Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-10
2002-09-17
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S250000, C544S346000, C544S350000
Reexamination Certificate
active
06451796
ABSTRACT:
SUMMARY
This invention is related to fused pyrazine derivatives and adhesion molecules expression inhibitors containing fused pyrazine derivatives as active ingredient. More particularly, this invention is related to adhesion molecules expression inhibitors containing fused pyrazine derivatives of the formula (I):
wherein all the symbols are the same meaning as hereinafter defined, and non-toxic salts thereof, and novel fused pyrazine derivatives of the above formula (I) and non-toxic salts thereof, and processes for the preparation thereof.
BACKGROUND
Cellular adhesions are basic responses in the organism and relate to various biological phenomenon deeply. In diseases, there are various examples which are mediated by excess reactions or disordered reactions. Inflammatory reaction, which protect a host from a foreign matter, is essentially one of the defensive response in the organism and it is thought that acceleration of leukocytes adhesion to endothelial cells is a central process in the early step in this reaction. Leukocytes are one of the major cells in inflammation and migrate into the inflammatory tissues and secrete chemical mediators, cytokines or enzymes and develop inflammation. Therefore, it has been thought leukocytes extravasation from the vascular flow is an important process in inflammatory development and the process, which is leukocytes-endothelial cells adhesion, is essential in the early step in transmigration.
Cellular migration is at least classified following 4 steps:
1) tethering of leukocytes to endothelial cells,
2) rolling of leukocytes,
3) firm adhesion of leukocytes to endothelial cells,
4) transmigration of leukocytes.
Recently, it has been reported these various cellular adhesions are mediated by cell surface molecular groups which are called adhesion molecules and explained the distinct molecular groups specifically play a central role in the previous each adhesion step. That is to say, it has been explained tethering and rolling process are induced by interaction of carbohydrate and selectin, such as E-selectin, and subsequent firm adhesion and extravasation processes are mediated by interaction of integrin family on leukocytes and immunoglobulin superfamily, such as ICAM-1 (Intercellular Adhesion Molecule-1) and VCAM-1 (Vascular Cell Adhesion Molecule-1).
Any of endothelial adhesion molecules which are E-selectin, VCAM-1 and ICAM-1 are induced molecules stimulated by inflammatory cytokines, such as TNF and IL-1. In fact, it has been reported that these adhesion molecules expression are upregulated in the various lesional sites. Therefore the upregulation of adhesion molecules develops cellular adhesion and participates in disease formation, such as chronic inflammation.
It has been suggested these cellular adhesions to endothelial cells participate not only inflammatory reaction but also tumor metastasis, allergic reaction and immune reaction. Furthermore, the reports which showed the upregulation of VCAM-1 and the increase of ICAM-1 concentration in HIV infected patients have suggested the relation between adhesion molecules expression and HIV infection [Clinical Immunology and Immunopathology, 81, 6-21 (1996)].
From these viewpoints, it is expected the inhibition of adhesion molecules expression which are E-selectin, VCAM-1 and ICAM-1 suppresses the cellular adhesion and links the treatment for various diseases.
The present invitation provides a useful new therapeutic agent which has inhibitory activity on these adhesion molecules expression
According to a further aspect, the present invitation provides the use of the compounds for treatment and/or prevention of disorders mediated by cellular adhesion and infiltration, such as inflammation, rheumatoid arthritis, allergies, asthma, atopic dermatitis, psoriasis, suppression of ischemia reperfusion injury, nephritis, hepatitis, multiple sclerosis, ulcerative colitis, adult respiratory distress syndrome (ARDS), suppression of transplant rejection, sepsis, diabetes, autoimmune diseases, tumor metastasis, arteriosclerosis and AIDS [The Hand Book of Immunopharmacology, Adhesion Molecule, Academic Press, (1994), Trends in Pharmacological Science 16, 418-423, (1995), Molecular Medicine Today, 3, 418-423 (1997), Molecular Medicine Today, 3, 310-321 (1997), Japanese Journal of Inflammation, 17, 459-467 (1997)].
For example, 1,2,4-triazolo-[4,3-a]pyrazine derivatives of the formula (X):
in the specification of GB 1235910,
and the formula (Y):
in the specification of GB 1146770, are disclosed to be useful as treatment of bronchial disorder.
