the ortho-position thereof with respect to the binding position of W
1
by a group selected from carboxyl, an alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, an alkylsulfonylcarbamoyl, an arylsulfonylcarbamoyl, tetrazolyl, cyano, an alkoxy and an alkylsulfonylamino, and said aryl being optionally further substituted by a halogen, cyano, an optionally substituted alkoxy or an optionally substituted alkyl,
or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[9] The compound
Hume William Ewan
Kitoh Makoto
Nagata Ryu
Tokunaga Teruhisa
Birch & Stewart Kolasch & Birch, LLP
McKane Joseph K.
Saeed Kamal
Sumitomo Pharmaceuticals Co. Ltd.
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