In the specification of U.S. Pat. Nos. 4,200,750, 4,198,508, 4,191,767, 4,191,766, BE 878028 and BE 862608, imidazo-[1,2-a]quinoxaline derivatives are disclosed to be useful as immunosuppressants, anti-inflammatory agents, antifungal agents, antiyeast agents, treatment of bronchial disorder.
Besides, in the specification of WO 9535296, fused imidazole derivatives of the formula (Z):
are disclosed to have an inhibitory activity of adhesion molecules expression.
DISCLOSURE OF THE INVENTION
Energetic investigations have been carried out in order to make adhesion molecules expression inhibitors. The present inventors have found that fused pyrazine derivatives of the formula (I) accomplished the present purpose.
Fused pyrazine derivatives of the formula (I) of the present invention are not known as adhesion molecules expression inhibitors at all. Besides, a lot of fused pyrazine derivatives of the formula (I) are novel compounds.
The present invention is related to:
(i) adhesion molecules expression inhibitors containing fused pyrazine derivatives of the formula (I):
wherein R
1
and R
2
each, independently, is (i) hydrogen, (ii) C1-8 alkyl, (iii) C1-8 alkoxy, (iv) C1-8 alkylthio, (v) Cyc1, (vi) nitrile, (vii) formyl, (viii) —COOR
14
, in which R
14
is hydrogen or C1-8 alkyl, (ix) —CONR
15
R
16
, in which R
15
and R
16
each, independently, is hydrogen, C1-8 alkyl or phenyl, (x) C1-8 alkyl or C2-8 alkenyl substituted by 1 or 2 of hydroxy, C1-4 alkoxy, phenoxy, halogen atom, nitrile, C2-5 acyl, —COOR
14
, —CONR
15
R
16
, or —NR
17
R
18
, in which R
17
and R
18
each, independently, is hydrogen, C1-8 alkyl or acetyl, (xi) C1-8 alkyl, C1-8 alkoxy or C1-8 alkylthio substituted by Cyc1, or R
1
and R
2
, taken together with carbon atoms which are attached to each of them, is
in which Cyc1 is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18 membered mono-, bi- or tri-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1 of sulfur, the above carbocyclic ring or heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) halogen atom, (v) nitrile, (vi) hydroxy, (vii) benzyloxy, (viii) —NR
101
R
102
, in which R
101
and R
102
each, independently, is hydrogen or C1-8 alkyl, (ix) —COOR
103
, in which R
103
is hydrogen or C1-8 alkyl, (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenyloxy, (xiv) C1-8 alkyl or C1-8 alkoxy substituted by phenyl, phenyloxy, hydroxy, —NR
101
R
102
or —COOR
103
;
is C3-7 mono-carbocyclic ring or 3-7 membered mono-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1 of sulfur;
R
3
is
1) hydrogen,
2) C1-8 alkyl,
3) C2-8 alkenyl,
4) C1-8 alkoxy,
5) C1-8 alkylthio,
6) halogen atom,
7) nitro,
8) cyano,
9) hydroxy,
10) formyl,
11) C2-5 acyl,
12) —NR
4
R
5,
in which R
4
and R
5
each, independently, is hydrogen, C1-8 alkyl or acetyl,
13) —COOR
6
, in which R
6
is hydrogen or C1-8 alkyl,
14) —CONR
19
R
20
, in which R
19
and R
20
each, independently, is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by hydroxy, 5-7 membered mono-heterocyclic ring containing 1-2 of nitrogen(s), or 1 of nitrogen and 1 of oxygen, or R
19
and R
20
, taken together is ═CH—NR
21
R
22
, in which R
21
and R
22
each, independently, is hydrogen or C1-4 alkyl,
15) trihalomethyl,
16) trihalomethoxy,
17) phenyl,
18) phenyloxy,
19) phenylthio, or
20) C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio or C1-8 alkylamino subs
Kobayashi Kaoru
Ohno Hiroyuki
Sato Kiyoyuki
Tatsumi Tadashi
Ono Pharmaceutical Co. Ltd.
Shah Mukund J.
Sughrue & Mion, PLLC
Truong Tamthom N.
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